WO2024074585A2

WO2024074585A2 - MICROPARTICLE AND IMPLANT FORMULATIONS FOR cGMP ANALOG THERAPY

Info

Publication number: WO2024074585A2
Application number: PCT/EP2023/077507
Authority: WO
Inventors: Ming Yang; Peipei ZHANG; David Mckenzie
Original assignee: Mireca Medicines Gmbh
Priority date: 2022-10-05
Filing date: 2023-10-05
Publication date: 2024-04-11

Abstract

The invention describes microparticles, aggregating microparticles and implants of guanosine-3', 5'- cyclic monophosphate (cGMP) analogs of Formula I, Formula II, or Formula III suitable for the treatment and/or prophylaxis of disorders associated with cGMP-signaling processes, including retinal dystrophies such as retinitis pigmentosa as well as Stargardt disease, and macular degeneration.

Description

MICROPARTICLE AND IMPLANT FORMULATIONS FOR cGMP ANALOG THERAPY FIELD OF THE INVENTION The present invention provides microparticles and implants for delivery of polymer linked multimeric guanosine-3′,5′-cyclic monophosphate (cGMP) analogs of Formula I and Formula II or related monomeric compounds of Formula III that modulate, inhibit or activate the cGMP-signaling system, for example, modulate, inhibit or activate a cGMP-dependent protein kinase G (PKG). The invention also provides the therapeutic and/or prophylactic use of the microparticles and implants comprising a compound of Formula I, Formula II, or Formula III for the treatment and/or prophylaxis of a disorder associated with a cGMP- signaling process, including but not limited to a retinal dystrophy such as retinitis pigmentosa as well as Stargardt disease, and macular degeneration. BACKGROUND Guanosine-3′,5′-cyclic monophosphate (cGMP) is a purine nucleobase-containing cyclic nucleotide that was discovered as an endogenous molecule in 1963. It is well known to act as a second messenger, wherein its intracellular level is altered as a response to (primary) signaling molecules such as toxins, hormones, or nitric oxide, which in turn induces diverse cellular processes, such as gene expression, chemotaxis, proliferation, differentiation, and apoptosis. Several diseases like retinal degeneration, cardiovascular diseases, asthma, or diabetes are associated with unusually high or low levels of cGMP (Schwede, F.; Maronde, E.; Genieser, H.; Jastorff, B., Cyclic nucleotide analogs as biochemical tools and prospective drugs. Pharmacol Ther 2000, 87 (2-3), 199-226; Schmidt, H. H.; Hofmann, F.; Stasch, J., In cGMP: Generators, Effectors and Therapeuti Implications, Springer-Verlag Heidelberg: Berlin, 2009; pp 447-506; (c) Schlossmann, J.; Schinner, E., cGMP becomes a drug target. Naunyn Schmiedebergs Arch Pharmacol 2012, 385 (3), 243-52.) The physiology of photoreceptors and the phototransduction cascade critically depends on the cGMP signaling. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and ^{formulated inhibitory cGMP analogs (A. Tolone, S. Belhadj, A. Rentsch, F. Schwede, F. Paquet-Durand,} Genes (Basel). 2019 Jun 14;10(6):453. doi: 10.3390/genes10060453. PMID: 31207907; PMCID: PMC6627777.) The idea that PKG activity plays a role in cell death has been widely established (A. Tolone, S. Belhadj, A. Rentsch, F. Schwede, F. Paquet-Durand, Genes (Basel). 2019 Jun 14;10(6):453. doi: 10.3390/genes10060453. PMID: 31207907; PMCID: PMC6627777.) Activation of PKG has been used for the induction of apoptosis in colon cancer cells and in human breast cancer cells, and is linked to pro- apoptotic effects in ovarian cancer. Excessive activation of PKG has been shown to cause cell death in certain neuronal cell types. The cGMP/PKG-dependent cell death is an important mechanism in photoreceptor degeneration, and the existence of a non-apoptotic cell death mechanisms involving cGMP- dependent overactivation of PKG was demonstrated. This evidence makes PKG a potential target for neuroprotective strategies (A. Tolone, S. Belhadj, A. Rentsch, F. Schwede, F. Paquet-Durand, Genes (Basel).2019 Jun 14;10(6):453. doi: 10.3390/genes10060453. PMID: 31207907; PMCID: PMC6627777.) Certain cGMP-derived PKG inhibitors, for example, Rp-8-Br-cGMPS, have been found to offer some protection for rd1 and rd2 photoreceptors both in vitro and in in vivo mouse retinitis pigmentosa models (Paquet-Durand et al., 2009). However, these PKG inhibitors require frequent re-administration (i.e. every other day) of the PKG inhibitor by subtenonal or intravitreal injection, which is not practical for a chronic disease. US Patent No.5,625,056, assigned to BIOLOG Life Science Institute, discloses sulfur-modified SP- and R_P-isomeric cyclic guanosine-3′,5′-phosporothioates and their pharmaceutically acceptable salts. The disclosed compounds are cell membrane permeable inhibitors (R_P-isomers, R_P-cGMPS) and stimulators (SP-isomers) of cGMP dependent protein kinase which are resistant against phosphodiesterase degradation. A number of R_P-cGMPS analogs, such as R_P-8-Br-cGMPS and R_P-8-Br-PET-cGMPS, with partially improved membrane permeability and biological activity have been developed (Kawada, T.; Toyosato, A.; Islam, M. O.; Yoshida, Y.; Imai, S., cGMP-kinase mediates cGMP- and cAMP-induced Ca2+ desensitization of skinned rat artery. Eur J Pharmacol 1997, 323 (1), 75-82; U.S. Pat. No.5,625,056; and Butt, E.; Pohler, D.; Genieser, H. G.; Huggins, J. P.; Bucher, B., Inhibition of cyclic GMP-dependent protein kinase-mediated effects by (Rp)-8-bromo-PET-cyclic GMPS. Br J Pharmacol 1995, 116(8), 3110-6). Analogs like R_P-8-Br- PET-cGMPS have demonstrated suboptimal efficacies or even partially agonistic properties (Paquet- Durand, F.; Hauck, S. M.; van Veen, T.; Ueffing, M.; Ekstrom, P., PKG activity causes photoreceptor cell death in two retinitis pigmentosa models. J Neurochem 2009, 108 (3), 796-810.) Targeted liposomal delivery of cGMP analogs has been disclosed in U.S. Patent No.10,322,087, assigned to Mireca Medicines GmbH, and described in E. Vighi et al., “Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration”, PNAS, March 12, 2018, vol. 115, no.13, E2997 - E3006. The proposed solution for the targeted delivery of cGMP analogs offered in the ʼ087 patent and the cited article is to use a liposomal drug delivery vehicle to facilitate transfer ^{of cGMP analogs into retina across the blood-retinal barrier. Glutathione-targeted PEGylated liposomes} were used as delivery vehicles which were administered intravenously or intraperitoneally. In particular, conjugates of cGMP analogs in pharmaceutically acceptable nanocontainers (liposomes), optionally linked with ligands for glutathione transporters (for example, glutathione) that specifically mediate enhanced binding, endo- or transcytosis to and across the blood-ocular barrier have been described. The ʼ087 patent provides a liposome encapsulating a cGMP analog, wherein the ligand for a glutathione transporter is conjugated to the liposome through a bifunctional conjugation agent comprising a vitamin E derivative or a phospholipid bonded to one end of the conjugation agent and the ligand for a glutathione transporter bonded to the other end of the conjugation agent, and the conjugation agent is PEG with polymerization number of about 6-210. Unfortunately, liposomal delivery of these compounds has been difficult, and other solutions are needed. U.S. Patent No.11,407,781, assigned to Graybug Vision, Inc., discloses new equatorially modified polymer linked multimers (PLM) of cGMP analogs that inhibit the cGMP signaling system. The ʼ781 patent also discloses monomeric compounds, which can be used either as monomeric precursors of the multimers, or as monomeric drugs with inhibitory activity. The cGMP analogs disclosed in the ʼ781 patent are chemically conjugated multimers of equatorially modified guanosine-3′,5′-cyclic nucleotide monophosphate analogs, including tethered di-, tri- and tetramers of guanosine-3′,5′-cyclic nucleotide monophosphate analogs or monomeric precursor cGMP-analogs. See also PCT/EP/2017/071859 assigned to Graybug Vision, Inc. that discloses additional polymer linked multimers of guanosine-3,5-cyclic monophosphates and monomers that act primarily as agonists of the cGMP pathway. To treat ocular diseases, the drug must be delivered in therapeutic levels and for a sufficient duration to achieve efficacy. This seemingly straightforward goal is difficult to achieve in practice. For example, topical eyedrops are used to deliver drugs to the eye. Although eye drops are easy to administer, ocular bioavailability with eye drops is typically low because blinking, tear wash out, and nasolacrimal drainage often prevent the solution from residing on the eye long enough to penetrate through the required layers of the eye, including the initial tear film. Further, topical eye drops are unable to reach the posterior of the eye. However, despite the proposed solutions for cGMP delivery mentioned above, such as liposomal drug delivery vehicle, a good solution has not emerged, and there is still a need in improved methods and means of delivery of cGMP analogs, including sustained and prolonged delivery and administration to the eye. It is thus an object of the present invention to provide new formulations for the delivery of guanosine-3′,5′-cyclic monophosphate (cGMP) analogs that modulate, inhibit or activate the cGMP- signaling pathway. Another object of the invention is to provide new formulations for delivery and administration of cGMP analogs useful for the treatment and/or prophylaxis of ocular diseases, such as retinal dystrophies, retinitis pigmentosa and macular degeneration. SUMMARY The present invention provides new advantageous microparticle and implant formulations comprising polymer linked multimeric (PLM) guanosine-3′,5′-cyclic monophosphate (cGMP) analogs of Formula I and Formula II or related monomeric compounds of Formula III, or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable lipophilic salt thereof, that modulate, inhibit or activate the cGMP-signaling system, for example, modulate, inhibit or activate a cGMP-dependent protein kinase G (PKG). The invention as presented is the advantageous delivery of a compound of Formula I, II, III or a pharmaceutically acceptable salt thereof, including a lipophilic salt, to administer the compound to a host in need thereof in an efficient and controlled manner. The drugs can be delivered to the eye or to any part of the body in need of such therapy, including systemically, topically, parenterally, intravitreally, suprachoroidally, by injection, implant, or any other means described herein or as otherwise useful. The invention also provides therapeutic and/or prophylactic use of the microparticles and implants comprising a compound of Formula I, Formula II, and Formula III, or pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, for the treatment and/or prophylaxis of disorders associated with cGMP-signaling processes. In certain embodiments, the advantageous and beneficial properties of microparticle and implant formulations according to the invention include adequate drug loading and/or controlled drug release profiles of a compound of Formula I, Formula II, and Formula III or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. In certain embodiments, high drug loading and/or controlled drug release profiles of a compound of Formula I, Formula II, and Formula III are achieved when a pharmaceutically acceptable lipophilic salt of a compound of Formula I, Formula II, and Formula III is used to load a microparticle or implant according to the invention. Non-limiting examples of cGMP analogues that can be administered within the formulations of the present invention include:

or a pharmaceutically acceptable salt thereof. In certain advantageous embodiments the compound of Formula I, Formula II, or Formula III is provided as a lipophilic salt form for longer controlled delivery, for example a lipophilic salt selected from monoalkyl ammonium salts; dialkyl ammonium salts; benzyl alkyl ammonium salts; trialkyl ammonium salts; quaternary ammonium salts, such as tetraalkyl ammonium salts; benzyl trialkyl ammonium salts; dibenzyl dialkyl ammonium salts; alkyl dimethyl benzyl ammonium salts; tetraalkyl phosphonium salts; benzyl trialkyl phosphonium salts; imidazolium salts; N-alkyl-morpholinium salts; N,N-dialkyl-morpholinium salts; alkyl pyridinium salts; N-alkyl piperidinium salts; and N,N-dialkyl piperidinium salts. In certain embodiments the lipophilic salt form of a compound described herein can be loaded at higher concentrations in a microparticle or implant described herein. In certain embodiments, a lipophilic salt of a compound of Formula I, Formula II, or Formula III is formed from the compound of Formula I, Formula II, or Formula III and a lipophilic amine. In certain embodiments, the lipophilic amine to form a pharmaceutically acceptable lipophilic salt of the compound of Formula I, Formula II, or Formula III is benzathine (N,N'-dibenzylethylenediamine), benethamine (N-benzyl- 2-phenylethanamine), or triethyl amine. In certain embodiments, a pharmaceutically acceptable lipophilic salt of the compound of Formula I, Formula II, or Formula III is a benzathine salt, benethamine salt, or triethyl amine salt. In certain embodiments, pharmaceutically acceptable lipophilic salts of a compound of Formula I, Formula II, or Formula III are selected from: Compound 188-BEN, which is 8-bromo-(4-methyl-β-phenyl-1,N²-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp- isomer, N-benzyl-2-phenylethan-1-aminium salt; Compound 188-BEZ, which is 8-bromo-(4-methyl-β-phenyl-1,N²-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp- isomer, N-benzyl-2-(benzylamino)ethan-1-aminium salt; Compound 221-BEN, which is 8-bromo-(β-phenyl-1,N²-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp-isomer, N-benzyl-2-phenylethan-1-aminium salt; and Compound 221-BEZ, which is 8-bromo-(β-phenyl-1,N²-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp-isomer which is N-benzyl-2-(benzylamino)ethan-1-aminium salt; wherein BEN is used as an abbreviation for benethamine (N-benzyl-2-phenylethanamine) and BEZ is used as an abbreviation for benzathine (N,N'-dibenzylethylenediamine), or their protonated forms. For example, for compounds of general structure

when the molecule is a BEN salt Cat⁺ is

when the molecule is a BEZ salt Cat⁺ is

Additional examples of lipophilic salts include a hexylamine, heptylamine, octylamine, di-n- propylamine, diisopropylamine, N-ethylbutylamine, di-n-butylamine, diisobutylamine, N-sec-butyl-n- propylamine, triisopropylamine, tributylamine, N,N-diisopropyl methylamine, N,N,-diisopropyl ethylamine, N,N,-dimethyl butylamine, N,N-Dimethyl octylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, N-isopropyl cyclohexylamine, N,N-dimethyl cyclohexyl amine, N,N-diethyl cyclohexyl amine, dicyclohexylamine, 2,6-dimethyl piperidine, 3,5-dimethyl piperidine, 2,2,6,6-tetramethyl piperidine, N- methyl piperidine, N-ethyl piperidine, benzylamine, N-methyl benzylamine, N-ethyl benzylamine, or N,N- dimethyl benzylamine salt of a cGMP analogue described herein. In certain embodiments, a compound of Formula I or Formula II is the active agent in a pharmaceutical composition of the present invention.

or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof; wherein: G units G¹ and G² are independently compounds of Formula IIIA and G units G³ and G⁴ independently from G¹ and G² and independently from each other are compounds of Formula IIIA or absent, wherein in case of Formula II G⁴ is always absent if G³ is absent,

and wherein in Formula IIIA X, Y and Z are N R₁, R₄, R₅, and R8 independently can be equal or individual for each G unit (G¹, G², G³ and G⁴), while R₁ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR9R₁0, carbamoylR11R12, NH-carbamoylR11R12, O- carbamoylR11R12, SiR13R14R15 wherein R9, R10, R11, R12, R13, R14, R15 independently from each other can be H, alkyl, aryl, aralkyl; R2 is absent; R3 is OH; R⁴ can independently be absent, H, amino, alkyl, aralkyl, nitro, N-oxide, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazolinone as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl wherein each alkyl, aryl, and aralkyl group is optionall substituted with 1, 2, or 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, NH(alkyl), and N(alkyl)₂;

R₅ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR30R31, carbamoylR32R33, NH-carbamoylR32R33, O-carbamoylR32R33, SiR34R35R36 wherein R30, R31, R32, R33, R34, R35, R36 independently from each other can be H, alkyl, aryl, aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazolinone ring as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl; R₆ is OH; R₇ is =O, O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O- aralkyl, O-acyl, SH, S-alkyl, S-aryl, S-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, O-PAP, S-BAP, or O-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and R₈ is O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O- acyl, O-PAP, O-BAP, SH, S-alkyl, S-aryl, S-aralkyl, SeH, Se-alkyl, Se-aryl or Se-aralkyl, borano (BH₃), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, Se-PAP, S-BAP or Se-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and wherein linking residues LR¹, LR², LR³ and LR⁴ independently can replace or covalently bind to any of the particular residues R₁, R₄ and/or R₅ of the G units (G^{1 - 4}) they connect, wherein in case they bind to any of the residues R₁, R₄ and/or R₅, an endstanding group of the particular residue ( R₁, R₄ and/or R₅), as defined above, is transformed or replaced in the process of establishing the connection and is then further defined as part of the particular linking residue (LR^{1 - 4}) within the assembled compound, while LR¹ is (a) a tri- or tetravalent branched hydrocarbon moiety or (b) a divalent hydrocarbon moiety each with or without incorporated heteroatoms such as, but not limited to, O, N, S, Si, Se, B, wherein in certain embodiments the backbone contains 1 to 28 carbon atoms and can be saturated or unsaturated, substituted or unsubstituted, while each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom and in case poly ethylene glycol (PEG) moieties are incorporated in accordance to the definition, the typical number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500) in case of divalent linking residue (LR¹) or 1 to 750 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 750) in case of trivalent linking residue (LR¹) or 1 to 1000 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 1000) in case of tetravalent linking residue (LR¹), and, if substituted, substituents include, but are not limited to, optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, a^{mino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, epoxy,} methoxy, ethynyl, and/or substituents can further be connected to each other, forming a ring system with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic; LR², LR³ and LR⁴ are divalent hydrocarbon moieties with or without incorporated heteroatoms such as, but not limited to, optionally heteroatoms O, N, S, Si, Se, B, wherein the backbone typically contains 1 to 28 carbon atoms and can be, saturated or unsaturated, substituted or unsubstituted, while each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom and in case poly ethylene glycol (PEG) moieties are incorporated in accordance to the definition, the typical number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500) and, if substituted, substituents include, but are not limited to, optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, epoxy, methoxy, ethynyl, and/or substituents can further be connected to each other, forming a ring system with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic; wherein in case of Formula II if G⁴ is absent, LR⁴ is absent, too, and wherein in case of Formula II if G³ and G⁴ are absent, LR³ and LR⁴ are absent, too, and wherein G¹, G², G³ and G⁴ can further be salts and/or hydrates while, optionally, non-limiting examples of suitable salts of the particular phosphate moiety are lithium, sodium, potassium, calcium, magnesium, zinc or ammonium, and trialkylammonium, dialkylammonium, alkylammonium, e.g., triethylammonium, trimethylammonium, diethylammonium and octylammonium; and wherein G¹, G², G³ and G⁴ can optionally be isotopically or radioactively labeled, be PEGylated, immobilized or be labeled with a dye or another reporting group, wherein the reporting group(s) and/or dye(s) (^{a) are coupled to} G^{1, G2, G3 and/or G4 via a linking residue (LR5), bound covalently to or} replacing any of the particular residues R₁, R₄ and/or R₅ independently for each G unit (G¹, G², G³ and/or G⁴) while LR⁵ can be as defined for LR² or (b) in case of Formula I can replace G³ and/or G⁴ and wherein examples of optionally suitable dyes include, but are not limited to, fluorescent dyes such as fluorescein, anthraniloyl, N-methylanthraniloyl, dansyl or the nitro-benzofurazanyl (NBD) system, rhodamine-based dyes such as Texas Red or TAMRA, cyanine dyes such as Cy^TM3, Cy^TM5, Cy^TM7, EVOblue^TM10, EVOblue^TM30, EVOblue^TM90, EVOblue^TM100 (EVOblue^TM-family), the BODIPY^TM- family, Alexa Fluor^TM-family, the DY-family, such as DY-547P1, DY-647P1, coumarines, acridines, oxazones, phenalenones, fluorescent proteins such as GFP, BFP and YFP, and near and far infrared dyes and wherein reporting groups optionally include, but are not limited to, quantum dots, biotin and tyrosylmethyl ester; and wherein PEGylated refers to the attachment of a single or multiple LR^PEG group(s) independently, wherein LR^PEG can be as defined for LR², with the provisos that in this case (i) of LR² only one terminus is connected to a G unit (G¹, G², G³ and/or G⁴) by covalently binding to or replacing any of the particular residues R₁, R₄ and/or R₅ independently for each G unit (G¹, G², G³ and/or G⁴), and (ii) the other terminus of LR² is either an alkyl group or a reactive group that allows for conjugation reactions and/or hydrogen bonding while, optionally, non-limiting examples of reactive groups are, -NH₂, -SH, -OH, -COOH, - N3, -NHS-ester, halogen group, epoxide, ethynyl, allyl and with the proviso (iii) that LR^PEG has incorporated ethylene glycol moieties (-(CH₂CH₂O)_n- with n = 2 to 500). In other aspects, a compound of Formula III is the active agent in a pharmaceutical composition of the present invention.

or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, wherein each variable is as described herein. In certain embodiments the compound of Formula III is of Formula:

or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof. Non-limiting examples of compounds of Formula III include:

or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof. In some embodiments, the controlled release formulation is a microparticle. In certain embodiments, the microparticle is treated as described herein to form an aggregated microparticle (which may be a pellet or a depot) in vivo. In certain aspects, the microparticle comprises a biodegradable polymeric material or biodegradable polymeric materials, an excipient or excipients, a surfactant or surfactants as defined herein, and a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt or salts thereof, including pharmaceutically acceptable lipophilic salt thereof. In certain embodiments, the biodegradable polymeric material is PLGA (poly(lactic-co-glycolic acid)), PLA (polylactic acid), PLGA-PEG (co-polymer of poly(lactic-co-glycolic acid) and polyethylene glycol), PLA-PEG (co-polymer of polylactic acid and polyethylene glycol)or a combination thereof. In certain embodiments, the microparticle according to the invention includes from about 0.5 percent to about 10 percent PLGA-PEG, about 0.5 percent to about 5 percent PLGA-PEG, about 0.5 percent to about 4 percent PLGA-PEG, about 0.5 percent to about 3 percent PLGA-PEG, or about 0.1 percent to about 1, 2, 5, or 10 percent PLGA-PEG. In other embodiments, PLA-PEG or PCL-PEG is used in place of PLGA-PEG. In other embodiments, any combination of PLGA-PEG, PLA-PEG or PCL-PEG is used in the polymeric composition with any combination of PLGA, PLA or PCL. Each combination is considered specifically described as if set out individually herein. In certain embodiments, the polymeric formulation includes up to about 1, 2, 3, 4, 5, 6, 10, or 14% of the selected pegylated polymer. In some embodiments, the present invention provides mildly surface treated solid biodegradable microparticles that on injection in vivo, aggregate to a larger particle (pellet) in a manner that reduces unwanted side effects of the smaller particles and are suitable for long term (for example, up to, or alternatively at least, three months, four months, five months, six months or seven months or longer) sustained delivery of a compound of Formula I, Formula II, or Formula III. In certain embodiments, the mildly surface treated solid biodegradable microparticles are suitable for ocular injection, at which point the particles aggregate to form a pellet that remains outside the visual axis so as not to significantly impair vision. The particles can aggregate into one or several pellets. The size of the aggregate depends on the concentration and volume of the microparticle suspensions injected and the diluent in which the microparticles are suspended. In certain embodiments, the invention is thus surface-modified solid aggregating microparticles that include at least one biodegradable polymer, wherein the surface-modified solid aggregating microparticles have a solid core, include a compound of Formula I, Formula II, or Formula III, have a modified surface which has been treated under mild conditions at a temperature at or less than about 18 °C to remove surface surfactant, are sufficiently small to be injected in vivo, and are capable of aggregating in vivo to form at least one pellet of at least 500 μm in vivo to provide sustained drug delivery in vivo for at least one month, two months, three months, four months, five months, six months or seven months or more. The surface modified solid aggregating microparticles are suitable, for example, for an intravitreal injection, implant, including an ocular implant, periocular delivery, or delivery in vivo outside of the eye. In other embodiments, the invention is an injectable material that includes the microparticles of the present invention in a pharmaceutically acceptable carrier for administration in vivo. The injectable material may include a compound that inhibits aggregation of microparticles prior to injection and/or a viscosity enhancer and/or a salt. In certain embodiments, the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 1 to about 700 mg/ml. In certain examples, the injectable material has a concentration of the surface-modified solid aggregating microparticles that is not more than about 1, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650 or 700 mg/ml. In certain embodiments, the injectable material has a concentration of the surface-modified solid aggregating microparticles of about 200-400 mg/ml, 150-450 or 100-500 mg/ml. In certain embodiments, the injectable material has a concentration of the surface-modified solid aggregating microparticles of about up to 150, 200, 300 or 400 mg/ml. In other embodiments, the present invention further includes a process for the preparation of surface-modified solid aggregating microparticles that includes: (i) a first step of preparing microparticles comprising one or more biodegradable polymers by dissolving or dispersing the polymer(s) and a compound of Formula I, Formula II, or Formula III, in one or more solvents to form a solution or dispersion of the polymer and a compound of Formula I, Formula II, or Formula III, mixing the solution or dispersion of the polymer and a compound of Formula I, Formula II, or Formula III with an aqueous phase containing a surfactant to produce solvent-laden microparticles and then removing the solvent(s) to produce polymer microparticles that contain a compound of Formula I, Formula II, or Formula III, polymer and surfactant; and (ii) a second step of mildly treating the surface of microparticles of step (i) at a temperature at or below about 18, 15, 10, 8 or 5 °C optionally up to about 1, 2, 3, 4, 5, 10, 30, 40, 50, 60, 70, 80, 90100, 11, 120 or 140 minutes with an agent that removes surface surfactant, surface polymer, or surface oligomer in a manner that does not significantly produce internal pores; and (iii) isolating the surface treated microparticles. The process can be achieved in a continuous manufacturing line or via one step or in stepwise fashion. In certain embodiments, wet biodegradable microparticles can be used without isolation to manufacture surface treated solid biodegradable microparticles. In certain embodiments, the surface treated solid biodegradable microparticles do not significantly aggregate during the manufacturing process. In other embodiments, the surface treated solid biodegradable microparticles do not significantly aggregate when resuspended and loaded into a syringe. In some embodiments, the syringe is approximately 30, 29, 28, 27, 26 or 25 gauge, with either normal or thin wall. In yet another embodiment, a method for the treatment of an ocular disorder is provided that includes administering to a host in need thereof mildly surface-modified solid aggregating microparticles that include an effective amount of a compound of Formula I, Formula II, or Formula III, wherein the surface- modified solid aggregating microparticles are injected into the eye and aggregate in vivo to form at least one pellet of at least 500 μm that provides sustained drug delivery for at least approximately one, two, three, four, five, six or seven or more months in such a manner that the pellet stays substantially outside the visual axis so as not to significantly impair vision. In certain embodiments, the surface treated solid biodegradable microparticles release about 1 to about 20 percent, about 1 to about 15 percent, about 1 to about 10 percent, or about 5 to 20 percent, for example, up to about 1, 5, 10, 15 or 20 percent, of a compound of Formula I, Formula II, or Formula III over the first twenty-four-hour period. In certain embodiments, the surface treated solid biodegradable microparticles release less compound of Formula I, Formula II, or Formula III in vivo in comparison to non-treated solid biodegradable microparticles over up to about 1, 2, 3, 4, 5, 6, 7 day or even up to about a 1, 2, 3, 4, or 5 month period. In certain embodiments, the surface treated solid biodegradable microparticles induce less inflammation in vivo in comparison to non-treated solid biodegradable microparticles over the course of treatment. This invention addresses the problem of intraocular therapy using small drug loaded particles (for example, 20 to 40 μm, 10 to 30, 20 to 30, or 25 to 30 μm average diameter, or for example, not greater than about 20, 25, 26, 27, 28, 29, 30, 35 or 40 μm average diameter (Dv)) that tend to disperse in the eye due to body movement and/or aqueous flow in the vitreous. The dispersed microparticles can cause vision disruption and aggravation from floaters, inflammation, etc. The microparticles of the invention aggregate in vivo to form at least one pellet of at least 500 μm and minimize vision disruption and inflammation. Further, the aggregated pellet of the surface treated microparticles is biodegradable so the aggregated pellet of the surface treated microparticles does not have to be surgically removed. In certain embodiments of the present invention, a durable controlled release formulation comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, in a biodegradable microparticle or implant is provided that is suitable for long-term ocular therapy. In certain embodiments, the implant provides sustained linear release of a compound of Formula I, Formula II, or Formula III for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months or more. In certain aspects, the implant comprises a biodegradable polymeric material or biodegradable polymeric materials, an excipient or excipients, a surfactant or surfactants as defined herein, and a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof. In certain embodiments, the biodegradable polymeric material is PLGA (poly(lactic-co-glycolic acid)), PLA (polylactic acid), PLGA-PEG (co-polymer of poly(lactic- co-glycolic acid) and polyethylene glycol), PLA-PEG (co-polymer of polylactic acid and polyethylene glycol)or a combination thereof. In certain embodiments, an implant is formed prior to insertion for in vivo delivery. The implant can be any desired shape, and is typically a rod or cylinder, including a cylindrical pellet. The rod is typically, for example, in the range of at least about 150 to about 1000 micrometers or less (μm, microns) in diameter and at least about 1 to about 10 millimeters (mm) or less in length. A cylindrical pellet is typically, for example, in the range of at least about 400 to about 1000 microns or less in width, and often no more than about 10 mm in length, and in the range, for example, of at least about 400 to about 1000 microns or less in heightM. In certain embodiments, the implant has a length of between at least about 3 to about 10 or less mm and for every 6 mm of implant, the average dose of compound of Formula I, Formula II, or Formula III ranges from at least about 0.10 mg to at least about 1.10 mg. In certain embodiments, the average dose of a compound of Formula I, Formula II, or Formula III for every 6 mm of implant is at least about 0.10 mg, 0.20 mg, 0.30 mg, 0.40 mg.0.50 mg, 0.60 mg, 0.70 mg, 0.80 mg, 0.90 mg, 1.0 mg, or 1.10 mg. In certain embodiments, the implant comprises compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, and has a length of between at least about 3 to about 10 mm or less and for every 6 mm of implant, the average dose of compound of Formula I, Formula II, or Formula III ranges from at least about 0.50 mg to at least about 1.10 mg and the average dose of compound of Formula I, Formula II, or Formula III ranges from about 0.05 mg to about 0.40 mg. In certain embodiments, the average dose of compound of Formula I, Formula II, or Formula III for every 6 mm of implant is at least about 0.50 mg, 0.60 mg, 0.70 mg, 0.80 mg, 0.90 mg, 1.0 mg, or 1.10 mg and the average dose of compound of Formula I, Formula II, or Formula III for every 6 mm of implant is at least about 0.05 mg, 0.10 mg, 0.20 mg, 0.30 mg, or 0.40 mg. In certain embodiments, the durable ocular implant comprising a compound of Formula I, Formula II, or Formula III is provided, and the implant is constructed of at least about 80, 85, 90, 95 or even about 100% by weight of a compound of Formula I, Formula II, or Formula III. In another aspect, the implant is a blend of a high load of Formula I, Formula II, or Formula III in a biodegradable polymeric material. In certain embodiments, the implant is a blend of a high load of Formula I, Formula II, or Formula III in a biodegradable polymeric material and an excipient, such as a sugar or a plasticizer. In certain embodiments, the plasticizer is polyethylene glycol. In other embodiments, the implant comprises a compound of Formula I, Formula II, or Formula III and an excipient and does not have a polymeric material. The implant can be administered via needle or device into any area of the eye that requires therapy or which can serve as a depot location for drug release, including but not limited to the vitreous, suprachoroidal, subchoroidal, subconjunctival, scleral, episcleral, intracameral or other convenient location, or as selected by the health care practitioner. These polymeric implants allow for drug delivery directly at the target site and are administered via a procedure that is minimally invasive. In certain embodiments, the implant delivers a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, for one month, two months, three ^{months, fourth months, five months, six months or more, limiting the amount of required injections.} In certain embodiments, the polymeric implant of the present invention is in the shape of a rod, a cylindrical pellet, a disc, a wafer, a sheet, or a plug. The implant of the present invention can be, for example, fabricated by a variety of techniques, including compression, solvent casting, hot melt extrusion, injection molding, and 3D printing. In certain embodiments, the implant is inserted via a needle, including but not limited to a 21, 22, 23, 24, 25, 26 or 27 gauge needle, which may optionally have a thin or ultra-thin needle wall. In certain embodiments, the implant is inserted intravitreally. In an alternative embodiment, the implant is inserted into the subconjunctival or suprachoroidal space. In certain embodiments, the needle is attached to an applicator, a device, or an inserter for minimally invasive injections. In other embodiments, the implant is delivered using a non-needle based medical device. In an alternative embodiment, the implant is surgically inserted. In certain embodiments, a powder of a compound of Formula I, Formula II, or Formula III is used to formulate the implant via, for example, compression, solvent casting, or hot melt extrusion. In alternative embodiments, microparticles comprising a compound of Formula I, Formula II, or Formula III are used as the starting material to formulate the implants via, for example, compression, solvent casting, or hot melt extrusion. In this embodiments, pre-mixing in not required because the components are already well-mixed during the microparticle formulation. The drug load of the microparticles used as a starting material can be any amount that fulfills the intended purpose, including but not limited to up to at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 1045%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% by weight. Example 14 is a non-limiting illustrative example of the process to form an implant from microparticles. In certain embodiments, the microparticles are surface- treated as described herein. In certain embodiments, the microparticles are not surface-treated as described herein. As described herein, implants of the present invention can also be formulated from (a) microparticles comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, and (b) unencapsulated compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof. In certain embodiments, the unencapsulated compound of Formula I, Formula II, or Formula III is used in micronized form. In certain embodiments, these implants are formed via compression, solvent casting, or hot melt extrusion. In certain embodiments, the implant comprises up to at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% by weight of unencapsulated compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof. Alternatively, the implant is formulated from (a) microparticles that comprise both a prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including ^{pharmaceutically acceptable lipophilic salt thereof, and a compound of Formula I, Formula II, or Formula III} or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, and (b) unencapsulated micronized compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof. The present invention also includes implants formulated from (a) microparticles that comprise both a prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and/or a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and (b) unencapsulated prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and micronized compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the unencapsulated prodrug of compound of Formula I, Formula II, or Formula III is micronized. In certain embodiments, the biodegradable implant is polymeric, and the polymer comprises no more than about 10, no more than about 20, no more than about 30, no more than about 40, no more than about 50, or no more than about 60 weight percent of the implant with the balance of the weight being a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, and other non-active agents dispersed in the biocompatible biodegradable polymer. Example 14 provides a non-limiting illustrative embodiment of a compound of Formula I, Formula II, or Formula III formulated into a polymeric implant for ocular delivery. In certain embodiments, the implant is polymeric, and the polymer comprises no more than about 30, 40, or 50 weight percent of the implant with the balance of the weight being a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, or other non-active agents and the implant exhibits a hardness rating of at least about 5 gram-force needed to compress the implant at 30% of strain. In certain embodiments, the implant is non-polymeric and a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable lipophilic salt thereof, comprises about 100 weight percent of the implant and the implant exhibits a hardness rating of at least about 5 gram-force needed to compress the implant at 30% of strain. In certain embodiments, the non-active ingredient is an additive, such as a plasticizer, which helps to improve the flexibility and processability of the implant. Non-limiting examples of plasticizers as non- active ingredients include benzyl alcohol, benzyl benzoate, ethyl heptanoate, propylene carbonate, triacetin, and triethyl citrate. Non-limiting examples of polymers included in the implants and polymeric microparticles of the present invention include, but are not limited to: poly(lactide co-glycolide); poly(lactic acid); poly(lactide-co- glycolide) covalently linked to polyethylene glycol; more than one biodegradable polymer or copolymer mixed together, for example, a mixture of poly(lactide-co-glycolide) and poly(lactide-co-glycolide) covalently linked to polyethylene glycol, a mixture of poly(lactic acid) and poly(lactide-co-glycolide) covalently linked to polyethylene glycol, or a mixture of poly(lactic acid), poly(lactide-co-glycolide) and poly(lactide-co- ^{glycolide) covalently linked to polyethylene glycol; and, poly(lactic acid).} In certain embodiments, the controlled-release formulation comprises a biodegradable polymer such as PLGA, PLA, PLGA-PEG, PLA-PEG or a combination thereof. In some embodiments, the formulation comprises PLGA and PLGA-PEG, or PLGA, PLA and PLGA-PEG. In some embodiments, the formulation comprises PLA and PLGA-PEG or PLA-PEG. In certain embodiments, the biodegradable implant (or insert) does not include a polymer, but instead the implant is made from a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof with the balance of the weight being a non-active agent or excipient, or a second biologically active compound. In certain embodiments, the implant is non-polymeric and a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, comprises about 100 weight percent of the implant. In certain embodiments the polymeric or non-polymeric implant exhibits a hardness rating of at least about 5 gram-force needed to compress the implant at 30% of strain. In certain embodiments, the implant exhibits a hardness rating of at least about 10 gram-force, 15 gram-force, 20 gram-force, 40 gram- force, 50 gram-force, 70 gram-force, 100 gram-force, 120 gram-force, 150 gram-force, 170 gram-force, or more when measured in vitro. In certain embodiments, the hardness is measured in vitro in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water. In certain embodiments, the microparticles, which may be treated for in vivo aggregation, or the implant, of the present invention comprise an effective amount of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, to treat a host with an ocular or other disorder that can benefit from local delivery. Nonlimiting examples of such diseases include dry and wet age-related macular degeneration (AMD), cytomegalovirus (CMV) infection, choroidal neovascularization, acute macular neuroretinopathy, macular edema (such as cystoid macular edema and diabetic macular edema), diabetic retinopathy (including proliferative diabetic retinopathy) and glaucoma. The present invention describes implants comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable lipophilic salt thereof, and includes at least the following embodiments: (a) a biodegradable implant described herein comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof; (b) a biodegradable implant formed from microparticles comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof; (c) a biodegradable implant formed from (a) microparticles that comprise a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and (b) unencapsulated compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof; (d) a biodegradable implant formed from (a) microparticles that comprise a compound of Formula ^{I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and (b) unencapsulated} micronized compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof; (e) the implant of (a)-(d) wherein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof is encapsulated or dispersed in at least one biodegradable polymer; (f) the implant of (e) wherein the implant comprises PLGA; (g) the implant of (e) or (f) wherein the implant comprises PLA; (h) the implant of (e)-(g) wherein the implant further comprises PLGA conjugated to PEG; (i) the implant of (e)-(h) wherein the implant further comprises PLA conjugated to PEG; (j) the implant of (e)-(i) wherein the implant further comprises PEG; (k) the implant of (a)-(j) wherein the implant further comprises a non-active excipient; (l) the implant of (k) wherein the excipient is a plasticizer; (m) the implant of (l) wherein the plasticizer is benzyl alcohol; (n) the implant of (l) wherein the plasticizer is triethyl citrate; (o) the implant of (a)-(n) wherein the implant releases a compound of Formula I, Formula II, or Formula III over a sustained period of at least one month; (p) the implant of (a)-(n) wherein the implant releases a compound of Formula I, Formula II, or Formula III over a sustained period of at least two months; (q) the implant of (a)-(n) wherein the implant releases a compound of Formula I, Formula II, or Formula III over a sustained period of at least three months; (r) the implant of (a)-(n) wherein the implant releases a compound of Formula I, Formula II, or Formula III over a sustained period of at least four months; (s) the implant of (a)-(n) wherein the implant releases a compound of Formula I, Formula II, or Formula III over a sustained period of at least five months; (t) the implant of (a)-(n) wherein the implant releases a compound of Formula I, Formula II, or Formula III over a sustained period of at least six months or more; (u) the implant of (a)-(t) wherein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof comprises between about 15 – 40 weight percent of the implant; (v) the implant of (a)-(t) wherein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof comprises between about 40 – 65 weight percent of the implant; (w) the implant of (a)-(t) wherein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof comprises between about 65 – 99 weight percent of the implant; (x) the implant of (a)-(t) wherein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof comprises 100% weight percent of the implant; (y) the implant of (a)-(x) wherein the implant exhibits a hardness rating of at least 5-gram force needed to compress the particle at 30% strain in vitro in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 ^{times that of water;} (z) the implant of (y) wherein the implant exhibits a hardness rating of at least 10-gram force need to compress the particle at 30% strain; (aa) the implant of (y) wherein the implant exhibits a hardness rating of at least 15-gram force need to compress the particle at 30% strain; (bb) the implant of (y) wherein the implant exhibits a hardness rating of at least 30-gram force need to compress the particle at 30% strain; (cc) the implant of (y) wherein the implant exhibits a hardness rating of at least 40-gram force need to compress the particle at 30% strain; (dd) the implant of (a)-(cc) in the shape of a rod; (ee) the implant of (a)-(cc) in the shape of a cylindrical pellet; (ff) the implant of (a)-(cc) in the shape of a sphere; (gg) the implant of (a)-(ee) wherein the length of implant is between about 3 and 10 mm; (hh) the implant of (gg) wherein the diameter of the implant is between about 0.3 and 0.6 mm; (aaa) a method to treat a medical disorder selected from glaucoma, a disorder or abnormality related to an increase in intraocular pressure (IOP), a disorder mediated by nitric oxide synthase (NOS), or a disorder requiring neuroprotection such as to regenerate/repair optic nerves. In other embodiments more generally, the disorder treated is allergic conjunctivitis, anterior uveitis, cataracts, wet or dry age-related macular degeneration, neovascular age-related macular degeneration, or diabetic retinopathy comprising administering the implant of embodiments (a)-(hh); (bbb) the method of (aaa) wherein the implant is administered intravitreally; (ccc) the method of (aaa) wherein the implant is administered to the suprachoroidal space; (ddd) the method of (aaa) wherein the implant is administered to the subconjunctival space; (eee) the method of (aaa) wherein the disorder is glaucoma; (fff) the method of (eee) wherein the glaucoma is primary open angle glaucoma; and (ggg) embodiments (aaa)-(fff) wherein the host is a human. The present invention also describes microparticles comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof, and includes at least the following embodiments: (a) solid microparticles described herein comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and surfactant wherein the microparticles are sufficiently small to be injected in vivo; (b) the solid microparticles of (a) wherein the microparticles are surface-modified biodegradable solid aggregating microparticles and wherein (i) the drug loading of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof is about at least 40% by weight or greater; (^{ii) the microparticles have a modified surface which has been treated under mild conditions} to partially remove surfactant; (iii) are sufficiently small to be injected in vivo; and (iv) aggregate in vivo to form at least one aggregated microparticle depot of at least 500 μm in vivo in a manner that provides sustained drug delivery in vivo for at least one month; (c) embodiment (b) wherein the drug loading is 60% by weight or greater; (d) embodiment (b) wherein the drug loading is 70% by weight or greater; (e) embodiment (b) wherein the drug loading is 85% by weight or greater; (f) embodiment (b) wherein the drug loading is 90% by weight or greater; (g) embodiment (b) wherein the drug loading is about 100% by weight; (h) embodiments (a)-(g) wherein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof is encapsulated or dispersed in at least one hydrophobic polymer and at least one hydrophobic polymer conjugated to a hydrophilic polymer; (i) embodiment (h) wherein the at least one hydrophobic polymer is PLGA; (j) embodiment (h) wherein the at least one hydrophobic polymer is PLA; (k) embodiments (h)-(j) wherein at least one hydrophobic polymer conjugated to a hydrophilic polymer is PLGA conjugated to PEG; (l) embodiments (h)-(k) wherein at least one hydrophobic polymer conjugated to a hydrophilic polymer is PLA conjugated to PEG; (m) embodiments (a)-(g) wherein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof is encapsulated or dispersed in PLGA and PLGA conjugated to PEG; (n) embodiments (a)-(g) wherein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof is encapsulated or dispersed in PLGA, PLA, and PLGA conjugated to PEG; (o) the surface-modified biodegradable solid aggregating microparticles of embodiments (b)-(n) wherein the surface-modified biodegradable solid aggregating microparticles are surface treated with a base and an organic solvent; (p) embodiment (o) wherein the base is sodium hydroxide, potassium hydroxide, or lithium hydroxide; (q) embodiment (p) wherein the base is sodium hydroxide; (r) embodiment (o)-(q) wherein the organic solvent in an alcohol; (s) embodiment (r) wherein the alcohol is methanol; (t) a suspension of microparticles as described in embodiments (a)-(s) in a diluent for injection that includes an additive that softens the surface of the microparticle before administration to prepare the microparticles for aggregation; (u) embodiment (t) wherein the additive is a plasticizer; (^{v) embodiment (u) wherein the plasticizer is benzyl alcohol;} (w) embodiment (u) wherein the plasticizer is triethyl citrate; (x) embodiments (t)-(w) wherein the aggregated microparticle depot exhibits a hardness rating of at least 10 gram-force needed to compress the depot at 30% strain in vitro in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water; (y) embodiment (x) wherein the hardness rating is at least 20 gram-force; (z) embodiment (x) wherein the hardness rating is at least 40 gram-force; (aa) embodiment (x) wherein the hardness rating is at least 50 gram-force; (bb) embodiment (x) wherein the hardness rating is at least 70 gram-force; (cc) embodiment (x) wherein the hardness rating is at least 100 gram-force; (dd) a method to treat a medical disorder selected from (i) glaucoma, a disorder or abnormality related to an increase in intraocular pressure (IOP), a disorder mediated by nitric oxide synthase (NOS), or a disorder requiring neuroprotection such as to regenerate/repair optic nerves; (ii) allergic conjunctivitis, anterior uveitis, cataracts, wet or dry age-related macular degeneration, neovascular age-related macular degeneration, or diabetic retinopathy or (iii) cytomegalovirus (CMV) infection, choroidal neovascularization, acute macular neuroretinopathy, macular edema (such as cystoid macular edema and diabetic macular edema), Behcet’s disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy), retinal arterial occlusive disease, central retinal vein occlusion, uveitis retinal disease, retinal detachment, ocular trauma, damage caused by ocular laser treatment or photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction or retinitis pigmentosa; comprising administering the biodegradable solid microparticles of embodiments (a)-(cc) in a host in need thereof;; (ee) the method of (dd) wherein the microparticles are administered intravitreally; (ff) the method of (dd) wherein the microparticles are administered to the suprachoroidal space; (gg) the method of (dd) wherein the microparticles are administered to the subconjunctival space; (hh) the method of (dd) wherein the disorder is glaucoma; (ii) the method of (hh) wherein the glaucoma is primary open angle glaucoma; and (jj) embodiments (dd)-(ii) wherein the host is a human. BRIEF DESCRIPTION OF THE FIGURES Figure 1 provides examples of a trimeric compound for use in the formulas of the present invention. Figure 2 shows the protective effect of exemplary compounds of the invention against cell death in primary rod-like cells (compared to known compounds Rp-8-Br-cGMPS and Rp-8-Br-PET-cGMPS). Legend: Primary rod-like cells derived from the rd1 mutant mouse undergo spontaneous cell death 11 days after differentiation. Rod-like cells were exposed to compounds at day 10 of culture and analyzed 24 hours ^{later. A.: 0.1 µM concentration of tested compounds. B.: 1 µM concentration of tested compounds.} Percentage of dying cells was evaluated by Ethidium Homodimer assay. Untreated cells are shown as control sample (black bar). Reference compounds Rp-8-Br-cGMPS and Rp-8-Br-PET-cGMPS are shown as dashed bars. Data are shown as means ±SD from at least three biological replicates. Figure 3 shows the culturing paradigm for rd1 explant experiments. Legend: The animals at the age of postnatal day 5 (PN5) were killed by decapitation and retinas were dissected out with retinal pigment epithelium attached as described previously (Caffe, A. R.; Ahuja, P.; Holmqvist, B.; Azadi, S.; Forsell, J.; Holmqvist, I.; Soderpalm, A. K.; van Veen, T., Mouse retina explants after long-term culture in serum free medium. J Chem Neuroanat 2001, 22 (4), 263-73). The retinas were flattened out on the membranes of commercially available 6-well culture inserts, after which 1.5 ml of a custom made culturing medium was added to each well. These explants were then kept in culture for two days without any treatment after which the test analog of the invention at the desired concentration was added at a medium change at PN7 ("7" in Figure). There was then a new medium change at PN9 ("9" in Figure), with same concentration of analog of the invention, upon which the cultures were kept until PN11 ("11" in Figure). At this time point the experiment was finished by a fixation procedure. This paradigm is therefore called PN5+2+4. Controls, i.e. rd1 explants without any treatment, used the same paradigm. Healthy animals (wild type, wt) may be used for comparisons. The lighter part of horizontal bar represents the first period, with no treatment, and the darker part indicates the actual treatment period. Figure 4 shows the protective effects of exemplary compounds of the invention against cell death in retinal explants (compared to known compounds Rp-8-Br-cGMPS and Rp-8-Br-PET-cGMPS). Legend: Effects of selected analogs at given concentrations of the invention on the cell death of photoreceptors of rd1 explants. The cell death was assessed by so called TUNEL stain on fixated and sectioned material, after which the number of dying cells was counted and analyzed, and compared with that from untreated rd1 explants. In order to allow more direct comparisons between the different analogs and concentrations a ratio of treated/untreated specimens was calculated. The left-most bar represents untreated explants as such, which then have the ratio 1.0 since there is no effect. The next bar then concerns Rp-8-Br-PET- cGMPS at 50 µM, where the effect ratio was about 0.78, meaning that this treatment reduced the photoreceptor cell death by more than 20 %. The rest of the treatments can be interpreted in the same way. Bars represent standard deviation and the number of tests was 8. Figure 5 shows example of a trimeric compound according to the invention. Figures 6, 7, and 8 demonstrate the in vitro activation of PKG isoforms by polymer linked cGMP derivatives featuring different spacer lengths with and without PET-modification (Figure 3), varied linking position (Figure 4) and unequal cGMP (analog) units with and without unequal linking positions (Figure 5). Legend: PKG isozymes Iα (0.2 nM), Iβ (0.15 nM) and II (0.5 nM) were incubated with different concentrations (10 pM to 6 µM) of compounds of the invention and cGMP as reference compound at room temperature for 60 min. The activation values of the compounds are expressed as relative PKG activation compared to cGMP with cGMP set as 1 for each kinase isozyme. The Ka-values of cGMP for half-maximal ^{kinase activation were 28 nM for Iα, 425 nM for Iβ and 208 nM for II.} Figure 9 shows the expression of PKG isoforms in 661W cells. Legend: RT-PCR on cDNA from mRNA extracted from 661W cell. The 661W cell line expresses the PKG isoforms Iα and II. Heart and muscle tissues were used as positive controls. Figure 10 shows increased cell death in the 661W cell line after treatment with different polymer linked dimeric cGMP analogs. Legend: 661W cells were exposed to compounds for 16 hours at different concentrations (1 nM to 10 µM) and percentage of dying cells was evaluated by Ethidium Homodimer assay. Untreated cells are shown as control sample (black bar). Reference compound 8-Br-PET-cGMP is shown as dashed bars. Data are presented as means ±SD from at least three biological replicates. Results not including standard deviation refer to single measurements. Asterisks indicate the P value of the unpaired Student’s t-test (* P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001), statistically assessing significant differences between untreated and treated cells, wherein a p value ≤0.05 was considered significant. Figure 11 shows molecular structures of Compound 221 (Left) and Compound 188 (Right) in Na+ salt form. Figure 12 shows a representative microscopic image of Compound 221-loaded microparticles. Figure 13 shows the in vitro drug release profiles of microparticles containing 221-BEN or 221- BEZ. Figure 14 shows a representative microscopic image of microparticles containing Compound 188- BEZ. Figure 15 shows the in vitro drug release profiles of microparticles containing Compound 188-BEZ. Figure 16 shows the in vitro drug release profiles of implants containing Compound 221 with different salt forms (TEA, free acid and Na+). Figure 17 shows the in vitro drug release profiles of implants containing Compound 221 with different salt forms (BEN, and Ca2+). DETAILED DESCRIPTION The present invention provides new advantageous microparticle and implant formulations comprising polymer linked multimeric (PLM) guanosine-3′,5′-cyclic monophosphate (cGMP) analogs of Formula I and Formula II or related monomeric compounds of Formula III, or pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable lipophilic salt thereof, that modulate, inhibit or activate the cGMP-signaling system, for example, modulate, inhibit or activate a cGMP-dependent protein kinase G (PKG). The invention is also directed to the therapeutic and/or prophylactic use of the microparticles and implants comprising a compound of Formula I, Formula II, and Formula III, or pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable lipophilic salt thereof, for the treatment and/or prophylaxis of disorders associated with cGMP-signaling processes. In certain aspects these formulations are suitable for long-term ocular therapy. The microparticles and implants of the present invention can be prepared using the technologies ^{described in the following applications and patents, for example.} GrayBug Vision, Inc. discloses aggregating microparticles for ocular therapy in granted U.S. Patent Nos.10,441,548 and 11,331,276; U.S. Application Nos. US 2018-0326078, US 2020-0000735, US 2020- 0230246, US 2021-0214374 and US 2021-0275456. PCT Applications WO 2018/209155 and WO 2019/209883; and U.S. Application No.2021-0085607 describe aggregating microparticles and processes for making aggregating microparticles. GrayBug Vision, Inc. also discloses implants for ocular therapy in PCT Application WO 2021/237096. GrayBug Vision, Inc. discloses prodrugs for the treatment of ocular therapy in granted U.S. Patent Nos. 9,808,531; 9,956,302; 10,098,965; 10,117,950; 10,111,964; 10,159,747; 10,458,876; PCT Applications WO 2019/118924 and WO 2019/210215; and U.S. Application No.2021-0040111. In certain embodiments, the advantageous and beneficial properties of microparticle and implant formulations according to the invention include high drug loading and/or controlled drug release profiles of a compound of Formula I, Formula II, and Formula III or pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salts. In certain embodiments, high drug loading and/or controlled drug release profiles of a compound of Formula I, Formula II, and Formula III are achieved when a pharmaceutically acceptable lipophilic salt of a compound of Formula I, Formula II, and Formula III is used to load a microparticle or implant according to the invention. In certain embodiments, higher drug loading and/or longer drug release profiles are achieved for: Lipophilic salt 221-BEN, which is 8-bromo-(β-phenyl-1,N²-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp-isomer, N-benzyl-2-phenylethan-1-aminium salt; Lipophilic salt 221-BEZ, which is 8-bromo-(β-phenyl-1,N²-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp-isomer which is N-benzyl-2-(benzylamino)ethan-1-aminium salt; Lipophilic salt 188-BEN, which is 8-bromo-(4-methyl-β-phenyl-1,N²-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp- isomer, N-benzyl-2-phenylethan-1-aminium salt; and Lipophilic salt 188-BEZ, which is 8-bromo-(4-methyl-β-phenyl-1,N²-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp- isomer, N-benzyl-2-(benzylamino)ethan-1-aminium salt of formulas:

, wherein BEN is used as an abbreviation for benethamine (N-benzyl-2-phenylethanamine) and BEZ is used as an abbreviation for benzathine (N,N'-dibenzylethylenediamine), or their protonated forms. For example, in 221-BEN and 118-BEN:

^{and in 221-BEZ and 118-BEZ:}

. In certain embodiments, microparticles or implants according to the invention comprise pharmaceutically acceptable lipophilic salts of a compound of Formula I, Formula II, or Formula III. In certain embodiments, pharmaceutically acceptable lipophilic salts of a compound of Formula I, Formula II, or Formula III include monoalkyl ammonium salts, dialkyl ammonium salts, benzyl alkyl ammonium salts, trialkyl ammonium salts, quaternary ammonium salts, such as tetraalkyl ammonium salts, benzyl trialkyl ammonium salts, dibenzyl dialkyl ammonium salts, alkyl dimethyl benzyl ammonium salts, tetraalkyl phosphonium salts, benzyl trialkyl phosphonium salts, imidazolium salts, N-alkyl-morpholinium salts, N,N-dialkyl-morpholinium salts, alkyl pyridinium salts, N-alkyl piperidinium salts, and N,N-dialkyl piperidinium salts. In certain embodiments, a pharmaceutically acceptable lipophilic salt of a compound of Formula I, Formula II, or Formula III is formed from the compound of Formula I, Formula II, or Formula III and a lipophilic amine. In certain embodiments, the lipophilic amine to form a pharmaceutically acceptable lipophilic salt of the compound of Formula I, Formula II, or Formula III is benzathine (N,N'- dibenzylethylenediamine), benethamine (N-benzyl-2-phenylethanamine), or triethyl amine. In certain embodiments, a pharmaceutically acceptable lipophilic salt of the compound of Formula I, Formula II, or Formula III is a benzathine salt, benethamine salt, or triethyl amine salt. In certain embodiments, the durable controlled release formulation of Formula I, Formula II, or Formula III in a biodegradable microparticle suitable for long-term ocular therapy can be prepared with a drug (i.e., Formula I, Formula II, or Formula III) load of about 40% or greater, for example about 43% or greater, about 44% or greater, about 45% or greater, about 50% or greater, about 60% or greater, about 75% or greater, about 90% or greater or even as high as about 100%. In certain embodiments, the controlled-release formulation comprises a biodegradable polymer such as PLGA, PLA, PLGA-PEG, PLA- PEG or a combination thereof. The present invention further includes a suspension of aggregating biodegradable microparticles with high loading of one or more active agents described herein, for example loadings of 40% by weight or greater, for example greater than about 45%, 50%, 60%, 75%, 90% or even as high as about 100% by weight in a diluent for injection that comprises an additive that softens the surface polymer of the microparticle and improves aggregation prior to injection. In certain embodiments, the additive is a plasticizer, for example benzyl alcohol or triethyl citrate. In other embodiments, a durable ocular implant comprising a compound of Formula I, Formula II, or Formula III is provided. In certain embodiments, the biodegradable implant is polymeric and the polymer comprises no more than about 10, no more than about 20, no more than about 30, no more than about 40, no more than about 50, or no more than about 60 weight percent of the implant with the balance of the weight being a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof or other non-active agents dispersed in the biocompatible biodegradable polymer. In certain embodiments, the biodegradable implant is polymeric, and the polymer comprises no more than about 70, no more than about 80, no more than about 90, or no more than about 95, weight percent of the implant with the balance of the weight being a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof or other non-active agents dispersed in the biocompatible biodegradable polymer. In an alternative embodiment, a durable ocular implant comprising both a prodrug of compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof is provided. In certain embodiments, the biodegradable implant is polymeric and the polymer comprises no more than about 10, no more than about 20, no more than about 30, no more than about 40, no more than about 50, or no more than about 60 weight percent of the implant with the balance of the weight being a prodrug of compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof or other non-active agents dispersed in the biocompatible biodegradable polymer. In certain embodiment, the implant is non-polymeric and a prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof comprises about 100 weight percent of the implant. I. Terminology Listed below are the definitions of various terms and phrases used to describe the compounds of the present invention. These definitions apply to the terms as they are used throughout the specification. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs. Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the ^{art to which this invention belongs.} The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Halogen refers to F, Cl, Br, and I. Alkyl refers to an alkyl group, which is a hydrocarbon moiety with 1 to 28, for example 1 to 20 carbon atoms, with or without (integrated) heteroatoms such as but not limited to O, S, Si, N, Se, B, wherein the point of attachment unless specified otherwise is a carbon atom. Its constitution can be: Linear saturated hydrocarbon moiety - including, but not limited to, methyl, ethyl, propyl, butyl and pentyl; or Linear unsaturated hydrocarbon moiety – containing in certain embodiments 2 to 20 carbon atoms, including, but not limited to, ethylen, propylen, butylen and pentylen; or Branched saturated hydrocarbon moiety – deviating from the general alkyl definition by containing at least 3 carbon atoms and including, but not limited to, isopropyl, sec-butyl and tert-butyl; or Branched unsaturated hydrocarbon moiety - deviating from the general alkyl definition by containing at least 3 carbon atoms and including, but not limited to, isopropenyl, isobutenyl, isopentenyl and 4-methyl-3-pentenyl; or Cyclic saturated hydrocarbon moiety – containing in certain embodiments 3 to 8 ring atoms and including, but not limited to, cyclopentyl, cyclohexyl, cycloheptyl, piperidino, piperazino; or Cyclic unsaturated hydrocarbon moiety – containing in certain embodiments 3 to 8 ring atoms. Herein the term “saturated” means the group has no carbon-carbon double and no carbon-carbon triple bonds. However, in the substituted case of saturated groups one or more carbon-oxygen or carbon- nitrogen double bonds may be present, which may occur as part of keto-enol and imine-enamine tautomerization respectively. Independent from its constitution, an alkyl group, as defined herein, can be substituted or unsubstituted. Substituents include, but are not limited to, one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, ^{cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, epoxy, methoxy, ethynyl. In case alkyl, as} defined herein, contains a poly ethylene glycol (PEG) moiety, the typical number of carbon atoms can be exceeded by the number present in the PEG moiety, wherein the PEG moiety can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500). It has to be noted, that -(EO)_n- is used as an abbreviated expression for -(CH₂CH₂O)_n- with n indicating the number of ethylene glycol groups. The number of ethylene glycol groups especially may be n = 1 –500 or as stated in the particular example. Aralkyl refers to an alkyl group as described above, that connects to an unsubstituted or substituted aromatic or heteroaromatic hydrocarbon moiety, consisting of one or more aromatic or heteroaromatic rings with 3-8 ring atoms each. Substituents for both the alkyl and aryl part include, but are not limited to, one or more halogen atoms, alkyl or haloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, amino, nitro, cyano, hydroxy, mercapto, carboxy, azido, methoxy, methylthio. Aryl refers to an aryl group, which is an unsubstituted or substituted aromatic or heteroaromatic hydrocarbon moiety, consisting of one or more aromatic or heteroaromatic rings with 3-8 ring atoms each. Substituents include, but are not limited to, one or more halogen atoms, haloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, amino, nitro, cyano, hydroxy, mercapto, carboxy, azido, methoxy, methylthio. Acyl refers to a -C(O)-alkyl group, wherein the alkyl group is as defined above. Aracyl refers to a –C(O)-aryl group, wherein the aryl group is as defined above. Carbamoyl refers to a -C(O)-NH₂ group, wherein the hydrogens can independently from each other be substituted with an alkyl group, aryl group or aralkyl group, wherein alkyl group, aryl group or aralkyl group are as defined above. O-acyl refers to an –O-C(O)-alkyl group, wherein the alkyl group is as defined above. O-alkyl refers to an alkyl group, which is bound through an O-linkage, wherein the alkyl group is as defined above. O-aracyl refers to a -O–C(O)-aryl group, wherein the aryl group is as defined above. O-aralkyl refers to an aralkyl group, which is bound through an O-linkage, wherein the aralkyl group is as defined above. O-aryl refers to an aryl group, which is bound through an O-linkage, wherein the aryl group is as defined above. O-carbamoyl refers to a carbamoyl group, which is bound through an O-linkage, wherein the carbamoyl group is as defined above. S-alkyl refers to an alkyl group, which is bound through a S-linkage, wherein the alkyl group is as defined above. S-aryl refers to an aryl group, which is bound through a S-linkage, wherein the aryl group is as ^{defined above. S-aralkyl refers to an aralkyl group, which is bound through a S-linkage, wherein the aralkyl} group is as defined above. S-aralkyl refers to an aralkyl group, which is bound through an S-linkage, wherein the aralkyl group is as defined above. Se-alkyl refers to an alkyl group, which is bound through a Se-linkage, wherein the alkyl group is as defined above. Se-aryl refers to an aryl group, which is bound through a Se-linkage, wherein the aryl group is as defined above. Se-aralkyl refers to an aralkyl group, which is bound through a Se-linkage, wherein the aralkyl group is as defined above. NH-alkyl and N-bisalkyl refer to alkyl groups, which are bound through an N linkage, wherein the alkyl groups are as defined above. NH-aryl and N-bisaryl refer to aryl groups, which are bound through an N linkage, wherein the aryl groups are as defined above. NH-carbamoyl refers to a carbamoyl group, which is bound through an N-linkage, wherein the carbamoyl group is as defined above. Amido-alkyl refers to an alkyl group, which is bound through a NH-C(O)- linkage, wherein the alkyl group is as defined above. Amido-aryl refers to an aryl group, which is bound through a NH-C(O)- linkage, wherein the aryl group is as defined above. Amido-aralkyl refers to an aralkyl group, which is bound through a NH-C(O)- linkage, wherein the aralkyl group is as defined above. Endstanding group refers to a group of a particular residue (R₁, R₄ and/or R₅) which is (sterically) accessible and capable for covalently binding to a particular linking residue (LR^{1 – 4}). This may be a group at the actual terminal end of the residue (R₁, R₄ and/or R₅) or at any terminal end of any sidechain of the residue (R₁, R₄ and/or R₅), or which is otherwise located in the residue (R₁, R₄ and/or R₅) and sufficiently (sterically) accessible and capable for covalently binding to a particular linking residue (LR^{1 – 4}). The definition of the term endstanding group, if applicable, is independently also valid for the residues LR⁵ and/or LR^PEG. Further, the term terminus refers to an endtsanding group which is actually a terminal end of the concerned residue. The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. The term “a pharmaceutically acceptable salt” refers to a salt that is suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid, trifluoroacetic acid and the like. Examples of pharmaceutically ^{acceptable salts include alkali or organic salts of acidic residues such as phosphates and thiophosphates.} Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent agent formed, for example, from non-toxic inorganic bases or organic bases, for example amines, and parent agent containing phosphate and/or thiophosphate acid group. In certain aspects the pharmaceutically acceptable salt is a lipophilic salt. Lipophilic salts are capable of associating with or dissolving in a fat, lipid, oil, and/or non-polar solvent. In certain embodiments, the terms “lipophilicity” and “hydrophobicity” may be used to describe the same tendency of a compound to dissolve in fats, oils, lipids, and non-polar solvents. The established measure of “lipophilicity” of a drug molecule is the coefficient of partition between octanol as the lipophilic phase and an aqueous phase, reported as logP_octanol, as described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 1^st Edition, Chapter 4: “Pharmaceutical Aspects of the Drug Salt Form”. In certain embodiments, lipophilic salts of a compound of Formula I, Formula II, or Formula III have a higher lipophilicity than a non-salt form of compound of Formula I, Formula II, or Formula III thereby allowing for increased transport and permeation through and across biological barriers and membranes, including cell membranes. An amphiphilic pharmaceutically acceptable excipient can also increase the lipophilicity of the formulation comprising a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable lipophilic salt thereof. In certain embodiments, the excipient increases the lipophilicity of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable lipophilic salt thereof. In certain embodiments, the excipient is a surfactant. In some embodiments, the excipient is an anionic or cationic surfactant. In certain embodiments, the excipient is an anionic or cationic surfactant that forms an ion pair or salt with a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable lipophilic salt thereof. Such anionic or cationic surfactants are typically characterized by having a lipophilic end and an anionic or cationic portion. Exemplary excipients useful in the present invention include aliphatic sulfates (e.g., sodium dodecyl(lauryl) sulfate), aliphatic phosphates, fatty acids, and salts and derivatives thereof. Term “lipophilic” as used herein describes the tendency of a compound to associate and/or dissolve in fats, oils, lipids, and non-polar and fat-like solvents. Lipophilic compounds have affinity for oils, fats, and lipids. The term “carrier” refers to a diluent, excipient, or vehicle. A “dosage form” means a unit of administration of a composition that includes a surface treated microparticle and a compound of Formula I, Formula II, or Formula III or an implant and a compound of Formula I, Formula II, or Formula III. Examples of dosage forms include injections, suspensions, liquids, emulsions, implants, particles, spheres, topical, gel, mucosal, and the like. A “dosage form” can also include, for example, a surface treated microparticle comprising a pharmaceutically active compound in a carrier. The term “microparticle” means a particle whose size is measured in micrometers (μm). Typically, the microparticle has an average diameter of from about 0.5 or 1 μm to 100 or 150 μm. In some embodiments, the microparticle has an average diameter of from about 1 μm to 60 μm, for instance from ^{about 1 μm to 40 μm; from about 10 μm to 40 μm; from about 20 μm to 40 μm; from about 25 μm to 40 μm;} from about 25 µm to about 30 µm; from about 20 μm to 35 μm. For example, the microparticle may have an average diameter of from 20 μm to 40 μm, and in certain embodiments, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33. As used herein, the term “microsphere” means a substantially spherical microparticle. A “patient” or “host” or “subject” is typically a human, however, may be more generally a mammal. In an alternative embodiment it can refer to, for example, a cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, bird and the like. Unless otherwise stated, the subject is a human. The term “mild” or “mildly” when used to describe the surface modification of the microparticles means that the modification (typically the removal, or partial removal, of surfactant from the surface, as opposed to the inner core, of the particle) is less severe, pronounced or extensive than when carried out at room temperature with the otherwise same conditions. In general, the surface modification of the solid microparticles of the present invention is carried out in a manner that does not create significant channels or large pores that would significantly accelerate the degradation of the microparticle in vivo, yet serves to soften and decrease the hydrophilicity of the surface to facilitate in vivo aggregation. The term “solid” as used to characterize the mildly surface treated microparticle means that the particle is substantially continuous in material structure as opposed to heterogeneous with significant channels and large pores that would undesirably shorten the time of biodegradation. The term “sonicate” means to subject the microparticle suspension to ultrasonic vibration or high frequency sound waves. The term “vortex” means to mix by means of a rapid whirling or circular motion. “Hardness,” is a measure of resistance to deformation in units of the gram-force (gf) required to compress the microparticle aggregate depot at 30% of strain. In certain embodiments, the aggregated microparticle depot of the present invention exhibits a hardness of at least about 40 gram-force, at least 50 gram-force, 70 gram-force, at least about 100 gram-force, or at least about 150 gram-force. In certain embodiments, hardness is measured via a Texture Analyzer. “Gram-force” is a metric unit of force (gf), and is used in this application as a measure of microparticle hardness. The term “additive” is used to describe any reagent or solvent that increases the plasticity or flexibility of a polymer, decreases the viscosity or the glass transition temperature of a polymer, or partially dissolves a polymer. In some embodiments, the additive is a plasticizer. Non-limiting examples of additives of the present invention include triethyl citrate, benzyl alcohol, polyethylene glycol, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, DMSO, triacetin, benzyl acetate, benzyl benzoate, acetyltributyl citrate, dibutyl sebacate, dimethylphthalate, tributyl O-acetylcitrate, ethanol, methanol, polysorbate 80, ethyl acetate, propylene carbonate, isopropyl acetate, methyl acetate, methyl ethyl ketone, butyl lactate, and isovaleric acid. “Aggregated microparticle depot” (or alternatively “aggregated microparticle pellet”, or “aggregated ^{microparticle”) as used herein, is a solid aggregation of individual microparticles wherein the individual} microparticles prior to aggregation typically have a mean diameter between about, for example, 10 μm and about 60 or 75 microns, and more typically between about 20 and about 40 microns (or between about 15 and about 40 or between about 25 and about 40 microns or 20 and 30 microns). The aggregated microparticle depot of the present invention are distinct from ocular implants which are injected in vivo in an already formed shape, and also are distinct from microparticles that are held together by a depot-forming material such as a gel, or other material intended to hold the microparticles together other than the microparticles themselves. “Implant” refers to a polymeric device or element that is structured, sized, or otherwise configured to be implanted, for example, by injection or surgical implantation, in a specific region of the body so as to provide therapeutic benefit by releasing one or more active agents over an extended period of time at the site of implantation. For example, intraocular implants are polymeric devices or elements that are structured, sized, or otherwise configured to be placed in the eye, for example, by injection or surgical implantation, and to treat one or more diseases or disorders of the eye by releasing one or more drugs over an extended period. “Light transmittance” is the percentage of light that is transmitted through the solution of microparticles suspended in a diluent, for example hyaluronate solution as described in Example 2. In certain embodiments, a solution of microparticles suspended in a diluent has a light transmittance of greater than about 90%, greater than about 92%, greater than about 94%, greater than about 96%, greater than 98%, or greater than 99%. In certain embodiments, the term “prodrug” means a derivative of the compound of Formula I, Formula II, or Formula III that is converted within the body to a compound of Formula I, Formula II, or Formula III by metabolic or physicochemical transformation. Prodrugs can be used to achieve better bioavailability, solubility and absorption, enhanced delivery and tissue or organ targeting, and higher chemical stability, long shelf-life, and better processibility. For example, in certain embodiments the prodrug is an ester or amide of a compound of Formula I, Formula II, or Formula III wherein the ester or amide moiety can be removed by an esterase or amidase. II. Compounds of Formula I, Formula II, and Formula III In certain embodiments, the microparticle or implant formulations of the present invention comprise a compound of Formula I or Formula II:

or a pharmaceutically acceptable salt thereof; wherein: G units G¹ and G² are independently compounds of Formula IIIA and G units G³ and G⁴ independently from G¹ and G² and independently from each other are compounds of Formula IIIA or absent, wherein in case of Formula II G⁴ is always absent if G³ is absent,

and wherein in Formula IIIA X, Y and Z are N R₁, R₄, R₅, and R8 independently can be equal or individual for each G unit (G¹, G², G³ and G⁴), while R₁ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR9R10, carbamoylR11R12, NH-carbamoylR11R12, O- carbamoylR11R12, SiR13R14R15 wherein R9, R10, R11, R12, R13, R14, R15 independently from each other can be H, alkyl, aryl, aralkyl; R₂ is absent; R₃ is OH; R₄ can independently be absent, H, amino, alkyl, aralkyl, nitro, N-oxide, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazolinone as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl;

R₅ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR30R31, carbamoylR32R33, NH-carbamoylR32R33, O-carbamoylR32R33, SiR34R35R36 wherein R30, R31, R32, R33, R34, R35, R36 independently from each other can be H, alkyl, aryl, aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazolinone ring as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl; R₆ is OH; R₇ is =O, O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O- aralkyl, O-acyl, SH, S-alkyl, S-aryl, S-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, O-PAP, S-BAP, or O-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and R₈ is O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O- acyl, O-PAP, O-BAP, SH, S-alkyl, S-aryl, S-aralkyl, SeH, Se-alkyl, Se-aryl or Se-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, Se-PAP, S-BAP or Se-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and wherein linking residues LR¹, LR², LR³ and LR⁴ independently can replace or covalently bind to any of the particular residues R₁, R₄ and/or R₅ of the G units (G^{1 - 4}) they connect, wherein in case they bind to any of the residues R₁, R₄ and/or R₅, an endstanding group of the particular residue (R₁, R₄ and/or R₅), as defined above, is transformed or replaced in the process of establishing the connection and is then further defined as part of the particular linking residue (LR^{1 - 4}) within the assembled compound, while LR¹ is (a) a tri- or tetravalent branched hydrocarbon moiety or (b) a divalent hydrocarbon moiety each with or without incorporated heteroatoms such as, but not limited to, O, N, S, Si, Se, B, wherein in certain embodiments the backbone contains 1 to 28 carbon atoms and can be saturated or unsaturated, substituted or unsubstituted, while each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom and in case poly ethylene glycol (PEG) moieties are incorporated in accordance to the definition, the typicald number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500) in case of divalent linking residue (LR¹) or 1 to 750 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 750) in case of trivalent l^{inking residue (LR1)} or 1 to 1000 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 1000) in case of tetravalent linking residue (LR¹), and, if substituted, substituents include, but are not limited to, optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, epoxy, methoxy, ethynyl, and/or substituents can further be connected to each other, forming a ring system with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic; LR², LR³ and LR⁴ are divalent hydrocarbon moieties with or without incorporated heteroatoms such as, but not limited to, optionally heteroatoms O, N, S, Si, Se, B, wherein in certain embodiments the backbone contains 1 to 28 carbon atoms and can be, saturated or unsaturated, substituted or unsubstituted, while each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom and in case poly ethylene glycol (PEG) moieties are incorporated in accordance to the definition, the typical number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500) and, if substituted, substituents include, but are not limited to, optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, epoxy, methoxy, ethynyl, and/or substituents can further be connected to each other, forming a ring system with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic; wherein in case of Formula II if G⁴ is absent, LR⁴ is absent, too, and wherein in case of Formula II if G³ and G⁴ are absent, LR³ and LR⁴ are absent, too, and wherein G¹, G², G³ and G⁴ can further be salts and/or hydrates w^{hile, optionally, non-limiting examples of suitable salts of the particular phosphate moiety are} lithium, sodium, potassium, calcium, magnesium, zinc or ammonium, and trialkylammonium, dialkylammonium, alkylammonium, e.g., triethylammonium, trimethylammonium, diethylammonium and octylammonium; and wherein G¹, G², G³ and G⁴ can optionally be isotopically or radioactively labeled, be PEGylated, immobilized or be labeled with a dye or another reporting group, wherein the reporting group(s) and/or dye(s) (a) are coupled to G¹, G², G³ and/or G⁴ via a linking residue (LR⁵), bound covalently to or replacing any of the particular residues R₁, R₄ and/or R₅ independently for each G unit (G¹, G², G³ and/or G⁴) while LR⁵ can be as defined for LR² or (b) in case of Formula I can replace G³ and/or G⁴ and wherein examples of optionally suitable dyes include, but are not limited to, fluorescent dyes such as fluorescein, anthraniloyl, N-methylanthraniloyl, dansyl or the nitro-benzofurazanyl (NBD) system, rhodamine-based dyes such as Texas Red or TAMRA, cyanine dyes such as Cy^TM3, Cy^TM5, Cy^TM7, EVOblue^TM10, EVOblue^TM30, EVOblue^TM90, EVOblue^TM100 (EVOblue^TM-family), the BODIPY^TM- family, Alexa Fluor^TM-family, the DY-family, such as DY-547P1, DY-647P1, coumarines, acridines, oxazones, phenalenones, fluorescent proteins such as GFP, BFP and YFP, and near and far infrared dyes and wherein reporting groups optionally include, but are not limited to, quantum dots, biotin and tyrosylmethyl ester; and wherein PEGylated refers to the attachement of a single or multiple LR^PEG group(s) independently, wherein LR^PEG can be as defined for LR², with the provisos that in this case (i) of LR² only one terminus is connected to a G unit (G¹, G², G³ and/or G⁴) by covalently binding to or replacing any of the particular residues R₁, R₄ and/or R₅ independently for each G unit (G¹, G², G³ and/or G⁴), and (ii) the other terminus of LR² is either an alkyl group or a reactive group that allows for conjugation reactions and/or hydrogen bonding while, optionally, non-limiting examples of reactive groups are, -NH₂, -SH, -OH, -COOH, - N3, -NHS-ester, halogen group, epoxide, ethynyl, allyl and with the proviso (iii) that LR^PEG has incorporated ethylene glycol moieties (-(CH₂CH₂O)_n- with n = 2 to 500). I^{n certain embodiments, the microparticle or implant formulations of the present invention comprise} a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein each variable is as described herein. Embodiments of Formula I, Formula II, and Formula III The person skilled in the art is well aware that a particular linking residue (LR^{1 – 4}) may represent a radical depending on the number of particular G units it binds to. Thus, in compounds of Formula II, the particular linking residue (LR^{1 – 4}) may be a biradical, or in case it is (intermediary) bound to only one particular G unit it may be a monoradical. Similarly, in case of compounds Formula I, depending on the number of particular G units it binds to, the particular linking residue (LR¹) may be a biradical, triradical, or tetraradical, or in case it is (intermediary) bound to only one particular G unit it may be a monoradical. If an otherwise considered monovalent group is used with the modifier “divalent” as in “divalent alkyl” then this adds a second attachment point. Non-limiting examples of divalent alkyl would be -CH₂-, - CH₂CH₂-, -CH₂C(CH₃)₂CH₂-. Whenever side chains or residues are depicted as “floating groups” on a ring system, for example, in the formula:

then these side chains (or residues) may replace any hydrogen atom attached to any of the ring atoms, including depicted, implied, or expressly defined hydrogen, as long as a stable structure is formed. All resulting substitution patterns are thus included. For the given example, this corresponds to

The person skilled in the art understands that many compounds that fall under formula III and formula IIIA as defined above have tautomeric forms. It has to be noted that according to this specification all tautomeric forms fall under formula III or formula IIIA if at least one of the tautomers falls under formula III or formula IIIA as defined above. In the chair form of saturated six-membered rings, bonds to ring atoms, and the molecular entities attached to such bonds, are termed “axial” or “equatorial” according to whether they are located about the periphery of the ring (“equatorial”), or whether they are orientated above or below the approximate plane of the ring (“axial”). Due to the given stereochemistry of the cyclic phosphate ring, the axial position can only be above the approximate plane of the ring. In naturally occurring cyclic nucleotide monophosphates (cNMP), both R7 and R8 are oxygen, and the phosphorus double bond is “distributed or dislocated” between both atoms. In water at physiological pH, the compound has a negative charge between both oxygens, and a corresponding cation, such as H+ or Na+. Compounds of the present invention have the equatorial (R8) oxygen replaced by a different function, e.g., sulfur, while the axial (R7) oxygen can optionally be replaced too. Irrespective of the nature of the newly introduced R7 and/or R8, the corresponding compound structures herein are presented as charged compounds with a dislocated double bond at the phosphorus, as long as this is in accordance with valency rules. This style is chosen to account for, depict and disclose all possible “locations” of the phosphorous double bond and distribution of electron density or charge each within a single structure. The dislocated double bond, as used herein, depending on the nature of the particular R7 and R8, however, does not necessarily refer to an equally distributed charge or electron density between R7 and R8. If R7 and R8 are not equal the phosphorus atom has four different ligands and becomes chiral resulting in two stereoisomeric forms. To describe the configuration of the chiral phosphorus, the Rp/Sp- nomenclature is used. Therein R/S follows the Cahn-Ingold-Prelog rules while “p” stands for phosphorus. To give an example: if the equatorial residue R8 is sulfur (while axial R7 is oxygen), the corresponding cyclic guanosine- 3', 5'-monophosphorothioate compound (cGMPS-analog) is Rp- configurated at phosphorus, if the equatorial residue R8 is a borano group, the corresponding cyclic guanosine- 3', 5'-monoboranophosphate compound (cGMPB-analog) is Sp-configurated at phosphorus. The person skilled in the art knows that for the use in the field of the medicine especially as part of medicaments certainly only physiologically acceptable salts of the compounds according to the invention may be used. ^{Further Embodiments of Structures of Formula I, Formula II, and Formula III} In certain embodiments, the invention relates to a compound according to the definition hereinabove, wherein in case of Formula I G⁴ is absent, or, wherein in case of Formula II G⁴ and LR⁴ are absent. In other embodiments the invention relates to a compound according to the definition hereinabove, wherein in case of Formula I, G³ and G⁴ are absent, or, wherein in case of Formula II, G³, G⁴, LR³ and LR⁴ are absent. In other embodiments the invention relates to a compound according to the definition hereinabove, wherein in case of Formula I, G², G³, G⁴ and LR¹ are absent, or, wherein in case of Formula II, G², G³, G⁴, LR², LR³ and LR⁴ are absent. In this case the embodiment represents a compound which is a precursor of the multimers of the invention. In certain embodiments, the invention relates to a compound according to any definition hereinabove, wherein all R8 are SH. According to the invention in certain embodiments, linking residues LR¹, LR², LR³ and LR⁴ are further subdivided as depicted in Formula Ib and Formula IIb,

wherein: coupling functions C¹, C^1’, C², C^2’, C³, C^3’, C⁴ and C^4’ independently from each other can be absent or as defined by structures selected from the group consisting of

connectivity can be as depicted or reversed as exemplified by G¹-O-C(O)-NH-S² versus G¹-NH-C(O)-O-S² and wherein in case the coupling function (C¹, C^1’, C², C^2’, C³, C^3’, C⁴ and/or C^4’) does not replace the residue of the G unit (R₁, R₄ and/or R₅ of G^{1 - 4}) but bind to it, the particular residue (R₁, R₄ and/or R₅) involved in coupling of G units (or G unit with dye(s) or other reporting group(s)) independently from each other is as defined further above, wherein an endstanding group is replaced by or transformed to a coupling function or selected from the group depicted hereinafter (wherein if present, Q1 connects to the G unit)

n₁ = 0 – 4, n₂ = 0-4, n₃ = 0-4,

and wherein the linker (L) is selected from the group consisting of

_while n for each sidechain within a particular linker of the list herebefore can have an equal or individual value as defined and all chiral, diastereomeric, racemic, epimeric, and all geometric isomeric forms of linkers (L) of the list herebefore, though not explicitly depicted, are included herein and cationic linkers (L) such as ammonium-derivatives are salts containing chloride-, bromide-, iodide- phosphate-, carbonate-, sulfate-, acetate- or any other physiologically accepted counterion and wherein spacers (S¹, S², S³ and S⁴) can be equal or individual within a particular compound, be absent or be - (CH₂)_n1-(CH₂CH₂ß)_m-(CH₂)_n2- (with ß = O, S or NH; m = 1 to 500, n1 = 0 to 8, n2 = 0 to 8, while both n1 and n2 can independently be equal or individual), or -(CH₂)_n- (with n = 1 to 24). Particularly, in certain embodiments of the invention, wherein, in some embodiments, linking residues LR¹, LR², LR³ and LR⁴ are further subdivided as depicted in Formula Ib and Formula IIb, containing spacer moieties (S^1-4), coupling functions (C^1-4, C^1’-4’) and a linker (L, only multimers of structure Ib), coupling functions (C^1-4, C^1’-4’) establish covalent bonds between the spacer and a G unit (G^1-4) by connecting to or replacing any of the residues R₁, R₄ and/or R₅ (compare formula structure III) and/or the spacer and a linker (L), dye or another reporting group and/or (in case the particular spacer is absent) a G unit (G^1-4) and a dye or another reporting group by connecting to or replacing any of the residues R₁, R₄ and/or R₅ and/or (in case the particular spacer is absent and/or a G unit is replaced by a dye or other reporting group) the linker (L) and a dye or another reporting group or a G unit (G^1-4, by connecting to or replacing any of the residues R₁, R₄ and/or R₅). Coupling functions (C^1-4, C^1’-4’) are generated in a reaction between endstanding groups of the particular precursor parts according to well established methods of the art. Non-limiting examples of precursor endstanding groups (of monomeric G units and (commercially available) linkers, dyes, reporting groups and spacers) and the corresponding coupling functions (C^1-4, C^1’-4’), to which they are transformed within the assembled (mono- or multimeric) compound according to the invention, are as depicted in Table 1. Coupling functions (C^1-4, C^1’-4’) can independently further be absent or be equal or individual within a particular mono- or multimeric compound. Table 1 Endstanding groups and corresponding coupling functions (C^1-4, C^1’-4’)

A person skilled in the art understands, that synthetic equivalents of the precursor endstanding groups of Table 1, such as but not limited to NHS esters instead of carboxylic acids or triflates instead of halogens can be used as well to generate the particular corresponding coupling function. A person skilled in the art further understands, that endstanding groups of the synthetic precursors (residues R₁, R₄ and/or R₅, linker (L), dye, reporting group and spacer (S^1-4)) can be interchanged amongst each other, resulting in reversed connectivity of the coupling function within the mono- or multimeric analog. A non-limiting example of a multimeric compound according to the invention, illustrating the used and defined variables above is given in the figures. Compounds for Use in the Present Invention According the invention, in certain embodiments, R1 is selected from group consisting of H, halogen, azido, nitro, alkyl, acyl, aryl, OH, O-alkyl, O-aryl, SH, S-alkyl, S-aryl, S-aralkyl, S(O)-alkyl, S(O)- aryl, S(O)-aralkyl, S(O)-benzyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, amino, NH-alkyl, NH-aryl, NH-aralkyl, NR9R10, SiR13R14R15 wherein R9, R10, R13, R14, R15 are alkyl. According to the invention, in certain embodiments, R1 is selected from the group consisting of H, Cl, Br, I, F, N₃, NO₂, OH, SH, NH₂, CF₃, 2-furyl, 3-furyl, 2-bromo-5-furyl, (2-furyl)thio, (3-(2-methyl)furyl)thio, (3- furyl)thio, 2-thienyl, 3-thienyl, (5-(1-methyl)tetrazolyl)thio, 1,1,2-trifluoro-1-butenthio, (2-(4- phenyl)imidazolyl)thio, (2-benzothiazolyl)thio, (2,6-dichlorophenoxypropyl)thio, 2-(N-(7-nitrobenz-2-oxa- 1,3-diazol-4-yl)amino)ethylthio, (4-bromo-2,3-dioxobutyl)thio, [2-[(fluoresceinylthioureido)amino]ethyl]thio, 2,3,5,6-tetrafluorophenylthio, (7-(4-methyl)coumarinyl)thio, (4-(7-methoxy)coumarinyl)thio, (2-naphtyl)thio, (2-(1-bromo)_naphtyl)thio, benzimidazolyl-2-thiobenzothiazolylthio, 4-pyridyl, (4-pyridyl)thio, 2-pyridylthio, 5- amino-3-oxopentylamino, 8-amino-3,6-dioxaoctylamino, 19-amino-4,7,10,13,16- pentaoxanonadecylamino, 17-amino-9-aza-heptadecylamino, 4-(N-methylanthranoyl)aminobutylamino, dimethylamino, diethylamino, 4-morpholino, 1-piperidino, 1-piperazino, triphenyliminophosphoranyl or as depicted in Table 2. Table 2 Residue R₁.

According to the invention, in certain embodiments, R1 is selected from the group consisting of H, Cl, Br, I, F, N₃, NO₂, OH, SH, NH₂, CF₃, 2-furyl, 3-furyl, (2-furyl)thio, (3-(2-methyl)furyl)thio, (3-furyl)thio, 2- thienyl, 3-thienyl, (5-(1-methyl)tetrazolyl)thio, 1,1,2-trifluoro-1-butenthio, (2-(4-phenyl)imidazolyl)thio, (2- benzothiazolyl)thio, (2,6-dichlorophenoxypropyl)thio, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)- amino)ethylthio, (4-bromo-2,3-dioxobutyl)thio, [2-[(fluoresceinylthioureido)amino]ethyl]thio, 2,3,5,6- tetrafluorophenylthio, (7-(4-methyl)coumarinyl)thio, (4-(7-methoxy)coumarinyl)thio, (2-naphtyl)thio, (2-(1- bromo)_naphtyl)thio, benzimidazolyl-2-thio, benzothiazolylthio, 4-pyridyl, (4-pyridyl)thio, 2-pyridylthio, 5- amino-3-oxopentylamino, 8-amino-3,6-dioxaoctylamino, 19-amino-4,7,10,13,16-pentaoxanonadecyl- amino, 17-amino-9-aza-heptadecylamino, 4-(N-methylanthranoyl)aminobutylamino, dimethylamino, diethylamino, 4-morpholino, 1-piperidino, 1-piperazino, triphenyliminophosphoranyl or as depicted in Table 3. Table 3 Residue R₁.

According to the invention, in certain embodiments, R1 is selected from the group consisting of H, Cl, Br, SH, 2-furyl, 3-furyl, (2-furyl)thio, (3-(2-methyl)furyl)thio, (3-furyl)thio, 2-thienyl, 3-thienyl, (5-(1- methyl)tetrazolyl)thio, 1,1,2-trifluoro-1-butenthio, (2-(4-phenyl)imidazolyl)thio, (2-benzothiazolyl)thio, (2,6- ^{dichlorophenoxypropyl)thio, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)ethylthio, (4-bromo-2,3-} dioxobutyl)thio, [2-[(fluoresceinylthioureido)amino]ethyl]thio, 2,3,5,6-tetrafluorophenylthio, (7-(4- methyl)coumarinyl)thio, (4-(7-methoxy)coumarinyl)thio, (2-naphtyl)thio, (2-(1-bromo)_naphtyl)thio, benzimidazolyl-2-thio, benzothiazolylthio, 4-pyridyl, (4-pyridyl)thio, 2-pyridylthio, triphenyl- iminophosphoranyl or as depicted in Table 4. Table 4 Residue R₁.

In addition to the above or independent to the above, in certain embodiments, according the invention, R4 is selected from group consisting of H, amino, alkyl, aralkyl, nitro, N-oxide or R4 can form together with Y and R5 and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazolinone as depicted above (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl. According to the invention, in certain embodiments, R4 is absent or selected from the group ^{consisting of amino, N-oxide or as depicted in Table 5.} Table 5 Residue R₄.

According to the invention, in certain embodiments, R4 is absent or selected from the group consisting of amino, N-oxide or as depicted in Table 6.

Table 6 Residue R₄.

According to the invention, in certain embodiments, R4 is absent or as depicted in Table 7. Table 7 Residue R₄.

In addition to the above or independent to the above, in certain embodiments according to the invention, R₅ is selected from the group consisting of H, halogen, azido, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido-alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, NH- carbamoyl-alkyl, NH-carbamoyl-aryl, NH-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, SH, S-alkyl, S- aryl, S-aralkyl, amino, NH-alkyl, NH-aryl, NH-aralkyl, NR30R31, SiR34R35R36 wherein R30, R31, R34, R35, R36 are alkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazolinone ring as depicted above (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl. According to the invention, in certain embodiments, R₅ is selected from the group consisting of H, NH₂, F, Cl, Br, I, nitro, methyl, ethyl, n-propyl, n-hexyl, 6-amino-n-hexyl, trifluoromethyl, phenyl, 4-N,N- dimethylaminophenyl, benzyl, 4-azidobenzyl, amido-n-butyl, amidoisobutyl, amido(6-amino-n-hexyl), OH, methyloxy, n-hexyloxy, phenyloxy, benzyloxy, SH, methylthio, ethylthio, 6-amino-n-hexylthio, phenylthio, 4- azidophenylthio, benzylthio, 4-azidobenzylthio, methylamino, NH-benzyl, NH-phenyl, NH-4-azidophenyl, NH-phenylethyl, NH-phenylpropyl, 2-aminoethylamino, n-hexylamino, 6-amino-n-hexylamino, 8-amino-3,6- dioxaoctylamino, dimethylamino, 1-piperidino, 1-piperazino, trimethylsilyl, triethylsilyl, tert- butyldimethylsilyl or can form together with R₄, Y and the carbon bridging Y and R₅ a ring system as depicted in Table 5 (entry 2 and 3). According to the invention, in certain embodiments, R₅ is selected from the group consisting of H, NH₂, F, Cl, Br, I, nitro, SH, methylthio, ethylthio, 6-amino-n-hexylthio, phenylthio, 4-azidophenylthio, benzylthio, 4-azidobenzylthio, methylamino, NH-benzyl, NH-phenyl, NH-4-azidophenyl, NH-phenylethyl, NH-phenylpropyl, 2-aminoethylamino, n-hexylamino, 6-amino-n-hexylamino, 8-amino-3,6-dioxaoctylamino, dimethylamino, 1-piperidino, 1-piperazino or can form together with R₄, Y and the carbon bridging Y and R₅ a ring system as depicted in Table 6 (entry 2 and 3). According to the invention, in certain embodiments, R₅ is NH₂, or can form together with R₄, Y and the carbon bridging Y and R₅ a ring system as depicted in Table 7 (entry 2 and 3). In addition to the above or independent to the above, in certain embodiments according to the invention, R8 is selected from group consisting of SH, S-alkyl, S-aryl, S-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, Se-PAP, S-BAP or Se-BAP wherein PAP is a photo-activatable protecting group with PAP = o-nitro-benzyl, 1-(o- nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro-benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxy- m^{ethoxy)coumarin-4-yl)methyl (BCMCM-caged).} and wherein BAP is a bio-activatable protecting group with BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4-pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4- octanoyloxybenzyl, 4-benzoyloxybenzyl. According to the invention, in certain embodiments, R8 is selected from the group consisting of SH, methylthio, acetoxymethylthio, pivaloyloxymethylthio, methoxymethylthio, propionyloxymethylthio, butyryloxymethylthio, cyanoethylthio, phenylthio, benzylthio, 4-acetoxybenzylthio, 4-pivaloyloxybenzylthio, 4-isobutyryloxybenzylthio, 4-octanoyloxybenzylthio, 4-benzoyloxybenzylthio, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN). According to the invention, in certain embodiments, R8 is selected from the group consisting of SH, methylthio, acetoxymethylthio, pivaloyloxymethylthio, methoxymethylthio, propionyloxymethylthio, butyryloxymethylthio, cyanoethylthio, phenylthio, benzylthio, 4-acetoxybenzylthio, 4-pivaloyloxybenzylthio, 4-isobutyryloxybenzylthio, 4-octanoyloxybenzylthio, 4-benzoyloxybenzylthio. According to the invention, in certain embodiments R8 is SH. In addition to the above or independent to the above, in certain embodiments according to the invention, residues involved in connecting a G unit with another G unit or a dye or another reporting group can be R₁, R₄ and/or R₅ in which case the particular residue is as defined for certain embodiments above, wherein an endstanding group is replaced by or transformed to the coupling function or selected from the group depicted in Table 8 (wherein if present, Q1 connects to the G unit). Table 8 Residues R₁, R₄ and R₅ involved in connecting a G unit with another G unit or a dye or another reporting group (if present Q1 connects to the G unit)

According to the invention, in certain embodiments, residues involved in connecting a G unit with ^{another G unit or a dye or another reporting group can be R1, R4 and/or R5, in which case the particular} residue is as defined for certain embodiments, wherein an endstanding group is replaced by or transformed to a coupling function or s^{elected from the group depicted in Table 9 (wherein if present, Q1 connects to the G unit)} Table 9 Residues R₁, R₄ and R₅ involved in connecting a G unit with another G unit or a dye or another reporting group (if present Q₁ connects to the G unit)

In addition to the above or independent to the above, in certain embodiments according to the invention, coupling functions (C^1-4 and C^1’-4’) are absent or selected from the group depicted in Table 10. Table 10 Coupling functions (C^1-4 and C^1’-4’).

According to the invention, in certain embodiments, coupling functions (C^1-4 and C^1’-4’) are absent or selected from the group depicted in Table 11. Table 11 Coupling functions (C^1-4 and C^1’-4’).

In addition to the above or independent to the above, in certain embodiments according to the invention, the linker (L) is absent or selected from the group depicted in Table 12. Table 12 Linker (L).

While n for each sidechain within a particular linker can have an equal or individual value as defined. In addition to the above or independent to the above, in certain embodiments, in case of Formula I according to the invention, G⁴ or G⁴ and G³ are absent o^{r in case of Formula II, G4 and LR4 or G4, LR4, G3 and LR3 are absent.} According to the invention, in certain embodiments, in case of Formula I, G⁴ and G³ are absent or in case of Formula II, G⁴, LR⁴, G³ and LR³ are absent. Certain embodiments of the invention based on the above exemplifications, are as defined in anyone of the claims 5, 6, 7 and 8. I^{n certain embodiments according to the invention, the compounds are compounds as shown in} the tables. It has to be noted that in case of doubt the chemical structure as depicted in the formula is the valid one. The compounds of the tables are displayed as the free acid. The present invention, however, also comprises salts of these compounds, featuring cations such as but not limited to Na⁺, Li⁺, NH4⁺, Et3NH⁺ ^{and (i-Pr)2EtNH+.} Table 13 Structures of novel compounds according to the invention.

Table 14 Structures of novel monomeric precursor compounds according to the invention.

^{Table 15 Structures of novel equatorially modified polymer linked multimeric cGMP compounds according} _{to the invention.}

It has to be noted, that the term equatorially modified, as used herein, refers to modifications of the R8 position as depicted in formula III or formula IIIA. For the non-limiting example of the invention, wherein R₈ is SH, representing a phosphorothioate group, the resulting configuration is typically Rp. Care should be ^{taken, not to confuse this situation with the mirrored case (displayed below), which is not part of the} invention and wherein the sulfur modification is also in equatorial position, but the resulting configuration is Sp.

Monomeric equatorially modified precursor cGMP analogs (G units) for the synthesis of equatorially modified polymer linked multimeric cGMP analogs (PLMs) are compounds of Formula III. As described above, potencies to prevent cell death in primary rod-like cells and retinal explants from rd1 mouse, is strongly increased, once the monomeric precursor is linked to additional one(s) within a PLM. Non-limiting examples of new robust and regioselective methods for the transformation of monomeric precursors into exemplary equatorially modified PLMs are given in the examples section. In addition, Table 1 gives an overview of exemplary endstanding groups, that can be used for coupling reactions and the corresponding coupling functions within the PLM, to which they are transformed according to established methods of the art. In certain embodiments of the invention, the monomeric compound of Formula III or Formula IIIA and/or monomeric precursor according to Formula III, of any compound of the invention as described herein above, the monomeric compound of Formula III and/or the monomeric precursor of the invention is selected from the group depicted in the tables. Table 16 Structures of novel monomeric precursor compounds according to the invention.

As described above, the compounds according to the present invention may further be labelled, according to well-known labelling techniques. For example, fluorescent dyes may be coupled to the compounds in order to, but not limited to, localize the intracellular distribution of cyclic nucleotide binding ^{proteins in living cells by means of confocal or other microscopy, for fluorescence correlation spectrometry,} for fluorescence energy transfer studies, or for determination of their concentration in living cells. It should be understood that hydrates of the compounds are also within the scope of the present invention. Instead of or additional to fluorescent dyes the compounds according to the inventions may be labelled with (radio) nuclides. The person skilled in the art knows many techniques and suitable isotopes that can be used for this. As described above, the invention also comprises PEGylated forms of the specified compounds, wherein PEGylation is generally known to greatly improve water solubility, pharmacokinetic and biodistribution properties. The invention further comprises prodrug forms of the described compounds, wherein the negative charge of the equatorially modified phosphate moiety is masked by a bio-activatable protecting group. It is widely accepted that such structures increase lipophilicity and with that, membrane-permeability and bioavailability resulting in a 10-1000 fold enhanced potency compared to the mother-compound. Such bio- activatable protecting groups can be introduced according to well-known techniques of the art and include, but are not limited to acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, acetoxyethyl, acetoxybutyl, acetoxyisobutyl. Non-limiting examples of corresponding residue R8 according to the invention are acetoxymethylthio, propionyloxymethylthio and butyryloxymethylthio. More labile examples of protecting groups include alkyl or aryl groups as well as substituted alkyl or aryl groups. Non- limiting examples for chemically labile protection groups of the R8 position are methyl, ethyl, 2-cyanoethyl, propyl, benzyl, phenyl and polyethylene glycol. These compounds are inactive per se, but extremely membrane-permeable, leading to strongly increased intracellular concentrations. Upon hydrolysis of the ester bond, the biologically active mother compounds are released. Compounds according to the invention can also feature a photolysable group (also-called “caged”- or photo- activatable protecting group), which can be introduced according to well-known techniques of the art. For example, but not limited to, caged groups may be coupled to an R8 thio-function, leading to compounds with significantly increased lipophilicity and bioavailability. Non-limiting examples for caged groups are o- nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro-benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4- yl)methyl (BCMCM-caged). The compounds according to the present invention can also be immobilized to insoluble supports, such as, but not limited to, agarose, dextran, cellulose, starch and other carbohydrate-based polymers, to synthetic polymers such as polacrylamide, polyethyleneimine, polystyrol and similar materials, to apatite, glass, silica, gold, graphene, fullerenes, carboranes, titania, zirconia or alumina, to the surface of a chip suitable for connection with various ligands. The compounds according to the present invention can also be encapsulated within nanoparticles or liposomes for directed or non-directed delivery and release purposes of the compounds as described in the literature (Bala, I.; Hariharan, S.; Kumar, M. N., PLGA nanoparticles in drug delivery: the state of the art. Crit Rev Ther Drug Carrier Syst 2004, 21 (5), 387-422; (b) Basu, S. C.; Basu, M., Liposome Methods and Protocols. Humana Press: 2002; (c) Gregoriadis, G., Liposome Technology. Informa Healthcare: 2006; (d) Paquet-Durand, F.; Gaillard, P. J.; Maringo, V.; Ekström, P.; Genieser, H.-G.; Rentsch, A. Targeted liposomal delivery of cGMP analogs. PCT/EP2016/055659). Further, the compounds according to the present invention are suitable for use as research tool compound, for example as research tool compound in regard of a disease or disorder, for example a disease or disorder selected from the group consisting of retinal disease or disorder or neuronal or neurodegenerative disease or disorder. The terms “research tool” or” research tool compound” as used herein defines any experimental use in laboratory and preclinical research of a compound, and particularly excludes any use in humans as well as any use in the prophylaxis and/or medical treatment. Particularly, the said terms relate to any experimental use in laboratory and preclinical research of a compound, wherein the compound is not applied in human, but used in a laboratory and/or preclinical setting to study a disease or disorder, for example a disease or disorder selected from the group consisting of retinal disease or disorder or neuronal or neurodegenerative disease or disorder. The compounds according to the present invention are suitable for use in the treatment of a disease or disorder, for example a disease or disorder selected from the group consisting of retinal disease or disorder or neuronal or neurodegenerative disease or disorder. I^{t is to be understood herein that the treatment of a pathology, condition or disorder also includes} the prevention thereof, even if not explicitly mentioned, unless specifically otherwise indicated. In certain embodiments, the equatorially modified cGMP-analogs of the invention are used for treating or preventing a disease or condition of the retina. Diseases and conditions of the retina are typically treated with equatorially modified cGMP analogs that inhibit the disease-related unbalanced cGMP-system, and include rare hereditary diseases of the retina such as retinitis pigmentosa, Stargardt's disease, fundus flavimaculatus, juvenile Best's disease, adult vitelliform foveomacular dystrophy (adult vitelliform degeneration), familial drusen (North Carolina macular dystrophy), Bietti's crystalline dystrophy, progressive cone dystrophies, Alport's syndrome, benign familial fleck retina, Leber's congenital amaurosis, congenital monochromatism and hereditary macular dystrophies. In addition, these equatorially modified cGMP-analogs of the invention may be used to treat secondary pigmentary retinal degeneration as it occurs in a number of metabolic and neurodegenerative diseases, various syndromes and other eye diseases, including: retinitis pigmentosa and hearing loss also associated with Usher syndrome, Waardenburg's syndrome, Alström's syndrome, Alport's syndrome, Refsum's syndrome, and other systemic conditions, all of which have their own systemic manifestations, short stature, renal dysfunction, and polydactyly are some signs of Bardet-Biedl syndrome or Laurence- Moon syndrome when associated with pigmentary retinopathy, the mucopolysaccharidoses may be associated with retinitis pigmentosa (e.g., Hurler's syndrome, Scheie's syndrome, Sanfilippo's syndrome), as well as the mitochondrial disorder Kearns-Sayre syndrome. In addition to those mentioned above, these include: Friedreich's ataxia, mucopolysaccharidosis, muscular dystrophy (myotonic dystrophy), Batten's syndrome, Bassen-Kornzweig syndrome, homocystinuria, oxalosis, eye and retinal trauma, glaucoma with retinal pigment epithelial changes, end-stage chloroquine retinopathy, end-stage thioridazine retinopathy, end-stage syphilitic neuroretinitis and cancer-related retinopathy. These equatorially modified cGMP- analogs of the invention may also be used to treat other common diseases of the retina such as e.g. diabetic retinopathy, age related macular degeneration, macular Hole/Pucker, ocular malignancies, such as retinoblastoma, retinal detachment and river blindness/Onchocerciasis. Furthermore, the equatorially modified cGMP-analogs of the invention may be used to treat entirely different conditions that are associated with the disease-related unbalanced cGMP-system such as neuronal or neurodegenerative disorders, stroke, anosmia, inflammatory and neuropathic pain, axonal regrowth and recovery after spinal cord injury. The equatorially modified cGMP-analogs of the invention may also be used to treat cardiovascular diseases, hypotension, acute shock, and cancer. This also includes certain parasitic diseases like malaria, sleeping disease (African trypanosomiasis), and Chagas disease, in which the parasite survival is critically depending on the active cGMP-system. In another aspect, the invention relates to a method for treating or preventing any of the above pathologies, conditions or disorders by administration of a therapeutically or prophylactically effective amount of an equatorially modified cGMP-analog of the invention to a subject in need of prophylaxis or therapy. III. Lipophilic Salts of a Compound of Formula I, Formula II, or Formula III In certain embodiments, microparticles or implants according to the invention comprise lipophilic salts of a compound of Formula I, Formula II, or Formula III. In certain embodiments, lipophilic salts are capable of associating with or dissolving in a fat, lipid, oil, or non-polar solvent. In certain embodiments, the terms “lipophilicity” and “hydrophobicity” may be used to describe the same tendency of a compound to dissolve in fats, oils, lipids, and non-polar solvents. In certain embodiments, lipophilic salts of a compound of Formula I, Formula II, or Formula III have a higher lipophilicity than a non-salt form of compound of Formula I, Formula II, or Formula III thereby allowing for increased transport and permeation through and across biological barriers and membranes of a host. In certain embodiments, lipophilic salts of a compound of Formula I, Formula II, or Formula III enhance permeation of a compound of Formula I, Formula II, or Formula III through hydrophobic barriers in a host. In certain embodiments, use of lipophilic salts of a compound of Formula I, Formula II, or Formula III in drug loaded microparticles or implants results in enhanced drug loading of Formula I, Formula II, or Formula III in microparticles or implants of the present invention. In certain embodiments, the enhanced loading of lipophilic salts of the compound of Formula I, Formula II, or Formula III in microparticles or implants of the invention is achieved as a result of higher solubility of the lipophilic salts in polymers, such as poly lactic-co-glycolic acid (PLGA), polylactic acid (PLA), PLGA conjugated to polyalkylene glycol, such as PLGA-PEG, from which microparticles or implants of the invention are formed. In certain embodiments, increase in loading of microparticles or implants with Formula I, Formula II, or Formula III as a result of using lipophilic salts of the compound of Formula I, Formula II, or Formula III, as compared to the compound of Formula I, Formula II, or Formula III, is at least about 1-100-fold, for example at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, or at least about 20-fold. In certain embodiments, lipophilic salts of a compound of Formula I, Formula II, or Formula III include monoalkyl ammonium salts, dialkyl ammonium salts, benzyl alkyl ammonium salts, trialkyl ammonium salts, ethylene diammonium salts, quaternary ammonium salts, such as tetraalkyl ammonium salts, benzyl trialkyl ammonium salts, dibenzyl dialkyl ammonium salts, alkyl dimethyl benzyl ammonium salts, tetraalkyl phosphonium salts, benzyl trialkyl phosphonium salts, imidazolium salts, N-alkyl- morpholinium salts, N,N-dialkyl-morpholinium salts, alkyl pyridinium salts, N-alkyl piperidinium salts, and N,N-dialkyl piperidinium salts. In certain embodiments, a lipophilic salt of a compound of Formula I, Formula II, or Formula III is formed from the compound of Formula I, Formula II, or Formula III and a pharmaceutically acceptable lipophilic amine. In certain embodiments, the pharmaceutically acceptable lipophilic amines to form a pharmaceutically acceptable lipophilic salts of the compound of Formula I, Formula II, or Formula III are ^{suitable non-toxic amines, such as lower alkylamines, for example triethylamine, lower alkanolamines, for} example diethanolamine or triethanolamine, procaine, cycloalkylamines, for example dicyclohexylamine, benzylamines, for example N-methylbenzylamine, N-ethylbenzylamine, N-benzyl-beta-phenethylamine, N,N'-dibenzylethylenediamine or dibenzylamine, and heterocyclic amines, e.g. morpholine, piperazine, heteroaromatic amines, for example N-ethylpiperidine, or the like. In certain embodiments, suitable amines for the synthesis of lipophilic salts of a compound of Formula I, Formula II, or Formula III have formula R’-NH₂ (primary amines), R’-NH-R’’ (secondary amines), or R’-N(R’’)-R’’’ (tertiary amines), wherein substituents R’, R’’, and R’’’ are the same or different and are selected from hydrogen, akyl, cycloalkyl, spirocycloalkyl fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, heteroaryl, fused aryl, fused heteroaryl, each of which may be substituted, for example, with akyl, cycloalkyl, spirocycloalkyl fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, heteroaryl, fused aryl, fused heteroaryl, halogen, C(O)OH, C(O)ONH₂, C(O)ONR’R’’, C(O)O-R’, C(O)O-alkyl, O-R’, O-alkyl, O-aryl, S-R’, S-alkyl, NH₂, NHR’, NR’R’’, or SO2-R’. Suitable amines include diamines (N,N'- dibenzylethylenediamine). In certain embodiments, the pharmaceutically acceptable lipophilic amine to form a pharmaceutically acceptable lipophilic salt of the compound of Formula I, Formula II, or Formula III is benzathine (N,N'-dibenzylethylenediamine), benethamine (N-benzyl-2-phenylethanamine), or triethyl amine. In certain embodiments, a pharmaceutically acceptable lipophilic salt of the compound of Formula I, Formula II, or Formula III is a benzathine salt, benethamine salt, or triethyl amine salt. Figure 11 shows molecular structures of Compounds 221 and 188 in Na+ salt form. Table 17 summarizes various salt forms of Compounds 221 and 188 of the present invention. Table 17 Compound 221 and Compound 188 in various salt forms

IV. Microparticles In certain embodiments, the present invention provides solid microparticles comprising a compound of Formula I, Formula II, or Formula III or a prodrug or a pharmaceutically acceptable salt thereof and surfactant wherein the microparticles are sufficiently small to be injected in vivo and wherein a compound of Formula I, Formula II, or Formula III has the structure as described herein. In certain embodiments, the particle is not surface-treated before use. In certain embodiments, these microparticles are suitable for long term (for example, up to or at least three months, up to four months, up to five months, up to six months, up to seven months, up to eight months, up to nine months or longer) sustained delivery of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the microparticles are suitable for ocular injection. The microparticles of the present invention can be administered via intravitreal, intrastromal, intracameral, subtenon, sub-retinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, circumcorneal, or tear duct injections. In certain embodiments, the microparticles are injected via subchoroidal injection. In certain embodiments, the microparticles are injected via subconjunctival injection. In certain embodiments, the microparticles are injected via intravitreal injection. In an alternative embodiment, the microparticles are also suitable for systemic, parenteral, transmembrane, transdermal, buccal, subcutaneous, endosinusial, intra-abdominal, intra-articular, intracartilaginous, intracerebral, intracoronal, dental, intradiscal, intramuscular, intratumor, topical, or vaginal delivery in any manner useful for in vivo delivery. In certain embodiments, the microparticles comprise at least one biodegradable polymer, for example at least one hydrophobic polymer and at least one hydrophobic polymer conjugated to a hydrophilic polymer. In certain embodiments, the hydrophobic polymer is poly lactic-co-glycolic acid (PLGA) and/or polylactic acid (PLA). In certain embodiments, the hydrophobic polymer conjugated to a hydrophilic polymer is PLGA conjugated to polyalkylene glycol, such as polyethylene glycol (PEG). In certain embodiments, the controlled-release formulation comprises a biodegradable polymer such as PLGA, PLA, PLGA-PEG, PLA-PEG or a combination thereof. In some embodiments, the microparticle comprises PLGA and PLGA-PEG, or PLGA, PLA and PLGA-PEG. In some embodiments, the microparticle comprises PLA and PLGA-PEG or PLA-PEG. In certain embodiments, microparticle includes poly(lactic-co-glycolic acid) (PLGA). In other embodiments, microparticle includes a polymer or copolymer that has at least PLGA and PLGA- polyethylene glycol (PEG) (referred to as PLGAPEG). In certain embodiments, microparticle includes poly(lactic acid) (PLA). In other embodiments, microparticle includes a polymer or copolymer that has at least PLA and PLA-polyethylene glycol (PEG) (referred to as PLA-PEG). In certain embodiments, the surface treated microparticle includes polycaprolactone (PCL). In other embodiments, microparticle includes a polymer or copolymer that has at least PCL and PCL-polyethyleneglycol (PEG) (referred to as PCL-PEG). In other embodiments, microparticle includes at least PLGA, PLGA-PEG and polyvinyl alcohol (PVA). In other embodiments, microparticle includes at least PLA, PLA-PEG and polyvinyl alcohol (PVA). In other embodiments, microparticle includes at least PCL, PCL-PEG and polyvinyl alcohol (PVA). In other embodiments, any combination of PLA, PLGA or PCL can be mixed with any combination of PLA-PEG, ^{PLGA-PEG or PCL-PEG, with or without PVA, and each combination of each of these conditions is} considered independently disclosed as if each were separately listed. In certain examples, microparticle includes from about 0.5 percent to about 10 percent PLGA-PEG, about 0.5 percent to about 5 percent PLGA-PEG, about 0.5 percent to about 4 percent PLGA-PEG, about 0.5 percent to about 3 percent PLGA-PEG, or about 0.1 percent to about 1, 2, 5, or 10 percent PLGA-PEG. In other embodiments, PLA-PEG or PCL-PEG is used in place of PLGA-PEG. In other embodiments, any combination of PLGA-PEG, PLA-PEG or PCL-PEG is used in the polymeric composition with any combination of PLGA, PLA or PCL. Each combination is considered specifically described as if set out individually herein. In certain embodiments, the polymeric formulation includes up to about 1, 2, 3, 4, 5, 6, 10, or 14% of the selected pegylated polymer. In certain embodiments, the polyvinyl alcohol is a partially hydrolyzed polyvinyl acetate. For example, the polyvinyl acetate is at least about 78% hydrolyzed so that the polyvinyl acetate is substantially hydrolyzed. In one example, the polyvinyl acetate is at least about 88% to 98% hydrolyzed so that the polyvinyl acetate is substantially hydrolyzed. In certain embodiments, the microparticle including a compound of Formula I, Formula II, or Formula III contains from about 80 percent or 89 percent to about 99 percent PLGA, for example, at least about 80, 85, 90, 95, 96, 97, 98 or 99 percent PLGA. In other embodiments, PLA or PCL is used in place of PLGA. In yet other embodiments, a combination of PLA, PLGA and/or PCL is used. In some examples, the microparticle contains from about 0.01 percent to about 0.5 percent PVA (polyvinyl alcohol), about 0.05 percent to about 0.5 percent PVA, about 0.1 percent to about 0.5 percent PVA, or about 0.25 percent to about 0.5 percent PVA. In some examples, the microparticle contains from about 0.001 percent to about 1 percent PVA, about 0.005 percent to about 1 percent PVA, about 0.075 percent to about 1 percent PVA, or about 0.085 percent to about 1 percent PVA. In some examples, the microparticle contains from about 0.01 percent to about 5.0 percent PVA, about 0.05 percent to about 5.0 percent PVA, about 0.1 percent to about 5.0 percent PVA, about 0.50 percent to about 5.0 percent PVA. In some examples, the microparticle contains from about 0.10 percent to about 1.0 percent PVA or about 0.50 percent to about 1.0 percent. In some embodiments, the microparticle contains up to about 0.10, 0.15, 0.20, 0.25, 0.30, 0.40 or 0.5% PVA. Any molecular weight PVA can be used that achieves the desired results. In certain embodiments, the PVA has a molecular weight of up to about 10, 15, 20, 25, 30, 35 or 40 kD. In some embodiments, the PVA is partially hydrolyzed polyvinyl acetate, including but not limited to, up to about 70, 75, 80, 85, 88, 90 or even 95% hydrolyzed polyvinyl acetate. In certain embodiments, the PVA is about 88% hydrolyzed polyvinyl acetate. In certain embodiments, the PVA polymer has a molecule weight of 20,000 to 40,000 g/mol. In certain embodiments, the PVA polymer has a molecular weight of 24,000 to 35,000 g/mol. In certain embodiments, the PLGA polymer has a molecular weight of 30,000 to 60,000 g/mol (also kilodalton, kDa or kD). In certain embodiments, the PLGA polymer has a molecular weight of 40,000 to 50,000 g/mol (for example, 40,000; 45,000 or 50,000g/mol). In certain embodiments, the PLA polymer has ^{a molecular weight of 30,000 to 60,000 g/ mol (for example, 40,000; 45,000 or 50,000g/mol). In certain} embodiments, the PCL polymer is used in the same range of kDa as described for PLGA or PLA. In certain embodiments, the microparticle comprises a compound of Formula I, Formula II, or Formula III. The encapsulation efficiency of a compound of Formula I, Formula II, or Formula III in the microparticle can range widely based on specific microparticle formation conditions and the properties of the therapeutic agent, for example from about 20 percent to about 90 percent, about 40 percent to about 85 percent, about 50 percent to about 75 percent. In some embodiments, the encapsulation efficiency is for example, up to about 50, 55, 60, 65, 70, 75 or 80 percent. The amount of a compound of Formula I, Formula II, or Formula III in the microparticle is dependent on the molecular weight, potency, and pharmacokinetic properties of a compound of Formula I, Formula II, or Formula III. In certain embodiments, a compound of Formula I, Formula II, or Formula III is present in an amount of at least 1.0 weight percent to about 40 weight percent based on the total weight of the surface treated microparticle. In some embodiments, a compound of Formula I, Formula II, or Formula III is present in an amount of at least 1.0 weight percent to about 35 weight percent, at least 1.0 weight percent to about 30 weight percent, at least 1.0 weight percent to about 25 weight percent, or at least 1.0 weight percent to about 20 weight percent based on the total weight of the surface treated microparticle. Nonlimiting examples of weight of active material in the microparticle are at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15% by weight. In one example, the microparticle has about 10% by weight of a compound of Formula I, Formula II, or Formula III. In certain embodiments, the invention provides a process for producing a microparticle comprising a microparticle and a compound of Formula I, Formula II, or Formula III encapsulated in the microparticle; which process comprises: (a) preparing a solution or suspension (organic phase) comprising: (i) PLGA or PLA (ii) PLGA-PEG or PLA-PEG (iii) a compound of Formula I, Formula II, or Formula III and (iv) one or more organic solvents; (b) preparing an emulsion in an aqueous polyvinyl alcohol (PVA) solution (aqueous phase) by adding the organic phase into the aqueous phase and mixing at about 3,000 to about 10,000 rpm for about 1 to about 30 minutes; (c) hardening the emulsion including solvent-laden microparticles including a compound of Formula I, Formula II, or Formula III by stirring at about room temperature until solvent substantially evaporates; (d) centrifuging the microparticle including a compound of Formula I, Formula II, or Formula III; (e) removing the solvent and washing the microparticle including a compound of Formula I, Formula II, or Formula III with water; (f) filtering the microparticle including a compound of Formula I, Formula II, or Formula III to remove aggregates or particles larger than the desired size; (g) optionally lyophilizing the microparticle comprising a compound of Formula I, Formula II, or Formula III and storing the microparticle as a dry powder in a manner that maintains stability for up to about ^{6, 8, 10, 12, 20, 22, or 24 months or more.} In certain embodiments of the present invention, the controlled release formulation is a microparticle, optionally with a diameter from about 25 μm to about 45 μm. In certain embodiments, the microparticle is treated as described herein to form an aggregated microparticle (which may be a pellet or a depot), in vivo of at least about 500 microns. In certain embodiments, a durable controlled release formulation of compound of Formula I, Formula II, or Formula III in a biodegradable microparticle is provided that is suitable for long-term ocular therapy and is prepared with a Formula I, Formula II, or Formula III load of about 40% or greater, for example about 45% or greater, about 50% or greater, about 60% or greater, about 75% or greater, about 90% or greater or even as high as about 100% by weight. In certain embodiments, the microparticles of the present invention have a drug loading of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof of greater than about 40%, 43%, 44%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% by weight. In certain embodiments, the microparticles have a drug load between about 40% and about 65%, between about 55% and about 75%, between about 65% and about 85%, between about 75% and 95%, or between about 85% and 100% by weight. In an alternative embodiment, the microparticles have a drug load between about 1 and about 15%, between about 15 and about 30%, or between about 30 and about 40% by weight. In certain embodiments, the microparticles comprise at least one biodegradable polymer. In certain embodiments, these polymeric microparticles have a drug load of at least or greater than about 40%, 45%, 50%, 60%, 70%, or 80% by weight. In certain embodiments, the at least one biodegradable polymer is PLGA and/or PLA and PLGA conjugated to PEG. In certain embodiments, the microparticles comprise at least one non-active agent, such as an excipient or a non-active agent. In certain embodiments, these microparticles have a drug load of at least or greater than about 40%, 45%, 50%, 60%, 70%, or 80% by weight. In certain embodiments, the non- active agent is a sugar, for example mannitol. In certain embodiments, the microparticles comprise at least one biodegradable polymer and at least one non-active agent, such as an excipient or a non-active agent. In certain embodiments, these microparticles have a drug load of at least or greater than about 40%, 45%, 50%, 60%, 70%, or 80% by weight. In certain embodiments, the at least one biodegradable polymer is PLGA and/or PLA and PLGA conjugated to PEG. In certain embodiments, the non-active agent is a sugar, for example mannitol. In certain embodiments, the microparticles comprise about 100% of a compound of Formula I, Formula II, or Formula III or a prodrug or a pharmaceutically acceptable salt thereof. The microparticles typically have a size in their longest dimension, or their diameter if they are substantially spherical, of more than about 1 μm and less than about 100 μm. The microparticles more typically have a size in their longest dimension, or their diameter, of less than about 75 μm. The microparticles, for example, may have a size in their longest dimension, or their diameter, of about 1 or ^{more μm and about 40 or less μm, more typically, between about 20 μm and about 40 μm. Polymer particles} of the desired size may, for example, in certain embodiments, pass through a sieve or filter with a pore size of about 40 μm. In certain embodiments the microparticle has a mean diameter between about 10 and 60 μm, about 20 and 50 μm, about 20 and 40 μm, about 20 and 30 μm, about 25 and 40 μm, or about 25 and 35 μm. The microparticles of the present invention provide sustained delivery of a compound of Formula I, Formula II, or Formula III for at least about one month, or at least about two months, or at least about three months, or at least four months, or at least five months, or at least six months, or at least seven months, or at least eight months, or at least nine months, or at least ten months, or at least eleven months, or at least twelve months. In an alternative embodiment, the microparticles comprise a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the microparticles are mildly surface-treated and upon injection in vivo, aggregate to a microparticle depot in a manner that reduces unwanted side effects of the smaller particles and are suitable for long term (for example, up to or at least three month, up to four month, up to five month, up to six months, up to seven months, up to eight months, up to nine months or longer) sustained delivery of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof is administered in a surface treated microparticle that provides for a sustained release that is substantially linear. In other embodiments, the release is not linear; however, even the lowest concentration of release over the designated time period is at or above a therapeutically effective dose. In certain embodiments, the midly surface treated solid biodegradable microparticles are suitable for ocular injection, at which point the particles aggregate to form a microparticle depot and thus remain outside the visual axis as not to significantly impair vision. The particles can aggregate into one or several pellets or depots. The size of the aggregate depends on the mass (weight) of the particles injected. The mildly surface treated biodegradable microparticles provided herein are distinguished from “scaffold” microparticles, which are used for tissue regrowth via pores that cells or tissue material can occupy. In contrast, the present microparticles are designed to be solid materials of sufficiently low porosity so that they can aggregate to form a larger combined particle that erodes primarily by surface erosion for long-term controlled drug delivery. The surface modified solid aggregating microparticles of the present invention are suitable, for example, for intravitreal injection, periocular delivery, or delivery in vivo outside the eye. In certain embodiments, the surface-modified solid aggregating microparticles comprise a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and surfactant wherein the microparticles: a) have a modified surface which has been treated under mild conditions to partially remove surfactant; b^{) are sufficiently small to be injected in vivo;} c) aggregate in vivo to form at least one aggregated microparticle depot of at least 500 μm in vivo in a manner that provides sustained drug delivery in vivo for at least one month; and d) have a weight loading of about 40% or greater of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the surface-modified microparticles of the present invention have a drug loading of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof of greater than about 40%, 43%, 44%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% by weight. In certain embodiments, the surface-modified microparticles comprise at least one biodegradable polymer, for example at least one hydrophobic polymer and at least one hydrophobic polymer conjugated to a hydrophilic polymer. In certain embodiments, the hydrophobic polymer is poly lactic-co-glycolic acid (PLGA) and/or polylactic acid (PLA). In certain embodiments, the hydrophobic polymer conjugated to a hydrophilic polymer is PLGA conjugated to polyalkylene glycol, such as polyethylene glycol (PEG). In certain embodiments, the surface treated microparticle includes poly(lactic-co-glycolic acid) (PLGA). In other embodiments, the surface treated microparticle includes a polymer or copolymer that has at least PLGA and PLGA-polyethylene glycol (PEG) (referred to as PLGAPEG). In certain embodiments, the surface treated microparticle includes poly(lactic acid) (PLA). In other embodiments, the surface treated microparticle includes a polymer or copolymer that has at least PLA and PLA-polyethylene glycol (PEG) (referred to as PLA-PEG). In certain embodiments, the surface treated microparticle includes polycaprolactone (PCL). In other embodiments, the surface treated microparticle includes a polymer or copolymer that has at least PCL and PCL-polyethyleneglycol (PEG) (referred to as PCL-PEG). In other embodiments, the surface treated microparticle includes at least PLGA, PLGA-PEG and polyvinyl alcohol (PVA). In other embodiments, the surface treated microparticle includes at least PLA, PLA-PEG and polyvinyl alcohol (PVA). In other embodiments, the surface treated microparticle includes at least PCL, PCL-PEG and polyvinyl alcohol (PVA). In other embodiments, any combination of PLA, PLGA or PCL can be mixed with any combination of PLA-PEG, PLGA-PEG or PCL-PEG, with or without PVA, and each combination of each of these conditions is considered independently disclosed as if each were separately listed. In certain embodiments, the surface treated microparticle includes from about 0.5 percent to about 10 percent PLGA-PEG, about 0.5 percent to about 5 percent PLGA-PEG, about 0.5 percent to about 4 percent PLGA-PEG, about 0.5 percent to about 3 percent PLGA-PEG, or about 0.1 percent to about 1, 2, 5, or 10 percent PLGA-PEG. In other embodiments, PLA-PEG or PCL-PEG is used in place of PLGA-PEG. In other embodiments, any combination of PLGA-PEG, PLA-PEG or PCL-PEG is used in the polymeric composition with any combination of PLGA, PLA or PCL. Each combination is considered specifically described as if set out individually herein. In certain embodiments, the polymeric formulation includes up to ^{about 1, 2, 3, 4, 5, 6, 10, or 14% of the selected pegylated polymer.} In certain embodiments, the polyvinyl alcohol is a partially hydrolyzed polyvinyl acetate. For example, the polyvinyl acetate is at least about 78% hydrolyzed so that the polyvinyl acetate is substantially hydrolyzed. In one example, the polyvinyl acetate is at least about 88% to 98% hydrolyzed so that the polyvinyl acetate is substantially hydrolyzed. In certain embodiments, the surface treated microparticle including a compound of Formula I, Formula II, or Formula III contains from about 80 percent or 89 percent to about 99 percent PLGA, for example, at least about 80, 85, 90, 95, 96, 97, 98 or 99 percent PLGA. In other embodiments, PLA or PCL is used in place of PLGA. In yet other embodiments, a combination of PLA, PLGA and/or PCL is used. In certain embodiments, the microparticle contains from about 0.01 percent to about 0.5 percent PVA (polyvinyl alcohol), about 0.05 percent to about 0.5 percent PVA, about 0.1 percent to about 0.5 percent PVA, or about 0.25 percent to about 0.5 percent PVA. In certain embodiments, the microparticle contains from about 0.001 percent to about 1 percent PVA, about 0.005 percent to about 1 percent PVA, about 0.075 percent to about 1 percent PVA, or about 0.085 percent to about 1 percent PVA. In certain embodiments, the microparticle contains from about 0.01 percent to about 5.0 percent PVA, about 0.05 percent to about 5.0 percent PVA, about 0.1 percent to about 5.0 percent PVA, about 0.50 percent to about 5.0 percent PVA. In certain embodiments, the microparticle contains from about 0.10 percent to about 1.0 percent PVA or about 0.50 percent to about 1.0 percent. In certain embodiments, the microparticle contains up to about 0.10, 0.15, 0.20, 0.25, 0.30, 0.40 or 0.5% PVA. Any molecular weight PVA can be used that achieves the desired results. In certain embodiments, the PVA has a molecular weight of up to about 10, 15, 20, 25, 30, 35 or 40 kD. In some embodiments, the PVA is partially hydrolyzed polyvinyl acetate, including but not limited to, up to about 70, 75, 80, 85, 88, 90 or even 95% hydrolyzed polyvinyl acetate. In certain embodiments, the PVA is about 88% hydrolyzed polyvinyl acetate. In certain embodiments, the PVA polymer has a molecule weight of 20,000 to 40,000 g/mol. In certain embodiments, the PVA polymer has a molecular weight of 24,000 to 35,000 g/mol. In certain embodiments, a surface treated microparticle comprises a compound of Formula I, Formula II, or Formula III. The encapsulation efficiency of a compound of Formula I, Formula II, or Formula III in the microparticle can range widely based on specific microparticle formation conditions and the properties of the therapeutic agent, for example from about 20 percent to about 90 percent, about 40 percent to about 85 percent, about 50 percent to about 75 percent. In some embodiments, the encapsulation efficiency is for example, up to about 50, 55, 60, 65, 70, 75 or 80 percent. The amount of a compound of Formula I, Formula II, or Formula III in the surface treated microparticle is dependent on the molecular weight, potency, and pharmacokinetic properties of a compound of Formula I, Formula II, or Formula III. In certain embodiments, a compound of Formula I, Formula II, or Formula III is present in an amount of at least 1.0 weight percent to about 40 weight percent based on the total weight of the surface treated ^{microparticle. In some embodiments, a compound of Formula I, Formula II, or Formula III is present in an} amount of at least 1.0 weight percent to about 35 weight percent, at least 1.0 weight percent to about 30 weight percent, at least 1.0 weight percent to about 25 weight percent, or at least 1.0 weight percent to about 20 weight percent based on the total weight of the surface treated microparticle. Nonlimiting examples of weight of active material in the microparticle are at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15% by weight. In one example, the microparticle has about 10% by weight of a compound of Formula I, Formula II, or Formula III. The present invention further includes a suspension of aggregating biodegradable microparticles with high loading of a compound of Formula I, Formula II, or Formula III described herein, for example loadings of 40% by weight or greater, for example greater than about 45%, 50%, 60%, 75%, 90% or even as high as about 100% by weight in a diluent for injection that comprises an additive that softens the surface polymer of the microparticle and improves aggregation prior to injection. In certain embodiments, the additive is a plasticizer, for example benzyl alcohol or triethyl citrate. In some embodiments, the aggregated microparticle depot exhibits a hardness rating of at least about 10, 15, 20, 40, 50, 60, 70, 80, 90, 100, or more gram-force needed to compress the depot at 30% of strain when measured in vitro. The hardness of the aggregated microparticle depot can be confirmed in vitro in vitreous fluid, in phosphate buffered saline, or in water or other physiologically acceptable aqueous solution, including an aqueous solution that includes one or more components of the vitreous, which are well-known. The vitreous humor fluid in vivo typically contains 98-99% water, salts, sugars, vitrosin, fibrils with glycosaminoglycan, hyaluronan (i.e., hyaluronic acid), opticin, and various proteins. The vitreous humor typically has a viscosity of approximately 2-4 times that of water. In certain embodiments, the hardness is tested in a hyaluronic acid-based solution with a viscosity that in certain embodiments approximately mimics that of the vitreous. In certain embodiments, the hardness is measured in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water. It is advantageous to provide an aggregated microparticle depot with increased hardness and durability because the viscosity of vitreous fluid decreases with age while ocular diseases and problems become more prevalent. It is also advantageous to provide a microparticle with high drug load to limit the amount of non-therapeutic polymeric carrier delivered with the active agent. In certain embodiments, the microparticles of the present invention with high drug loads and minimal polymeric content are able to provide sustained drug release over an extensive time period, for example one month, two months, three months, four months, five months, six months or more. This long-term drug release requires fewer invasive procedures to administer the drug. In certain embodiments, the aggregating biodegradable microparticles with high loading of one or more active agents described herein, for example loadings of 40% or greater, for example greater than about 45%, 50%, 60%, 75%, 90% or even as high as about 100%, aggregate in vivo to an aggregated ^{microparticle depot with improved hardness and durability for long-term ocular therapy. In certain} embodiments, the aggregating microparticles have a drug load of at least about 60%. In certain embodiments, the aggregating microparticles have a drug load of about 100%. In certain embodiments, the microparticles of the present invention with drug loads ranging from about 40%-100% form an aggregated microparticle depot in vivo of at least 500 microns that exhibits a hardness rating of at least about 10 gram- force, and in some embodiments, at least about 20, 40, 50, 70, and even 100 or greater gram-force needed to compress the depot at 30% of strain. In certain embodiments, the hardness is measured in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water. In certain embodiments, the surface-modified microparticles comprise one or more non-active agents, such as an excipient, for example a sugar or a plasticizer. In certain embodiments, the sugar is mannitol. In certain embodiments, the plasticizer comprises polyethylene glycol. In certain embodiments, surface-treated aggregating microparticles that encapsulate a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof aggregate to a microparticle depot in vivo that exhibits increased hardness and durability. For example, in certain embodiments, the microparticle depot exhibits a hardness rating in vitro in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water of at least about 10, and in some embodiments, at least about 15, 20, 30, 40, 50, 60, 70, 75, 100, 120, 150, or more gram-force needed to compress the particle at 30% of strain. In certain embodiments, the fluid is vitreous fluid in a human eye. In certain embodiments, the hardness of the microparticle depot, upon injection in the vitreous, increase at least two-fold, at least three-fold, at least four-fold, at least five-fold, or more in four hours or less following injection compared to microparticles administered immediately after injection (for example, less than one minute or even 30 seconds after administration). In certain embodiments, the hardness increases in about three hours or less, in two hours or less, in one hour or less, in thirty minutes or less, in fifteen minutes or less, in ten minutes or less, in five minutes or less, in two minutes or less, or in one minute or less. In certain embodiments, the surface-modified microparticles have a drug loading between about 40% and about 65% by weight of compound of Formula I, Formula II, or Formula III and the microparticles aggregate to a microparticle depot in vivo of at least 500 microns that exhibits a hardness rating of at least about 10, 20, 40, 50, 60, 70, 75, 100, 120, 150, 170, 200, or more gram-force needed to compress the particle at 30% of strain in vitro in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water. In certain embodiments, the surface-modified microparticles have a drug loading between about 65% and about 85% by weight of compound of Formula I, Formula II, or Formula III and the microparticles aggregate to a microparticle depot in vivo of at least 500 microns that exhibits a hardness rating of at least ^{about 10, 20, 40, 50, 60, 70, 75, 100, 120, 150, 170, 200, or more gram-force needed to compress the} particle at 30% of strain. In certain embodiments, the surface-modified microparticles have a drug loading between about 85% and about 100% by weight of compound of Formula I, Formula II, or Formula III and the microparticles aggregate to a microparticle depot in vivo of at least 500 microns that exhibits a hardness rating of at least about 10, 20, 40, 50, 60, 70, 75, 100, 120, 150, 170, 200, or more gram-force needed to compress the particle at 30% of strain. The surface modified solid aggregating microparticles are suitable, for example, for an intravitreal injection, implant, including an ocular implant, periocular delivery or delivery in vivo outside of the eye. In certain embodiments, microparticles have also been treated for enhanced wettability by subjecting the microparticle suspensions to vacuum or sonication as described herein. In certain embodiments, the surface treatment is carried out at a temperature of not more than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 °C. In certain embodiments, the surface treatment is carried out at a reduced temperature of about 5 to about 18 °C, about 5 to about 16 °C, about 5 to about 15 °C, about 0 to about 10 °C, about 0 to about 8 °C, or about 1 to about 5 °C, about 5 to about 20 °C, about 1 to about 10 °C, about 0 to about 15 °C, about 0 to about 10 °C, about 1 to about 8 °C, or about 1 to about 5 °C. Each combination of each of these conditions is considered independently disclosed as if each combination were separately listed. Alternatively, the surface treatment is conducted at a temperature at or less than about 10 °C, 8 °C or 5 °C. The decreased temperature of processing (less than room temperature, and typically less than 18 °C) assists to ensure that the particles are only “mildly” surface treated. In certain embodiments, the surface treatment includes treating microparticles with a surface- treatment agent comprising a base, for example, sodium hydroxide or potassium hydroxide, and an organic solvent (such as an alcohol, for example ethanol or methanol, or an organic solvent such as DMF, DMSO or ethyl acetate) as otherwise described herein. In certain embodiments, the surface treatment includes treating microparticles with aqueous base. More generally, a hydroxide base is used, for example, potassium hydroxide. An organic base can also be used. In other embodiments, the surface treatment as described above is carried out in aqueous acid, for example hydrochloric acid. In certain embodiments, the surface treatment includes treating microparticles with phosphate buffered saline and ethanol. Additional non-limiting examples of a base for the surface-treatment include lithium hydroxide, calcium hydroxide, magnesium hydroxide, lithium amide, sodium amide, barium carbonate, barium hydroxide, barium hydroxide hydrate, calcium carbonate, cesium carbonate, cesium hydroxide, lithium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, strontium carbonate, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, triethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, ^{dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]non-7-ene, 2,6-} lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, and Trizma. Additional non-limiting examples of an organic solvent for the surface-treatment include ether, acetone, acetonitrile, THF, dimethylacetamide, carbon disulfide, chloroform, 1,1-dichloroethane, dichloromethane, heptane, hexane, methanol, methyl acetate, methyl t-butyl ether (MTBE), pentane, propanol, 2-propanol, toluene, N-methyl pyrrolidinone (NMP), acetamide, piperazine, triethylenediamine, diols, and CO2.. The pH of the surface treatment will of course vary based on whether the treatment is carried out in basic, neutral or acidic conditions. When carrying out the treatment in base, the pH may range from about 7.5 to about 14, including not more than about 8, 9, 10, 11, 12, 13 or 14. When carrying out the treatment in acid, the pH may range from about 6.5 to about 1, including not less than 1, 2, 3, 4, 5, or 6. When carrying out under neutral conditions, the pH may typically range from about 6.4 or 6.5 to about 7.4 or 7.5. When carrying out the treatment in base, the pH may, for example, range from about 7.0 or 7.5 to about 14, including not more than about 8, 9, 10, 11, 12, 13 or 14. In certain embodiments, the surface- treatment can be conducted in a pH between about 7.5 and 8.5. In certain embodiments, the surface treatment can be conducted at a pH between about 8 and about 10. In certain embodiments, the surface treatment can be conducted at a pH between about 10.0 and about 13.0. In certain embodiments, the surface treatment can be conducted at a pH between about 10.0 and about 12.0. In certain embodiments, the surface treatment can be conducted at a pH between about 12 and about 14. Non-limiting examples of surface-treatment conditions include ethanol with an aqueous organic base; ethanol and aqueous inorganic base; ethanol and sodium hydroxide; and, ethanol and potassium hydroxide. In certain embodiments, the surface treatment includes treating microparticles under acidic or neutral conditions, for example at a pH ranging from about 7.5 to about 1, including not more than 1, 2, 3, 4, 5, 6, or 7. When carrying out the treatment in acid, the pH may range from about 6.5 to about 1, including not less than 1, 2, 3, 4, 5, 6, 7, or 8. When carrying out under neutral conditions, the pH may typically range from about 6.4 or 6.5 to about 7.4 or 7.5. In certain embodiments, the surface treatment as described above is carried out in an inorganic acid including, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; or organic acids including, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH₂)_n-COOH where n is 0-4, and the like. Each combination of each of these conditions described herein is considered independently disclosed as if each combination were separately listed. A key aspect of the present invention is that the treatment, whether done in basic, neutral or acidic ^{conditions, includes a selection of the combination of the time, temperature, pH agent and solvent that} causes a mild treatment that does not significantly damage the particle in a manner that forms pores, holes or channels. Each combination of each of these conditions is considered independently disclosed as if each combination were separately listed. The treatment conditions should simply mildly treat the surface in a manner that allows the particles to remain as solid particles, be injectable without undue aggregation or clumping, and form at least one aggregate particle of at least 500 µm. In certain embodiments, the treatment partially removes the surface surfactant. In certain embodiments, the surface treatment includes treating microparticles with an organic solvent at a reduced temperature of about 0 to about 18 °C, about 0 to about 16 °C, about 0 to about 15 °C, about 0 to about 10 °C, about 0 to about 8 °C, or about 0 to about 5 °C. In certain embodiments, the organic solvent is ethanol. In certain embodiments, the surface treatment includes treating microparticles with an aqueous solution of pH = 6.6 to 7.4 or 7.5 and an organic solvent at a reduced temperature of about 0 to about 18 °C, about 5 to about 15 °C, or about 7 to about 13 °C. In certain embodiments, the organic solvent is ethanol. In certain embodiments, the surface treatment includes treating microparticles with an aqueous solution of pH = 6.6 to 7.4 or 7.5 and ethanol at a reduced temperature of about 1 to about 10 °C, about 1 to about 15 °C, about 5 to about 15 °C, or about 0 to about 5 °C. In certain embodiments, the surface treatment includes treating microparticles with an aqueous solution of pH = 6.6 to 7.4 or 7.5 and an organic solvent at a reduced temperature of about 0 to about 10 °C, about 5 to about 8 °C, or about 0 to about 5 °C. In certain embodiments, the surface treatment includes treating microparticles with an aqueous solution of pH = 1 to 6.6 and ethanol at a reduced temperature of about 0 to about 10 °C, about 0 to about 8 °C, or about 0 to about 5 °C. In certain embodiments, the surface treatment includes treating microparticles with an organic solvent at a reduced temperature of about 0 to about 18 °C, about 0 to about 16 °C, about 0 to about 15 °C, about 0 to about 10 °C, about 0 to about 8 °C, or about 0 to about 5 °C. In some embodiments, the microparticles of the present invention have been mildly surface-treated, for example with a surface-treatment agent comprising an aqueous base in an organic solvent, such as NaOH in EtOH, and aggregate in vivo to an aggregated microparticle depot of at least 500 μm. In certain embodiments, the surface treatment includes treating microparticles with a base at a concentration between about 2.5 mM and about 12 mM and an organic solvent at a reduced temperature of about 0 to about 18 °C, about 5 to about 15 °C, or about 7 to about 13 °C. In certain embodiments, the organic solvent is ethanol. In certain embodiments, the base is NaOH. In certain embodiments, the base concentration is between about 2.5 mM and about 10 mM, between about 2 mM and about 4 mM, between about 4 mM and 8 mM, or between about 5 mM and 7.5 mM. In certain embodiments, the base concentration is about 2.5 mM, about 5.0 mM, about 7.5 mM, or about 10 mM. In certain embodiments, the organic solvent concentration in the base/organic solvent solution is between about 10% and about 80%, ^{between about 20% and about 70%, between about 30% and about 60%, between about 40% and about} 55%, or between about 45% and about 50%. In certain embodiments, the concentration is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%. In certain embodiments, the organic solvent is an alcohol, for example ethanol. In certain embodiments, the surface treatment conditions include treating a microparticle with 2.5 mM NaOH/ethanol wherein the solution is approximately 90:10, 30:70, 45:55, 55:45, 60:40, 65:35, 70:20, or 75: 25, v:v. In certain embodiments, the surface treatment conditions include treating a microparticle with 5.0 mM NaOH/ethanol wherein the solution is approximately 90:10, 30:70, 45:55, 55:45, 60:40, 65:35, 70:20, or 75: 25, v:v. In certain embodiments, the surface treatment conditions include treating a microparticle with 7.5 mM NaOH/ethanol wherein the solution is approximately 90:10, 30:70, 45:55, 55:45, 60:40, 65:35, 70:20, or 75: 25, v:v. In certain embodiments, the surface treatment conditions include treating a microparticle with 10 mM NaOH/ethanol wherein the solution is approximately 90:10, 30:70, 45:55, 55:45, 60:40, 65:35, 70:20, or 75: 25, v:v. In certain embodiments, the microparticles have a mean size of about 20 µm to about 50 µm, 25 µm to about 45 µm, 25 µm to about 30 µm, or 30 to 33 µm and a median size of about 31 µm to about 33 µm after surface treatment with approximately 2.0 mM NaOH/ethanol to 8.0 mM NaOH/ethanol (approximately 30:70, v:v). In certain embodiments, the microparticles have a mean size of about 20 µm to about 50 µm, 25 µm to about 45 µm, 25 µm to about 30 µm or 30 to 33 µm and a median size of about 31 µm to about 33 µm after surface treatment with approximately 2.0 mM NaOH/ethanol to 8.0 mM NaOH/ethanol (approximately 50:50, v:v). In certain embodiments, the microparticles have a mean size of about 20 µm to about 50 µm, about 25 µm to about 45 µm, about 25 µm to about 30 µm or 30 to 33 µm and a median size of about 31 µm to about 33 µm after surface treatment with approximately 2.0 mM NaOH/ethanol to 8.0 mM NaOH/ethanol (approximately 70:30, v:v). In certain embodiments, the microparticles have a drug loading between about 45% and about 60% of compound of Formula I, Formula II, or Formula III and are surface treated with approximately 2.0 mM NaOH/ethanol to 6.0 mM NaOH/ethanol where the concentration of ethanol in the solution is between about 50% and 60% by volume. In certain embodiments, the microparticles with a drug loading of about 45% are surface-treated with approximately 5.0 mM NaOH/EtOH (45:55, v/v). In certain embodiments, the microparticles with a drug loading of about 45% are surface-treated with approximately 2.5 mM NaOH/EtOH (45:55 or 50:50, v/v). In certain embodiments, the microparticles have a drug loading of 100% and are surface treated ^{with approximately 2.0 mM NaOH/ethanol to 6.0 mM NaOH/ethanol where the concentration of ethanol in} the solution is between about 20% and 40% by volume. In certain embodiments, the microparticles with a drug loading of 100% are surface-treated with approximately 2.5 mM NaOH/EtOH (70:30, v/v). In order for the surface treated microparticles to form a consolidated aggregate, the temperature around the particles, for example in the human or non-human animal where the composition is administered, is approximately equal to, or greater than, the glass transition temperature (Tg) of the polymer particles. At such temperatures the polymer particles will cross-link to one or more other polymer particles to form a consolidated aggregate. By cross-link it is meant that adjacent polymer particles become joined together. For example, the particles may cross-link due to entanglement of the polymer chains at the surface of one particle with polymer chains at the surface of another particle. There may be adhesion, cohesion or fusion between adjacent particles. Where more than one type of polymer is used, each surface treated microparticle may have a different solidifying or setting property. For example, the surface treated microparticles may be made from similar polymers but may have different gelling pHs or different melting temperatures or glass transition points. Typically, the injectable surface treated microparticles which are formed of a polymer or a polymer blend have a glass transition temperature (T_g) either close to or just above body temperature (such as from about 30 °C to 45 °C, e.g., from about 35 °C to 40 °C, for example, from about 37 °C to 40 °C). Accordingly, at room temperature the surface treated microparticles are below their Tg and behave as discrete particles, but in the body the surface treated microparticles soften and interact/stick to themselves. Typically, agglomeration begins within 20 seconds to about 15 minutes of the raise in temperature from room to body temperature. The surface treated microparticles may be formed from a polymer which has a Tg from about 35 °C to 40 °C, for example from about 37 °C to 40 °C, wherein the polymer is a poly(α-hydroxyacid) (such as PLA, PGA, PLGA, or PDLLA or a combination thereof), or a blend thereof with PLGA-PEG. Typically, these particles will agglomerate at body temperature. The injectable surface treated microparticles may comprise only poly(α-hydroxyacid) particles or other particle types may be included. The microparticles can be formed from a blend of poly(D,L-lactide-co-glycolide) (PLGA), PLGA-PEG and PVA which has a Tg at or above body temperature. In certain embodiments, at body temperature the surface treated microparticles will interact to form a consolidated aggregate. The injectable microparticle may comprise only PLGA/PLGA- PEG/PVA surface treated microparticles or other particle types may be included. The composition may comprise a mixture of temperature sensitive surface treated microparticles and non-temperature sensitive surface treated microparticles. Non-temperature sensitive surface treated microparticles are particles with a glass transition temperature which is above the temperature at which the composition is intended to be used. Typically, in a composition comprising a mixture of temperature sensitive surface treated microparticles and non-temperature sensitive particles the ratio of temperature sensitive to non-temperature sensitive surface treated microparticles is about 3:1, or lower, for example, 4:3. The temperature sensitive surface treated microparticles are advantageously capable of crosslinking ^{to each other when the temperature of the composition is raised to or above the glass transition of these} microparticles. By controlling the ratio of temperature sensitive surface treated microparticles to non- temperature sensitive surface treated microparticles it may be possible to manipulate the porosity of the resulting consolidated aggregate. The surface treated microparticles may be solid, that is with a solid outer surface, or they may be porous. The particles may be irregular or substantially spherical in shape. In certain embodiments, the microparticles have a mean size of about 25 µm to about 50 µm, 25 µm to about 45 µm, 25 µm to about 30 µm and a median size of about 29 µm to about 31 µm before surface treatment. Further, in various embodiments, the surface-modified solid aggregating microparticles of the disclosed invention can aggregate to produce at least one depot when administered in vivo that has a diameter of at least about 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 1 mm, 1.5 mm, 2 mm, 3 mm, 4 mm, or 5 mm. Formation of the consolidated aggregate from the composition, once administered to a human or non-human animal, typically takes from about 20 seconds to about 24 hours, for example, between about 1 minute and about 5 hours, between about 1 minute and about 1 hour, less than about 30 minutes, less than about 20 minutes. Typically, the solidification occurs in between about 1 minute and about 20 minutes from administration. In certain embodiments, the surface-modified solid aggregating microparticles of the present invention produce a microparticle depot in vivo that releases a compound of Formula I, Formula II, or Formula III, without a burst of more than about 10 percent or 15 percent of the total payload of a compound of Formula I, Formula II, or Formula III over a one week, or a five, four, three, two day or one day period. In some embodiments, the long-term controlled drug delivery is accomplished by a combination of surface erosion of an aggregated microparticle depot over several months (for example, one, two, three, or four months or more) followed by erosion of remaining parts of the aggregated microparticle depot, followed by slow release of active material from in vivo proteins to which it has bound over the period of long term release from the aggregated particle. In other embodiments, the microparticle degrades substantially by surface erosion over a period of at least about one, two, three, four, five or six months or more. In certain embodiments, the agent that removes surface surfactant is not a degrading agent of the biodegradable polymer under the conditions of the reaction. The hydrophilicity of the microparticles can be decreased by removing surfactant. In certain embodiments, the surface-treated microparticles contain less surfactant than a microparticle prior to the surface modification. In certain embodiments, the surface-treated microparticles contain from about 0.001 percent to about 1 percent surfactant following surface-treatment. In certain embodiments, the surface-modified solid aggregating microparticles are more hydrophobic than the microparticles prior to the surface modification. In alternative embodiments, the weight percent of surface-modified solid aggregating microparticles that are not aggregated into a larger depot in vivo is about 10 percent or less, 7 percent or less, 5 percent or less, or 2 percent or less by total weight administered. I^{n certain embodiments, the surface-modified solid aggregating microparticles do not cause} substantial inflammation in the eye. In other embodiments, the surface-modified solid aggregating microparticles do not cause an immune response in the eye. In certain embodiments, the microparticles after surface treatment have about the same mean size and median size. In other embodiments, the microparticles after surface treatment have a mean size which is larger than the median size. In other embodiments, the microparticles after surface treatment have a mean size which is smaller than the median size. In certain embodiments, a surface-modified solid aggregating microparticle is manufactured using a wet microparticle. In certain embodiments, a surface-modified solid aggregating microparticle is less inflammatory than a non-surface treated microparticle. In certain embodiments, the agent that removes the surface surfactant of a surface-modified solid aggregating microparticle comprises a solvent that partially dissolves or swells the surface-modified solid aggregating microparticle. In certain embodiments, the surface-modified solid aggregating microparticles are capable of releasing a compound of Formula I, Formula II, or Formula III over a longer period of time compared to a non-surface treated microparticle. In certain embodiments, a microparticle comprising a compound of Formula I, Formula II, or Formula III allows a substantially zero or first order release rate of a compound of Formula I, Formula II, or Formula III from the consolidated aggregate once the consolidated aggregate has formed. A zero order release rate is a constant release of a compound of Formula I, Formula II, or Formula III over a defined time; such release is difficult to achieve using known delivery methods. In certain embodiments, the microparticles of the present invention have a solid core. In certain embodiments, the solid core is less than 10 percent porosity, 8 percent porosity, 7 percent porosity, 6 percent porosity, 5 percent porosity, 4 percent porosity, 3 percent porosity, or 2 percent porosity. Porosity as used herein is defined by ratio of void space to total volume of the surface-modified solid aggregating microparticle. The encapsulation efficiency of the process of manufacturing microparticles depends on the microparticle forming conditions and the properties of a compound of Formula I, Formula II, or Formula III. In certain embodiments, the encapsulation efficiency can be greater than about 50 percent, greater than about 75 percent, greater than about 80 percent, or greater than about 90 percent. In certain embodiments, the solid biodegradable microparticles release about 1 to about 20 percent, about 1 to about 15 percent, about 1 to about 10 percent, or about 5 to 20 percent, for example, up to about 1, 5, 10, 15 or 20 percent, of a compound of Formula I, Formula II, or Formula III over the first twenty-four- hour period. In certain embodiments, the microparticles have only residual solvents that are pharmaceutically ^acceptable. In certain embodiments, the microparticles afford a total release of greater than eighty percent by day 14. In certain embodiments, the microparticles have syringeability with a regular-walled 26-, 27-, 28-, 29- or 30-gauge needle of 200 mg/ml with no clogging of the syringe. In certain embodiments, the microparticles have syringeability with a thin-walled 26-, 27-, 28-, 29- or 30-gauge needle of 200 mg/ml with no clogging of the syringe. In certain embodiments, the microparticles have an endotoxin level of less than 0.02 EU/mg. In certain embodiments, the microparticles have a bioburden level of less than 10 CFU/g. In certain embodiments, the microparticles have an endotoxin level of less than 0.02 EU/mg. In certain embodiments, the microparticles have a bioburden level of less than 10 CFU/g. In certain embodiments, the microparticles are suspended in a diluent of 10X ProVisc-diluted (0.1% HA in PBS) solution comprising additive that improves particle aggregation. In certain embodiments, the microparticles are suspended in a diluent of 20X-diluted ProVisc (0.05% HA in PBS) comprising additive that improves particle aggregation. In certain embodiments, the microparticles are suspended in a diluent of 40X-diluted ProVisc (0.025% HA in PBS) comprising additive that improves particle aggregation. Non-limiting examples of additives include triethyl citrate, benzyl alcohol, polyethylene glycol, N- methyl-2-pyrrolidone (NMP), 2-pyrrolidone, DMSO, triacetin, benzyl acetate, benzyl benzoate, acetyltributyl citrate, dibutyl sebacate, dimethylphthalate, tributyl O-acetylcitrate, ethanol, methanol, polysorbate 80, ethyl acetate, propylene carbonate, isopropyl acetate, methyl acetate, methyl ethyl ketone, butyl lactate, and isovaleric acid. In certain embodiments, the microparticles are suspended in a diluent of 10X ProVisc-diluted (0.1% HA in PBS) solution comprising benzyl alcohol. In certain embodiments, the microparticles are suspended in a diluent of 20X-diluted ProVisc (0.05% HA in PBS) comprising benzyl alcohol. In certain embodiments, the microparticles are suspended in a diluent of 40X-diluted ProVisc (0.025% HA in PBS) comprising benzyl alcohol. In certain embodiments, the microparticles are suspended in a diluent of 10X ProVisc-diluted (0.1% HA in PBS) solution comprising triethyl citrate. In certain embodiments, the microparticles are suspended in a diluent of 20X-diluted ProVisc (0.05% HA in PBS) comprising triethyl citrate. In certain embodiments, the microparticles are suspended in a diluent of 40X-diluted ProVisc (0.025% HA in PBS) comprising triethyl citrate. In certain embodiments, the particles are suspended in the diluent comprising additive that improves particle aggregation at a concentration of 100 mg/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL or 500 mg/mL. In certain embodiments, the particles are suspended in 10X-diluted ProVisc (0.1% HA in PBS) solution comprising additive that improves particle aggregation, and the suspension has a final concentration of 200 mg/mL. In certain embodiments, the particles are suspended in 10X-diluted ProVisc (0.1% HA in PBS) solution comprising additive that ^{improves particle aggregation, and the suspension has a final concentration of 400 mg/mL. In certain} embodiments, the particles are suspended in a 20X-diluted ProVisc (0.05% HA in PBS) solution comprising additive that improves particle aggregation, and the suspension has a final concentration of 200 mg/mL. In certain embodiments, the particles are suspended in a 20X-diluted ProVisc (0.05% HA in PBS) solution comprising additive that improves particle aggregation, and the suspension has a final concentration of 400 mg/mL. In certain embodiments, the particles are suspended in a 40X-diluted ProVisc (0.025% HA in PBS) solution comprising additive that improves particle aggregation, and the suspension has a concentration of 200 mg/mL. In certain embodiments, the particles are suspended in a 40X-diluted ProVisc (0.025% HA in PBS) solution comprising additive that improves particle aggregation, and the suspension has a concentration of 400 mg/mL. In certain embodiments, the diluent for suspending particles is ProVisc comprising additive that improves particle aggregation. In certain embodiments, the diluent for suspending particles is sodium hyaluronate comprising additive that improves particle aggregation. In some embodiments, the microparticles are diluted from about 10-fold to about 40-fold, from about 15-fold to about 35-fold, or from about 20-fold to about 25-fold. In some embodiments, the diluent for suspending particles is a 10X-diluted ProVisc (0.1% HA in PBS) solution, a 20X-diluted ProVisc (0.05% HA in PBS) solution, or a 40X-diluted ProVisc (0.025% HA in PBS) solution comprising additive. In some embodiment, the particles are suspended in the diluent comprising additive at a concentration of at least about 100 mg/mL, 200 mg/mL, 300 mg/mL, 400 mg/mL, or 500 mg/mL. In further embodiments, the additive is benzyl alcohol. In further embodiments, the additive is triethyl citrate. In some embodiments, the diluent comprises more than one additive, for example benzyl alcohol and triethyl citrate. In certain embodiments, the additive is benzyl alcohol. In certain embodiments, the additive is triethyl citrate. In certain embodiments, the additive is selected from polyethylene glycol, N-methyl-2- pyrrolidone (NMP), 2-pyrrolidone, and DMSO. In certain embodiments, the additive is selected from triacetin, benzyl acetate, benzyl benzoate, and acetyltributyl citrate. In certain embodiments, the additive is selected from dibutyl sebacate, dimethylphthalate, tributyl O-acetylcitrate, ethanol, and methanol. In certain embodiments, the additive is selected from polysorbate 80, ethyl acetate, propylene carbonate, and isopropyl acetate. In certain embodiments, the additive is selected from methyl acetate, methyl ethyl ketone, butyl lactate, and isovaleric acid. In certain embodiments, the diluent contains approximately from about 0.01% to about 10% by weight of additive, from about 0.01% to about 0.1% by weight of additive, from about 0.05% to about 0.5% by weight of additive, from about 0.1% to about 1.0% by weight of additive, from about 0.1% to about 10% by weight of additive, from about 0.5% to about 5% by weight of additive, from about 0.5% to about 4% by weight of additive, from about 0.5% to about 3% by weight of additive, from about 0.5% to about 2.0% by weight of additive, from about 0.1% to about 0.5% by weight of additive, from about 0.1% to about 0.25% by weight of additive, from about 0.2% to about 2% by weight of additive, or from about 0.01% to about 0.05% by weight of additive. T^{he diluent is present in an amount in a range of from about 0.5 weight percent to about 95 weight} percent of the drug delivery particles. The diluent can also be an aqueous diluent. Examples of aqueous diluent include, but are not limited to, an aqueous solution or suspension, such as saline, plasma, bone marrow aspirate, buffers, such as Hank's Buffered Salt Solution (HBSS), HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid), Ringers buffer, ProVisc®, diluted ProVisc®, ProVisc® diluted with PBS, Krebs buffer, Dulbecco's PBS, normal PBS; sodium hyaluronate solution (HA, 5 mg/mL in PBS), simulated body fluids, plasma platelet concentrate and tissue culture medium or an aqueous solution or suspension comprising an organic solvent. ProVisc® is a sterile, non-pyrogenic, high molecular weight, non- inflammatory highly purified fraction of sodium hyaluronate, dissolved in physiological sodium chloride phosphate buffer. In certain embodiments, the diluent is PBS. In certain embodiments, the diluent is HA, 5 mg/mL in PBS. In certain embodiments, the diluent is ProVisc® diluted with water. In certain embodiments, the diluent is ProVisc® dilution in PBS. In certain embodiments, the diluent is ProVisc® 5-fold diluted with water. In certain embodiments, the diluent is ProVisc® 5-fold dilution in PBS. In certain embodiments, the diluent is ProVisc® 10-fold diluted with water. In certain embodiments, the diluent is ProVisc® 10-fold dilution in PBS. In certain embodiments, the diluent is ProVisc® 20-fold dilution with water. In certain embodiments, the diluent is ProVisc® 20-fold dilution in PBS. In certain embodiments, the diluent is HA, 1.25 mg/mL in an isotonic buffer solution with neutral pH. In certain embodiments, the diluent is HA, 0.625 mg/mL in an isotonic buffer solution with neutral pH. In certain embodiments, the diluent is HA, 0.1-5.0 mg/mL in PBS. In certain embodiments, the diluent is HA, 0.5-4.5 mg/mL in PBS. In certain embodiments, the diluent is HA, 1.0-4.0 mg/mL in PBS. In certain embodiments, the diluent is HA, 1.5-3.5 mg/mL in PBS. In certain embodiments, the diluent is HA, 2.0-3.0 mg/mL in PBS. In certain embodiments, the diluent is HA, 2.5-3.0 mg/mL in PBS. V. Implants In certain embodiments, the present invention provides biodegradable implants that encapsulate and/or have dispersed therein a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention provides biodegradable implants that encapsulate and/or have dispersed therein both a prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and a compound of Formula I, Formula II, or ^{Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the implant comprises a} prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt, a compound of Formula I, Formula II, or Formula III, and a compound of Formula I, Formula II, or Formula III and a pharmaceutically acceptable salt. In certain embodiments, the implants are intraocular implants. Suitable implants include, but are not limited to, rods, discs, pellets, and wafers. In certain embodiments, the implant is formed of any of the biodegradable polymers described herein. In certain embodiments, the implant comprises poly lactic-co- glycolic acid (PLGA) and/or polylactic acid (PLA). In certain embodiments, the implant further comprises PLGA conjugated to a polyalkylene glycol, such as polyethylene glycol (PEG). The composition of the polymer matrix may be selected based on the time required for in vivo stability, i.e., that time required for distribution of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof to the site where delivery is desired, and the time desired for delivery. The implants may be of any geometry such as fibers, sheets, films, microspheres, spheres, prisms, circular discs, rods, or plaques. In certain embodiments, a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and/or a prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof is delivered in an implant that is a blend of two polymers, for example (i) a PLGA polymer or PLA polymer as described herein and (ii) a PLGA-PEG or PLA-PEG copolymer. In other embodiments, the implant is a blend of three polymers, such as, for example, (i) a PLGA polymer; (ii) a PLA polymer; and (iii) a copolymer of PLGA-PEG or PLA-PEG. In certain embodiments, the implant is a blend of (i) a PLGA polymer; (ii) a PLGA polymer that has a different ratio of lactide and glycolide monomers than the PLGA in (i); and (iii) a PLGA-PEG or PLA-PEG copolymer. In an additional embodiment, the implant is a blend of (i) a PLA polymer; (ii) a PLGA polymer; (iii) a PLGA polymer that has a different ratio of lactide and glycolide monomers than the PLGA in (ii); and (iv) a PLGA-PEG or PLA-PEG copolymer. Any ratio of lactide and glycolide in the PLGA can be used that achieves the desired therapeutic effect. In certain illustrative non-limiting embodiments, the ratio of PLA to PLGA by weight in a polymer blend as described is about 77/22, 69/30, 49/50, 54/45, 59/40, 64/35, 69/30, 74/25, 79/20, 84/15, 89/10, 94/5, or 99/1. In certain embodiments, a blend of two polymers has (i) PLGA and (ii) PLGA with a different ratio of lactide and glycolide monomers than PLGA in (i) wherein the ratio by weight is about 74/20/5 by weight, about 69/20/10 by weight, about 69/25/5 by weight, or about 64/20/15 by weight. In certain embodiments, the PLGA in (i) has a ratio of lactide to glycolide of about 85/15, about 75/25, or about 50/50. In certain embodiments the PLGA in (ii) has a ratio of lactide to glycolide of about 85/15, about 75/25, or about 50/50. In certain embodiments, a blend of three polymers has (i) PLA (ii) PLGA (iii) PLGA with a different ratio of lactide and glycolide monomers than PLGA in (ii) wherein the ratio by weight is about 74/20/5 by weight, about 69/20/10 by weight, about 69/25/5 by weight, or about 64/20/15 by weight. In certain ^{embodiments, the PLGA in (ii) has a ratio of lactide to glycolide of about 85/15, about 75/25, or about 50/50.} In certain embodiments the PLGA in (iii) has a ratio of lactide to glycolide of about 85/15, about 75/25, or about 50/50. In certain aspects, the drug may be delivered in an implant that is a blend of PLGA or PLA and PEG-PLGA, including but not limited to (i) PLGA + approximately by weight 1% PEG-PLGA or (ii) PLA + approximately by weight 1% PEG-PLGA. In certain aspects, the drug may be delivered in a blend of (iii) PLGA/PLA + approximately by weight 1% PEG-PLGA. In certain embodiments, the blend of PLA, PLGA, or PLA/PGA with PLGA-PEG contains approximately from about 0.5% to about 10% by weight of a PEG- PLGA, from about 0.5% to about 5% by weight of a PEG-PLGA, from about 0.5% to about 4% by weight of a PEG-PLGA, from about 0.5% to about 3% by weight of a PEG-PLGA, from about 1.0% to about 3.0% by weight of a PEG-PLGA, from about 0.1% to about 10% of a PEG-PLGA, from about 0.1% to about 5% of a PEG-PLGA, from about 0.1% to about 1% PEG-PLGA, or from about 0.1% to about 2% PEG-PLGA. In certain non-limiting embodiments, the ratio by weight percent of PLGA to PEG-PLGA in a two polymer blend as described is about or at least about 40/1, 45/1, 50/1, 55/1, 60/1, 65/1, 70/1, 75/1, 80/1, 85/1, 90/1, 95/1, 96/1, 97/1, 98/1, 99/1. The PLGA can be acid or ester capped. In non-limiting aspects, the drug can be delivered in a two polymer blend of PLGA75:254A + approximately 1% PEG-PLGA50:50; PLGA85:15 5A + approximately 1% PEG-PLGA5050; PLGA75:25 6E + approximately 1% PEG- PLGA50:50; or PLGA50:502A + approximately 1% PEG-PLGA50:50. In certain non-limiting embodiments, the ratio by weight percent of PLA/PLGA-PEG in a polymer blend as described is about or at least about 40/1, 45/1, 50/1, 55/1, 60/1, 65/1, 70/1, 75/1, 80/1, 85/1, 90/1, 95/1, 96/1, 97/1, 98/1, 99/1. The PLA can be acid capped or ester capped. In cetain aspects, the PLA is PLA 4.5A. In non-limiting aspects, the drug is delivered in a blend of PLA 4.5A + 1% PEG-PLGA. The PEG segment of the PEG-PLGA may have, for example, in non-limiting embodiments, a molecular weight of at least about or about 1 kDa, 2 kDa, 3 kDa, 4 kDa, 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa, or 10 kDa, and typically not greater than 10 kDa, 15 kDa, 20 kDa, or 50 kDa, or in some embodiments, 6 kDa, 7 kDa, 8 kDa, or 9kDa. In certain embodiment, the PEG segment of the PEG-PLGA has a molecular weight between about 3 kDa and about 7 kDa or between about 2 kDa and about 7 kDa. Non-limiting examples of the PLGA segment of the PEG-PLGA is PLGA50:50, PLGA75:25, or PLGA85:15. In certain embodiments, the PEG-PLGA segment is PEG (5 kDa)-PLGA50:50. When the drug is delivered in a blend of PLGA + PEG-PLGA, any ratio of lactide and glycolide in the PLGA or the PLGA-PEG can be used that achieves the desired therapeutic effect. Non-limiting illustrative embodiments of the ratio of lactide/glycolide in the PLGA or PLGA-PEG are about or at least about 5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or 95/5 by weight percent. In certain embodiments, the PLGA is a block co-polymer, for example, diblock, triblock, multiblock, or star-shaped block. In certain embodiments, the PLGA is a random co-polymer. In certain aspects, the PLGA is PLGA75:254A; PLGA85:155A; PLGA75:256E; or PLGA50:502A. I^{n certain embodiments, the biodegradable polymer(s) comprises no more than about 10, no more} than about 20, no more than about 30, no more than about 40, no more than about 50, no more than about 60, no more than about 70, no more than about 80, or no more than about 90 weight percent of the implant with the balance of the weight being a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt and/or a prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof or other non-active agents dispersed in the biocompatible biodegradable polymer. In certain embodiments, the non-active agent is a plasticizer that increases the flexibility and processability of the implant. Non-limiting examples of the non-active agent include benzyl alcohol, benzyl benzoate, ethyl heptanoate, propylene carbonate, triacetin, and triethyl citrate. In certain embodiments, the non-active agent is benzyl alcohol. Intraocular implants are generally biocompatible with physiological conditions of an eye and do not cause adverse side effects. Generally, intraocular implants may be placed in an eye without disrupting vision of the eye. In certain embodiments the implants of the present invention comprise about 35-55% by weight a prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and 15-30% by weight a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof with the remaining weight being at least one polymer and non-active excipients. Implant size is determined by factors such as toleration for the implant, location of the implant, size limitations in view of the proposed method of implant insertion, and/or ease of handling. The size and shape of the implant can also be used to control the rate of release, period of treatment, and drug concentration at the site of implantation. Larger implants will deliver a proportionately larger dose, but depending on the surface to mass ratio, may have a slower release rate. The particular size and geometry of the implant are chosen to suit the site of implantation. The vitreous chamber in humans is able to accommodate relatively large implants of varying geometries, having a length of about 1 mm to about 15 mm and a diameter of between about 100 μm and about 1000 μm. In certain embodiments, the implant has a length of at least about 2 mm to no less than about 12 mm, at least about 3 mm to about 10 mm or less, at least about 4 mm to about 7 mm or less, or at least about 5 mm to about 6 mm or less. In certain embodiments, the diameter is between at least about 100 μm to about 800 μm or less, at least about 200 μm to about 600 μm or less, or between at least about 300 μm to about 500 μm or less. In certain embodiments, the implant has a diameter between at least about 200 μm and 600 μm or less and length between at least about 3 mm and 10 mm or less. In an alternative embodiment, the implant has a diameter between about at least 300 μm and 600 μm or less and length between about at least 1 mm and 10 mm or less. I^{n certain embodiments, the implant is in the shape of a cylindrical pellet with a width ranging from} at least about 400 μm to about 1200 μm or less, a length of not more than 15 mm, and a height ranging from at least 400 μm to 1200 μm or less. In certain embodiments, the cylindrical pellet has a width between about at least 400 μm to about 600 μm or less, at least about 500 μm to about 700 μm or less, at least about 600 μm to about 800 μm or less, at least about 700 μm to about 900 μm or less, at least about 800 μm to about 1000 μm or less, or at least about 900 μm to about 1100 μm or less. In certain embodiments, the cylindrical pellet has a length of not more than about 15 mm, not more than about 12 mm, not more than about 10 mm, not more than about 9 mm, not more than about 8 mm, not more than about 7 mm, not more than about 6 mm, not more than about 5 mm, not more than about 4 mm, not more than about 3 mm, not more than about 2 mm, or not more than about 1 mm. In certain embodiments, the cylindrical pellet has a width between about at least 400 μm to about 600 μm or less, about at least 500 μm to about 700 μm or less, at least about 600 μm to about 800 μm or less, at least about 700 μm to about 900 μm or less, at least about 800 μm to about 1000 μm or less, or about at least 900 μm to about 1100 μm or less. In certain embodiments, the cylindrical pellet has a height between at least about 700 μm and about 1000 μm or less, a length of not more than about 7 mm, and a width between at least about 800 μm and about 1100 μm or less. In certain embodiments, the cylindrical pellet has a height between at least about 800 μm and about 950 μm or less, a length of not more than about 7 mm, and a width between at least about 900 μm and 1000 μm or less. In one particular embodiment, the cylindrical pellet has a height of about 900 μm, a length of about 7 mm, and a width of about 1000 μm. In certain embodiments, the implant is a rod with a diameter of between at least about 550 μm and about 50 μm or less. In certain embodiments, the implant is a rod with a diameter of between about at least 550 μm and about 100 μm or less, between at least about 450 μm and about 150 μm or less, between at least about 400 μm and about 200 μm or less, or between at least about 350 μm and about 250 μm or less. In certain embodiments, the implant is a rod with a diameter of between at least about 500 μm and about 350 μm or less. In certain embodiments, the implant is a rod with a diameter of between at least about 500 μm and about 400 μm or less or between at least about 400 μm and about 300 μm or less. In alternative embodiments, the implant is a rod with a diameter greater than about 550 μm, for example greater than about 575 μm, greater than about 600 μm, greater than about 625 μm, or greater than about 650 μm. In a further embodiment, the implant is a rod with a length of no greater than about 10 mm, no greater than about 9 mm, no greater than about 8 mm, no greater than about 7 mm, no greater than about 6 mm, no greater than about 5.5 mm, no greater than about 5 mm, no greater than about 4.5 mm, no greater than about 4 mm, no greater than about 3.5 mm, no greater than about 3 mm, no greater than about 2.5 mm, no greater than about 2 mm, no greater than about 1.5 mm, or no greater than about 1 mm. In certain embodiments, the implant is a rod with a diameter between at least about 550 μm and 100 μm or less, between at least about 500 μm and 300 μm or less, or between at least about 500 μm and 400 μm or less with a length of no greater than 7 mm or 6 mm. In certain embodiments, the implant is a rod with a diameter between at least about 500 μm and about 400 μm or less with a length of no greater than ^{6 mm.} In certain embodiments, the implant is a rod with a diameter between at least about 400 μm and 100 μm or less, between at least about 400 μm and 200 μm or less, or between at least about 400 μm and 300 μm or less with a length of no greater than 4 mm or 3.5 mm. In certain embodiments, the implant is a rod with a diameter between at least about 400 μm and about 300 μm or less with a length of no greater than 3.5 mm. In certain embodiments, the implant is a rod with a diameter between at least about 250 μm and 100 μm or less or between about at least 200 μm and 100 μm or less with a length of no greater than about 10 mm. In certain embodiments, the implant is a rod with a diameter between at least about 250 μm and about 150 μm or less with a length of no greater than about 10 mm. In certain embodiments, the implant, for example the rod or cylindrical pellet, has syringeability with a regular-walled 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, or 30-gauge needle with no clogging of the syringe. In certain embodiments, the implant, for example the rod or cylindrical pellet, has syringeability with a regular-walled 21-, 22-, 23-, 24-, or 25-gauge needle with no clogging of the syringe. In certain embodiments, the implant, for example the rod, has syringeability with a thin-walled or ultra thin-walled 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, or 30-gauge needle with no clogging of the syringe. In certain embodiments, the implant has syringeability with a thin-walled or ultra thin-walled 27-gauge. In certain embodiments, the implant, for example the rod, has syringeability with a thin-walled or ultra thin- walled 26-, 27-, 28-, 29-, or 30-gauge needle with no clogging of the syringe. In certain embodiments, the implant has syringeability with a thin-walled or ultra thin-walled 27-gauge. Intraocular implants may also be designed to be least somewhat flexible so as to facilitate both insertion of the implant in the eye, such as in the vitreous humor, and subsequent accommodation of the implant. The total weight of the implant is usually at least about 250 to 5000 μg or less, for example, at least about 500 - 1000 μg or less. In certain embodiments, the intraocular implant has a mass of about 500 μg, 750 μg, or 1000 μg. In certain embodiments, the biodegradable polymer(s) comprises no more than about 10, no more than about 20, no more than about 30, no more than about 40, no more than about 50, no more than about 60, no more than about 70, no more than about 80, or no more than about 90 weight percent of the implant with the balance of the weight being a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof or other non-active agents dispersed in the biocompatible biodegradable polymer. In certain embodiments, the implant exhibits a hardness rating in vitro in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water of at least 5, and in some embodiments, at least about 10, 15, 20, 30, 40, 50, 60, 70, 75, 100, 120, 150, or more gram-force needed to compress the implant at 30% of strain. In certain embodiments, the implant exhibits a hardness rating about at least about 40 gram- force need to compress the particle at 30% of strain. I^{n certain embodiments, the biodegradable polymer(s) comprises between about 10 and about 30} weight percent of the implant and the implant exhibits a hardness rating in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water of at least about 40, 50, 60, 70, 75, 100, 120, 150, or more gram- force needed to compress the implant at 30% of strain. In certain embodiments, the implant exhibits a hardness rating about at least about 40 gram-force need to compress the particle at 30% of strain. In certain embodiments, the hardness is measured in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water. In certain embodiments, the biodegradable polymer(s) comprises between about 30 and about 50 weight percent of the implant and the implant exhibits a hardness rating in vivo in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water of at least 40, 50, 60, 70, 75, 100, 120, 150, or more gram-force needed to compress the implant at 30% of strain. In certain embodiments, the implant exhibits a hardness rating about at least about 40 gram-force need to compress the particle at 30% of strain. In certain embodiments, the implant is non-polymeric and a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof comprises between about 85 and about 100 weight percent of the implant with the balance of the weight being non-active agents or excipients. In certain embodiments, a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof comprises 100 weight percent of the implant. In certain embodiments, the non-polymeric implant comprises between about 85 and about 100 weight percent of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and exhibits a hardness rating in vivo in a fluid selected from vitreous, water, phosphate buffered saline, or an aqueous physiologically acceptable solution with a viscosity not more than about 4 times that of water of at least 5, and in some embodiments, at least about 10, 15, 20, 30, 40, 50, 60, 70, 75, 100, 120, 150, or more gram-force needed to compress the implant at 30% of strain. In certain embodiments, the non-polymeric implant comprises about 100 weight percent of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof and exhibits a hardness rating of at least about 40 gram-force needed to compress the implant at 30% of strain. In certain embodiments, the implant is inserted via a needle, including but not limited to a 21, 22, 23, 24, 25, 26, 27, 29, 30, or 31 gauge needle, which may optionally have a thin or ultra-thin needle wall. In an alternative embodiment, the needle has an inner diameter of between about 100 μm and 1000 μm and a length between about 1 mm and 15 mm. In certain embodiments, the needle has an inner diameter of between about 100 μm and about 300 μm, between about 200 μm and about 400 μm, between about 300 μm and about 500 μm, between about 400 μm and about 700 μm, between about 500 μm and about 800 μm, or between about 600 μm and about 900 μm. In certain embodiments, the needle has a length of ^{about 2 mm to about 12 mm, about 3 mm to about 10 mm, about 5 mm to about 7 mm, or about 6 mm to} about 10 mm. In certain embodiments, the needle has an inner diameter of between about 200 μm and about 600 μm and a length between about 3 mm and 10 mm. In certain embodiments, the needle has an inner diameter of between about 400 μm and about 500 μm and a length between about 4 mm and 6 mm. In certain embodiments, the implant has a length of between at least about 3 to about 10 mm or less and for every 6 mm of implant, the average dose of a compound of Formula I, Formula II, or Formula III ranges from about 0.10 mg to about 1.10 mg. In certain embodiments, the average dose of a compound of Formula I, Formula II, or Formula III for every 6 mm of implant is at least about 0.10 mg, 0.20 mg, 0.30 mg, 0.40 mg.0.50 mg, 0.60 mg, 0.70 mg, 0.80 mg, 0.90 mg, 1.0 mg, or 1.10 mg. The implants of the present invention provide sustained delivery of a prodrug of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt and/or a compound of Formula I, Formula II, or Formula III for at least one month, or at least two months, or at least three months, or at least four months, or at least five months, or at least six months, or at least seven months, or at least eight months, or at least nine months, or at least ten months, or at least eleven months, or at least twelve months. In an alternative embodiment, the implant comprises a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, an implant comprising a compound of Formula I, Formula II, or Formula III allows a substantially zero or first order release rate of a compound of Formula I, Formula II, or Formula III from the implant. A zero order release rate is a constant release of a compound of Formula I, Formula II, or Formula III over a defined time and such release is difficult to achieve using known delivery methods. The present invention also includes pharmaceutical compositions of the implants as described herein. In certain embodiments, the pharmaceutical composition comprises an additive that improves the flexibility of the implant, for example a plasticizer. In certain embodiments, the plasticizer is benzyl alcohol. In other embodiments, a method for the treatment of an ocular disorder is provided that includes administering to a host in need thereof the polymeric implants described herein that include an effective amount of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt and/or a prodrug of a compound of Formula I, Formula II, or Formula III, wherein the implant is injected into the eye and provides sustained drug delivery for at least approximately one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more months. In certain embodiments, the solid biodegradable implant releases about 1 to about 20 percent, about 1 to about 15 percent, about 1 to about 10 percent, or about 5 to 20 percent, for example, up to about 1, 5, 10, 15 or 20 percent, of a compound of Formula I, Formula II, or Formula III over the first twenty-four-hour period. Implants can be manufactured using any suitable technique known in the art. Examples of suitable techniques for the preparation of implants include solvent evaporation methods, phase separation methods, interfacial methods, molding methods, injection molding methods, extrusion methods, coextrusion methods, carver press method, die cutting methods, compression, solvent casting, 3D printing and combinations ^{thereof. In certain embodiments, the implant is splinted, or exposed to heat, and typically compressed. In} certain embodiments, the splintered by exposing the pellet to a hot water bath. In certain embodiments, implant is not splinted. Suitable methods for the manufacture of implants can be selected in view of many factors including the properties of the polymer/polymers present in the implant, the properties of the one or more drugs present in the implant, and the desired shape and size of the implant. Suitable methods for the preparation of implants are described, for example, in U.S. Pat. No.4,997,652 and U.S. Patent Application Publication No. US 2010/0124565. In certain embodiments, extrusion methods may be used to avoid the need for solvents during implant manufacture. When using extrusion methods, the polymer/polymers and a compound of Formula I, Formula II, or Formula III are chosen so as to be stable at the temperatures required for manufacturing, usually at least about 85° C. However, depending on the nature of the polymeric components and the one or more compounds, extrusion methods can employ temperatures of about 25° C to about 150° C, for example, about 65° C to about 130° C. Implants may be coextruded in order to provide a coating covering all or part of the surface of the implant. Such coatings may be erodible or non-erodible, and may be impermeable, semi-permeable, or permeable to the compound, water, or combinations thereof. Such coatings can be used to further control release of the compound from the implant. In certain embodiments, the implant is manufactured using hot-melt extrusion wherein the material is subjected to elevated temperature or pressure to cause the material to soften or melt. Compression methods may be used to make the implants. Compression methods frequently yield implants with faster release rates than extrusion methods. Compression methods may employ pressures of about 50-150 psi, for example, about 70-80 psi, even more for example, about 76 psi, and use temperatures of about 0° C to about 115° C, for example, about 25° C. In certain embodiments, a powder of a compound of Formula I, Formula II, or Formula III is used to formulate the implant via, for example, compression, solvent casting, or hot melt extrusion. In alternative embodiments, microparticles comprising a compound of Formula I, Formula II, or Formula III are used as the starting material to formulate the implants via, for example, compression, solvent casting, or hot melt extrusion. In this embodiments, pre-mixing in not required because the components are already well-mixed during the microparticle formulation. The drug load of the microparticles used as a starting material can up to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% by weight. Example 15 is a non-limiting illustrative example of the process to form an implant from microparticles. In certain embodiments, the microparticles are surface-treated as described herein. In certain embodiments, the microparticles are not surface-treated. In certain embodiments, implants of the present invention can also be formulated from (a) microparticles comprising a compound of Formula I, Formula II, or Formula III or a prodrug or a ^{pharmaceutically acceptable salt thereof and (b) unencapsulated compound of Formula I, Formula II, or} Formula III or a prodrug or a pharmaceutically acceptable salt thereof. In certain embodiments, the unencapsulated compound of Formula I, Formula II, or Formula III is micronized. In certain embodiments, these implants are formed via compression, solvent casting, or hot melt extrusion. In certain embodiments, the implant comprises about 0.05 to 0.1%, about 0.1% to 1.0%, about 1.0% to 5.0%, about 5.0% to about 10%, about 10% to about 30% by weight of unencapsulated compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the implant comprises greater than about 30%, greater than about 40%, or greater than about 50% by weight of unencapsulated compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof. VI. Biodegradable Polymers In certain embodiments, the formulations of the present invention that encapsulate a compound of Formula I, Formula II, or Formula III or a prodrug or a pharmaceutically acceptable salt thereof include one or more biodegradable polymers or copolymers. These polymers should be biocompatible in that they can be administered to a patient without an unacceptable adverse effect. Biodegradable polymers are well known to those in the art and are the subject of extensive literature and patents. The biodegradable polymer or combination of polymers can be selected to provide the target characteristics of the microparticles, including the appropriate mix of hydrophobic and hydrophilic qualities, half-life and degradation kinetics in vivo, compatibility with a compound of Formula I, Formula II, or Formula III to be delivered, appropriate behavior at the site of injection, etc. In certain embodiments, the implant or the microparticles of the present invention include poly(lactic-co-glycolic acid) (PLGA). In other embodiments, the implant or microparticles include a polymer or copolymer that has at least PLGA and PLGA-polyethylene glycol (PEG) (referred to as PLGA-PEG). In certain embodiments, the implant or the microparticle includes poly(lactic acid) (PLA). In other embodiments, the implant or the microparticles include a polymer or copolymer that has at least PLA and PLA-polyethylene glycol (PEG) (referred to as PLA-PEG). In other embodiments, the implant or the microparticles include at least PLGA, PLGA-PEG and polyvinyl alcohol (PVA). In other embodiments, the implant or the microparticles include at least PLA, PLA-PEG and polyvinyl alcohol (PVA). Each combination of each of these conditions is considered independently disclosed as if each were separately listed. In certain embodiments, implant or the microparticles comprise (a) PLGA and/or PLGA and (b) a hydrophobic polymer covalently bound to a hydrophilic biodegradable polymer. The PLA and/or PLGA, for example, comprises at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of the microparticle. In certain embodiments, the PLA and/or PLGA has a molecular weight between about 30 and 60 kD, about 35 and 55kD, or about 40 and 50kD. The implant ormicroparticle further includes a hydrophobic polymer covalently bound to a hydrophilic biodegradable polymer. Hydrophobic degradable polymers are known in the art, and include, but are not ^{limited to, polyglycolic acid (PGA), poly(D,L-lactide-co-glycolide) (PLGA), and poly D,L-lactic acid (PDLLA);} polycaprolactone; polyanhydrides, such as polysebacic anhydride, poly(maleic anhydride); and copolymers thereof. Hydrophilic polymers are known in the art and include, for example poly(alkylene glycols) such as polyethylene glycol (PEG), polyethylene oxide (PEO), and poly(ethylene glycol) amine; polysaccharides; poly(vinyl alcohol) (PVA); polypyrrolidone; polyacrylamide (PAM); polyethylenimine (PEI); poly(acrylic acid); poly(vinylpyrolidone) (PVP); or a copolymer thereof. Hydrophobic polymers covalently bound to hydrophilic polymers include, for example, PLGA-PEG, PLA-PEG, PCL-PEG in an amount from about 0.5 percent to about 10 percent, about 0.5 percent to about 5 percent, about 0.5 percent to about 4 percent, about 0.5 percent to about 3 percent, or about 0.1 percent to about 1, 2, 5, or 10 percent. In certain embodiments, the hydrophobic polymer covalently bound to the hydrophilic polymer is PLGA-PEG. In certain embodiments, the ratio of PLA and/or PLGA to hydrophobic polymer covalently bound to a hydrophilic polymer in the microparticle or implant is between about 40/1 to about 120/1 by weight. In certain embodiments, the ratio by weight of PLA and/or PLGA to hydrophobic polymer covalently bound to hydrophilic polymer in the microparticle is about 45/1, 50/1, 55/1, 60/1, 65/1, 70/1, 75/1, 80/1, 85/1, 90/1, 95/1, 96/1, 97/1, 98/1, 99/1, 99.5/1, 99.9/1, 100/1, 101/1, 102/1, 103/1, 104/1, 105/1, or greater than 105/1. In certain embodiments, the hydrophobic polymer covalently bound to a hydrophilic polymer is PLGA-PEG. In certain embodiments, the microparticle or implant contains PLA, PLGA, and PLGA-PEG. In certain embodiments, the ratio by weight of PLA/PLGA/PLGA-PEG in the microparticle is about 5/95/1, 10/90/1, 15/85/1, 20/80/1, 25/75/1, 30/70/1, 35/65/1, 40/60/1, 45/55/1, 40/60/1, 45/55/1, 50/50/1, 55/45/1, 60/40/1, 65/35/1, 70/30/1, 75/25/1, 80/20/1, 85/15/1, 90/10/1, 95/5/1, or 100/1/1. In certain embodiments, PLA-PEG or PLC-PEG is substituted for PLGA-PEG. In certain embodiments, the microparticle or implant comprises PLA/PLGA45k-PEG5k. The PLA can be ester or acid end-capped. In certain embodiments, the PLA is acid end-capped. In certain embodiments, the microparticle or implant comprises PLA/PLGA45k-PEG5k in a ratio by weight of between about 100/1 to 80/20, about 100/1, 95/5, 90/10, 85/15, or 80/20. In certain embodiments, the microparticle or implant comprises PLA/PLGA7525/PLGA45k-PEG5k in a ratio of between about 99/1/1 to 1/99/1, about 99/1/1, 95/5/1, 90/10/1, 85/15/1, 80/20/1, 75/25/1, 70/30/1, 65/35/1, 60/40/1, 55/45/1, 50/50/1, 45/55/1, 40/60/1, 35/65/1, 30/70/1, 25/75/1, 20/80/1, 15/85/1, 10/90/1, 5/95/1, or 1/99/1. The PLGA7525 and PLA can be acid or ester end capped. In certain embodiments, both the PLGA7525 and PLA are acid end- capped. In certain embodiments, the microparticles comprise PLA/PLGA5050/PLGA45k-PEG5k. In certain embodiments, the microparticle or implant comprise PLA/PLGA5050/PLGA45k-PEG5k in a ratio by weight of about 99/1/1, 95/5/1, 90/10/1, 85/15/1, 80/20/1, 75/25/1, 70/30/1, 65/35/1, 60/40/1, 55/45/1, 50/50/1, 45/55/1, 40/60/1, 35/65/1, 30/70/1, 25/75/1, 20/80/1, 15/85/1, 10/90/1, 5/95/1, or 1/99/1. The PLA and PLGA5050 can be acid or ester end-capped. In certain embodiments, both the PLA and PLGA are acid end-capped. In certain embodiments, the microparticle includes PLGA. In certain embodiments, the microparticle includes PLA. I^{n certain embodiments, the microparticle includes a copolymer of PLGA and PEG.} In certain embodiments, the microparticle includes a copolymer of PLA and PEG. In certain embodiments, the microparticle includes PLGA and PLGA-PEG. In certain embodiments, the microparticle includes PLA and PLGA-PEG. In certain embodiments, the microparticle includes PLA and PLA-PEG. In certain embodiments, the microparticle includes PLGA and PLA-PEG. In certain embodiments, the microparticle includes PLGA, PLGA-PEG and PVA. In certain embodiments, the microparticle includes PLA, PLGA-PEG and PVA. In certain embodiments, the microparticle includes PLGA, PLA, and PLGA-PEG. In certain embodiments, the microparticle includes PLGA, PLA, PLGA-PEG and PVA. In certain embodiments, the microparticle comprises PLGA and PLGA-PEG, and combinations thereof. In certain embodiments, the microparticle includes PVA. In certain embodiments, the microparticles include PLGA, PLGA-PEG, PVA, or combinations thereof. In certain embodiments, the microparticles include the biocompatible polymers PLA, PLA-PEG, PVA, or combinations thereof. In certain embodiments, the implant includes PLGA. In certain embodiments, the implant includes PLA. In certain embodiments, the implant includes a copolymer of PLGA and PEG. In certain embodiments, the implant includes a copolymer of PLA and PEG. In certain embodiments, the implant includes PLGA and PLGA-PEG. In certain embodiments, the implant includes PLA and PLGA-PEG. In certain embodiments, the implant includes PLA and PLA-PEG. In certain embodiments, the implant includes PLGA and PLA-PEG. In certain embodiments, the implant includes PLGA, PLGA-PEG and PVA. In certain embodiments, the implant includes PLA, PLGA-PEG and PVA. In certain embodiments, the implant includes PLGA, PLA, and PLGA-PEG. In certain embodiments, the implant includes PLGA, PLA, PLGA-PEG and PVA. In certain embodiments, the implant comprises PLGA and PLGA-PEG, and combinations thereof. In certain embodiments, the implant includes PVA. In certain embodiments, the implant includes PLGA, PLGA-PEG, PVA, or combinations thereof. In certain embodiments, the implant includes the biocompatible polymers PLA, PLA-PEG, PVA, or combinations thereof. In certain embodiments, the implant or the microparticles contain from about 80 percent or 89 percent to about 99 percent PLGA, for example, at least about 80, 85, 90, 95, 96, 97, 98 or 99 percent PLGA. In other embodiments, PLA is used in place of PLGA. In yet other embodiments, a combination of ^{PLA, PLGA and/or PCL is used.} In certain examples, the implant or the microparticle includes from about 0.5 percent to about 10 percent PLGA-PEG, about 0.5 percent to about 5 percent PLGA-PEG, about 0.5 percent to about 4 percent PLGA-PEG, about 0.5 percent to about 3 percent PLGA-PEG, or about 0.1 percent to about 1, 2, 5, or 10 percent PLGA-PEG. In other embodiments, PLA-PEG or PCL-PEG is used in place of PLGA-PEG. In other embodiments, any combination of PLGA-PEG, PLA-PEG or PCL-PEG is used in the polymeric composition with any combination of PLGA, PLA or PCL. Each combination is considered specifically described as if set out individually herein. In certain embodiments, the polymeric formulation includes up to about 1, 2, 3, 4, 5, 6, 10, or 14% of the selected pegylated polymer. In certain embodiments, the PLGA polymer has a molecular weight of 30,000 to 60,000 g/mol (also kilodalton, kDa or kD). In certain embodiments, the PLGA polymer has a molecular weight of 40,000 to 50,000 g/mol (for example 40,000; 45,000 or 50,000g/mol). In certain embodiments, the PLA polymer has a molecular weight of 30,000 to 60,000 g/ mol (for example 40,000; 45,000 or 50,000g/mol). In certain embodiments, the PCL polymer is used in the same range of kDa as described for PLGA or PLA. In certain embodiments the implant or the microparticle includes 5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, 95/5 PLGA as a biodegradable polymer. In certain embodiments, the polymeric implant or the microparticles include 50/50 PLGA as a biodegradable polymer. Poly lactic acid (PLA), polyglycolic acid (PGA), and poly(D,L-lactide-co-glycolide) (PLGA) are poly(α-hydroxy acids). Alternative poly(α-hydroxy acids) include, but are not limited to, poly D,L-lactic acid (PDLLA), polyesters, poly (ε-caprolactone), poly (3-hydroxy-butyrate), poly (s-caproic acid), poly (p- dioxanone), poly (propylene fumarate), poly (ortho esters), polyol/diketene acetals, polyanhydrides, poly (sebacic anhydride) (PSA), poly (carboxybis-carboxyphenoxyphosphazene) (PCPP), poly [bis (p- carboxyphenoxy) methane] (PCPM), copolymers of SA, CPP and CPM (as described in Tamat and Langer in Journal of Biomaterials Science Polymer Edition, 3, 315-353, 1992 and by Domb in Chapter 8 of The Handbook of Biodegradable Polymers, Editors Domb A J and Wiseman R M, Harwood Academic Publishers), and poly (amino acids). In certain embodiments, the implant or the microparticle includes about at least 90 percent hydrophobic polymer and about not more than 10 percent hydrophilic polymer. Examples of hydrophobic polymers include polyesters such as poly lactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactide-co- glycolide) (PLGA), and poly D,L-lactic acid (PDLLA); polycaprolactone; polyanhydrides, such as polysebacic anhydride, poly(maleic anhydride); and copolymers thereof. Examples of hydrophilic polymers include poly(alkylene glycols) such as polyethylene glycol (PEG), polyethylene oxide (PEO), and poly(ethylene glycol) amine; polysaccharides; poly(vinyl alcohol) (PVA); polypyrrolidone; polyacrylamide (PAM); polyethylenimine (PEI); poly(acrylic acid); poly(vinylpyrolidone) (PVP); or a copolymer thereof. In certain embodiments, the implant or the microparticle includes about at least 85 percent ^{hydrophobic polymer and at most about 15 percent hydrophilic polymer.} In certain embodiments, the implant or the microparticle includes about at least about 80 percent hydrophobic polymer and at most about 20 percent hydrophilic polymer. In certain embodiments, the implant or the microparticle includes PLA. In certain embodiments, the PLA is acid-capped. In certain embodiments, the PLA is ester-capped. In certain embodiments, the implant or the microparticles of the present invention are a blend of two polymers, for example (i) a PLGA polymer or PLA polymer as described herein and (ii) a PLGA-PEG or PLA-PEG copolymer. In other embodiments, the implant or the microparticles is a blend of three polymers, such as, for example, (i) a PLGA polymer; (ii) a PLA polymer; and, (iii) a copolymer of PLGA- PEG or PLA-PEG. In an additional embodiment, the implant or the microparticles is a blend of (i) a PLA polymer; (ii) a PLGA polymer; (iii) a PLGA polymer that has a different ratio of lactide and glycolide monomers than the PLGA in (ii); and, (iv) a PLGA-PEG or PLA-PEG copolymer. Any ratio of lactide and glycolide in the PLGA can be used that achieves the desired therapeutic effect. In certain illustrative non- limiting embodiments, the ratio of PLA to PLGA by weight in a polymer blend as described is 77/22, 69/30, 49/50, 54/45, 59/40, 64/35, 69/30, 74/25, 79/20, 84/15, 89/10, 94/5, or 99/1. In certain embodiments, a blend of three polymers that has (i) PLA (ii) PLGA (iii) PLGA with a different ratio of lactide and glycolide monomers than PLGA in (ii) wherein the ratio by weight is 74/20/5 by weight, 69/20/10 by weight, 69/25/5 by weight, or 64/20/15 by weight. In certain embodiments, the PLGA in (ii) has a ratio of lactide to glycolide of 85/15, 75/25, or 50/50. In certain embodiments the PLGA in (iii) has a ratio of lactide to glycolide of 85/15, 75/25, or 50/50. In certain aspects, the implant or the microparticles comprises a blend of PLGA or PLA and PEG- PLGA, including but not limited to (i) PLGA + approximately by weight 1% PEG-PLGA or (ii) PLA + approximately by weight 1% PEG-PLGA. In certain aspects, the implant or the microparticles comprises a blend of (iii) PLGA/PLA + approximately by weight 1% PEG-PLGA. In certain embodiments, the blend of PLA, PLGA, or PLA/PGA with PLGA-PEG contains approximately from about 0.5% to about 10% by weight of a PEG-PLGA, from about 0.5% to about 5% by weight of a PEG-PLGA, from about 0.5% to about 4% by weight of a PEG-PLGA, from about 0.5% to about 3% by weight of a PEG-PLGA, from about 1.0% to about 3.0% by weight of a PEG-PLGA, from about 0.1% to about 10% of a PEG-PLGA, from about 0.1% to about 5% of a PEG-PLGA, from about 0.1% to about 1% PEG-PLGA, or from about 0.1% to about 2% PEG- PLGA. In certain non-limiting embodiments, the ratio by weight percent of PLGA to PEG-PLGA in a two polymer blend as described is in the range of about or between the ranges of 40/1, 45/1, 50/1, 55/1, 60/1, 65/1, 70/1, 75/1, 80/1, 85/1, 90/1, 95/1, 96/1, 97/1, 98/1, 99/1. The PLGA can be acid or ester capped. In non-limiting aspects, the drug can be delivered in a two polymer blend of PLGA75:254A + approximately 1% PEG-PLGA50:50; PLGA85:15 5A + approximately 1% PEG-PLGA5050; PLGA75:25 6E + approximately 1% PEG-PLGA50:50; or, PLGA50:502A + approximately 1% PEG-PLGA50:50. In certain non-limiting embodiments, the ratio by weight percent of PLA/PLGA-PEG in a polymer ^{blend as described is in the range of about or between the ranges of 40/1, 45/1, 50/1, 55/1, 60/1, 65/1,} 70/1, 75/1, 80/1, 85/1, 90/1, 95/1, 96/1, 97/1, 98/1, 99/1. The PLA can be acid capped or ester capped. In cetain aspects, the PLA is PLA 4.5A. In non-limiting aspects, the drug is delivered in a blend of PLA 4.5A + 1% PEG-PLGA. The PEG segment of the PEG-PLGA may have, for example, in non-limiting embodiments, a molecular weight of at least about or between 1 kDa, 2 kDa, 3 kDa, 4 kDa, 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa, or 10 kDa, and typically not greater than 10 kDa, 15 kDa, 20 kDa, or 50 kDa, or in some embodiments, 6 kDa, 7 kDa, 8 kDa, or 9kDa. In certain embodiment, the PEG segment of the PEG-PLGA has a molecular weight between about 3 kDa and about 7 kDa or between about 2 kDa and about 7 kDa. Non-limiting examples of the PLGA segment of the PEG-PLGA is PLGA50:50, PLGA75:25, or PLGA85:15. In certain embodiments, the PEG-PLGA segment is PEG (5 kDa)-PLGA50:50. In a blend of PLGA + PEG-PLGA, any ratio of lactide and glycolide in the PLGA or the PLGA-PEG can be used that achieves the desired therapeutic effect. Non-limiting illustrative embodiments of the ratio of lactide/glycolide in the PLGA or PLGA-PEG are in the range of about or between the ranges of 5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or 95/5. In certain embodiments, the PLGA is a block co-polymer, for example, diblock, triblock, multiblock, or star-shaped block. In certain embodiments, the PLGA is a random co-polymer. In certain aspects, the PLGA is PLGA75:254A; PLGA85:155A; PLGA75:256E; or PLGA50:502A. In other embodiments, the implant or the microparticles includes a polyethylene oxide (PEO) or polypropylene oxide (PPO). In certain aspects, the polymer can be a random, block, diblock, triblock or multiblock copolymer (for example, a polylactide, a polylactide-co-glycolide, polyglycolide or Pluronic). For injection into the eye, the polymer is pharmaceutically acceptable and typically biodegradable so that it does not have to be removed. It should be understood by one skilled in the art that by manufacturing a microparticle from multiple polymers with varied ratios of hydrophobic, hydrophilic, and biodegradable characteristics that the properties of the microparticle can be designed for the target use. As an illustration, a microparticle or implant manufactured with 90 percent PLGA and 10 percent PEG is more hydrophilic than a microparticle or implant manufactured with 95 percent PLGA and 5 percent PEG. Further, a microparticle or implant manufactured with a higher content of a less biodegradable polymer will in general degrade more slowly. This flexibility allows the polymeric formulations of the present invention to be tailored to the desired level of solubility, rate of release of pharmaceutical agent, and rate of degradation. VII. Surfactants In certain embodiments, the manufacture of the microparticle or the implant of the present invention includes a surfactant. Examples of surfactants include, for example, polyoxyethylene glycol, polyoxypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, glycerol alkyl ester, glyceryl laurate, cocamide MEA, cocamide DEA, ^{dodecyldimethylamine oxide, and poloxamers. Examples of poloxamers include, poloxamers 188, 237, 338} and 407. These poloxamers are available under the trade name Pluronic® (available from BASF, Mount Olive, N.J.) and correspond to Pluronic® F-68, F-87, F-108 and F-127, respectively. Poloxamer 188 (corresponding to Pluronic® F-68) is a block copolymer with an average molecular mass of about 7,000 to about 10,000 Da, or about 8,000 to about 9,000 Da, or about 8,400 Da. Poloxamer 237 (corresponding to Pluronic® F-87) is a block copolymer with an average molecular mass of about 6,000 to about 9,000 Da, or about 6,500 to about 8,000 Da, or about 7,700 Da. Poloxamer 338 (corresponding to Pluronic® F-108) is a block copolymer with an average molecular mass of about 12,000 to about 18,000 Da, or about 13,000 to about 15,000 Da, or about 14,600 Da. Poloxamer 407 (corresponding to Pluronic® F-127) is a polyoxyethylene-polyoxypropylene triblock copolymer in a ratio of between about E101 P56 E101 to about E106 P70 E106, or about E101 P56E101, or about E106 P70 E106, with an average molecular mass of about 10,000 to about 15,000 Da, or about 12,000 to about 14,000 Da, or about 12,000 to about 13,000 Da, or about 12,600 Da. Additional examples of surfactants that can be used in the invention include, but are not limited to, polyvinyl alcohol (which can be hydrolyzed polyvinyl acetate), polyvinyl acetate, Vitamin E-TPGS, poloxamers, cholic acid sodium salt, dioctyl sulfosuccinate sodium, hexadecyltrimethyl ammonium bromide, saponin, TWEEN® 20, TWEEN® 80, sugar esters, Triton X series, L-a-phosphatidylcholine (PC), 1 ,2- dipalmitoylphosphatidycholine (DPPC), oleic acid, sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil, sunflower seed oil, lecithin, oleic acid, and sorbitan trioleate. In certain embodiments, the surfactant is polyvinyl alcohol (PVA). Any molecular weight PVA can be used that achieves the desired results. In certain embodiments, the PVA has a molecular weight of up to about 10, 15, 20, 25, 30, 35 or 40 kD. In some embodiments, the PVA is partially hydrolyzed polyvinyl acetate, including but not limited to, up to about 70, 75, 80, 85, 88, 90 or even 95% hydrolyzed polyvinyl acetate. In certain embodiments, the PVA is about 88% hydrolyzed polyvinyl acetate. In certain embodiments, the PVA polymer has a molecule weight of 20,000 to 40,000 g/mol. In certain embodiments, the PVA polymer has a molecular weight of 24,000 to 35,000 g/mol. In certain embodiments, the polyvinyl alcohol is a partially hydrolyzed polyvinyl acetate. For example, the polyvinyl acetate is at least about 78% hydrolyzed so that the polyvinyl acetate is substantially hydrolyzed. In one example, the polyvinyl acetate is at least about 88% to 98% hydrolyzed so that the polyvinyl acetate is substantially hydrolyzed. In some examples, the microparticle or implant contains from about 0.01 percent to about 0.5 ^{percent surfactant, about 0.05 percent to about 0.5 percent surfactant, about 0.1 percent to about 0.5} percent surfactant, or about 0.25 percent to about 0.5 percent surfactant. In some examples, the microparticle or implant contains from about 0.001 percent to about 1 percent surfactant, about 0.005 percent to about 1 percent surfactant, about 0.075 percent to about 1 percent surfactant, or about 0.085 percent to about 1 percent surfactant. In some examples, the microparticle or implant contains from about 0.01 percent to about 5.0 percent surfactant, about 0.05 percent to about 5.0 percent surfactant, about 0.1 percent to about 5.0 percent surfactant, about 0.50 percent to about 5.0 percent surfactant. In some examples, the microparticle or implant contains from about 0.10 percent to about 1.0 percent surfactant or about 0.50 percent to about 1.0 percent. In some embodiments, the microparticle or implant contains up to about 0.10, 0.15, 0.20, 0.25, 0.30, 0.40 or 0.5% surfactant. Any molecular weight surfactant can be used that achieves the desired results. In certain embodiments, the surfactant has a molecular weight of up to about 10, 15, 20, 25, 30, 35 or 40 kd. In certain embodiments, the surfactant is PVA. In some embodiments, the PVA is partially hydrolyzed polyvinyl acetate, including but not limited to, up to about 70, 75, 80, 85, 88, 90 or even 95% hydrolyzed polyvinyl acetate. In certain embodiments, the PVA is about 88% hydrolyzed polyvinyl acetate. In certain embodiments, the PVA polymer has a molecule weight of 20,000 to 40,000 g/mol. In certain embodiments, the PVA polymer has a molecular weight of 24,000 to 35,000 g/mol. It should be recognized by one skilled in the art that some surfactants can be used as polymers in the manufacture of the microparticle. It should also be recognized by one skilled in the art that in some manufacture the microparticle or implant may retain a small amount of surfactant which allows further modification of properties as desired. VIII. Excipients Non-limiting examples of excipients that may be included in the implant or microparticle formulations of the present invention include a sugar, plasticizer, buffering agent, preservative, thermal binder, drug stabilizer, drug solubilizer or drug-release controlling excipient. Other excipients may be added to improve the processability, increase the dissolution rate and bioavailability of a compound of Formula I, Formula II, or Formula III, control or modulate release of a compound of Formula I, Formula II, or Formula III, and/or stabilize a compound of Formula I, Formula II, or Formula III. Preservatives which may be used include, but are not limited to, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol. Examples of buffering agents that may be employed include, but are not limited to, sodium carbonate, sodium borate, sodium phosphate, sodium acetate, croscarmellose sodium, sodium bicarbonate, and the like, as approved by the FDA for the desired route of administration. Electrolytes such as sodium chloride and potassium chloride may also be included in the formulation. Non-limiting examples of sugars include sucrose, mannitol, trehalose, glucose, arabinose, fucose, ^{mannose, rhamnose, xylose, D-xylose, glucose, fructose, ribose, D-ribose, galactose, dextrose, dextran,} lactose, maltodextrin, maltose, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, and polyglycitol. In an alternative embodiment, the sugar is selected from aspartame, saccharin, stevia, sucralose, acesulfame potassium, advantame, alitame, neotame, and sucralose. Non-limiting examples of plasticizers include polyethylene glycol, glycerin, poloxamer 188, MGHS 40, triethyl citrate, benzyl alcohol, polyethylene glycol, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, DMSO, triacetin, benzyl acetate, benzyl benzoate, acetyltributyl citrate, dibutyl sebacate, dimethylphthalate, tributyl O-acetylcitrate, ethanol, methanol, polysorbate 80, ethyl acetate, propylene carbonate, isopropyl acetate, methyl acetate, methyl ethyl ketone, butyl lactate, and isovaleric acid. Non-limiting examples of stabilizing and solubilizing agents include acacia, alginic acid, colloidal silicone dioxide, cellulose, carboxymethylcellulose calcium, gelatin, glyceryl monostearate, hydroxy propyl cellulose, hydroxyl propyl methyl cellulose, hypromellose, methyl cellulose, Polysorbate 80, propylene glycol, Polaxamer 407 or 188, polyoxy140 stearate, sucrose, sodium alginate, and sorbiton monooleate. In certain embodiments, a formulation of the present invention, for example, an implant comprises a thermal binder. Non-limiting examples of thermal binders include cross-linked polyvinylpyrrolidone or microcrystalline cellulose, alginate, candelilla wax, carnuba wax, corn starch, copolyvidone, starch pregelatinized, acacia gum, gum tragacanth, gelatin, sucrose, starch paste, sodium alginate, methyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose, and magnesium aluminum silicate. In certain embodiments a formulation of the present invention, for example, an implant contains an excipient for hot-melt extrusion. Non-limiting examples of an excipient for hot melt extrusion include a polymer. Non-limiting examples of polyvinyl-based homopolymers include poly(vinyl pyrrolidone) (Kollidon®), poly(vinyl acetate) (Sentry® plus), and polyvinyl alcohol (Elvanol®). Non-limiting examples of polyvinyl-based copolymers include polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®), polyvinyl alcohol–polyethylene glycol Copolymer (Kollicoat IR®), polyvinylpyrrolidone- co-vinyl acetate (Kollidon® VA64), poly(ethylene-co-vinyl acetate) (Elvax® 40W), ethylene-vinyl acetate copolymer (Evatane®), poly(vinyl acetate-co-methacrylic acid) (CIBA-I). Non-limiting examples of macrogols (PEG) or polyethylenoxides (PEO) homopolymers include polyehtyleneglycol (Carbowax®) and polyethyleneoxide (Polyox® WSR). Non-limiting examples of poly-acrylate homopolymers include carbomer (Carbopol® 974P) and polycarbophil (Noveon® AA-1). Non- limiting examples of polymethacrylate copolymers include poly(dimethylaminoethylmethacrylate- comethacrylic esters) (Eudragit® E), ammonio methacrylate copolymer (Eudragit® RS/RL), poly(methyl acrylate-co- methyl methacrylateco-methacrylic acid) 7:3:1 (Eudragit® 4135F), poly(methacrylic acid-co-methyl methacrylate) 1:2 (Eudragit® S), and poly(methacylic acid-co-ethyl acrylate) 1:1 (Eudragit® L100-55). Non- limiting examples of polysaccharides, such as cellulose derivatives or chitosans, include hydroxypropyl ^{methylcellulose acetate succinate (Aqoat-AS®), hydroxypropyl cellulose (Klucel®), hydroxypropyl} methylcellulose (Methocel®), ethyl cellulose (Ethocel®), cellulose acetate butyrate (CAB 381-0.5), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate (Aqoat-AS®), hydroxypropyl methylcellulose phthalate, and chitosan. A non-limiting example of a polypropylene oxide copolymer is a poloxamer (Lutrol® F127). IX. Sustained Release of a Compound of Formula I, Formula II, or Formula III The rate of release of a compound of Formula I, Formula II, or Formula III can be related to the concentration of the compound dissolved in the microparticles or the implants of the present invention. In some embodiments, the polymeric composition of the microparticle or implant includes non-therapeutic agents that are selected to provide a desired solubility of a compound of Formula I, Formula II, or Formula III in the microparticle or implant. The selection of the polymeric composition can be made to provide the desired solubility of a compound of Formula I, Formula II, or Formula III in the microparticle or the implant, for example, a hydrogel may promote solubility of a hydrophilic material. In some embodiments, functional groups can be added to the polymer to increase the desired solubility of a compound of Formula I, Formula II, or Formula III in the microparticle or the implant. In some embodiments, additives may be used to control the release kinetics of a compound of Formula I, Formula II, or Formula III, for example, the additives may be used to control the concentration of a compound of Formula I, Formula II, or Formula III by increasing or decreasing the solubility of a compound of Formula I, Formula II, or Formula III in the polymer so as to control the release kinetics of a compound of Formula I, Formula II, or Formula III. The solubility may be controlled by including appropriate molecules and/or substances that increase and/or decrease the solubility of the dissolved form of a compound of Formula I, Formula II, or Formula III in the microparticle or implant. The solubility of a compound of Formula I, Formula II, or Formula III may be related to the hydrophobic and/or hydrophilic properties of the microparticle or the implant and a compound of Formula I, Formula II, or Formula III. Oils and hydrophobic molecules can be added to the polymer(s) to increase the solubility of a compound of Formula I, Formula II, or Formula III in the microparticle or the implant. Instead of, or in addition to, controlling the rate of migration based on the concentration of a compound of Formula I, Formula II, or Formula III dissolved in the microparticle or implant, the surface area of the polymeric composition can be controlled to attain the desired rate of drug migration out of the microparticle or implant comprising compound of Formula I, Formula II, or Formula III. For example, a larger exposed surface area will increase the rate of migration of a compound of Formula I, Formula II, or Formula III to the surface, and a smaller exposed surface area will decrease the rate of migration of a compound of Formula I, Formula II, or Formula III to the surface. The exposed surface area can be increased in any number of ways, for example, by castellation of the exposed surface, a porous surface having exposed channels connected with the tear or tear film, indentation of the exposed surface, or protrusion of the ^{exposed surface. The exposed surface can be made porous by the addition of salts that dissolve and leave} a porous cavity once the salt dissolves. In the present invention, these trends can be used to decrease the release rate of the active material from the polymeric composition by avoiding these paths to quicker release. For example, the surface area can be minimized, or channels can be avoided. The system of the invention can allow for a release of compound of Formula I, Formula II, or Formula III to be sustained for some time, for example, release can be sustained for at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 10 hours, at least about 12 hours, at least about 24 hours, at least 48 hours, at least a week, more than one week, at least a month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least twelve months, or more. In certain embodiments, the microparticles that produce a microparticle depot in vivo release a compound of Formula I, Formula II, or Formula III without a burst of more than about 1 percent to about 5 percent of total payload over a 24 hour period or a 12 hour period. In certain embodiments, the microparticles or the implant releases a compound of Formula I, Formula II, or Formula III without a burst of more than about 1 percent to about 5 percent of total payload over a 24 hour period or a 12 hour period. In certain embodiments, the microparticles that produce a microparticle depot in vivo release a compound of Formula I, Formula II, or Formula III without a burst of more than about 10 percent of total payload over a 24 hour period or a 12 hour period. In certain embodiments, the microparticles or the implant releases a compound of Formula I, Formula II, or Formula III without a burst of more than about 10 percent of total payload over a 24 hour period or a 12 hour period. In certain embodiments, the solid aggregating microparticles that produce a microparticle depot in vivo release a compound of Formula I, Formula II, or Formula III without a burst of more than about 15 percent of total payload over a 24 hour period or a 12 hour period. In certain embodiments, the microparticles or the implant releases a compound of Formula I, Formula II, or Formula III without a burst of more than about 15 percent of total payload over a 24 hour period or a 12 hour period. In certain embodiments, the solid aggregating microparticles that produce a microparticle depot in vivo release a compound of Formula I, Formula II, or Formula III without a burst of more than about 20 percent of total payload over a 24 hour period or a 12 hour period. In certain embodiments, the microparticles or the implant releases a compound of Formula I, Formula II, or Formula III without a burst of more than about 20 percent of total payload over a 24 hour period or a 12 hour period. In certain embodiments, a compound of Formula I, Formula II, or Formula III is released in an amount effective to have a desired local or systemic physiological or pharmacologically effect. In certain embodiments, delivery of a compound of Formula I, Formula II, or Formula III means that a compound of Formula I, Formula II, or Formula III is released from the composition into the environment around the composition, for example, the vitreal fluid. ^{X. Pharmaceutically Acceptable Carriers} The formulations of the present invention can be administered in any suitable pharmaceutically acceptable carrier. The carrier can be present in an amount effective in providing the desired viscosity to the drug delivery system. Advantageously, the viscous carrier is present in an amount ranging from about 0.5 wt percent to about 95 wt percent of the drug delivery composition. The specific amount of the viscous carrier used depends upon a number of factors including, for example and without limitation, the specific viscous carrier used, the molecular weight of the viscous carrier used, the viscosity desired for the present drug delivery system being produced and/or used and like factors. Examples of useful viscous carriers include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomers, polyacrylic acid, cellulosic derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol (which can be partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof and mixtures thereof. Typically, the composition comprises from about 20 percent to about 80 percent of the injectable formulations described herein and from about 20 percent to about 80 percent carrier; from about 30 percent to about 70 percent of the injectable formulations described herein and from about 30 percent to about 70 percent carrier; e.g., the composition may comprise from about 40 percent to about 60 percent of the injectable formulations described herein and from about 40 percent to about 60 percent carrier; the composition may comprise about 50 percent of the formulations described herein and about 50 percent carrier. The aforementioned percentages all refer to percentage by weight. In certain embodiments, the composition contains the microparticles of the present invention and has a range of concentration of the microparticles of about 50-700 mg/ml, 500 or less mg/ml, 400 or less mg/ml, 300 or less mg/ml, 200 or less mg/ml, or 150 or less mg/ml. The carrier can also be an aqueous carrier. Example of aqueous carriers include, but are not limited to, an aqueous solution or suspension, such as saline, plasma, bone marrow aspirate, buffers, such as Hank's Buffered Salt Solution (HBSS), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), Ringers buffer, ProVisc®, diluted ProVisc®, ProVisc® diluted with PBS, Krebs buffer, Dulbecco's PBS, normal PBS; sodium hyaluronate solution (HA, 5 mg/mL in PBS), simulated body fluids, plasma platelet concentrate and tissue culture medium or an aqueous solution or suspension comprising an organic solvent. In certain embodiments, the carrier is PBS. In certain embodiments, the carrier is HA, 5 mg/mL in PBS. In certain embodiments, the carrier is ProVisc® diluted with water. In certain embodiments, the carrier is ProVisc® dilution in PBS. In certain embodiments, the carrier is ProVisc® 5-fold diluted with water. In certain embodiments, the carrier is ProVisc® 5-fold dilution in PBS. In certain embodiments, the carrier is ProVisc® 10-fold diluted with water. In certain embodiments, the carrier is ProVisc® 10-fold dilution in PBS. I^{n certain embodiments, the carrier is ProVisc® 20-fold dilution with water.} In certain embodiments, the carrier is ProVisc® 20-fold dilution in PBS. In certain embodiments, the carrier is HA, 1.25 mg/mL in an isotonic buffer solution with neutral pH. In certain embodiments, the carrier is HA, 0.625 mg/mL in an isotonic buffer solution with neutral pH. In certain embodiments, the carrier is HA, 0.1-5.0 mg/mL in PBS. In certain embodiments, the carrier is HA, 0.5-4.5 mg/mL in PBS. In certain embodiments, the carrier is HA, 1.0-4.0 mg/mL in PBS. In certain embodiments, the carrier is HA, 1.5-3.5 mg/mL in PBS. In certain embodiments, the carrier is HA, 2.0-3.0 mg/mL in PBS. In certain embodiments, the carrier is HA, 2.5-3.0 mg/mL in PBS. The carrier may, optionally, contain one or more suspending agent. The suspending agent may be selected from carboxy methylcellulose (CMC), mannitol, polysorbate, poly propylene glycol, poly ethylene glycol, gelatin, albumin, alginate, hydroxyl propyl methyl cellulose (HPMC), hydroxyl ethyl methyl cellulose (HEMC), bentonite, tragacanth, dextrin, sesame oil, almond oil, sucrose, acacia gum and xanthan gum and combinations thereof. In certain embodiments, one or more additional additives or excipients or delivery enhancing agents may also be included e.g., surfactants and/or hydrogels, in order to further influence release rate and/or improve in vivo aggregation of microparticles. Non-limiting examples of additives include triethyl citrate, benzyl alcohol, polyethylene glycol, N- methyl-2-pyrrolidone (NMP), 2-pyrrolidone, DMSO, triacetin, benzyl acetate, benzyl benzoate, acetyltributyl citrate, dibutyl sebacate, dimethylphthalate, tributyl O-acetylcitrate, ethanol, methanol, polysorbate 80, ethyl acetate, propylene carbonate, isopropyl acetate, methyl acetate, methyl ethyl ketone, butyl lactate, and isovaleric acid. In certain embodiments, the diluent contains approximately from about 0.01% to about 10% by weight of additive or excipient, from about 0.01% to about 0.1% by weight of additive or excipient, from about 0.05% to about 0.5% by weight of additive or excipient, from about 0.1% to about 1.0% by weight of additive or excipient, from about 0.1% to about 10% by weight of additive or excipient, from about 0.5% to about 5% by weight of additive or excipient, from about 0.5% to about 4% by weight of additive or excipient, from about 0.5% to about 3% by weight of additive or excipient, from about 0.5% to about 2.0% by weight of additive or excipient, from about 0.1% to about 0.5% by weight of additive or excipient, from about 0.1% to about 0.25% by weight of additive or excipient, from about 0.2% to about 2% by weight of additive or excipient, or from about 0.01% to about 0.05% by weight of additive or excipient. The diluent is present in an amount in a range of from about 0.5 wt percent to about 95 wt percent of the drug delivery particles. The diluent can also be an aqueous diluent. Examples of aqueous diluent include, but are not limited to, an aqueous solution or suspension, such as saline, plasma, bone marrow ^{aspirate, buffers, such as Hank's Buffered Salt Solution (HBSS), HEPES (4-(2-hydroxyethyl)-1-} piperazineethanesulfonic acid), Ringers buffer, ProVisc®, diluted ProVisc®, ProVisc® diluted with PBS, Krebs buffer, Dulbecco's PBS, normal PBS; sodium hyaluronate solution (HA, 5 mg/mL in PBS), simulated body fluids, plasma platelet concentrate and tissue culture medium or an aqueous solution or suspension comprising an organic solvent. ProVisc® is a sterile, non-pyrogenic, high molecular weight, non- inflammatory highly purified fraction of sodium hyaluronate, dissolved in physiological sodium chloride phosphate buffer. XI. Methods of Administration In certain embodiments, the formulations described herein that comprise a compound of Formula I, Formula II, or Formula III or a prodrug or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, excipient, or diluent are used for the treatment of a disorder, including a human disorder. In certain embodiments, the formulation is a pharmaceutical composition for treating an eye disorder or eye disease. In certain embodiments, the microparticles or the implants of the present invention, as described herein, are used to treat a medical disorder which is glaucoma, a disorder or abnormality related to an increase in intraocular pressure (IOP), a disorder mediated by nitric oxide synthase (NOS), or a disorder requiring neuroprotection such as to regenerate/repair optic nerves. In other embodiments more generally, the disorder treated is allergic conjunctivitis, anterior uveitis, cataracts, wet or dry age-related macular degeneration, neovascular age-related macular degeneration, or diabetic retinopathy. In certain embodiments, the surface-modified microparticles or the implants are used to reduce intraocular pressure in a host in need thereof with glaucoma. In certain embodiments, the glaucoma is primary open angle glaucoma (POAG), primary angle closure glaucoma, pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, or irido corneal endothelial glaucoma (primary open angle glaucoma is also known as chronic open angle glaucoma, chronic simple glaucoma and glaucoma simplex). In certain embodiments, the glaucoma is primary open angle glaucoma (POAG). Another embodiment is provided that includes the administration of the microparticles or the implants of the present invention comprising an effective amount of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof to a host to treat an ocular or other disorder that can benefit from local delivery. The therapy can be delivered to the anterior or posterior chamber of the eye. In specific aspects, a microparticle or implant comprising an effective amount of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof is administered to treat a disorder of the cornea, conjunctiva, aqueous humor, iris, ciliary body, lens sclera, choroid, retinal pigment epithelium, neural retina, optic nerve, or vitreous humor. Any of the compositions described can be administered to the eye as described further herein in any desired form of administration, including via intravitreal, intrastromal, intracameral, subtenon, sub- ^{retinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, episcleral,} posterior juxtascleral, circumcorneal, tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion. In certain embodiments, the surface-modified aggregating microparticles or the implants of the present invention are administered via intravitreal administration. In certain embodiments, the surface-modified aggregating microparticles or the implants of the present invention are administered via suprachoroidal administration. Methods of treating or preventing ocular disorders, including glaucoma, myopia, presbyopia, a disorder or abnormality related to an increase in intraocular pressure (IOP), a disorder mediated by nitric oxide synthase (NOS), a disorder requiring neuroprotection such as to regenerate/repair optic nerves, allergic conjunctivitis, anterior uveitis, cataracts, dry or wet age-related macular degeneration (AMD) or diabetic retinopathy are disclosed comprising administering a therapeutically effective amount of a surface treated microparticle or an implant of the present invention comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof to a host, including a human, in need of such treatment. In certain embodiments, the host is a human. In other embodiments, an effective amount of a microparticle or an implant comprising a compound of Formula I, Formula II, or Formula III is provided to decrease intraocular pressure (IOP) caused by glaucoma. In an alternative embodiment, an effective amount of a surface treated microparticle or an implant comprising a compound of Formula I, Formula II, or Formula III is provided to decrease intraocular pressure (IOP), regardless of whether it is associated with glaucoma. In certain embodiments, the disorder is associated with an increase in intraocular pressure (IOP) caused by potential or previously poor patient compliance to glaucoma treatment. In yet another embodiment, the disorder is associated with potential or poor neuroprotection through neuronal nitric oxide synthase (NOS). The surface treated microparticle or implant comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof provided herein may thus dampen or inhibit glaucoma in a host, by administration of an effective amount in a suitable manner to a host, typically a human, in need thereof. Methods for the treatment of a disorder associated with glaucoma, increased intraocular pressure (IOP), optic nerve damage caused by either high intraocular pressure (IOP) or neuronal nitric oxide synthase (NOS) are provided that includes the administration of an effective amount of a surface treated microparticle or an implant comprising a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof are also disclosed. Additional non-limiting exemplary eye disorders or diseases treatable with the composition include age related macular degeneration, alkaline erosive keratoconjunctivitis, allergic conjunctivitis, allergic keratitis, anterior uveitis, Behcet's disease, blepharitis, blood-aqueous barrier disruption, chorioiditis, chronic uveitis, conjunctivitis, contact lens-induced keratoconjunctivitis, corneal abrasion, corneal trauma, corneal ulcer, crystalline retinopathy, cystoid macular edema, dacryocystitis, diabetic keratopathy, diabetic macular edema, diabetic retinopathy, dry eye disease, dry age-related macular degeneration, eosinophilic ^{granuloma, episcleritis, exudative macular edema, Fuchs' Dystrophy, giant cell arteritis, giant papillary} conjunctivitis, glaucoma, glaucoma surgery failure, graft rejection, herpes zoster, inflammation after cataract surgery, iridocorneal endothelial syndrome, iritis, keratoconjunctivitis sicca, keratoconjunctivitis inflammatory disease, keratoconus, lattice dystrophy, map-dot-fingerprint dystrophy, necrotic keratitis, neovascular diseases involving the retina, uveal tract or cornea, for example, neovascular glaucoma, corneal neovascularization, neovascularization resulting following a combined vitrectomy and lensectomy, neovascularization of the optic nerve, and neovascularization due to penetration of the eye or contusive ocular injury, neuroparalytic keratitis, non-infectious uveitis ocular herpes, ocular lymphoma, ocular rosacea, ophthalmic infections, ophthalmic pemphigoid, optic neuritis, panuveitis, papillitis, pars planitis, persistent macular edema, phacoanaphylaxis, posterior uveitis, post-operative inflammation, proliferative diabetic retinopathy, proliferative sickle cell retinopathy, proliferative vitreoretinopathy, retinal artery occlusion, retinal detachment, retinal vein occlusion, retinitis pigmentosa, retinopathy of prematurity, rubeosis iritis, scleritis, Stevens-Johnson syndrome, sympathetic ophthalmia, temporal arteritis, thyroid associated ophthalmopathy, uveitis, vernal conjunctivitis, vitamin A insufficiency-induced keratomalacia, vitritis, wet age-related macular degeneration, neovascular age-related macular degeneration, dry age- related macular degeneration, myopia, and presbyonia. In one aspect of the present invention, an effective amount of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof as described herein is incorporated into a microparticle or implant, e.g., for convenience of delivery and/or sustained release delivery. The use of materials in micrometer scale provides one the ability to modify fundamental physical properties such as solubility, diffusivity, and drug release characteristics. These micrometer scale agents may provide more effective and/or more convenient routes of administration, lower therapeutic toxicity, extend the product life cycle, and ultimately reduce healthcare costs. As therapeutic delivery systems, surface treated microparticles and implants can allow targeted delivery and sustained release. In another aspect of the present invention, the surface treated microparticle or implant is coated with a surface agent. XII. Manufacture of Microparticles Microparticle Formation Microparticles can be formed using any suitable method for the formation of polymer microparticles known in the art. The method employed for particle formation will depend on a variety of factors, including the characteristics of the polymers present in the drug or polymer matrix, as well as the desired particle size and size distribution. The type of drug(s) being incorporated in the microparticles may also be a factor as some drugs are unstable in the presence of certain solvents, in certain temperature ranges, and/or in certain pH ranges. Particles having an average particle size of between 1 micron and 100 microns are useful in the compositions described herein. In typical embodiments, the particles have an average particle size of ^{between 1 micron and 40 microns, more typically between about 10 micron and about 40 microns, more} typically between about 20 micron and about 40 microns. The particles can have any shape but are generally spherical in shape. In circumstances where a monodisperse population of particles is desired, the particles may be formed using a method which produces a monodisperse population of microparticles. Alternatively, methods producing polydispersed microparticle distributions can be used, and the particles can be separated using methods known in the art, such as sieving, following particle formation to provide a population of particles having the desired average particle size and particle size distribution. Common techniques for preparing microparticles include, but are not limited to, solvent evaporation, hot melt particle formation, solvent removal, spray drying, phase inversion, coacervation, and low temperature casting. Suitable methods of particle formulation are briefly described below. Pharmaceutically acceptable excipients, including pH modifying agents, disintegrants, preservatives, and antioxidants, can optionally be incorporated into the particles during particle formation. In certain embodiments, surface treated microparticles including a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof are obtained by forming an emulsion and using a bead column as described in, for example, US 8,916,196. In certain embodiments, surface treated microparticles including a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof are obtained by using a vibrating mesh or microsieve. In certain embodiments, surface treated microparticles including a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof are obtained by using slurry sieving. The processes of producing microspheres described herein are amenable to methods of manufacture that narrow the size distribution of the resultant particles. In certain embodiments, the particles are manufactured by a method of spraying the material through a nozzle with acoustic excitation (vibrations) to produce uniform droplets. A carrier stream can also be utilized through the nozzle to allow further control of droplet size. Such methods are described in detail in: Berkland, C., K. Kim, et al. (2001). "Fabrication of PLG microspheres with precisely controlled and monodisperse size distributions." J Control Release 73(1): 59-74; Berkland, C., M. King, et al. (2002). "Precise control of PLG microsphere size provides enhanced control of drug release rate." J Control Release 82(1): 137-147; Berkland, C., E. Pollauf, et al. (2004). "Uniform double-walled polymer microspheres of controllable shell thickness." J Control Release 96(1): 101-111. In other embodiments, microparticles of uniform size can be manufactured by methods that utilize microsieves of the desired size. The microsieves can either be used directly during production to influence the size of microparticles formed, or alternatively post production to purify the microparticles to a uniform size. The microsieves can either be mechanical (inorganic material) or biological in nature (organic material such as a membrane). One such method is described in detail in US patent 8,100,348. In certain embodiments, the surface treated microparticles have a particle size of 25 < Dv50 < 40 ^{µm, Dv90 <45 µm.} In certain embodiments, the surface treated microparticles have a particle size of Dv10 > 10 µm. In certain embodiments, the process of for preparing a microparticle or lyophilized or otherwise solidified material thereof or a suspension thereof, leading to an aggregated microparticle depot in vivo, can be used in combination with a selected method for forming aggregating microparticles described in U.S.S.N. 15/349,985 and PCT/US16/61706 (and the resulting materials thereof). For example, methods include providing solid aggregating microparticles that include at least one biodegradable polymer, wherein the solid aggregating microparticles have a solid core, include a compound of Formula I, Formula II, or Formula III, have a modified surface which has been treated under mild conditions at a temperature, that may optionally be at or less than about 18 °C, to remove surface surfactant, are sufficiently small to be injected in vivo, and are capable of aggregating in vivo to form at least one aggregated microparticle depot of at least 500 μm in vivo to provide sustained drug delivery in vivo for at least three months, four months, five months, six months seven months, eight months, nine months or more. In certain embodiments, sustained drug deliver in vivo is provided for up to one year. The solid aggregating microparticles are suitable, for example, for an intravitreal injection. As an illustration, the surface-modified solid aggregating microparticles can be prepared by the following process: A. a first step of preparing microparticles comprising one or more biodegradable polymers by dissolving or dispersing the polymer(s) and a compound of Formula I, Formula II, or Formula III, in one or more solvents to form a solution or dispersion of the polymer and a compound of Formula I, Formula II, or Formula III, mixing the solution or dispersion of the polymer and a compound of Formula I, Formula II, or Formula III with an aqueous phase containing a surfactant to produce solvent-laden microparticles and then removing the solvent(s) to produce polymer microparticles that contain a compound of Formula I, Formula II, or Formula III, polymer and surfactant; and B. a second step of mildly treating the surface of microparticles of step (i) at a temperature at or below about 18, 15, 10, 8 or 5 °C optionally up to about 1, 2, 3, 4, 5, 10, 30, 40, 50, 60, 70, 80, 90100, 11, 120 or 140 minutes with an agent that removes surface surfactant, surface polymer, or surface oligomer in a manner that does not significantly produce internal pores; and C. isolating the surface treated microparticles. In certain embodiments, the microparticles can be further subjected to one or more processes selected from 1) vacuum treatment prior to lyophilization or other form of reconstitutable solidification, or after the step of reconstitution wherein the microparticles are suspended in a diluent and the suspension is placed under vacuum prior to use; 2) excipient addition, wherein an excipient is added prior to lyophilization; and 3) sonication, prior to lyophilization or other form of reconstitutable solidification, or after the step of reconstitution; 4) sealing the vial containing the dry powder of particles under vacuum, including but not ^{limited to high vacuum; or 5) pre-wetting (i.e., resuspending) the microparticles in a diluent for 2-24 hours} before injecting into the eye, for example in a hyaluronic acid solution or other sterile solution suitable for ocular injection. The process of these steps can be achieved in a continuous manufacturing line or via one step or in step-wise fashion as appropriate. The optional process above can be carried out following isolation of the microparticles and/or upon reconstitution prior to injection. In certain embodiments, the surface treated solid biodegradable microparticles do not significantly aggregate during the manufacturing process. In other embodiments, the surface treated solid biodegradable microparticles do not significantly aggregate when resuspended and loaded into a syringe. In some embodiments, the syringe is approximately 30, 29, 28, 27, 26 or 25 gauge, with either normal or thin wall. In certain embodiments, the microparticles are prepared without one or more biodegradable polymers. In one nonlimiting embodiment, a process for preparing a suspension comprising a microparticle and a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof encapsulated in the microparticle and the resulting materials thereof; comprises: (a) preparing a solution or suspension (organic phase) comprising: (i) PLGA or PLA or PLA and PLGA, (ii) PLGA-PEG or PLA-PEG (iii) a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, for example, as described herein and (iv) one or more organic solvents; (b) preparing an emulsion in an aqueous polyvinyl alcohol (PVA) solution (aqueous phase) by adding the organic phase into the aqueous phase and mixing them until particle formation (for example at about 3,000 to about 10,000 rpm for about 1 to about 30 minutes); (c) removing additional solvent as necessary using known techniques; (d) centrifuging or causing the sedimentation of the microparticle that is loaded with a compound of Formula I, Formula II, or Formula III or prodrug thereof; (e) optionally removing additional solvent and/or washing the microparticle loaded with a compound of Formula I, Formula II, or Formula III or prodrug thereof with water; (f) filtering the microparticle loaded with a compound of Formula I, Formula II, or Formula III or prodrug thereof to remove aggregates or particles larger than the desired size; (g) optionally lyophilizing the microparticle comprising a compound of Formula I, Formula II, or Formula III and storing the microparticle as a dry powder in a manner that maintains stability for up to about 6, 8, 10, 12, 20, 22, or 24 months or more; and (h) optionally improving the aggregation potential of the particles by subjecting the particles to at least one process selected from 1) vacuum treatment prior to step (g), or after reconstitution wherein the microparticles are suspended in a diluent and the suspension is placed under vacuum; 2) excipient addition, wherein an excipient is added prior to lyophilization; and 3) sonication prior to step (g), or during reconstitution wherein the microparticles are suspended in a diluent and sonicated; 4) s^{ealing the vial containing the dry powder of particles under vacuum, including but not limited to} high vacuum; or 5) pre-wetting (i.e., resuspending) the microparticles in a diluent for 2-24 hours before injecting into the eye, for example in a hyaluronic acid solution or other sterile solution suitable for ocular injection. Vacuum Treatment In certain embodiments, the process for providing the microparticles of the present invention includes vacuum treatment wherein the particles are suspended in a diluent and subjected to negative pressure to remove unwanted air at the surface of the microparticles. Nonlimiting examples of the negative pressure can be about or less than 300, 200, 100, 150, 145, 143, 90, 89, 88, 87, 86, 85, 75, 50, 35, 34, 33, 32, 31, or 30 Torr for any appropriate time to achieve the desired results, including but not limited to 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 8, 5, or 3 minutes. In certain embodiments, microparticles are stored under negative pressure following the manufacturing and isolation process, wherein negative pressure is defined as any pressure lower than the pressure of ambient room temperature (approximately 760 Torr). In certain embodiments, the microparticles are stored at a pressure of less than about 700 Torr, 550 Torr, 500 Torr, 450 Torr, 400 Torr, 350 Torr, 300 Torr, 250 Torr, 200 Torr, 150 Torr, 100 Torr, 90 Torr, 80 Torr, 60 Torr, 40 Torr, 35 Torr, 32 Torr, 30 Torr, or 25 Torr following the manufacturing and isolation process. In certain embodiments, the microparticles are stored at a pressure of about 500 Torr to about 25 Torr following the manufacturing and isolation process. In certain embodiments, the microparticles are stored at a pressure of about 300 Torr to about 25 Torr following the manufacturing and isolation process. In certain embodiments, the microparticles are stored at a pressure of about 100 Torr to about 25 Torr following the manufacturing and isolation process. In certain embodiments, the microparticles are stored at a pressure of about 90 Torr to about 25 Torr following the manufacturing and isolation process. In certain embodiments, the microparticles are stored at a pressure of about 50 Torr to about 25 Torr following the manufacturing and isolation process. In certain embodiments, the microparticles are stored at a pressure of about 40 Torr to about 25 Torr following the manufacturing and isolation process. In certain embodiments, the microparticles are stored at a pressure of about 35 Torr to about 25 Torr following the manufacturing and isolation process. In a further embodiment, the microparticles are stored at a temperature of between about 2-8°C at a pressure that is less than about 700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, 30, or 25 Torr. In certain embodiments, the microparticles are stored at pressure for up to 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, or more following the manufacture and isolation process. In certain embodiments, the microparticles are stored for up to 1 week to up to 4 weeks at a pressure that is less than 700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, or 30 Torr. In certain embodiments, the microparticles are stored for up to 1 month to up to 2 months at a pressure that is less than 700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, or 30 Torr. In certain embodiments, the microparticles are stored for up to 3 months at a pressure that is less ^{than 700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, or 30 Torr} In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C following the manufacturing and isolation process and the microparticles are vacuumed less than about 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C following the manufacturing and isolation process and the microparticles are vacuumed 1 hour to 30 minutes prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C following the manufacturing and isolation process and the microparticles are vacuumed 30 minutes to 10 minutes prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C following the manufacturing and isolation process and the microparticles are vacuumed immediately prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C and the microparticles are vacuumed for less than 1 hour, 30 minutes, 20 minutes, 15 minutes, or 10 minutes at a strength of less than about 35 Torr immediately prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C and the microparticles are vacuumed for 1 hour to 30 minutes at a strength of less than about 35 Torr immediately prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C and the microparticles are vacuumed for 30 minutes to 10 minutes at a strength of less than about 35 Torr immediately prior to in vivo injection. In certain embodiments, the particles are suspended in a glass vial that is attached to a vial adapter and the vial adapter is in turn attached to a VacLok syringe. A negative pressure is created in the vial by pulling the plunger of the syringe into a locking position. In certain embodiments, the vacuum treatment is conducted in a syringe of the 60 mL, 30 mL, 20 mL, or 10 mL size. The vacuum is then held in the syringe with the vial facing up and the large syringe attached for up to at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 90 minutes, 100 minutes, or 129 minutes. The vacuum is released, the large syringe is detached, and a syringe is attached for in vivo injection. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 143 Torr for about at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, or 120 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of at least about 90, 89, 88, 87, 86, or 85 Torr for at least about at 10 minutes, 20 minutes, 30 minutes, or 40 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of at least about 87 Torr for at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes, 90 minutes, or 120 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of at least about 35, 34, 33, 32, 31, or 30 Torr for at least 5 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of at least about 35, 34, 33, 32, 31, or 30 Torr for at least 8 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of at least about 35, 34, 33, 32, 31, or 30 Torr for at least 10 ^{minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of at least} about 35, 34, 33, 32, 31, or 30 Torr for at least 20 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of at least about 35, 34, 33, 32, 31, or 30 Torr for at least 30 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of at least about 35, 34, 33, 32, 31, or 30 Torr for at least 40 minutes. In certain embodiments, the particles are subjected to 30 Torr for at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 35 Torr for at least 90 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 35 Torr for at least 60 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 35 Torr for at least 30 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 35 Torr for at least 15 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 35 Torr for at least 5 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 32 Torr for at least 30 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 32 Torr for at least 15 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 32 Torr for at least 5 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 30 Torr for at least 30 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 30 Torr for at least 15 minutes. In certain embodiments, the particles are subjected to vacuum treatment at a strength of about 30 Torr for at least 5 minutes. In an alternative embodiment, the particles are suspended in a diluent in a vial attached to a vial adapter that is further attached to a 60 mL VacLok syringe containing a plunger wherein the plunger is pulled to the 50 mL mark and locked to create a negative pressure of approximately 30 Torr and the pressure is held for at least about 3, 5, 8, 10, 15, 20, 25, 30, or 35 minutes. In an alternative embodiment, the particles are suspended in a diluent in a vial attached to a vial adapter that is further attached to a 60 mL VacLok syringe containing a plunger wherein the plunger is pulled to the 45 mL mark, locked, and held for at least about 3, 5, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. In an alternative embodiment, the particles are suspended in a diluent in a vial attached to a vial adapter that is further attached to a 60 mL VacLok syringe containing a plunger wherein the plunger is pulled to the 40 mL mark, locked, and the pressure is held for at least about 3, 5, 8, 10, 15, 20, 25, 30, or 35 minutes. In an alternative embodiment, the particles are suspended in a diluent in a vial attached to a vial adapter that is further attached to a 60 mL VacLok syringe containing a plunger wherein the plunger is pulled to the 35 mL mark, locked, and held for about at least 3, 5, 8, 10, 15, 20, 25, 30, or 35 minutes. In an alternative embodiment, the particles are suspended in a diluent in a vial attached to a vial adapter that is further attached to a 60 mL VacLok syringe containing a plunger wherein the plunger is pulled to the 30 mL mark, locked, and held for at least about 3, 5, 8, 10, 15, 20, 25, 30, or 35 minutes. In an alternative embodiment, the particles are suspended in a diluent in a vial attached to a vial adapter that is further attached to a 60 ^{mL VacLok syringe containing a plunger wherein the plunger is pulled to the 25 mL mark, locked, and held} for at least about 3, 5, 8, 10, 15, 20, 25, 30, or 35 minutes. In certain embodiments, the particles are suspended in a diluent and the suspension is exposed to a pressure of less than 40 Torr for between about 90 minutes and 1 minute, between about 60 minutes and 1 minute, between about 45 minutes and 1 minute, between about 30 minutes and 1 minute, between about 15 minutes and 1 minute, or between about 5 minutes and 1 minute. In certain embodiments, the particles are suspended in a diluent and the suspension is exposed to a pressure of less than 30 Torr for between about 90 minutes and 1 minute, between about 60 minutes and 1 minute, between about 45 minutes and 1 minute, between about 30 minutes and 1 minute, between about 15 minutes and 1 minute, or between about 5 minutes and 1 minute. In certain embodiments, the microparticles are suspended in a diluent of 10X ProVisc-diluted (0.1% HA in PBS) solution. In certain embodiments, the microparticles are suspended in a diluent of 20X-diluted ProVisc (0.05% HA in PBS). In certain embodiments, the microparticles are suspended in a diluent of 40X- diluted ProVisc (0.025% HA in PBS). In certain embodiments, the particles are suspended in the diluent at a concentration of 100 mg/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL or 500 mg/mL. In certain embodiments, the particles are suspended in 10X-diluted ProVisc (0.1% HA in PBS) solution and the suspension has a final concentration of 200 mg/mL. In certain embodiments, the particles are suspended in 10X-diluted ProVisc (0.1% HA in PBS) solution and the suspension has a final concentration of 400 mg/mL. In certain embodiments, the particles are suspended in a 20X-diluted ProVisc (0.05% HA in PBS) and the suspension has a final concentration of 200 mg/mL. In certain embodiments, the particles are suspended in a 20X-diluted ProVisc (0.05% HA in PBS) and the suspension has a final concentration of 400 mg/mL. In certain embodiments, the particles are suspended in a 40X-diluted ProVisc (0.025% HA in PBS) and the suspension has a concentration of 200 mg/mL. In certain embodiments, the particles are suspended in a 40X-diluted ProVisc (0.025% HA in PBS) and the suspension has a concentration of 400 mg/mL. The Addition of an Excipient In certain embodiments, the process for preparing the microparticles of the present invention is the addition of at least one excipient, typically prior to lyophilization that reduces the amount of air adhering to the particles. Particles are suspended in an aqueous solution and sonicated before being flash frozen in - 80 °C ethanol and lyophilized overnight. In certain embodiments, the particles are suspended in an aqueous sugar solution that is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% sugar. In certain embodiments, the sugar is sucrose. In certain embodiments, the sugar is mannitol. In certain embodiments, the sugar is trehalose. In certain embodiments, the sugar is glucose. In certain embodiments, the sugar is selected from arabinose, fucose, mannose, rhamnose, xylose, D-xylose, glucose, fructose, ribose, D-ribose, galactose, dextrose, dextran, lactose, maltodextrin, maltose, glycerol, erythritol, threitol, ^{arabitol, xylitol, ribitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol,} maltotriitol, maltotetraitol, and polyglycitol. In an alternative embodiment, the sugar is selected from aspartame, saccharin, stevia, sucralose, acesulfame potassium, advantame, alitame, neotame, and sucralose. In certain embodiments, the particles are suspended in an aqueous sugar solution that is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% sucrose. In certain embodiments, the particles are suspended in a 1% sucrose solution. In certain embodiments, the particles are suspended in a 10% sucrose solution. In certain embodiments, the particles are suspended in an aqueous sugar solution that is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% mannitol. In certain embodiments, the particles are suspended in a 1% mannitol solution. In certain embodiments, the particles are suspended in a 10% mannitol solution. In certain embodiments, the particles are suspended in a 1% trehalose solution. In certain embodiments, the particles are suspended in a 10% trehalose solution. In certain embodiments, the particles are suspended in an aqueous sugar solution that is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% trehalose. In an alternative embodiment, the particles are suspended in a small surfactant molecule, including, but not limited to tween 20 or tween 80. In an alternative embodiment, the particles are flash frozen in -80 °C methanol or isopropanol. Sonication In certain embodiments, the process for preparing the microparticles of the present invention is sonication wherein particles are suspended in a diluent and the suspension of microparticles is sonicated for at least 30 minutes, at least 25 minutes, at least 20 minutes, at least 15 minutes, at least 10 minutes, at least 8 minutes, at least 5 minutes, or at least 3 minutes. In certain embodiments, the particle solutions are sonicated at a frequency of 40 kHz. In certain embodiments, the particles are suspended in the diluent at a concentration of 100 mg/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL or 500 mg/mL. In certain embodiments, the diluent is hyaluronic acid. In an alternative embodiment, the diluent is selected from hyaluronic acid, hydroxypropyl methylcellulose, chondroitin sulfate, or a blend of at least two diluents selected from hyaluronic acid, hydroxypropyl methylcellulose, and chondroitin sulfate. In an alternative embodiment, the diluent is selected from aacia, tragacanth, alginic acid, carrageenan, locust bean gum, gellan gum, guar gum, gelatin, starch, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, Carbopol® homopolymers (acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol), and Carbopol® copolymers (acrylic acid and C10- C30 alkyl acrylate crosslinked with allyl pentaerythritol). In certain embodiments, a combination of vacuum treatment, the addition of excipients, and sonication can be used following isolation and reconstitution of the microparticles. In certain embodiments, the methods for enhancing wettability are conducted at least 1 hour prior to in vivo injection, at least 45 minutes prior to in vivo injection, at least 30 minutes prior to in vivo injection, at least 25 minutes prior to in vivo injection, at least 20 minutes prior to injection, at least 15 minutes prior to in vivo injection, at least 10 minutes prior to in vivo injection, or at least 5 minutes prior to in vivo injection. In certain embodiments, the ^{vacuum treatment, addition of an excipient, and/or sonication is conducted immediately before in vivo} injection. In certain embodiments, the particles are vacuumed at a strength of less than 35 Torr for less than 30 minutes and are immediately injected in vivo. In an alternative embodiment, the particles are vacuumed at a strength of less than 35 Torr for less than 20 minutes and are immediately injected in vivo. In an alternative embodiment, the particles are vacuumed at a strength of less than 35 Torr for less than 15 minutes and are immediately injected in vivo. In an alternative embodiment, the particles are vacuumed at a strength of less than 35 Torr for less than 10 minutes and are immediately injected in vivo. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C following the manufacturing and isolation process and the microparticles are held under negative pressure for about 24, 12, 8, 6, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes or less prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C following the manufacturing and isolation process and the microparticles are held under negative pressure 1 hour to 30 minutes prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C following the manufacturing and isolation process and the microparticles are vacuumed 30 minutes to 10 minutes prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C following the manufacturing and isolation process and the microparticles are vacuumed immediately prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C and the microparticles are vacuumed for less than 1 hour, 30 minutes, 20 minutes, 15 minutes, or 10 minutes at a strength of less than about 35 Torr immediately prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C and the microparticles are vacuumed for 1 hour to 30 minutes at a strength of less than about 35 Torr immediately prior to in vivo injection. In certain embodiments, the microparticles are stored at a temperature of between about 2-8°C and the microparticles are vacuumed for 30 minutes to 10 minutes at a strength of less than about 35 Torr immediately prior to in vivo injection. In certain embodiments, the microparticles are stored at negative pressure for up to 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, or more following the manufacture and isolation process. In certain embodiments, the microparticles are stored for up to 1 week to up to 4 weeks at a negative pressure that is less than 700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, or 30 Torr. In certain embodiments, the microparticles are stored for up to 1 month to up to 2 months at a negative pressure that is less than 700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, or 30 Torr. In certain embodiments, the microparticles are stored for up to 3 months at a negative pressure that is less than 700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, or 30 Torr. Solvent Evaporation I^{n this method, the drug (or polymer matrix and drug) is dissolved in a volatile organic solvent, such} as methylene chloride, acetone, acetonitrile, 2-butanol, 2-butanone, t-butyl alcohol, benzene, chloroform, cyclohexane, 1,2-dichloroethane, diethyl ether, ethanol, ethyl acetate, heptane, hexane, methanol, methyl tert-butyl ether, pentane, petroleum ether, iso-propanol, n-propanol, tetrahydrofuran, or mixtures thereof. The organic solution containing the drug is then suspended in an aqueous solution that contains a surface active agent such as poly(vinyl alcohol). The resulting emulsion is stirred until most of the organic solvent is evaporated, leaving solid microparticles. The resulting microparticles are washed with water and dried overnight in a lyophilizer. Microparticles with different sizes and morphologies can be obtained by this method. Microparticles which contain labile polymers, such as certain polyanhydrides, may degrade during the fabrication process due to the presence of water. For these polymers, the following two methods, which are performed in completely anhydrous organic solvents, can be used. Oil-In-Oil Emulsion Technique Solvent removal can also be used to prepare particles from drugs that are hydrolytically unstable. In this method, the drug (or polymer matrix and drug) is dispersed or dissolved in a volatile organic solvent such as methylene chloride, acetone, acetonitrile, benzene, 2-butanol, 2-butanone, t-butyl alcohol, chloroform, cyclohexane, 1,2-dichloroethane, diethyl ether, ethanol, ethyl acetate, heptane, hexane, methanol, methyl tert-butyl ether, pentane, petroleum ether, iso-propanol, n-propanol, tetrahydrofuran, or mixtures thereof. This mixture is then suspended by stirring in an organic oil (such as silicon oil, castor oil, paraffin oil, or mineral oil) to form an emulsion. Solid particles form from the emulsion, which can subsequently be isolated from the supernatant. The external morphology of spheres produced with this technique is highly dependent on the identity of the drug. Oil-In-Water Emulsion Technique In this method, the drug (or polymer matrix and drug) is dispersed or dissolved in a volatile organic solvent such as methylene chloride, acetone, acetonitrile, benzene, 2-butanol, 2-butanone, t-butyl alcohol, chloroform, cyclohexane, 1,2-dichloroethane, diethyl ether, ethanol, ethyl acetate, heptane, hexane, methanol, methyl tert-butyl ether, pentane, petroleum ether, iso-propanol, n-propanol, tetrahydrofuran, or mixtures thereof. This mixture is then suspended by stirring in an aqueous solution of surface active agent, such as poly(vinyl alcohol), to form an emulsion. Solid particles form from the emulsion, which can subsequently be isolated from the supernatant. The external morphology of spheres produced with this technique is highly dependent on the identity of the drug. As described in PCT/US2015/065894, microparticles with a therapeutic agent can be prepared using the oil-in-water emulsion method. In certain embodiments, microparticles comprising a compound of Formula I, Formula II, or Formula III can be prepared by dissolving 100 mg PEG-PLGA (5K, 45) in 1 mL ^{methylene chloride, and dissolving 20 mg of a compound of Formula I, Formula II, or Formula III in 0.5 mL} DMSO and triethylamine. The solutions are then mixed together, homogenized at 5000 rpm, 1 minute into an aqueous solution containing 1% polyvinyl alcohol (PVA) and stirred for 2 hours. The particles are collected, washed with double distilled water, and freeze dried. In certain embodiments, microparticles comprising a compound of Formula I, Formula II, or Formula III can also be prepared according to PCT/US2015/065894 by dissolving 200 mg PLGA (2A, Alkermers) in 3 mL methylene chloride, and 40 mg of a compound of Formula I, Formula II, or Formula III in 0.5 mL DMSO and triethylamine. The solutions are then mixed together and homogenized at 5000 rpm, 1 minute in 1% PVA and stirred for 2 hours. The particles are collected, washed with double distilled water, and freeze dried. Spray Drying In this method, the drug (or polymer matrix and drug) is dissolved in an organic solvent such as methylene chloride, acetone, acetonitrile, 2-butanol, 2-butanone, t-butyl alcohol, benzene, chloroform, cyclohexane, 1,2-dichloroethane, diethyl ether, ethanol, ethyl acetate, heptane, hexane, methanol, methyl tert-butyl ether, pentane, petroleum ether, iso-propanol, n-propanol, tetrahydrofuran, or mixtures thereof. The solution is pumped through a micronizing nozzle driven by a flow of compressed gas, and the resulting aerosol is suspended in a heated cyclone of air, allowing the solvent to evaporate from the microdroplets, forming particles. Particles ranging between 0.1-10 microns can be obtained using this method. Phase Inversion Particles can be formed from drugs using a phase inversion method. In this method, the drug (or polymer matrix and drug) is dissolved in a solvent, and the solution is poured into a strong non solvent for the drug to spontaneously produce, under favorable conditions, microparticles or nanoparticles. The method can be used to produce nanoparticles in a wide range of sizes, including, for example, about 100 nanometers to about 10 microns, typically possessing a narrow particle size distribution. Coacervation Techniques for particle formation using coacervation are known in the art, for example, in GB-B- 929 406; GB-B-929 40 1; and U.S. Patent Nos. 3,266,987, 4,794,000, and 4,460,563. Coacervation involves the separation of a drug (or polymer matrix and drug) solution into two immiscible liquid phases. One phase is a dense coacervate phase, which contains a high concentration of the drug, while the second phase contains a low concentration of the drug. Within the dense coacervate phase, the drug forms nanoscale or microscale droplets, which harden into particles. Coacervation may be induced by a temperature change, addition of a non-solvent or addition of a micro-salt (simple coacervation), or by the addition of another polymer thereby forming an interpolymer complex (complex coacervation). ^{Low Temperature Casting} Methods for very low temperature casting of controlled release microspheres are described in U.S. Patent No. 5,019,400 to Gombotz et al. In this method, the drug (or polymer matrix and sunitinib) is dissolved in a solvent. The mixture is then atomized into a vessel containing a liquid non-solvent at a temperature below the freezing point of the drug solution which freezes the drug droplets. As the droplets and non-solvent for the drug are warmed, the solvent in the droplets thaws and is extracted into the non-solvent, hardening the microspheres. Scale Up The processes for producing microparticles described in the Examples are amenable to scale up by methods known in the art. Examples of such methods include U.S. Patent 4,822,534; U.S. Patent 5,271,961; U.S. Patent 5,945,126; U.S. Patent 6,270,802; U.S. Patent 6,361,798; U.S. Patent 8,708,159; and U.S. publication 2010/0143479. U.S. Patent 4,822,534 describes a method of manufacture to provide solid microspheres that involves the use of dispersions. These dispersions could be produced industrially and allowed for scale up. U.S. Patent 5,271,961 disclosed the production of protein microspheres which involved the use of low temperatures, usually less than 45 °C. U.S. Patent 5,945,126 describes the method of manufacture to produce microparticles on full production scale while maintaining size uniformity observed in laboratory scale. U.S. Patent 6,270,802 and U.S. Patent 6,361,798 describe the large scale method of manufacture of polymeric microparticles whilst maintaining a sterile field. U.S. Patent 8,708,159 describes the processing of microparticles on scale using a hydrocyclone apparatus. U.S. publication 2010/0143479 describes the method of manufacture of microparticles on large scale specifically for slow release microparticles. XSpray has disclosed a device and the use of supercritical fluids to produce particles of a size below 10 µM (U.S. Patent 8,167,279). Additional patents to XSpray include U.S. Patent 8,585,942 and U.S. Patent 8,585,943. Sun Pharmaceuticals has disclosed a process for the manufacture of microspheres or microcapsules, WO 2006/123359, herein incorporated by reference. As an example, Process A involves five steps that include 1) the preparation of a first dispersed phase comprising a therapeutically active ingredient, a biodegradable polymer and an organic solvent 2) mixing the first dispersed phase with an aqueous phase to form an emulsion 3) spraying the emulsion into a vessel equipped to remove an organic solvent and 4) passing the resulting microspheres or microcapsules through a first and second screen thereby collecting a fractionated size of the microspheres or microcapsules and 5) drying the microspheres or microcapsules. Xu, Q. et al. have disclosed the preparation of monodispersed biodegradable polymer microparticles using a microfluidic flow-focusing device (Xu, Q., et al “Preparation of Monodispersed Biodegradable Polymer Microparticles Using a Microfluidic Flow-Focusing Device for Controlled Drug Delivery”, Small, Vol 5(13): 1575-1581, 2009). Duncanson, W.J. et al. have disclosed the use of microfluidic devices to generate microspheres ^{(Duncanson, W.J. et al. “Microfluidic Synthesis of Monodisperse Porous Microspheres with Size-tunable} Pores”, Soft Matter, Vol 8, 10636-10640, 2012). U.S. Patent No. 8,916,196 to Evonik describes an apparatus and method for the production of emulsion based microparticles that can be used in connection with the present invention. XIII. Manufacture of Implants Various techniques may be employed to make implants within the scope of the present invention. Useful techniques include phase separation methods, interfacial methods, extrusion methods, including hot melt extrusion, compression methods, molding methods, injection molding methods, heat press methods, 3D printing, and the like. Choice of the technique, and manipulation of the technique parameters employed to produce the implants can influence the release rates of the drug. Room temperature compression methods can result in an implant with discrete microparticles of drug and polymer interspersed. Extrusion methods can result in implants with a progressively more homogenous dispersion of the drug within a continuous polymer matrix, as the production temperature is increased. The use of extrusion methods can allow for large-scale manufacture of implants and result in implants with a homogeneous dispersion of the drug within the polymer matrix. When using extrusion methods, the polymers and active agents that are chosen are often stable at temperatures required for manufacturing, usually at least about 50° C. Extrusion methods use temperatures of about 25° C to about 150° C, for example about 60° C to about 130° C. Extrusion methods may be used to avoid the need for solvents in manufacturing. An implant may be produced by bringing the temperature to about 60 °C to about 150 °C for drug/polymer mixing, such as about 130 °C, for a time period of about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, a time period may be about 10 minutes, for example about 0 to 5 minutes. The implants are then extruded at a temperature of about 60 °C to about 130 °C, such as about 80 °C. In addition, the implant may be coextruded so that a coating is formed over a core region during the manufacture of the implant. Different extrusion methods may yield implants with different characteristics, including but not limited to the homogeneity of the dispersion of the active agent within the polymer matrix. For example, using a piston extruder, a single screw extruder, and a twin-screw extruder will generally produce implants with progressively more homogeneous dispersion of the active. When using one extrusion method, extrusion parameters such as temperature, extrusion speed, die geometry, and die surface finish will have an effect on the release profile of the implants produced. Hot-melt extrusion is used a process wherein a blended composition is heated and/or compressed to a molten (or softened) state and subsequently forced through an orifice, where the extruded product (extrudate) is formed into its final shape, in which it solidifies upon cooling. Compression methods may be used to make the implants, and typically yield implants with faster release rates than extrusion methods. Compression methods may use pressures of about 50-150 psi, for ^{example about 70-80 psi, for example about 76 psi, and use temperatures of about 0 °C to about 65 °C, for} example about 25 °C. In certain embodiments, the temperature is in the range of about 0 °C to about 50 °C, about 0 °C to about 45 °C, about 0 °C to about 35 °C, about 0 °C to about 25 °C, or about 0 °C to about 15 °C. In certain embodiments, the implants are molded, for example in polymeric molds. In particular, the implants are made by molding the materials intended to make up the implants in mold cavities. The molds can be polymer-based molds and the mold cavities can be formed into any desired shape and dimension. Uniquely, as the implants and particles are formed in the cavities of the mold, the implants are highly uniform with respect to shape, size, and composition. Due to the consistency among the physical and compositional makeup of each implant of the present pharmaceutical compositions, the pharmaceutical compositions of the present disclosure provide highly uniform release rates and dosing ranges. The methods and materials for fabricating the implants of the present disclosure are further described and disclosed in the U.S. Patent. Nos.8,518,316; 8,444,907; 8,420,124; 8,268,446; 8,263,129; 8,158,728; 8,128,393; 7,976,759; and U.S. Patent. Application Publication Nos.2013-0249138, 2013-0241107, 2013-0228950, 2013-0202729, 2013- 0011618, 2013-0256354, 2012-0189728, 2010-0003291, 2009-0165320, 2008-0131692. The mold cavities can be formed into various shapes and sizes. For example, the cavities may be shaped as a prism, rectangular prism, triangular prism, pyramid, square pyramid, triangular pyramid, cone, cylinder, torus, or rod. The cavities within a mold may have the same shape or may have different shapes. In certain aspects of the disclosure, the shapes of the implants are a cylinder, rectangular prism, or a rod. In a particular embodiment, the implant is a rod. The mold cavities can be dimensioned from nanometer to micrometer to millimeter dimensions and larger. For certain embodiments of the disclosure, mold cavities are dimensioned in the micrometer and millimeter range. In certain embodiments, a rod mold cavity with dimensions of about 150 to 1200 micrometers in diameter and about 1 to 10 millimeters in length is used to produce implants of the present invention. In certain embodiments, a rod mold cavity with dimensions of about 150 to 1000 micrometers in diameter and about 1 to 10 millimeters in length is used to produce implants of the present invention. In certain embodiments, a rod mold cavity with dimensions of about 250 to 650 micrometers in diameter and about 3 to 10 millimeters in length is used to produce implants of the present invention. In certain embodiments, a rod mold cavity with dimensions of about 300 to 500 micrometers in diameter and about 3 to 8 millimeters in length is used to produce implants of the present invention. Once manufactured, the implants may remain on an array for storage, or may be harvested immediately for storage and/or utilization. Implants and particles described herein may be fabricated using sterile processes or may be sterilized after fabrication. In other methods, single implants can be made using polymers with differing release characteristics where separate drug-polymer blends are prepared that are then co-extruded to create implants that contain different areas or regions having different release profiles. The overall drug release profile of these co- ^{extruded implants is different than that of an implant created by initially blending the polymers together and} then extruding them. For example, first and second blends of drug or active agent can be created with different polymers and the two blends can be co-axially extruded to create an implant with an inner core region having certain release characteristics and an outer shell region having second, differing release characteristics EXAMPLES Example 1: Representative Synthetic Methods List of Acronyms cAMP adenosine-3',5'-cyclic HEPES 4-(2-hydroxyethyl)-1- monophosphate piperazineethanesulfonic acid cGMP guanosine-3’,5’-cyclic HOBt 1-hydroxybenzotriazole monophosphate cGMPS guanosine-3’,5’-cyclic HPLC high performance liquid monophosphorothioate chromatography CNGC cyclic nucleotide gated ion channel (i-Pr)₂EtNH⁺ diisopropylethylammonium Cy cyclohexyl i-PrOH 2-propanol Cyp cyclopentyl m/z mass-to-charge ratio Da Dalton MeCN acetonitrile DAPI 4′,6-diamidino-2-phenylindole MTBE tert-butyl methyl ether DBU 1,8-diazabicyclo[5.4.0]undec-7-ene M^w molecular weight DMEM/F12 Dulbecco's modifiziertes eagle N2 N2-supplement for cell medium in combination with Ham's culture F-12 medium DMF N,N-dimethylformamide NHS N-hydroxysuccinimid DMSO dimethyl sulfoxide PBS phosphate buffered saline dppf 1,1'- Pd(dppf)Cl₂ 1,1'-bis(diphenylphosphino)- Bis(diphenylphosphino)ferrocene ferrocene- palladium(II)dichloride ECM extracellular matrix PDE phosphodiesterase EDC 1-ethyl-3-(3- PEG polyethylene glycol dimethylaminopropyl)carbodiimide EGTA ethylene glycol-bis(2- PET β-Phenyl-1,N²-etheno aminoethylether)-N,N,N’,N’- tetraacetic acid ESI-MS electrospray Ionization mass PFA paraformaldehyde spectrometry est. estimated PKG cGMP-dependent protein kinase Et³NH⁺ triethylammonium PLD polymer linked dimer FGF fibroblast growth factor PLM polymer linked multimer HCN hyperpolarization-activated cyclic PN postnatal nucleotide-gated PyBOP benzotriazole-1-yl- SD standard deviation oxytripyrrolidinophosphonium hexafluorophosphate RD retinal dystrophies TEA triethylammonium rd 1 retinal degeneration 1 TEAF triethylammonium formate rd 2 retinal degeneration 2 UV-VIS ultraviolet and visible (spectroscopy) RP retinitis pigmentosa VS vinylsulfone Rp as in Rp-cGMPS refers to ε extinction coefficient configuration of the chiral phosphorus, wherein R/S follows the Cahn-Ingold-Prelog rules while “p” stands for phosphorus. RP-18 reversed phase octadecyl modified λmax wavelength at which material absorbance is highest General Experimental Methods Synthetic methods for the compounds below are provided in WO 2018/010965 and WO2018/041942 and reproduced below for convivence. All applied solvents and reagents were available ^{from commercial suppliers. Rp-8-Br-cGMPS and Rp-8-Br-PET-cGMPS were available from Biolog Life} Science Institute (Bremen, Germany). Solvents used were specified as analytical or HPLC grade. Dimethyl sulfoxide was stored over activated molecular sieves for at least two weeks before use. Chromatographic operations were performed at ambient temperature. Both reaction progress and purity of isolated products were determined by reversed phase HPLC (RP-18, ODS-A-YMC, 120-S-11, 250 x 4 mm, 1.5 mL/min), ^{wherein UV detection was performed either at 263 nm, an intermediate wavelength suitable to detect most} cyclic GMP products and – impurities, or at the λmax of the particular starting material or product. Syntheses were typically performed in a 20-200 µmol scale in 2 mL polypropylene reaction vials with screw cap (reactions requiring inert gas atmosphere and/or degassing were performed in round bottom flasks (typically 10 or 25 mL)). Dissolution of poorly soluble reactants was achieved through sonification or heating (70 °C) prior to addition of reagents. In case dissolution was not elicited by these techniques, which mainly applied to some cGMP analogs carrying a PET-moiety, the suspension was used. Purification of products was accomplished by preparative reversed phase HPLC (RP-18, ODS-A-YMC, 12nm-S-10, 250 x 16 mm, UV 254 nm). The eluent composition is described in the particular synthetic example and, unless stated otherwise, can be used for analytical purposes as well. Desalting of products was accomplished by repeatedly freeze-drying or by preparative reversed phase HPLC (RP-18, ODS-A-YMC, 12nm-S-10, 250 x 16 mm, UV 254 nm) according to standard procedures for nucleotides. Solutions were frozen at -70 °C for 15 min prior to evaporation, in case a speedvac concentrator was used to remove the solvent. Products were either isolated as sodium or triethylammonium salt, depending on the applied buffer. Yields refer to the fraction of isolated product featuring the reported purity. They were calculated from UV-absorbance at the λmax, measured on a JASCO V-650 Spectrophotometer (JASCO Germany GmbH, Gross-Umstadt, Germany) according to Lambert-Beer's law. Extinction coefficients were estimated from literature known values of structurally related compounds. Mass spectra were obtained with an Esquire LC 6000 spectrometer (Bruker Daltronics, Bremen, Germany) in the ESI-MS mode with 50 % water / 50 % methanol as matrix. Experimental Procedures for the Preparation of 8-Thio-substituted equatorially modified Guanosine-3’,5’-cyclic monophosphate analogs General Procedure A: In a typical experiment, the corresponding thiol reactant (8 eq) and NaOH (2 M, 4 eq) were added successively to a solution of the corresponding 8-Br-substituted equatorially modified cGMP analog (sodium salt, 65 mM, 1 eq) in H₂O/i-PrOH (1:1, v/v). The reaction mixture was heated to 90 °C and stirred until the bromide starting material was completely consumed or no further reaction progress was observed. The solution was then allowed to reach room temperature, neutralized with HCl (1 M) and the solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL) and washed with MTBE (3 x).* The aqueous phase was evaporated under reduced pressure using a rotary evaporator, the residue redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the 8-thio-substituted equatorially modified cGMP analog. *In case the residue was not soluble in water, the obtained suspension was washed with MTBE and (if necessary) diluted with MeOH to dissolve remaining precipitate. General Procedure A2: In a typical experiment, the corresponding thiol(ate) reactant (4.5 eq) was added to a solution of the corresponding 8-Br-substituted equatorially modified cGMP analog (sodium salt, 65 mM, 1 eq) in H₂O/i- PrOH (1:1, v/v). The reaction mixture was stirred at room temperature until the bromide starting material ^{was completely consumed or no further reaction progress was observed. The solution was then adjusted} to pH 6 with NaOH (10 %) and the solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL) and washed with CH₂Cl₂ (3 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, the residue redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the 8-thio-substituted equatorially modified cGMP analog. General Procedure B: In a typical experiment, a solution of the 8-Br-substituted equatorially modified cGMP analog (sodium salt, 87 mM, 1 eq) was added portionwise over 2 h to a suspension of the corresponding dithiol (50 mM in water/i-PrOH, 2:3, v/v, 10 eq) and NaOH (2 M, 5 eq). The reaction mixture was heated to 90 °C and stirred until the bromide starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was suspended in water (1 mL), neutralized with HCl (1 M) and filtered. The crude product solution was subjected to preparative reversed phase HPLC and desalted, giving the thiol analog. General Procedure C: In a typical experiment, NaOH (2 M, 16 eq) and the corresponding thiol reactant (8 eq) were added successively to a solution of the 8-Br-substituted cGMP analog (sodium salt, 200 mM, 1 eq) in borate buffer (100 mM, pH 12). The reaction mixture was heated to 90 °C and stirred until the bromide starting material was completely consumed or no further reaction progress was observed. The solution was then allowed to reach room temperature and neutralized with HCl (1 M). The solvent was removed under reduced pressure using a rotary evaporator. The residue was dissolved in water (1 mL), subjected to preparative reversed phase HPLC and desalted. General Procedure D: In a typical experiment, N,N-diisopropylethylamine (2 eq) and the corresponding bromide (1 eq) were added successively to a solution of the 8-SH-substituted equatorially modified cGMP analog (sodium or triethylammonium salt, 100 mM, 1 eq) in DMSO. The reaction mixture was stirred until the thiol starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL), washed with ethyl acetate (3 x), subjected to preparative reversed phase HPLC and desalted. General Procedure E: For the formation of dimeric equatorially modified cGMP analogs general Procedure D was followed using N,N-diisopropylethylamine (2 eq), the corresponding bis-bromide spacer (0.5 eq) and the 8-SH- substituted equatorially modified cGMP analog (sodium or triethylammonium salt, 100 mM, 1 eq) in DMSO. Experimental Procedure for the Transformation of Carboxylic Acid Ester functionalized equatorially ^{modified Guanosine-3’,5’-cyclic monophosphate analogs into the corresponding Carboxylic Acid} or Amide General Procedure F: In a typical experiment, NaOH (2 M, 10 eq) was added to a solution of the corresponding ester (80 mM, 1 eq) in water/MeOH (1:1, v/v). The reaction mixture was stirred until the ester starting material was completely consumed or no further reaction progress was observed. The solution was then neutralized with HCl (1 M) and the solvent was removed under reduced pressure using a rotary evaporator. The residue was dissolved in water (1 mL), subjected to preparative reversed phase HPLC and desalted, giving the carboxylic acid analog. General Procedure G: In a typical experiment, the corresponding ester (1 eq) was dissolved in excess methanolic ammonia (4.2 M, 200 eq). The reaction mixture was stirred until the starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL), neutralized with HCl (1 M) and filtered through a syringe filter. The crude product was subjected to preparative reversed phase HPLC and desalted, giving the carboxylic acid amide analog. Experimental Procedures for the Formation of Amide Bonds with equatorially modified Guanosine- 3’,5’-cyclic monophosphate analogs General Procedure H: In a typical experiment, HOBt (1.1 eq), N,N-diisopropylethylamine (2.2 eq) and EDC (1.1 eq) were added successively to a solution of the corresponding acid-substituted equatorially modified cGMP analog (100 mM in DMSO, 1 eq) and the corresponding amine (1.1 eq)*. The reaction mixture was stirred until the starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL) and washed with ethyl acetate (5 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the coupled equatorially modified cGMP analog. *The less valuable reactant was added in slight excess, thus for the reaction with reversed functions the amine-substituted equatorially modified cGMP analog (100 mM in DMSO, 1 eq) and the acid reactant (1.1 eq) were used. General Procedure I: In a typical experiment, HOBt (1.1 eq), N,N-diisopropylethylamine (2.2 eq) and EDC (1.1 eq) were added successively to a solution of the corresponding acid-substituted equatorially modified cGMP analog (100 mM in DMSO, 1 eq) and the corresponding bis-amino spacer (0.5 eq). Workup was performed as described in general procedure H, giving the dimeric equatorially modified cGMP analog. G^{eneral Procedure J:} In a typical experiment, N,N-diisopropylethylamine (2.2 eq) and PyBOP (1.1 eq) were added successively to a solution of the corresponding carboxylic acid-substituted equatorially modified cGMP analog (100 mM in DMSO, 1 eq) and the corresponding amine (1.1 eq)*. The reaction mixture was stirred until the starting material was completely consumed or no further reaction progress was observed (usually < 10 min). Water (100 µL) was added, stirring was continued for 10 min and the solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL), if necessary the pH was adjusted to 6 with NaOH (2 M) or HCl (1 M) and the solution washed with ethyl acetate (5 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the coupled equatorially modified cGMP analog. *The less valuable reactant was added in slight excess, thus for the reaction with reversed functions the amine-substituted equatorially modified cGMP analog (100 mM in DMSO, 1 eq) and the acid reactant (1.1 eq) were used. General Procedure K: In a typical experiment, a solution of the corresponding carboxylic acid-substituted equatorially modified cGMP analog (100 mM in DMSO, 1 eq) was added portionwise over 40 min to a solution of the bis-amino spacer (400 mM in DMSO, 5 eq), N,N-diisopropyethylamine (2.2 eq) and PyBOP (1.1 eq). More PyBOP (1 eq) was added and the reaction mixture was stirred until the starting material was completely consumed or no further reaction progress was observed (usually < 10 min). Workup was performed as described in general procedure J, giving the monomeric equatorially modified cGMP analog coupling product. General Procedure L: General procedure J was followed using the corresponding acid-substituted equatorially modified cGMP analog (100 mM in DMSO, 1 eq), the bis-amino spacer (0.5 eq), N,N-diisopropylethylamine (2.2 eq) and PyBOP (1.1 eq) to obtain the dimeric equatorially modified cGMP analog. General Procedure M: General procedure J was followed using the corresponding amine-substituted equatorially modified cGMP analog (33 mM in DMSO, 1 eq), the linker tri-acid (0.3 eq), N,N-diisopropylethylamine (2 eq) and PyBOP (1.3 eq) to obtain the trimeric equatorially modified cGMP analog. General Procedure N: General procedure J was followed using the corresponding amine-substituted equatorially modified cGMP analog (diisopropylethylammonium salt, 50 mM in DMSO, 1 eq)*, the linker tetra-acid (tetra- diisopropylethylammonium salt, 0.25 eq)*, N,N-diisopropylethylamine (3 eq) and PyBOP (1.3 eq) to obtain the tetrameric equatorially modified cGMP analog. *To transform the reactants into the diisopropylethylammonium salt they were subjected to N,N- diisopropylethylamine (3 eq per acidic function) in water (0.1-0.3 M) and evaporated to dryness using a ^{speedvac concentrator at high vacuum.} Experimental Procedures for the Preparation of 8-Sulfonyl- and 8-Sulfoxide-substituted equatorially modified Guanosine-3’,5’-cyclic monophosphate analogs General Procedure O: In a typical experiment, a solution of OXONE^® (180 mM, 5 eq) in NaOAc buffer (2 M, pH 4.2) was added dropwise to a solution of the corresponding 8-thio-substituted guanosine analog (40 mM, 1 eq) in water/MeOH (1:1, v/v). The reaction mixture was stirred until the thio starting material was completely consumed or no further reaction progress was observed. The solution was then neutralized with NaOH (2 M) and filtered through a syringe filter. The solvent was removed under reduced pressure using a rotary evaporator. The residue was dissolved in water (1 mL), subjected to preparative reversed phase HPLC and desalted, giving the 8-sulfonyl-substituted guanosine analog. Transformation to the corresponding equatorially modified cGMP analog was then performed according to established thiophosphorylation protocol (Genieser, H.-G.; Walter, U.; Butt, E. Derivatives of cyclic guanosine-3',5'-monophosphorothioate. U.S. Patent 5,625,056 Apr.29, 1997). General Procedure P: General procedure O was followed, favoring the formation of the 8-sulfoxide-substituted equatorially modified cGMP analog through shorter reaction time and decreased equivalents of oxidizing agent OXONE^® (1.5 eq). Experimental Procedure for the Generation of 8-Azidoalkylthio-substituted equatorially modified Guanosine-3’,5’-cyclic monophosphate analogs General Procedure Q: In a typical experiment, NaN3 (22.5 eq) was added portionwise over 5 h to a solution of 1,2- dibromoalkane (1.5 M, 15 eq) in DMF in an amber flask. The reaction mixture was stirred for 23 h and the 8-SH-substituted equatorially modified cGMP analog (triethylammonium salt, 1 eq) as well as N,N- diisopropylethylamine (1 eq) were added successively. Stirring was continued until the equatorially modified cGMP analog starting material was completely consumed or no further reaction progress was observed (usually about 1 h). The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL) and washed with MTBE (5 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, the residue was redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the 8-azidoalkylthio-substituted analog. Experimental Procedures for the [3+2] Cycloaddition of Azides and Terminal Alkynes on equatorially modified Guanosine-3’,5’-cyclic monophosphate analogs General Procedure R: In a typical experiment, a solution of the corresponding azide (0.5 M in CH₂Cl₂, 1.1 eq) was added to the alkyne-substituted equatorially modified cGMP analog (40 mM in H₂O, 1 eq) in an amber flask. Bromotris(triphenylphosphine)copper(I) ([Cu(PPh3)3Br]) (0.05 eq) was added and the reaction mixture was stirred until the alkyne starting material was completely consumed or no further reaction progress was observed. The mixture was diluted with water (to 1.5 mL) and washed with CH₂Cl₂ (3 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, the residue was redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the triazole-containing product. General Procedure S: In a typical experiment [Cu(PPh₃)₃Br] (0.05 eq) was added to a solution of the corresponding azide (13 mM, 1 eq) and the corresponding alkyne (13 mM, 1 eq) in water/N,N-diisopropylethylamine (7:1, v/v) in an amber flask. The reaction mixture was stirred at 65 °C until the starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL) and washed with CH₂Cl₂ (3 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, the residue was redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the triazole-containing product. General Procedure T: General Procedure S was followed, using [Cu(PPh3)3Br] (0.05 eq), the corresponding azide- substituted equatorially modified cGMP analog (23 mM, 1 eq) and the corresponding bis-alkyne (12 mM, 2 eq) in water/N,N-diisopropylethylamine (8:1, v/v). Conditions were chosen to obtain both the monomeric and the dimeric triazole-containing product. General Procedure U: General Procedure S was followed, using [Cu(PPh3)3Br] (0.05 eq), the corresponding azide- substituted equatorially modified cGMP analog (33 mM, 1 eq) and the corresponding bis-alkyne (16 mM, 0.5 eq) in water/N,N-diisopropylethylamine (10:1, v/v) to obtain the dimeric triazole-containing product. Experimental Procedure for the Transformation of Azido-substituted equatorially modified Guanosine-3’,5’-cyclic monophosphate analogs into the corresponding Amines General Procedure V: In a typical experiment a solution of the azido-substituted equatorially modified cGMP analog (2.5 mM in water, 1 eq) in an amber flask was adjusted to pH 10 by addition of triethylamine and cooled to 10 °C. DL-Dithiothreitol (5 eq) was added and the reaction mixture was stirred until the azide starting material was completely consumed or no further reaction progress was observed (usually < 20 min). The mixture was evaporated to dryness under reduced pressure using a rotary evaporator. The residue was dissolved in water (1 mL), subjected to preparative reversed phase HPLC and desalted, giving the amine- substituted equatorially modified cGMP analog. Experimental Procedure for the Suzuki Cross-Coupling of Br-substituted equatorially modified Guanosine-3’,5’-cyclic monophosphate analogs with Organoboronic Acids General Procedure W: In a typical experiment aqueous K₂CO₃ (2 M, 3 eq) and Pd(dppf)Cl₂ (0.05 eq) were added successively to a solution of the Br-substituted equatorially modified cGMP analog (52 mM, 1 eq) and the boronic acid (72 mM, 1.4 eq) in EtOH/H₂O (1:1, v/v). The reaction mixture was immediately degased applying three cycles of freeze-pump-thaw technique and stirred at 90 °C under argon until the bromide starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was suspended in water and washed with CHCl3 (3 x). Methanol was added until dissolution of the precipitate (up to H₂O/MeOH = 1:1). If an organic phase, containing residual CHCl3, emerged from this composition, it was separated. The aqueous phase was then filtered through a Macherey-Nagel Chromafix C 18 (S) 270 mg cartridge (preconditioned with 10 mL of MeOH, 50 % MeOH and 30 % MeOH respectively) and rinsed with 30 % MeOH (6 mL). The solvent was removed under reduced pressure using a rotary evaporator. The residue was dissolved in water (1 mL), subjected to preparative reversed phase HPLC and desalted, giving the cross-coupling product. * All solvents used, were degassed through sonification under reduced pressure prior to the experiment. General Procedure X (preparation of bis boronic acid reagent 4-B(OH)₂PhS-(EO)₅-(CH₂)₂-4- SPhB(OH)₂): In a typical experiment, N,N-diisopropylethylamine (2 eq) was added to a solution of 4- mercaptophenylboronic acid (0.2 M, 1 eq) and Br- (EO)5-(CH₂)₂-Br (0.5 eq) in DMF. The reaction mixture was stirred until the boronic acid starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in methanol (1 mL) and subjected to preparative reversed phase HPLC (62 % MeOH) giving 4-B(OH)₂PhS-(EO)5-(CH₂)₂-4-SPhB(OH)₂ (34% yield). Experimental Procedure for the Preparation of 1, N²-functionalized equatorially modified Guanosine-3’,5’-cyclic monophosphate analogs General Procedure Y: In a typical experiment, DBU (7 eq) and the corresponding 2-bromo-aceto-reactant (3.5 eq) were added successively to a solution of the corresponding equatorially modified cGMP analog (50 mM, 1 eq) in DMSO. The reaction mixture was stirred under exclusion of light until the equatorially modified cGMP analog starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in methanol (0.5 mL) and the pH adjusted to 6-7 with HCl (1 M). In case a precipitate was formed ^{thereby, methanol was added to redissolve it. Otherwise, water was slowly added up until all components} just remained soluble (max. H₂O/MeOH = 5:1). The solution was subjected to preparative reversed phase HPLC and desalted, giving the 1, N²- etheno-functionalized equatorially modified cGMP analog. General Procedure Y2: In a typical experiment, DBU (2 eq) and the corresponding alkyl bromoacetate-reactant (1.1 eq) were added successively to a solution of the corresponding equatorially modified cGMP analog (100 mM, 1 eq) in DMSO. The reaction mixture was stirred until the equatorially modified cGMP analog starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in H₂O (0.5 mL) and the pH adjusted to 6-7 with HCl (1 M). The solution was subjected to preparative reversed phase HPLC and desalted, giving the 1,N²-acyl-functionalized equatorially modified cGMP analog. General Procedure Y3: In a typical experiment, N,N-diisopropylethylamine (2 eq) and PyBOP (1.1 eq) were added successively to a solution of the corresponding 1-carboxyalkyl-substituted equatorially modified cGMP analog (10 mM in DMSO, 1 eq). The reaction mixture was stirred until the equatorially modified cGMP analog starting material was completely consumed or no further reaction progress was observed. Water (100 µL) was added, stirring was continued for 10 min and the solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL), the pH adjusted to 5-6 with NaOH (2 M) and the solution washed with ethyl acetate (5 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the 1,N²-acyl-functionalized equatorially modified cGMP analog. Experimental Procedures for the Preparation of 1-substituted equatorially modified Guanosine- 3’,5’-cyclic monophosphate analogs General Procedure Z: In a typical experiment, DBU (4 eq) and the corresponding bromide- (or iodide-) reactant (4 eq) were added successively to a solution of the corresponding equatorially modified cGMP analog (50 – 300 mM, 1 eq) in DMSO. The reaction mixture was stirred until the equatorially modified cGMP analog starting material was completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in H₂O (0.5 mL) and, in case the resulting solution was not neutral, the pH was adjusted to 7 with HCl (1 M). The solution was washed with ethyl acetate (4 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, the residue was redissolved in water, subjected to preparative reversed phase HPLC and desalted, giving the 1-substituted equatorially modified cGMP analog. General Procedure Z2: In a typical experiment, DBU (2 eq) and the corresponding dibromide-reactant (0.5 eq) were added successively to a solution of the corresponding equatorially modified cGMP analog (15 mM, 1 eq) in DMSO. ^{The reaction mixture was stirred at 90 °C until the equatorially modified cGMP analog starting material was} completely consumed or no further reaction progress was observed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in H₂O (0.5 mL), the pH adjusted to 5-7 with HCl (1 M) and the solution was washed with ethyl acetate (4 x). The aqueous phase was evaporated under reduced pressure using a rotary evaporator, the residue was redissolved in water, subjected to preparative reversed phase hplc and desalted, giving the 1-substituted dimeric equatorially modified cGMP analog. The invention is further illustrated by the figures and examples of describing certain embodiments of the present invention are in the tables below which are, however, not intended to limit the invention in any way. Structural examples of novel compounds are depicted in the free acid form. After HPLC workup, compounds are obtained as salts of the applied buffer, but can be transformed to other salt forms or to the free acid by cation exchange according to standard procedures for nucleotides. Table 18 Examples of novel polymer linked multimeric cGMP compounds.

8 9

Table 19 Examples of monomeric precursors and/or monomeric compounds of the invention.

^{Table 20 Examples of novel equatorially modified polymer linked multimeric cGMP compounds according} _{to the invention.}

Monomeric precursors of the invention and/or momomeric compounds of the invention are further illustrated by the figures and examples describing certain embodiments of the present invention which are, however, not intended to limit the invention in any way. Structural examples of novel compounds are depicted in the free acid form. After HPLC workup, compounds are obtained as salts of the applied buffer, but can be transformed to other salt forms or to the free acid by cation exchange according to standard procedures for nucleotides.

Table 21 Examples of monomeric precursors and/or monomeric compounds of the invention.

Example 2: Primary rod-like cells: Assessment of cell death using the Ethidium Homodimer Assay Background Primary photoreceptors derived from retinal stem cells after differentiation in vitro have been ^{demonstrated to be an appropriate in vitro system to study mechanisms of cell death related to retinal} degeneration and to cGMP unbalance as well as to screen compounds with neuroprotective activities (Mussolino, C.; Sanges, D.; Marrocco, E.; Bonetti, C.; Di Vicino, U.; Marigo, V.; Auricchio, A.; Meroni, G.; Surace, E. M., Zinc-finger-based transcriptional repression of rhodopsin in a model of dominant retinitis pigmentosa. EMBO Mol Med 2011, 3 (3), 118-128; Sanges, D.; Comitato, A.; Tammaro, R.; Marigo, V., ^{Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-} 12 and is blocked by calpain inhibitors. Proc Natl Acad Sci USA 2006, 103 (46), 17366-17371; Comitato, A.; Sanges, D.; Rossi, A.; Humphries, M. M.; Marigo, V., Activation of Bax in Three Models of Retinitis Pigmentosa. Invest Ophthalmol Vis Sci 2014, 55 (6), 3555-3562). Data obtained by screening of drugs in this in vitro system can then be used for further research studies on retinal explants and in vivo in the eye of animal models of the disease. Experimental Part Primary rod-like cells were obtained by isolating stem cells from the ciliary epithelium of murine eyes. The cells are cultured until they form neurospheres in DMEM/F12 with FGF (20 ng/ml), Heparin (2 µg/ml), N2 (1x), Glucose (0,6%), HEPES (5 µM) and 1% Penicillin/Streptomycin. Single neurospheres are picked and plated onto glass slides coated with ECM in the same medium as before with the exception of reduced FGF concentration (10 ng/ml) to induce adhesion. Four days later, the medium is changed to DMEM/F12 with N2, Glucose, HEPES and Penicillin/Streptomycin supplemented with 1% FBS to allow differentiation into rod-like photoreceptors. Treatment with compounds begins at day 10 after neurosphere plating. This timepoint was chosen because cells derived from rd1 mutant eyes show a peak of cell death and activate cell death pathways like in the retina in vivo (Sanges, D.; Comitato, A.; Tammaro, R.; Marigo, V., Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors. Proc Natl Acad Sci USA 2006, 103 (46), 17366-17371). Compounds were dissolved in water and then diluted in the differentiation medium at concentrations of 1 nM to 100 µM.24 hours after treatment cells were washed with PBS and fixed in 4% PFA. Afterwards slides were dipped into 2 µM Ethidium Homodimer for 2 minutes and nuclei were stained with DAPI. Ethidium Homodimer stains nuclei of dying cells. To assess cell death, microphotographs were taken from three different slides for each compound concentration and the total number of cells, as well as the number of dying Ethidium Homodimer positive cells, were counted in each picture. To statistically assess significant differences between untreated and treated cells, the unpaired Student’s t-test was used and a p value ≤0.05 was considered significant (*≤0.05, **≤0.01, ***≤0.001). Results Figure 2 shows the protective effects of exemplary compounds of the invention. All tested compounds of the invention led to significantly improved survival rates of primary rod-like cells compared to not treated cells (black bars) and compared to the reference compounds Rp-8-Br-cGMPS and Rp-8-Br- PET-cGMPS (dashed bars) at both tested compound concentrations of 0.1 µM (Figure 2a) and 1 µM (Figure 2b). The most potent precedents of the exemplary compounds of the invention display 4.7- to 9-fold better reduction of cell death compared to the known compounds. Example 3: Retinal explants: Determination of photoreceptor cell death Background In addition to using cellular systems of degenerating retinal photoreceptors or photoreceptor-like cells for assessing the properties of various cyclic nucleotide analogs, it is possible to use a serum-free, organotypic explant culturing system, in which retinas from young animals are explanted and kept in culture for up to 3 weeks (Paquet-Durand, F.; Hauck, S. M.; van Veen, T.; Ueffing, M.; Ekstrom, P., PKG activity causes photoreceptor cell death in two retinitis pigmentosa models. J Neurochem 2009, 108 (3), 796-810; Caffe, A. R.; Ahuja, P.; Holmqvist, B.; Azadi, S.; Forsell, J.; Holmqvist, I.; Soderpalm, A. K.; van Veen, T., Mouse retina explants after long-term culture in serum free medium. J Chem Neuroanat 2001, 22 (4), 263- 73). The explant system will allow evaluation of the photoreceptor survival in an in vivo-like histological ^{context, with much of the cytoarchitecture kept intact, but without the risk of for instance degradation or} dilution, via body fluids etc., of any treatment compounds, which otherwise is a risk in vivo. The rd1 mouse is a very well studied model for RD and due to its degeneration characteristics, which include an early onset and a rapid progress of the photoreceptor cell death. The rd1 degeneration can readily be made to take place under the time frame of the explant culturing. This gives the benefit of easy pharmacological interventions to look for neuroprotective possibilities, which has been repeatedly taken advantage of (Paquet-Durand, F.; Hauck, S. M.; van Veen, T.; Ueffing, M.; Ekstrom, P., PKG activity causes photoreceptor cell death in two retinitis pigmentosa models. J Neurochem 2009, 108 (3), 796-810; Paquet- Durand, F.; Beck, S.; Michalakis, S.; Goldmann, T.; Huber, G.; Muhlfriedel, R.; Trifunovic, D.; Fischer, M. D.; Fahl, E.; Duetsch, G.; Becirovic, E.; Wolfrum, U.; van Veen, T.; Biel, M.; Tanimoto, N.; Seeliger, M. W., A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa. Hum Mol Genet 2011, 20 (5), 941-7). The studies have among other things allowed an outlining of some of the disease steps. Experimental Part The effects of different compounds of Formula I, Formula II and monomeric precursors thereof Formula III on the degeneration of retinal photoreceptors from model mice suffering from inherited retinal degeneration was investigated by means of a retinal explant system as described above. In this, retinas are dissected out from young animals, usually on postnatal day 5 (PN5) and cultured in serum free medium for several days (see also Figure 3 for the rd1 culturing paradigm), with medium change usually every second day. In order to observe the effects of the different analogs on the degeneration, the retinas are at the end of experiment fixated (preserved). After this they are prepared for histological and other analyses, notably so called TUNEL staining to allow a quantification of photoreceptor cell death. Results Figure 4 shows the outcome of a series of tests with the analogs of the invention, and in which the effects on the photoreceptor cell death is expressed as a ratio of treated to untreated (see figure legend). The left-most bar represents the untreated rd1 explants, while the other bars show selected analogs of the invention, used at concentrations that are either 50 µM, 10 µM or 1 µM. The effects of these analogs are compared with an analog previously available, Rp-8-Br-PET-cGMPS, in a concentration matched way. Note that at all concentrations of Rp-8-Br-cGMPS and Rp-8-Br-PET-cGMPS, there are one or more analogs of the invention that are performing better. Example 4: Activation of PKG isoforms by cGMP derivatives Experimental Part In vitro activation experiments with PKG isozymes Iα, Iβ and II were performed with the commercially available luminescence assay ADP-Glo^TM Kinase Assay (Cat. #V9101) from Promega Corporation (Madison, WI, USA) according to the manufacturer’s instruction manual (The ADP-GloTM ^{Kinase Assay Technical Manual #TM313), standardized and conducted by BIAFFIN GmbH & Co KG} (Kassel, Germany). Luminescence detection was accomplished with a LUMIstar Optima microplate luminometer from BMG LABTECH GmbH (Ortenberg, Germany). Bovine PKG type Iα was purified from bovine lung. Human PKGIß and PKGII were expressed in Sf9 cells and purified by affinity chromatography (Kawada, T.; Toyosato, A.; Islam, M. O.; Yoshida, Y.; Imai, S., cGMP-kinase mediates cGMP- and cAMP- induced Ca2+ desensitization of skinned rat artery. Eur J Pharmacol 1997, 323 (1), 75-82; Genieser, H.- G.; Walter, U.; Butt, E. Derivatives of cyclic guanosine-3',5'-monophosphorothioate. U.S. Patent 5,625,056 Apr.29, 1997). Concentrations of enzymes given below refer to the dimeric form. VASPtide (GL Biochem Ltd., Shanghai, China) was used as PKG-selective phosphorylation substrate peptide (Kawada, T.; Toyosato, A.; Islam, M. O.; Yoshida, Y.; Imai, S., cGMP-kinase mediates cGMP- and cAMP-induced Ca2+ desensitization of skinned rat artery. Eur J Pharmacol 1997, 323 (1), 75-82; Genieser, H.-G.; Walter, U.; Butt, E. Derivatives of cyclic guanosine-3',5'-monophosphorothioate. U.S. Patent 5,625,056 Apr.29, 1997). Assay conditions: PKG Iα (0.2 nM), 20 mM Tris (pH 7.4), 10 mM Mg2Cl₂, 1 mg/mL BSA, 0.15 mM β-mercaptoethanol, 2.5 % DMSO, 130 µM VASPtide, 50 µM ATP, room temperature, 60 min. PKG Iβ (0.15 nM), 20 mM Tris (pH 7.4), 10 mM Mg2Cl₂, 1 mg/mL BSA, 2.5 % DMSO, 130 µM VASPtide, 50 µM ATP, room temperature, 60 min. PKG II (0.5 nM), 20 mM Tris (pH 7.4), 10 mM Mg2Cl₂, 1 mg/mL BSA, 5 mM β-mercaptoethanol, 2.5 % DMSO, 130 µM VASPtide, 50 µM ATP, room temperature, 120 min. Different concentrations (10 pM to 6 µM) of the compounds of the invention and cGMP as reference compound were incubated with the respective PKG isozyme. To increase assay sensitivity in case of PKG II, cGMP and compounds of the invention were preincubated at room temperature for 30 min. The activation values of the compounds are expressed as relative PKG activation compared to cGMP with cGMP set as 1 for each kinase isozyme. The Ka-values of cGMP for half-maximal kinase activation were 28 nM for Iα, 425 nM for Iβ and 208 nM for II. Results Figures 6 to 8 show that all tested PLMs produce significantly higher relative PKG activation for at least 2 of the 3 PKG isozymes compared to the reference compound cGMP. Furthermore, it has to be noted, that the applied standard assay conditions only allowed to determine increased activation potencies of up to 140-fold for PKG Iα, 2832-fold for PKG Iß and 416-fold for PKG II, which is due to the employed enzyme concentration in the assays and the phenomenon that the isozymes were activity-titrated in some cases by the highly active compounds of the invention. The actual PKG activation potentials of these particular compounds of the invention appear to be significantly higher and are therefore expressed as ≥ 140-fold for PKG Iα, ≥ 2832-fold for PKG Iß and ≥ 416-fold for PKG II. A careful and more detailed analysis of the results is provided in the detailed description of the invention-section. Example 5: 661W cell line: Assessment of cell death using the Ethidium Homodimer Assay B^ackground To test the effect of PKG activators, the 661W cell line was used and increase in cell death after treatment was assessed. The 661W cell line is a photoreceptor precursor cell line, immortalized with the SV40 T antigen. As shown in the Figure 9, the 661W cells express PKG. This makes them a suitable model for examining PKG activity using cell death as readout since increased PKG activity was previously associated with increased cell death (Caffe, A. R.; Ahuja, P.; Holmqvist, B.; Azadi, S.; Forsell, J.; Holmqvist, I.; Soderpalm, A. K.; van Veen, T., Mouse retina explants after long-term culture in serum free medium. J Chem Neuroanat 2001, 22 (4), 263-73). Because of potentially complex outcomes from the activation of different PKG isoforms this analysis is interpreted as a proof of principle on the use of these compounds in PKG-expressing cells or tissues. Experimental Part The 661W cells were cultured in DMEM with 10% FBS (Fetal Bovine Serum), 2 mM Glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin. For the Ethidium Homodimer Assay, cells were plated in a 24 well plate on slides coated with ECM (extracellular matrix) at 20000 cells/well and left for 24 hours to attach to the slides. The next day the cells were treated with the compounds. Compounds were dissolved in water and then diluted in the medium at concentrations of 1 nM to 10 µM.16 hours after treatment cells were washed with PBS and fixed in 4% paraformaldehyde. Afterwards slides were dipped into 2 µM Ethidium Homodimer for 2 minutes and nuclei were stained with DAPI (4',6-diamidino-2-phenylindole). Ethidium Homodimer stains nuclei of dying cells. To assess cell death, microphotographs were taken from three different slides for each compound concentration and the total number of cells, as well as the number of dying Ethidium Homodimer positive cells, were counted in each picture. The value for untreated cells was set to 1. To statistically assess significant differences between untreated and treated cells, the unpaired Student’s t-test was used and a P value ≤ 0.05 was considered significant (* ≤ 0.05, ** ≤ 0.01, *** ≤ 0.001). Results Figure 10 shows percentage of cells undergoing cell death after treatment with non-limiting exemplary polymer linked dimeric cGMP analogs of the invention (12 compounds). Six of the tested compounds led to significantly increased cell death at one or more concentrations when compared to untreated cells. The most potent compounds of the invention display a 5-6 fold increase in cell death when compared to untreated cells and 3-4 fold increase in cell death when compared to the reference 8-Br-PET- cGMP. Example 6: Preparation of biodegradable non-surface treated microparticles containing PLGA Polymer microparticles comprising PLGA and diblock copolymer of PLGA and PEG with or without a compound of Formula I, Formula II, or Formula III can be prepared using a single emulsion solvent evaporation method. Briefly, PLGA (560 mg) and PLGA-PEG (5.6 mg) are co-dissolved in dichloromethane (DCM) (4 mL). A compound of Formula I, Formula II, or Formula III (90 mg) is dissolved in dimethyl sulfoxide (DMSO) (2 mL). The polymer solution and the drug solution are mixed to form a homogeneous solution ^{(organic phase). For empty non-surface treated microparticles, DMSO (2 mL) without drug is used. For} drug-loaded non-surface treated microparticles, the organic phase is added to an aqueous 1% PVA solution in PBS (200 mL) and homogenized at 5,000 rpm for 1 minute using an L5M-A laboratory mixer (Silverson Machines Inc., East Longmeadow, MA) to obtain an emulsion. For empty non-surface treated microparticles, 1 percent PVA solution in water (200 mL) is used. The emulsion (solvent-laden microparticles) is then hardened by stirring at room temperature for more than 2 hours to allow the DCM to evaporate. The microparticles are collected by sedimentation and centrifugation, washed three times in water, and filtered through a 40-μm sterile Falcon® cell strainer (Corning Inc., Corning, NY). The non- surface treated microparticles are either used directly in the surface treatment process or dried by lyophilization and stored as a dry powder at -20 °C until used. Example 7: Surface treatment of non-surface treated microparticles using NaOH(aq)/EtOH A pre-chilled solution containing 0.25 M NaOH (aq) and ethanol at a predetermined ratio is added to microparticles in a glass vial under stirring in an ice bath at approximately 4 °C to form a suspension at 100 mg/mL. The suspension is then stirred for a predetermined time (e.g., 3, 6 or 10 minutes) on ice and poured into a pre-chilled filtration apparatus to remove the NaOH(aq)/EtOH solution (ratio of 0.25 M NaOH (aq) to EtOH (v/v) = 30/70 or 50/50). The microparticles are further rinsed with pre-chilled water and transferred to a 50-mL centrifuge tube. The particles are then suspended in pre-chilled water and kept in a refrigerator for 30 minutes to allow the particles to settle. Following removal of the supernatant, the particles are resuspended and filtered through a 40-μm cell strainer to remove large aggregates. Subsequently, the particles are washed twice with water at room temperature and freeze-dried overnight. Example 8: In vitro assessment of particle aggregability Surface treated microparticles are suspended in phosphate buffered saline (PBS) at a concentration of 200 mg/mL. Thirty or fifty microliters of the suspension are injected into 1.5-2.0 mL of PBS or sodium hyaluronate solution (HA, 5 mg/mL in PBS) pre-warmed at 37 °C in a 2 mL microcentrifuge tube using a 0.5 mL insulin syringe with a permanent 27-gauge needle (Terumo or Easy Touch brand). The microcentrifuge tube is then incubated in a water bath at 37 °C for 2 hours. The aggregability of the microparticles is assessed by visual observation and/or imaging under gentle agitation by inverting and/or tapping and flicking the tubes containing the microparticles. Non-surface treated microparticles are used as a control. A successful surface treatment process is expected to result in surface treated microparticles that maintain good suspendability, syringeability and injectability. Most importantly, after the injection into PBS or sodium hyaluronate and the 2 hour incubation at 37 °C, the surface treated microparticles are expected to form consolidated aggregate(s) that do not break into smaller aggregates or free floating particles under gentle agitation, a key feature that differentiates surface treated microparticles from non-surface treated microparticles and surface treated microparticles with low aggregability. Example 9: Injectability and dosing consistency of surface treated microparticles A suspension of surface treated microparticles (with approximately 10 percent drug loading) at approximately 200 mg/mL is prepared by suspending the microparticles in 5-fold diluted ProVisc® solution containing 2 mg/mL of HA. After an incubation period of 2 hours at room temperature, 10 μL of the surface treated microparticles suspension is loaded into a 50 μL Hamilton syringe with an attached 27-gauge needle. Following brief vortexing to fully suspend the surface treated microparticles, the syringe is held horizontally for 2 minutes and vertically for 2 minutes prior to injection into a microcentrifuge tube. The injection is repeated using 3 different syringes and each syringe is tested 3 times. The surface treated microparticles in each tube are then dissolved in DMSO and the dose of drug was determined by UV-Vis spectrophotometry. Example 10: Preparation of biodegradable surface-treated microparticles comprising PLA Non-surface treated microparticles are first produced similarly as described in Example 6. Briefly, PLA and PLGA-PEG are co-dissolved in dichloromethane (DCM) and a compound of Formula I, Formula II, or Formula III is dissolved in dimethyl sulfoxide (DMSO). The polymer solution and the drug solution are mixed to form a homogeneous solution (organic phase). For empty microparticles, DMSO without drug is used. The organic phase is added to an aqueous 1% PVA solution and homogenized at 5,000 rpm for 1 minute using an L5M-A laboratory mixer (Silverson Machines Inc., East Longmeadow, MA) to obtain an emulsion. The emulsion (solvent-laden microparticles) is then hardened by stirring at room temperature for more than 2 hours to allow the DCM to evaporate. The microparticles are collected by sedimentation and centrifugation, washed three times in water, and filtered through a 40-μm sterile Falcon® cell strainer (Corning Inc., Corning, NY). The non-surface-treated microparticles are either used directly in the surface treatment process or dried by lyophilization and stored as a dry powder at -20 °C until used. A pre-chilled solution containing NaOH and ethanol is added to microparticles in a glass vial under stirring in an ice bath at approximately 4 °C to form a suspension. The suspension is then stirred for a predetermined time on ice and poured into a pre-chilled filtration apparatus to remove the NaOH (aq)/EtOH solution. The microparticles are further rinsed with pre-chilled water and transferred to a 50-mL centrifuge tube. The surface treated microparticles are then suspended in pre-chilled water and kept in a refrigerator for 30 minutes to allow the particles to settle. Following removal of the supernatant, the particles are resuspended and filtered through a 40-μm cell strainer to remove large aggregates. Subsequently, the particles are washed twice with water at room temperature and freeze-dried overnight. Example 11: Preparation of Surface Treated Microparticles Encapsulating Compound of Formula I, Formula II, or Formula III with 15, 30, and 45% Drug Loading Microparticles containing a compound of Formula I, Formula II, or Formula III can be formulated using an oil-in-water solvent evaporation microencapsulation method with a modified skid apparatus at a ^{200 g scale. The dispersed phase is comprised of a polymer blend encompassing PLA 4A (77 wt. %),} PLGA₈₅₁₅ 5A (22 wt. %) and PLGA₅₀₅₀-PEG_5K (1 wt. %) dissolved in methylene chloride (DCM) at a concentration of 260 mg/mL combined with a compound of Formula I, Formula II, or Formula III dissolved in dimethyl sulfoxide (DMSO) at a 2:1 (DCM:DMSO) ratio. Total drug mass is varied from 15, 30 and 45% by weight. The dispersed phase is mixed by vigorous vortexing and ultrasonication in a bath sonicator to ensure complete dissolution and homogenous mixing of the polymers and drug. The aqueous phase consists of water containing a 0.25 % PVA as a surfactant to stabilize the emulsification. The flow rate for the aqueous phase is set to 3 L/min. The dispersed phase is pumped at a flow rate of 12.5 mL/min and mixed with the continuous phase at 4200 rpms using a Silverson mixer to generate an oil-in-water emulsion and disperse the materials as droplets. The droplets are pumped into a reactor chamber and washed 3 times with water at ambient temperature to remove residual solvents. The particle slurry is subsequently surface-treated with the addition of 5 L of a chilled solution containing ethanol and sodium hydroxide and left to react for 30 minutes at 8-11 °C. The surface treated particle slurry is then washed 3 times with cold water. Large particles and aggregates can be removed using a 50 micron sieve and mannitol may be added as a stabilizer (5 wt %). The slurry can be filled into vials and lyophilized overnight. Table 22 Surface-Treatment Parameters of Microparticles with 15, 30, and 45% Drug Loading

Example 12: Preparation of Surface-Treated Microparticles of Compound of Formula I, Formula II, or Formula III with 60% Drug Loading Microparticles containing a compound of Formula I, Formula II, or Formula III can be formulated using an oil-in-water solvent evaporation microencapsulation method at a 20 g scale. The dispersed phase is comprised of a polymer blend encompassing PLA 4A (77 wt. %), PLGA8515 5A (22 wt. %) and PLGA5050-PEG5K (1 wt. %) dissolved in methylene chloride (DCM) at a concentration of 100 mg/mL combined with a compound of Formula I, Formula II, or Formula III dissolved in dimethyl sulfoxide (DMSO) at a 2:1 (DCM:DMSO) ratio. Total drug mass is 60% by weight. The dispersed phase is mixed by vigorous vortexing and/or ultrasonication in a bath sonicator to ensure complete dissolution and homogenous mixing of the polymers and drug. The aqueous phase consists of water containing a 0.25 % PVA as a surfactant to stabilize the emulsification. The flow rate for the aqueous phase is set to 3 L/min. The dispersed phase is pumped at a flow rate of 12.5 mL/min and mixed with the continuous phase at 3400 rpm using a Silverson mixer to generate an oil-in-water emulsion and disperse the materials as droplets. The droplets are pumped into a reactor chamber and washed 3 times with water at ambient temperature to remove residual solvents. The particle slurry is subsequently split to 5 sub-batches and each sub-batch is surface treated with the addition of 100 mL of a chilled solution containing ethanol and sodium hydroxide and left to react for 30 minutes in ice bath. The surface treated particle slurry can then be washed 3 times with cold water. Large particles and aggregates can be removed using a 40-micron cell strainer before lyophilization. The five surface treatment conditions for 60% drug loaded microparticles are listed in Table 23. Table 23 Surface treatment parameters for 60% drug loaded microparticles

Microparticles are suspended in a solution of 0.125% sodium hyaluronate buffer solution at a concentration of 200 mg/mL. Microparticles at a volume of 50 µL is injected into a round bottom glass test- tube filled with 4 mL of pre-warmed PBS (37 °C) and incubated at 37 °C for 15 minutes or 2 hours. At 15 minutes or 2 hours, the test-tubes are removed from the incubator and placed horizontally on a light box. Then the test tube is oscillated at 150 rpm for 1 minute to test the integrity of the depot and strength of the aggregates. An image of depot can be acquired before and after oscillation, respectively. The degree of particle aggregation can be assessed qualitatively based on visual inspection of the depot. Example 13: Preparation of Surface-Treated Microparticles Containing 100% of Compound of Formula I, Formula II, or Formula III A 100% drug loaded microparticle (without any polymers) can prepared. Microparticles of compound of Formula I, Formula II, or Formula III can be formulated using an oil-in-water solvent evaporation microencapsulation method at a 6 g scale. The dispersed phase is a compound of Formula I, Formula II, or Formula III dissolved in a mixture of DCM and DMSO (2:1 ratio) at a concentration of 200 mg/mL. The aqueous phase consists of water containing a 0.25 % PVA as a surfactant to stabilize the emulsification. The flow rate for the aqueous phase is set to 3 L/min. The dispersed phase is pumped at a flow rate of 12.5 mL/min and mixed with the continuous phase at 3200 rpm using a Silverson mixer to generate an oil-in-water emulsion and disperse the materials as droplets. The droplets are pumped into a reactor chamber and washed 3 times with water at ambient temperature to remove residual solvents. The lyophilized microparticle is further surface treated in ice bath at 30 mg/mL according to the conditions listed in Table 24. The surface treated particle slurry can then be washed 3 times with cold water. Large particles and aggregates can be removed using a 40 µm cell strainer before lyophilization. Table 24 Surface treatment parameters for microparticles of compound of Formula I, Formula II, or Formula III

Microparticles are suspended in a solution of 0.125% sodium hyaluronate buffer solution at a concentration of 200 mg/mL. Microparticles at a volume of 50 µL can be injected into a round bottom glass test-tube filled with 4 mL of pre-warmed PBS (37 °C) and incubated at 37 °C for 15 minutes or 2 hours. At 15 minute or 2 hours, the test-tubes are removed from the incubator and placed horizontally on a light box. Then the test tube is oscillated at 150 rpm for 1 min to test the integrity of the depot and strength of the aggregates. An image of depot can be acquired before and after oscillation, respectively. The degree of particle aggregation can be assessed qualitatively based on visual inspection of the depot. Example 14: Preparation of Implant of Compound of Formula I, Formula II, or Formula III Solvent Casting into a Water Bath A rod-like implant of a compound of Formula I, Formula II, or Formula III can be made by solvent casting method in water. PLA and a compound of Formula I, Formula II, or Formula III are added to N- methyl-2-pyrrolidone (NMP) at 2:1 polymer/API ratio to yield a final solution with solid concentration of 750 mg/mL. After all the solids are dissolved in NMP, 0.2-0.3 mL of the solution is withdrawn using a 1 mL syringe without needle. Then, a 27G needle is attached and completely submerged in water bath before injection. Afterwards, the solution is slowly injected through the needle and into the water. A small bulb can be formed on the needle tip and then is pulled to guide the stream away from the needle while continuing to inject NMP solution. A smooth and homogenous string can be formed. Once injection is complete, the string is detached from the needle, and the string is allowed to remain in water bath for approximately 16 hours (overnight) for the solvent extraction process. After overnight solvent extraction, the string can be removed from water bath, air dried and cut to ~1 cm long implant. The implant can be also observed under microscope to show that the implant edge is smooth and the diameter of this implant allows for potential insertion into a 27-gauge needle for administration. Compression An implant in the shape of a rectangular prism is cut from a larger pellet made by powder compression method. Using a cylindrical die and a manual pellet press, microparticles formulated with PLA, PLGA, PEG, and a compound of Formula I, Formula II, or Formula III can be compressed at approximately 100 bar to form a cylindrical pellet with a diameter of 13 mm. Smaller implants with widths ranging from 400 to 1000 um, lengths not more than 10 mm, and heights ranging from 400 to 1000 um can then be obtained from the non-sintered pellet using a razor blade. Compression with sintering A pellet is made using the compression method above. Subsequently, the cylindrical pellet is placed in a sealed vial and sintered in a heated bath at approximately 60 °C for 10 minutes. To evaluate the effect of sintering on the mechanical strength of the pellet, a sintered and a non-sintered pellet can be submerged in phosphate-buffered saline pre-heated at 37 °C. Both solutions are then placed on an oscillating rack for 1 minute. Smaller implants with widths ranging from 400 to 1000 um, lengths not more than 10 mm, and heights ranging from 400 to 1000 um can then be obtained from the sintered implant using a razor blade. Hot melt extrusion method Compound of Formula I, Formula II, or Formula III and biodegradable polymer excipients including PLA, PLGA, PLGA-PEG and/or PEG are accurately weighted and premixed in a sealed container by flipping the container plus vortexing. Various polymers are listed in Table 25. The resulting powder blend is fed into an extruder (HAAKE Twin Screw Compounder, Thermo Fisher Scientific), which is pre-heated to a preset temperature (50-80 °C) and screw speed (10-300 rpm). The blend is heated in the extruder and recirculated in the extruder chamber through an internal loop channel for a preset time (2-30 minutes). Then the filament can be extruded at pre-set screw speed (10-300 rpm) through a die, guided by a conveying belt and cut into the desired length (3-10 mm) for further testing. Table 25 Composition of formulations in the hot melt extrusion method

Example 15: Preparation of Implant Using Microparticles Loaded with a Compound of Formula I, Formula II, or Formula III Microparticles (6 g, 15%, 30%, 45% or 60% drug loaded microparticle as described in Examples 1 and 2) are accurately weighted and fed into an extruder (HAAKE Twin Screw Compounder, Thermo Fisher Scientific), which is pre-heated to a preset temperature (50-110 °C) and screw speed (10-300 rpm). The blend is heated in the extruder and recirculated in the extruder chamber through an internal loop channel for a preset time (2-30 minutes). Then the filament is extruded at a pre-set screw speed (10-300 rpm) through a die (0.3-0.5 mm in diameter) guided by a conveyor belt and cut into the desired length of 3-10 mm for further testing. Example 16: Microparticle Suspensions Comprising Plasticizer Preparation of microparticle suspension in a diluent incorporating 0.5% benzyl alcohol and subsequent reconstitution of microparticles The composition of the diluent for the microparticles consists of hyaluronic acid (0.125%), NaCl (6.53 g/L), KH₂PO₄ (0.23 g/L), Na₂HPO₄ (0.81 g/L), KCl (0.09 g/L) and benzyl alcohol (0.5%, w/w). Diluent is loaded into a 1 mL luer lock syringe attached to a vial adapter. A vial containing the microparticles is attached to the vial adapter and the diluent is transferred from the syringe into the vial. The vial is vortexed for 3 seconds to generate a suspension with a microparticle concentration of 200 mg/mL. The diluent ^{syringe is replaced, and the reconstituted suspension is loaded into the new syringe for injection.} In vitro aggregation testing in PBS The effect of benzyl alcohol (BA) on particle aggregation is evaluated in vitro using a test-tube aggregation method. Microparticles are reconstituted as described above in diluent containing 0.5% benzyl alcohol and compared to a control group (microparticles reconstituted in diluent without benzyl alcohol). ^{Round bottom glass test-tubes are filled with 8 mL of pre-warmed PBS (37 °C) and a 50 uL volume of} microparticle suspension is injected into the bottom of the test-tubes and incubated for 0, 5, 10, 15, or 120 minutes. At these selected timepoints, the test-tubes are removed from the incubator, topped with pre- warmed PBS to a final volume of 12 mL and placed horizontally on a light box. The test-tubes are subsequently rolled back and forth to displace the depot from the bottom of the test-tubes and an image of ^{the depot is acquired. The degree of particle aggregation is assessed qualitatively based on visual} inspection of the depot. Quantitation of depot hardness using a Texture Analyzer Mechanical testing of the relative hardness of the microparticle depot is conducted using a Texture Analyzer (Stable Micro Systems, UK) equipped with a 5 mm ball probe. The hardness of the depots is assessed by quantifying the force in grams required to compress the aggregate at 30% strain and a speed of 0.4 mm/s. Briefly, microparticles are reconstituted in diluent formulated with/without 0.5% benzyl alcohol (n =4 per group). The microparticle suspension (400 µL) is injected into a 2 mL HPLC vial filled with 1.8 mL of prewarmed PBS (37 °C) and incubated in a 37 °C water bath. At 15 minute and 2-hour incubation timepoints, samples are removed from the water bath and analyzed for hardness using the texture analyzer. Evaluation of aggregation strength in response to high oscillatory shear forces The strength of the microparticle aggregate is evaluated in relation to its resistance to dispersion due to high liquid shear forces generated by mechanical oscillation at speed. Briefly, a 50 µL microparticle suspension with and without 0.5% benzyl alcohol is injected into a round-bottom test-tube filled with 2 mL of PBS at 37 °C. The test-tube is incubated at 37 °C for 0, 5, or 10 minutes. Subsequently, the test-tubes are placed in an orbital shaker (Fisher Scientific, USA) and shaken at 400 rpms for 1 minute. Immediately post shaking, the test-tube is transferred to a UV/vis and analyzed for % UV transmittance to determine if any free-floating microparticles are displaced from the primary depot. Qualitative evaluation of aggregation strength in an artificial vitreous gel model In order to better predict microparticle aggregation kinetic and strength in human eyes, an artificial vitreous humor test medium with comparable mechanical and physiological properties can be utilized as in vitro evaluation. As such, an artificial vitreous phantom gel was developed for this specific application using hyaluronic acid solution for its viscoelastic potential and PureCol® EZ gel for the mechanical tissue- mimicking properties of vitreous collagen into the test bed. A 2.5 mL aqueous solution consisting of 0.25% HA and 0.1% PureCol EZ gel in water is slowly transferred into a plastic cuvette and incubated for 40-60 minutes at 37 °C to generate a gel. Microparticles are reconstituted as described previously in a diluent with or without 0.5% benzyl alcohol. A 50 µL volume of particle suspension is injected into the gel at a distance of approximately 6 mm from the bottom of the gel. The cuvette containing the particle aggregate is placed back into the incubator at 37 °C. At predetermined timepoints (0, 5, 10, 15 minutes incubation), the gel is removed from the incubator and the cuvette is carefully filled with 0.5% HA solution resulting in a 2-phase system consisting of a gel phase at ^{the bottom and a viscous aqueous phase at the top of the cuvette. The cuvette is capped ensuring no air} bubbles are present in the cuvette. The cuvette is subsequently inverted, and the aggregate is examined as it transitions through the gel phase and into the aqueous phase due to gravitational forces acting on the dense microparticle aggregate. Weak aggregates will shear and disperse as it migrates through the gel and aqueous phases, whereas stronger aggregates are expected to retain its morphology. The microparticle aggregate is then isolated from the aqueous phase and manipulated with tweezers to confirm the strength of the depot. Example 17: In vitro Drug Release of Microparticle Suspension The in vitro drug release of the microparticle suspended in the benzyl alcohol-containing diluent can be studied to determine if 0.5% benzyl alcohol as a plasticizer will negatively impact drug release. Microparticles are prepared using a continuous, single emulsion oil-in-water solvent evaporation microencapsulation method. Briefly, Resomer® Select 100 DL 4.5A (77 wt. %), Resomer® Select 8515 DLG 5.5A (22 wt. %) and Resomer® Select 5050 DLG mPEG5000 (1 wt. %) are dissolved in methylene chloride (DCM) at a concentration of 260 mg/mL. A compound of Formula I, Formula II, or Formula III is dissolved in DMSO (45 wt. % drug/polymer) and added to the polymer solution at a DCM to DMSO ratio of 2:1 under stirring to generate the dispersed phase. The continuous phase is comprised of phosphate buffered saline (pH 7) with 0.2% PVA as a surfactant. Emulsification can be achieved by mixing the dispersed phase with the continuous phase using a high-shear homogenizer at 4200 rpm. The microparticles are transferred to an in-process continuous centrifuge to remove small microparticles. The microparticle slurry is washed with water three times at ambient temperature to remove residual solvent and free drug and subsequently suspended in a surface treatment solution containing 5 mM NaOH in 75% ethanol at 5 °C. Post surface treatment, the microparticle suspension is washed with water three times to remove the surface treatment solution and sieved through a 50 µm filter to remove large particles. The concentration of the drug is determined using in-process sampling and the final suspension is adjusted to achieve target concentration. Mannitol (5 wt %) was added as an excipient during vial-filling and the particles were lyophilized. In vitro drug release kinetics can be evaluated using a static-dissolution setup. Briefly microparticles are reconstituted in a diluent containing 0.5% benzyl alcohol or a diluent without benzyl alcohol as described above. A volume containing 10 mg microparticle equivalence is injected into glass scintillation vials containing 4 mL of a release medium comprising PBS and 1% Tween 20 (pH 7.4). Samples are prepared in duplicate. The particles are incubated on an orbital shaker at 150 rpm at 37 °C. At various time points, 3 mL of release media is collected and replaced with fresh media to maintain sink conditions. Collected release samples are frozen and stored at -80 °C until analysis for drug content. The collected samples are filtered through a 0.2 µm syringe filter and analyzed by RP-HPLC. Example 18: Polymer Microparticles Containing Compound 221 or Compound 188 ^{Preparation of microparticles encapsulating Compound 221 or Compound 188} Microparticles containing Compound 221 were produced using an oil-in-water solvent evaporation microencapsulation method. The formulation process involves a dispersed phase containing the drug and polymers in organic solvents and a continuous phase that was composed of 1% polyvinyl alcohol (PVA) in water. A polymer blend of PLGA₇₅₁₂₅4A and PLGA₅₀₅₀-PEG_5K (99:1 weight ratio) was first dissolved in 2 mL methylene chloride (DCM) at a concentration of 300 mg/mL. The drug was dissolved in 1 mL dimethyl sulfoxide (DMSO) at a concentration of 67 mg/mL (for microparticles with 10% target loading formulation) or 258 mg/mL (for microparticles with 30% target loading). The polymer and drug solutions were then combined to form a homogeneous dispersed phase. The continuous phase contains 200 mL 1% PVA in DI water. The continuous phase was then homogenized with a lab mixer (Silverson L5M-A), and the dispersed phase was slowly injected into the continuous phase. After homogenization at 3,100 rpm for 1 min, the mixture was stirred at 500 rpm for 2 hours. The particles were then collected by sedimentation and centrifugation. After washing in DI water for three times, the microparticle suspension was filtered through a filter with a mesh size of 30 µm to remove unwanted large particles and lyophilized overnight. Compound 188-loaded microparticles were produced following a similar procedure. The morphology of the microparticles was characterized by light microscopy. The drug loading of the microparticles was quantitated by HPLC. The drug-loaded microparticles were suspended in a PBS buffer with 1% Tween 20 and incubated at 37 °C on a rotating platform to characterize the in vitro drug release. At selected time points, three quarters of the release medium was collected and replenished with fresh medium. The amount of drug in the release medium was determined by HPLC. Characterization of Compound 221-loaded microparticles Figure 12 is a representative microscopic image of Compound 221-loaded microparticles. Table 26 shows the loading levels of various Compound 221-loaded microparticles. Compared to formulations containing 221-BEN or 221-BEZ, 221-TEA and 221-FA salt forms led to a much lower drug loading in microparticles. Table 26 Summary of Compound 221-loaded microparticle formulations

Figure 13 shows the in vitro release profiles of microparticles containing 221-BEN or 221-BEZ. The sustained release of drug from 221-BEN and 221-BEZ microparticles lasted for approximately 43 days. ^{Characterization of Compound 188-loaded microparticles} Figure 14 is a representative microscopic image of Compound 188-loaded microparticles. Table 27 shows the loading levels of various Compound 188-loaded microparticles. Compared to formulations containing 188-BEN or 188-BEZ, Compound 188-Ca led to a much lower drug loading in microparticles. Table 27 Summary of Compound 188-loaded microparticle formulations

Figure 15 shows the in vitro release profiles of microparticles containing Compound 188-BEZ. In 49 days, approximately 32% of Compound 188-BEZ was release from the microparticles in a sustained manner, indicating a potential duration of several months. Example 19: Polymer Implant Containing Compound 221 Injectable polymer implants containing Compound 221 were produced by hot melt extrusion of the mixture of biodegradable polymers and Compound 221. Other technologies such as compression, solvent ^{casting, injection molding, hot molding and 3D printing may be applicable as well.} Preparation of Compound 221-loaded implants Compound 221 and biodegradable polymer excipients including PLGA and PLGA-PEG were weighed and thoroughly premixed in a sealed container. The ratio of polymers and drug are presented in Table 28. The powder blend was fed into an extruder (HAAKE Twin Screw Compounder, Thermo Fisher Scientific), which was pre-set to a temperature of 80-90 °C and a screw speed of 150 rpm. The blend was heated in the extruder and recirculated in the extruder chamber through an internal loop channel for a pre- set duration (e.g., 2-30 min). The filament was extruded at pre-set screw speed (e.g, 10-300 rpm) through a die, guided by a conveying belt and cut into desired length (3-10 mm) for further testing. T^{he drug loading of the implants was quantitated by HPLC. The in vitro drug release of the implants} was characterized in a PBS buffer with 1% Tween 20 at 37 °C. At selected time points, three quarters of the release medium was collected and replenished with fresh medium. The amount of drug in the release medium was determined by HPLC. Characterization of Compound 221 implants Table 28 Summary of Compound 221-loaded implant formulations

The release profile of Compound 221 from the implants was affected by the salt form. Implants containing 221-TEA reached a release duration of 40 days; Implants containing 221-FA reached a release duration of 26 days, while Implants containing 221-Na lasted for only 14 days (Figure 16). Implants containing 221-BEN or 221-Ca also reached a duration of 40 days with a relatively linear release profile. This specification has been described with reference to embodiments of the invention. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth herein. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.

Claims

CLAIMS 1. A microparticle comprising a polymer composition and a guanosine-3′,5′-cyclic monophosphate (cGMP) analog, wherein the polymer composition comprises about 95-99.5 wt.-% PLGA and the remainder PLGA-PEG, and wherein the microparticle comprises about 10-40 wt.-% of the cGMP analogue. 2. An implant comprising a compound of Formula I or Formula II

, or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof; wherein: G units G¹ and G² independently are compounds of Formula IIIA and G units G³ and G⁴ independently from G¹ and G² and independently from each other are compounds of Formula IIIA or absent, wherein in case of Formula II G⁴ is always absent if G³ is absent,

and wherein in Formula IIIA: X, Y and Z are N R₁, R₄, R₅, and R8 independently can be equal or individual for each G unit (G¹, G², G³ and G⁴), while R₁ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR9R10, carbamoylR11R12, NH-carbamoylR11R12, O- carbamoylR11R12, SiR13R14R15 wherein R9, R10, R11, R12, R13, R14, R15 independently from each other can be H, alkyl, aryl, aralkyl; R₂ is absent; R₃ is OH; R⁴ can independently be absent, H, amino, alkyl, aralkyl, nitro, N-oxide, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazolinone as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl, wherein each alkyl, aryl, and aralkyl group is optionall substituted with 1, 2, or 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, NH(alkyl), and N(alkyl)₂;

R₅ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR30R31, carbamoylR32R33, NH-carbamoylR32R33, O-carbamoylR32R33, SiR34R35R36 wherein R30, R31, R32, R33, R34, R35, R36 independently from each other can be H, alkyl, aryl, aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazolinone ring as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl R₆ is OH; R₇ is =O, O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O- aralkyl, O-acyl, SH, S-alkyl, S-aryl, S-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, O-PAP, S-BAP, or O-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and R₈ is O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O- acyl, O-PAP, O-BAP, SH, S-alkyl, S-aryl, S-aralkyl, SeH, Se-alkyl, Se-aryl or Se-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, Se-PAP, S-BAP or Se-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- b^{enzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl} (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and wherein linking residues LR¹, LR², LR³ and LR⁴ independently can replace or covalently bind to any of the particular residues R₁, R₄ and/or R₅ of the G units (G^{1 - 4}) they connect, wherein in case they bind to any of the residues R₁, R₄ and/or R₅, an endstanding group of the particular residue (R₁, R₄ and/or R₅), as defined above, is transformed or replaced in the process of establishing the connection and is then further defined as part of the particular linking residue (LR^{1 - 4}) within the assembled compound, while LR¹ is (a) a tri- or tetravalent branched hydrocarbon moiety or (b) a divalent hydrocarbon moiety each with or without incorporated heteroatoms such as, but not limited to, O, N, S, Si, Se, B, wherein I certain embodiments the backbone contains 1 to 28 carbon atoms and can be saturated or unsaturated, substituted or unsubstituted, while each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom and in case poly ethylene glycol (PEG) moieties are incorporated in accordance to the definition, the typical number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500) in case of divalent linking residue (LR¹) or 1 to 750 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 750) in case of trivalent linking residue (LR¹) or 1 to 1000 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 1000) in case of tetravalent linking residue (LR¹), and, if substituted, substituents include, but are not limited to, optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, a^{mino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, expoxy,} methoxy, ethynyl, and/or substituents can further be connected to each other, forming a ring system with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic; LR², LR³ and LR⁴ are divalent hydrocarbon moieties with or without incorporated heteroatoms such as, but not limited to, optionally heteroatoms O, N, S, Si, Se, B, wherein in certain embodiments the backbone contains 1 to 28 carbon atoms and can be, saturated or unsaturated, substituted or unsubstituted, while each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom and in case poly ethylene glycol (PEG) moieties are incorporated in accordance to the definition, the typical number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500) and, if substituted, substituents include, but are not limited to, optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, epoxy, methoxy, ethynyl, and/or substituents can further be connected to each other, forming a ring system with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic; wherein in case of Formula II if G⁴ is absent, LR⁴ is absent, too, and wherein in case of Formula II if G³ and G⁴ are absent, LR³ and LR⁴ are absent, too, and wherein G¹, G², G³ and G⁴ can further be salts and/or hydrates while, optionally, non-limiting examples of suitable salts of the particular phosphate moiety are lithium, sodium, potassium, calcium, magnesium, zinc or ammonium, and trialkylammonium, dialkylammonium, alkylammonium, e.g., triethylammonium, trimethylammonium, diethylammonium and octylammonium; and wherein G¹, G², G³ and G⁴ can optionally be isotopically or radioactively labeled, be PEGylated, immobilized or be labeled with a dye or another reporting group, w^herein the reporting group(s) and/or dye(s) (a) are coupled to G¹, G², G³ and/or G⁴ via a linking residue (LR⁵), bound covalently to or replacing any of the particular residues R₁, R₄ and/or R₅ independently for each G unit (G¹, G², G³ and/or G⁴) while LR⁵ can be as defined for LR² or (b) in case of Formula I can replace G³ and/or G⁴ and wherein examples of optionally suitable dyes include, but are not limited to, fluorescent dyes such as fluorescein, anthraniloyl, N-methylanthraniloyl, dansyl or the nitro-benzofurazanyl (NBD) system, rhodamine-based dyes such as Texas Red or TAMRA, cyanine dyes such as Cy^TM3, Cy^TM5, Cy^TM7, EVOblue^TM10, EVOblue^TM30, EVOblue^TM90, EVOblue^TM100 (EVOblue^TM-family), the BODIPY^TM- family, Alexa Fluor^TM-family, the DY-family, such as DY-547P1, DY-647P1, coumarines, acridines, oxazones, phenalenones, fluorescent proteins such as GFP, BFP and YFP, and near and far infrared dyes and wherein reporting groups optionally include, but are not limited to, quantum dots, biotin and tyrosylmethyl ester; and wherein PEGylated refers to the attachment of a single or multiple LR^PEG group(s) independently, wherein LR^PEG can be as defined for LR², with the provisos that in this case (i) of LR² only one terminus is connected to a G unit (G¹, G², G³ and/or G⁴) by covalently binding to or replacing any of the particular residues R₁, R₄ and/or R₅ independently for each G unit (G¹, G², G³ and/or G⁴), and (ii) the other terminus of LR² is either an alkyl group or a reactive group that allows for conjugation reactions and/or hydrogen bonding while, optionally, non-limiting examples of reactive groups are, -NH₂, -SH, -OH, -COOH, - N3, -NHS-ester, halogen group, epoxide, ethynyl, allyl and with the proviso (iii) that LR^PEG has incorporated ethylene glycol moieties (-(CH₂CH₂O)_n- with n = 2 to 500). 3. The implant according to claim 2, wherein the linking residues LR¹, LR², LR³ and LR⁴ are further subdivided as depicted in Formula Ib and IIb,

connectivity can be as depicted or reversed as exemplified by G¹-O-C(O)-NH-S² versus G¹-NH-C(O)-O-S² and wherein in case the coupling function (C¹, C^1’, C², C^2’, C³, C^3’, C⁴ and/or C^4’) does not replace the residue of the G unit (R₁, R₄ and/or R₅ of G^{1 - 4}) but bind to it, the particular residue (R₁, R₄ and/or R₅) involved in coupling of G units (or G unit with dye(s) or other reporting group(s)) independently from each other is as defined in any of the preceding claims, wherein an endstanding group is replaced by or transformed to the coupling function or selected from the group depicted hereinafter (wherein if present, Q1 connects to the G unit)

and wherein the linker (L) is selected from the group consisting of



while n for each sidechain within a particular linker of the list herebefore can have an equal or individual value as defined a^nd all chiral, diastereomeric, racemic, epimeric, and all geometric isomeric forms of linkers (L) of the list herebefore, though not explicitly depicted, are included herein and cationic linkers (L) such as ammonium-derivatives are salts containing chloride-, bromide-, iodide- phosphate-, carbonate-, sulfate-, acetate- or any other physiologically accepted counterion and wherein spacers (S¹, S², S³ and S⁴) can be equal or individual within a particular compound, be absent or be - (CH₂)_n1-(CH₂CH₂ß)m-(CH₂)_n2- (with ß = O, S or NH; m = 1 to 500, n1 = 0 to 8, n2 = 0 to 8, while both n1 and n2 can independently be equal or individual) or -(CH₂)_n- (with n = 1 to 24). 4. An implant comprising a compound of Formula III

, or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof; wherein X, Y and Z are N R₁, R₄, R₅, and R8 independently can be equal or individual for each G unit (G¹, G², G³ and G⁴), while R₁ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR9R10, carbamoylR11R12, NH-carbamoylR11R12, O- carbamoylR11R12, SiR13R14R15 wherein R9, R10, R11, R12, R13, R14, R15 independently from each other can be H, alkyl, aryl, aralkyl; R2 is absent; R3 is OH; R₄ can independently be absent, H, amino, alkyl, aralkyl, nitro, N-oxide, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazolinone as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl, wherein each alkyl, aryl, and aralkyl group is optionall substituted with 1, 2, or 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, NH(alkyl), and N(alkyl)₂;

R₅ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR30R31, carbamoylR32R33, NH-carbamoylR32R33, O-carbamoylR32R33, SiR34R35R36 wherein R30, R31, R32, R33, R34, R35, R36 independently from each other can be H, alkyl, aryl, aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazolinone ring as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl R₆ is OH; R₇ is =O, O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O- aralkyl, O-acyl, SH, S-alkyl, S-aryl, S-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, O-PAP, S-BAP, or O-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and R₈ is O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O- acyl, O-PAP, O-BAP, SH, S-alkyl, S-aryl, S-aralkyl, SeH, Se-alkyl, Se-aryl or Se-aralkyl, borano (BH₃), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, Se-PAP, S-BAP or Se-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl. 5. The implant according to any one of claims 2-3, wherein the compound is selected from the group consisting of Guanosine- 3', 5'- cyclic monophosphate- [8- thio- (pentaethoxy)- ethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thiomethylamidomethyl- (pentaethoxy)- propylamidomethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thiomethylamido- (octaethoxy)- ethylamidomethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- (4- thiophenylthio)- (pentaethoxy)- ethyl- (4- thiophenylthio) - 8]- guanosine- 3', 5'- cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (octaethoxy)- ethylamidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1, N²- etheno- β- phenyl- 4- yl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- (4- [1, 2, 3]- triazole- 1- yl)- β- phenyl- 1, N²- etheno)]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (octaethoxy)- ethylamidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thiomethylamido- (nonadecaethoxy)- ethylamidomethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; G^{uanosine- 3', 5'-cyclic monophosphate- [8- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)-} methyl- (4- [1, 2, 3]- triazole- 1- yl)- 8]- guanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (PEG pd 2000)- amidomethylthio- 8]- guanosine- 3', 5'-cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (nonadecaethoxy)- ethylamidomethylthio- 8]- guanosine- 3', 5'-cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (nonadecaethoxy)- ethylamidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (PEG pd 2000)- amidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; Benzene- 1, 3, 5- tri-[(8- amidomethyl- (pentaethoxy)- propylamidomethylthio)guanosine- 3', 5'- cyclic monophosphate]; Ethylene glycol- bis(2- aminoethylether)- N, N, N′, N′- tetra- [(8- methylamidoethylthio)guanosine- 3', 5'- cyclic monophosphate]; Guanosine- 3', 5'- cyclic monophosphate- [8- thio- (dodecanyl)- thio- 8]- guanosine- 3', 5'- cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'- cyclic monophosphate- [8- thio- (dodecanyl)- thio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'- cyclic monophosphate, triethyl ammonium salt; Guanosine- 3', 5'-cyclic monophosphate- [8- thioethylamidomethyl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- [1, 2, 3]- triazole- 1- yl)- methylamidoethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thioethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- thioethyl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- [1, 2, 3]- triazole- 1- yl)- ethylthio- 8]- guanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thio- (dodecanyl)- (4- thiophenyl- 4''- thiophenylthio)- (dodecanyl)- thio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- thioethylamidomethyl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- (4- [1, 2, 3]- triazole- 1- yl)- β- phenyl- 1, N²- etheno)]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thioethyl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- [1, 2, 3]- triazole- 1- yl)- ethylthio- 8]- β- phenyl- 1, N²- ethenoguanosine- 3', 5'-cyclic monophosphate; 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1- propylamidomethyl- (pentaethoxy)- ^{propylamidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate;} 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1- (pentaethoxy)- ethyl- 1]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1- propylamidomethyl- (pentaethoxy)- propylamidopropyl- 1]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1- propylamidomethyl- (pentaethoxy)- propylamidomethylthio- 8]- guanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- (phenyl- 4- thio)- (pentaethoxy)- ethyl- (4- thiophenyl)- 8]- guanosine- 3', 5'- cyclic monophosphate; β-1, N²-Acetyl-guanosine-3', 5'-cyclic monophosphate-[8-thiomethylamido- (octaethoxy)- ethylamidomethylthio-8]-β-1,N²-acetyl-guanosine- 3', 5'-cyclic monophosphate; 8- Phenylguanosine- 3', 5'-cyclic monophosphate- [1, N²- etheno- β- phenyl- 4- yl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- (4- [1, 2, 3]- triazole- 1- yl)- β- phenyl- 1, N²- etheno)]- 8- phenylguanosine- 3', 5'-cyclic monophosphate; or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof. 6. The implant according to any of one of claims 2-3, wherein the compound is selected from the group consisting of Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido- (octaethoxy)ethylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-Phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido- (octaethoxy)-ethylamidomethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-1, N2-Acetylguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido- (octaethoxy)-ethylamidomethylthio-8]-β-1, N2-acetylguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-Phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thio(pentaethoxy)- ethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido-(EO)_n- ethylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-Phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido- (EO)_n-ethylamidomethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thio-(pentaethoxy)-ethylthio-8]-guanosine- 3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thio-(dodecanyl)-thio-8]-guanosine-3′, 5′- cyclic monophosphorothioate[Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1, N2-etheno-β-phenyl-4-yl-(1-[1,2, 3]- ^{triazole-4-yl)-methoxy-(hexaethoxy)-methyl-(4-(4-[1,2,3]-triazole-1-yl)-β-phenyl-1, N2-etheno)]-8-} bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido(octaethoxy)- ethylamidomethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate [Rp]; Benzene-1, 3, 5-tri-[(8-amidomethyl-(pentaethoxy)propylamidomethylthio)guanosine-3′, 5′-cyclic monophosphorothioate[Rp]]; Ethylene glycol-bis(2-aminoethylether)-N, N, N′, N′-tetra-[(8-methylamidoethylthio)-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thioethylamidomethyl-(1-[1,2,3]-triazole-4- yl)-methoxy-(hexaethoxy)-methyl-(4-[1,2,3]-triazole-1-yl)-methylamidoethylthio-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thioethylamidomethyl(1-[1,2,3]-triazole-4- yl)-methoxy-(hexaethoxy)-methyl-(4-(4-[1,2,3]-triazole-1-yl)-β-phenyl-1, N2-etheno)]-8-bromoguanosine- 3′, 5′-cyclic monophosphorothioate [Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1-(pentaethoxy)ethyl-1]-8- bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1-propylamidomethyl-(pentaethoxy)- propylamidopropyl-1]-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1-propylamidomethyl-(pentaethoxy)- propylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1-propylamidomethyl-(pentaethoxy)- propylamidomethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-(phenyl-4-thio)(pentaethoxy)-ethyl-(4- thiophenyl)-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-(3-Thiophenyl)-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8- thiomethylamido-(PEG pd 2000)-amidomethylthio-8]-β-(3-thiophenyl)-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 7. The implant according to claim 4, wherein the compound is selected from the group consisting of 8- Amidomethylthioguanosine- 3', 5'- cyclic monophosphate; 8- (4- Boronatephenylthio)-guanosine- 3', 5'- cyclic monophosphate; 8- (4- Cyanobenzylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (4- (2- Cyanophenyl)- benzylthio)guanosine- 3', 5'- cyclic monophosphate; 8- Cyclohexylmethylthioguanosine- 3', 5'- cyclic monophosphate; 8- (2, 4- Dichlorophenylthio)guanosine- 3', 5'- cyclic monophosphate; 8- Diethylphosphonoethylthio-guanosine- 3', 5'- cyclic monophosphate; 8- Ethylthioguanosine- 3', 5'- cyclic monophosphate; 8- Hexylthioguanosine- 3', 5'- cyclic monophosphate; 8- (4- Isopropylphenylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (3- (2- Methyl)furanyl)thioguanosine- 3', 5'- cyclic monophosphate; 8- (5- (1- Methyl)tetrazolyl)thioguanosine- 3', 5'- cyclic monophosphate; 8- (4- Methoxybenzylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (7- (4- Methyl)coumarinyl)thio-guanosine- 3', 5'- cyclic monophosphate; 8- Methylacetylthioguanosine- 3', 5'- cyclic monophosphate; 8- (5- (1- Phenyl)tetrazolyl)thioguanosine- 3', 5'- cyclic monophosphate; 8- (2- Phenylethyl)thioguanosine- 3', 5'- cyclic monophosphate; 8- (2- (4- Phenyl)imidazolyl)thioguanosine- 3', 5'- cyclic monophosphate; 8- (2- Thiophenyl)thioguanosine- 3', 5'- cyclic monophosphate; 8- (1, 1, 2- Trifluoro- 1- butenthio)guanosine- 3', 5'- cyclic monophosphate; 8- Amidopropylthioguanosine- 3', 5'- cyclic monophosphate; 8- Amidoethylthioguanosine- 3', 5'- cyclic monophosphate; 8- Amidobutylthioguanosine- 3', 5'- cyclic monophosphate; 8- Acetamidoethylthioguanosine- 3', 5'- cyclic monophosphate; 8- (2- Benzothiazolyl)thioguanosine- 3', 5'- cyclic monophosphate; 8- (2- Boronatebenzylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Boronatebutylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Boronatebenzylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (3- Boronatebenzylthio)guanosine- 3', 5'- cyclic monophosphate; 8- Azidomethylamidoethylthio-guanosine- 3', 5'- cyclic monophosphate; 8- (3- Boronatephenyl)amidobutylthio-guanosine- 3', 5'- cyclic monophosphate; 8- Benzylamidobutylthioguanosine- 3', 5'- cyclic monophosphate; 8- Benzamidoethylthioguanosine- 3', 5'- cyclic monophosphate; 8- (3- Boronatephenyl)amidomethyl-thioguanosine- 3', 5'- cyclic monophosphate; 8- Benzylamidomethylthio-guanosine- 3', 5'- cyclic monophosphate; 8- (3- Boronatephenyl)amidoethylthio-guanosine- 3', 5'- cyclic monophosphate; 8- (3- Boronatephenyl)amidopropylthioguanosine- 3', 5'- cyclic monophosphate; 8- Carboxypropylthioguanosine- 3', 5'- cyclic monophosphate; 8- Carboxybutylthioguanosine- 3', 5'- cyclic monophosphate; 8- (2, 6- Dichlorophenoxypropyl)thio-guanosine- 3', 5'- cyclic monophosphate; 8- (4- Dimethylaminophenyl)amido-methylthioguanosine- 3', 5'- cyclic monophosphate; 8- (4- Dimethylaminophenyl)amido-butylthioguanosine- 3', 5'- cyclic monophosphate; 8- Ethylbutyrylthioguanosine- 3', 5'- cyclic monophosphate; 8- Methylpropionylthioguanosine- 3', 5'- cyclic monophosphate; 8- Methylvalerianylthioguanosine- 3', 5'- cyclic monophosphate; 8- Methoxyethylamidobutylthio-guanosine- 3', 5'- cyclic monophosphate; 8- Methoxyethylamidomethylthio-guanosine- 3', 5'- cyclic monophosphate; 8- Methoxyethylamidoethylthio-guanosine- 3', 5'- cyclic monophosphate; 8- Phenylamidomethylthio-guanosine- 3', 5'- cyclic monophosphate; 8- Phenylpropylthioguanosine- 3', 5'- cyclic monophosphate; 8- (3- Butynylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Acetamidophenylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Chlorophenylsulfonyl)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Chlorophenylsulfoxide)-guanosine- 3', 5'- cyclic monophosphate; 8- ((2- Ethoxyethyl)- 4- thiophenylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Thiophenyl- 4''- thiophenylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (2- Azidoethylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (3- Aminopropyl)- (pentaethoxy)- methylamidomethylthio-guanosine- 3', 5'- cyclic monophosphate; 8- (2- Aminoethyl)- (octaethoxy)- amidomethylthioguanosine- 3', 5'- cyclic monophosphate; 8- (2- Bromoethyl)- (pentaethoxy)- (4- thiophenylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (4- (Propargyloxy- (hexaethoxy)- methyl)- [1, 2, 3]- triazole- 1- yl)- methylamidoethylthio guanosine- 3', 5'- cyclic monophosphate; 8- (4- Carboxyphenylthio)guanosine- 3', 5'- cyclic monophosphate ; 8- (4- Hydroxyphenylsulfonyl)-guanosine- 3', 5'- cyclic monophosphate; 8- (4- Isopropylphenylsulfonyl)-guanosine- 3', 5'- cyclic monophosphate; 8- (4- Methylcarboxyphenylthio)-guanosine- 3', 5'- cyclic monophosphate; 8- Methylsulfonylguanosine- 3', 5'- cyclic monophosphate; 8- (1- Bromo- 2- naphthyl)methylthioguanosine- 3', 5'- cyclic monophosphate; 8- (2- (1- Benzyl- [1, 2, 3]- triazole- 4- yl)- ethylthio)guanosine- 3', 5'-cyclic monophosphate; 8- (3- Fluoro- 5- methoxybenzylthio)guanosine- 3', 5'- cyclic monophosphate; 8- Pentafluorobenzylthioguanosine- 3', 5'- cyclic monophosphate; 8- Triphenyliminophosphoranyl-guanosine- 3', 5'- cyclic monophosphate; 8- (4- Chlorophenyl)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Fluorophenyl)guanosine- 3', 5'- cyclic monophosphate; 8- (2- Furyl)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Hydroxyphenyl)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Isopropylphenyl)guanosine- 3', 5'- cyclic monophosphate; 8- Phenylguanosine- 3', 5'- cyclic monophosphate; β- Phenyl- 1, N²- etheno- 8- thioguanosine- 3', 5'- cyclic monophosphate; 8- (2- Aminophenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; ^{8- Cyclohexylthio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate;} 8- Cyclopentylthio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Methylphenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Methoxyphenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (3- (2- Methyl)furanyl)thio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (7- (4- Methyl)coumarinyl)thio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (2- Naphthyl)thio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; ß- Phenyl- 1, N²-etheno- 8- (2- thiophenyl)thioguanosine- 3', 5'-cyclic monophosphate; ß- Phenyl- 1, N²-etheno- 8- (2- phenylethyl)thioguanosine- 3', 5'- cyclic monophosphate; 8- Amidomethylthio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'-cyclic monophosphate; 8- Carboxymethylthio- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Boronatephenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- Ethylthio- ß- phenyl- 1, N2- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Fluorophenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- Methylthio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; ß- Phenyl- 1, N²- etheno- 8- propylthio- guanosine- 3', 5'- cyclic monophosphate; 8- Azidoethylthio- β- phenyl- 1, N²- ethenoguanosine- 3', 5'-cyclic monophosphate; ß- Phenyl- 1, N²- etheno- 8- (4- trifluoromethylphenylthio)guanosine- 3', 5'- cyclic monophosphate; 8- (4- Chlorophenylsulfonyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Isopropylphenylthio)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Isopropylphenylsulfonyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Chlorophenyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Hydroxyphenyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- (4- Isopropylphenyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (4- methoxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (4- methyl- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; alpha- Benzoyl- beta- phenyl- 1, N2- etheno- 8- bromoguanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (4- chloro- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (3- nitro- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (ß- tert.- butyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (2- methoxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (3- methoxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (2, 4- dimethoxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (4- pyridinyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (3- thiophen- yl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (4- fluoro- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- 1, N2- ethenoguanosine- 3', 5'- cyclic monophosphate; ^{8- Bromo- (3- hydroxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate;} 8- Bromo- (4- hydroxy- ß- phenyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (ß- (2, 3- dihydro-1, 4- benzodioxin)- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (4- methylsulfonamido- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (4- cyano- β- phenyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (α- phenyl- β- methyl- 1, N²- etheno)guanosine- 3', 5'-cyclic monophosphate; β- (4- Aminophenyl)- 1, N²- etheno- 8- bromoguanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (6- methoxy- 2- naphthyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (9- phenanthrenyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate; 8- Bromo- (4- trifluoromethyl- β- phenyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate; (4- Fluoro- ß- phenyl- 1, N2- etheno)- 8- methylthioguanosine- 3', 5'- cyclic monophosphate; (4- Methoxy- ß- phenyl- 1, N2- etheno)- 8- methylthioguanosine- 3', 5'- cyclic monophosphate; 1, N²- Etheno- 8- (2- phenylethyl)thioguanosine- 3', 5'- cyclic monophosphate; (4- Methoxy- ß- phenyl- 1, N2- etheno)- 8- propylthioguanosine- 3', 5'- cyclic monophosphate; β- 1, N²- Acetyl- 8- bromoguanosine- 3', 5'-cyclic monophosphate; 8- Bromo-δ- 1, N²- butyrylguanosine- 3', 5'-cyclic monophosphate; 8- Bromo- 1- (3- carboxypropyl)guanosine- 3', 5'-cyclic monophosphate; 1-[Aminomethyl- (pentaethoxy)- propylamidopropyl]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; 1-Benzyl- 8- bromoguanosine- 3', 5'-cyclic monophosphate; 2'- O- (2- Azidoacetyl)- 8- bromo- β- phenyl- 1, N²- ethenoguanosine- 3', 5'-cyclic monophosphate; or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 8. The implant according to claim 4, wherein the compound is selected from the group consisting of β-1, N2-Acetyl-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-(4-methyl-β-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-(3-thiophen-yl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-(2-naphthyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-(α-methyl-β-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 1-Benzyl-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Thioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Isopropylphenylthio)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Carboxymethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(2-Aminophenylthio)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Phenylamidomethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8^{-Carboxymethylthio-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer;} β-Phenyl-1, N2-etheno-8-phenylamidomethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; 8-(4-Hydroxyphenylthio)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; 8-(4-Isopropylphenylthio)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; 8-(2-Aminophenylthio)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; β-Phenyl-1, N2-etheno-8-thioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Isopropylphenylthio)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; β-(4-Azidophenyl)-1, N2-etheno-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(2-Aminoethyl)-(octaethoxy)-amidomethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; 8-(3-Aminopropyl)-(pentaethoxy)-methylamidomethylthio-guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Azidomethylamidoethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-(Propargyloxy-(hexaethoxy)-methyl)-[1,2,3]-triazole-1-yl)-methylamidoethylthioguanosine-3′, 5′- cyclic monophosphorothioate, Rp-isomer; 8-Bromo-1-(3-carboxypropyl)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-δ-1, N2-butyrylguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 1-[Aminomethyl-(pentaethoxy)-propylamidopropyl]-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Phenylguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(2-Furyl)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenyl)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Phenyl-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenyl)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenylsulfoxide)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenylsulfonyl)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenylsulfonyl)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 9. The implant according to claim 4 comprising a compound selected from:

or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 10. A microparticle comprising a compound of Formula I or Formula II

and wherein in Formula IIIA: X, Y and Z are N R₁, R₄, R₅, and R8 independently can be equal or individual for each G unit (G¹, G², G³ and G⁴), while R₁ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR9R10, carbamoylR11R12, NH-carbamoylR11R12, O- carbamoylR11R12, SiR13R14R15 wherein R9, R10, R11, R12, R13, R14, R15 independently from each other can be H, alkyl, aryl, aralkyl; R₂ is absent; R3 is OH; R₄ can independently be absent, H, amino, alkyl, aralkyl, nitro, N-oxide, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazolinone as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl, wherein each alkyl, aryl, and aralkyl group is optionall substituted with 1, 2, or 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, NH(alkyl), and N(alkyl)₂;

R₅ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR30R31, carbamoylR32R33, NH-carbamoylR32R33, O-carbamoylR32R33, SiR34R35R36 wherein R30, R31, R32, R33, R34, R35, R36 independently from each other can be H, alkyl, aryl, aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazolinone ring as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl R₆ is OH; R₇ is =O, O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O- aralkyl, O-acyl, SH, S-alkyl, S-aryl, S-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, O-PAP, S-BAP, or O-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and R₈ is O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O- acyl, O-PAP, O-BAP, SH, S-alkyl, S-aryl, S-aralkyl, SeH, Se-alkyl, Se-aryl or Se-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, Se-PAP, S-BAP or Se-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and wherein linking residues LR¹, LR², LR³ and LR⁴ independently can replace or covalently bind to any of the particular residues R₁, R₄ and/or R₅ of the G units (G^{1 - 4}) they connect, wherein in case they bind to any of the residues R₁, R₄ and/or R₅, an endstanding group of the particular residue (R₁, R₄ and/or R₅), as defined above, is transformed or replaced in the process of establishing the connection and is then further defined as part of the particular linking residue (LR^{1 - 4}) within the assembled compound, while LR¹ is (a) a tri- or tetravalent branched hydrocarbon moiety or (b) a divalent hydrocarbon moiety each with or without incorporated heteroatoms such as, but not limited to, O, N, S, Si, Se, B, wherein in certain embodiments the backbone contains 1 to 28 carbon atoms and can be saturated or unsaturated, substituted or unsubstituted, while each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom and in case poly ethylene glycol (PEG) moieties are incorporated in accordance to the definition, the typical number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500) in case of divalent linking residue (LR¹) or 1 to 750 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 750) in case of trivalent linking residue (LR¹) or 1 to 1000 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 1000) in case of tetravalent linking residue (LR¹), and, if substituted, substituents include, but are not limited to, optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, epoxy, methoxy, ethynyl, and/or substituents can further be connected to each other, forming a ring system with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic; LR², LR³ and LR⁴ are divalent hydrocarbon moieties with or without incorporated heteroatoms such as, but not limited to, optionally heteroatoms O, N, S, Si, Se, B, wherein the in certain embodiments backbone contains 1 to 28 carbon atoms and can be, saturated or unsaturated, substituted or unsubstituted, w^hile each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom and in case poly ethylene glycol (PEG) moieties are incorporated in accordance to the definition, the typical number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (-(CH₂CH₂O)_n- with n = 1 to 500) and, if substituted, substituents include, but are not limited to, optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, epoxy, methoxy, ethynyl, and/or substituents can further be connected to each other, forming a ring system with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic; wherein in case of Formula II if G⁴ is absent, LR⁴ is absent, too, and wherein in case of Formula II if G³ and G⁴ are absent, LR³ and LR⁴ are absent, too, and wherein G¹, G², G³ and G⁴ can further be salts and/or hydrates while, optionally, non-limiting examples of suitable salts of the particular phosphate moiety are lithium, sodium, potassium, calcium, magnesium, zinc or ammonium, and trialkylammonium, dialkylammonium, alkylammonium, e.g., triethylammonium, trimethylammonium, diethylammonium and octylammonium; and wherein G¹, G², G³ and G⁴ can optionally be isotopically or radioactively labeled, be PEGylated, immobilized or be labeled with a dye or another reporting group, wherein the reporting group(s) and/or dye(s) (a) are coupled to G¹, G², G³ and/or G⁴ via a linking residue (LR⁵), bound covalently to or replacing any of the particular residues R₁, R₄ and/or R₅ independently for each G unit (G¹, G², G³ and/or G⁴) while LR⁵ can be as defined for LR² or (b) in case of Formula I can replace G³ and/or G⁴ and wherein examples of optionally suitable dyes include, but are not limited to, fluorescent dyes such as f^{luorescein, anthraniloyl, N-methylanthraniloyl, dansyl or the nitro-benzofurazanyl (NBD) system,} rhodamine-based dyes such as Texas Red or TAMRA, cyanine dyes such as Cy^TM3, Cy^TM5, Cy^TM7, EVOblue^TM10, EVOblue^TM30, EVOblue^TM90, EVOblue^TM100 (EVOblue^TM-family), the BODIPY^TM- family, Alexa Fluor^TM-family, the DY-family, such as DY-547P1, DY-647P1, coumarines, acridines, oxazones, phenalenones, fluorescent proteins such as GFP, BFP and YFP, and near and far infrared dyes and wherein reporting groups optionally include, but are not limited to, quantum dots, biotin and tyrosylmethyl ester; and wherein PEGylated refers to the attachment of a single or multiple LR^PEG group(s) independently, wherein LR^PEG can be as defined for LR², with the provisos that in this case (i) of LR² only one terminus is connected to a G unit (G¹, G², G³ and/or G⁴) by covalently binding to or replacing any of the particular residues R₁, R₄ and/or R₅ independently for each G unit (G¹, G², G³ and/or G⁴), and (ii) the other terminus of LR² is either an alkyl group or a reactive group that allows for conjugation reactions and/or hydrogen bonding while, optionally, non-limiting examples of reactive groups are, -NH₂, -SH, -OH, -COOH, - N3, -NHS-ester, halogen group, epoxide, ethynyl, allyl and with the proviso (iii) that LR^PEG has incorporated ethylene glycol moieties (-(CH₂CH₂O)_n- with n = 2 to 500). 11. The microparticle according to claim 10, wherein the linking residues LR¹, LR², LR³ and LR⁴ are further subdivided as depicted in Formula Ib and IIb,

^{connectivity can be as depicted or reversed as exemplified by} G¹-O-C(O)-NH-S² versus G¹-NH-C(O)-O-S² and wherein in case the coupling function (C¹, C^1’, C², C^2’, C³, C^3’, C⁴ and/or C^4’) does not replace the residue of the G unit (R₁, R₄ and/or R₅ of G^{1 - 4}) but bind to it, the particular residue (R₁, R₄ and/or R₅) involved in coupling ^{of G units (or G unit with dye(s) or other reporting group(s)) independently from each other is} as defined in any of the preceding claims, wherein an endstanding group is replaced by or transformed to the coupling function or selected from the group depicted hereinafter (wherein if present, Q1 connects to the G unit)

and wherein the linker (L) is selected from the group consisting of

while n for each sidechain within a particular linker of the list herebefore can have an equal or individual value as defined a^nd all chiral, diastereomeric, racemic, epimeric, and all geometric isomeric forms of linkers (L) of the list herebefore, though not explicitly depicted, are included herein and cationic linkers (L) such as ammonium-derivatives are salts containing chloride-, bromide-, iodide- p^{hosphate-, carbonate-, sulfate-, acetate- or any other physiologically accepted counterion} and wherein spacers (S¹, S², S³ and S⁴) can be equal or individual within a particular compound, be absent or be - (CH₂)_n1-(CH₂CH₂ß)_m-(CH₂)_n2- (with ß = O, S or NH; m = 1 to 500, n1 = 0 to 8, n2 = 0 to 8, while both n1 and n2 can independently be equal or individual) or -(CH₂)_n- (with n = 1 to 24).

12. A microparticle comprising a compound of Formula III

, or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof; wherein X, Y and Z are N R₁, R₄, R₅, and R8 independently can be equal or individual for each G unit (G¹, G², G³ and G⁴), while R₁ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR9R10, carbamoylR11R12, NH-carbamoylR11R12, O- carbamoylR11R12, SiR13R14R15 wherein R9, R10, R11, R12, R13, R14, R15 independently from each other can be H, alkyl, aryl, aralkyl; R₂ is absent; R₃ is OH; R₄ can independently be absent, H, amino, alkyl, aralkyl, nitro, N-oxide, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R₅ and the carbon bridging Y and R₅ an imidazolinone as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl, wherein each alkyl, aryl, and aralkyl group is optionall substituted with 1, 2, or 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, NH(alkyl), and N(alkyl)₂;

R₅ can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, amido- alkyl, amido-aryl, amido-aralkyl, amido-O-alkyl, amido-O-aryl, amido-O-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O)₂-alkyl, S(O)₂-aryl, S(O)₂-aralkyl, S(O)₂-acyl, S(O)₂- aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR30R31, carbamoylR32R33, NH-carbamoylR32R33, O-carbamoylR32R33, SiR34R35R36 wherein R30, R31, R32, R33, R34, R35, R36 independently from each other can be H, alkyl, aryl, aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R₄, Y and the carbon bridging Y and R₅ an imidazolinone ring as depicted (structure IV, V, n = 1) or an homologous ring (n = 2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl R₆ is OH; R₇ is =O, O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O- aralkyl, O-acyl, SH, S-alkyl, S-aryl, S-aralkyl, borano (BH3), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, O-PAP, S-BAP, or O-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl; and R₈ is O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O- acyl, O-PAP, O-BAP, SH, S-alkyl, S-aryl, S-aralkyl, SeH, Se-alkyl, Se-aryl or Se-aralkyl, borano (BH₃), methylborano, dimethylborano, cyanoborano (BH₂CN), S-PAP, Se-PAP, S-BAP or Se-BAP, wherein PAP is a photo-activatable protecting group with non-limiting examples of, optionally, PAP = o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro- benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged); and wherein BAP is a bio-activatable protecting group with non-limiting examples of, optionally, BAP = methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4- pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl. 13. The microparticle according to any one of claims 10-11, wherein the compound is selected from the group consisting of Guanosine- 3', 5'- cyclic monophosphate- [8- thio- (pentaethoxy)- ethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thiomethylamidomethyl- (pentaethoxy)- propylamidomethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate Guanosine- 3', 5'- cyclic monophosphate- [8- thiomethylamido- (octaethoxy)- ethylamidomethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- (4- thiophenylthio)- (pentaethoxy)- ethyl- (4- thiophenylthio) - 8]- guanosine- 3', 5'- cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (octaethoxy)- ethylamidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1, N²- etheno- β- phenyl- 4- yl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- (4- [1, 2, 3]- triazole- 1- yl)- β- phenyl- 1, N²- etheno)]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (octaethoxy)- ethylamidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thiomethylamido- (nonadecaethoxy)- ethylamidomethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- [1, 2, 3]- triazole- 1- yl)- 8]- guanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (PEG pd 2000)- amidomethylthio- ^{8]- guanosine- 3', 5'-cyclic monophosphate;} β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (nonadecaethoxy)- ethylamidomethylthio- 8]- guanosine- 3', 5'-cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (nonadecaethoxy)- ethylamidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thiomethylamido- (PEG pd 2000)- amidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; Benzene- 1, 3, 5- tri-[(8- amidomethyl- (pentaethoxy)- propylamidomethylthio)guanosine- 3', 5'- cyclic monophosphate]; Ethylene glycol- bis(2- aminoethylether)- N, N, N′, N′- tetra- [(8- methylamidoethylthio)guanosine- 3', 5'- cyclic monophosphate]; Guanosine- 3', 5'- cyclic monophosphate- [8- thio- (dodecanyl)- thio- 8]- guanosine- 3', 5'- cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'- cyclic monophosphate- [8- thio- (dodecanyl)- thio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'- cyclic monophosphate, triethyl ammonium salt; Guanosine- 3', 5'-cyclic monophosphate- [8- thioethylamidomethyl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- [1, 2, 3]- triazole- 1- yl)- methylamidoethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thioethylthio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- thioethyl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- [1, 2, 3]- triazole- 1- yl)- ethylthio- 8]- guanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- thio- (dodecanyl)- (4- thiophenyl- 4''- thiophenylthio)- (dodecanyl)- thio- 8]- guanosine- 3', 5'- cyclic monophosphate; Guanosine- 3', 5'-cyclic monophosphate- [8- thioethylamidomethyl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- (4- [1, 2, 3]- triazole- 1- yl)- β- phenyl- 1, N²- etheno)]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; β- Phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate- [8- thioethyl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- [1, 2, 3]- triazole- 1- yl)- ethylthio- 8]- β- phenyl- 1, N²- ethenoguanosine- 3', 5'-cyclic monophosphate; 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1- propylamidomethyl- (pentaethoxy)- propylamidomethylthio- 8]- β- phenyl- 1, N²-ethenoguanosine- 3', 5'-cyclic monophosphate; 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1- (pentaethoxy)- ethyl- 1]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; 8- Bromoguanosine- 3', 5'-cyclic monophosphate- [1- propylamidomethyl- (pentaethoxy)- propylamidopropyl- 1]- 8- bromoguanosine- 3', 5'-cyclic monophosphate; 8^{- Bromoguanosine- 3', 5'-cyclic monophosphate- [1- propylamidomethyl- (pentaethoxy)-} propylamidomethylthio- 8]- guanosine- 3', 5'-cyclic monophosphate; Guanosine- 3', 5'- cyclic monophosphate- [8- (phenyl- 4- thio)- (pentaethoxy)- ethyl- (4- thiophenyl)- 8]- guanosine- 3', 5'- cyclic monophosphate; β-1, N²-Acetyl-guanosine-3', 5'-cyclic monophosphate-[8-thiomethylamido- (octaethoxy)- ethylamidomethylthio-8]-β-1,N²-acetyl-guanosine- 3', 5'-cyclic monophosphate; 8- Phenylguanosine- 3', 5'-cyclic monophosphate- [1, N²- etheno- β- phenyl- 4- yl- (1- [1, 2, 3]- triazole- 4- yl)- methoxy- (hexaethoxy)- methyl- (4- (4- [1, 2, 3]- triazole- 1- yl)- β- phenyl- 1, N²- etheno)]- 8- phenylguanosine- 3', 5'-cyclic monophosphate; or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 14. The microparticle according to any of claims 10-11, wherein the compound is selected from the group consisting of Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido- (octaethoxy)ethylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-Phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido- (octaethoxy)-ethylamidomethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-1, N2-Acetylguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido- (octaethoxy)-ethylamidomethylthio-8]-β-1, N2-acetylguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-Phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thio(pentaethoxy)- ethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido-(EO)_n- ethylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-Phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido- (EO)_n-ethylamidomethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thio-(pentaethoxy)-ethylthio-8]-guanosine- 3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thio-(dodecanyl)-thio-8]-guanosine-3′, 5′- cyclic monophosphorothioate[Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1, N2-etheno-β-phenyl-4-yl-(1-[1,2, 3]- triazole-4-yl)-methoxy-(hexaethoxy)-methyl-(4-(4-[1,2,3]-triazole-1-yl)-β-phenyl-1, N2-etheno)]-8- bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thiomethylamido(octaethoxy)- ^{ethylamidomethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate [Rp];} Benzene-1, 3, 5-tri-[(8-amidomethyl-(pentaethoxy)propylamidomethylthio)guanosine-3′, 5′-cyclic monophosphorothioate[Rp]]; Ethylene glycol-bis(2-aminoethylether)-N, N, N′, N′-tetra-[(8-methylamidoethylthio)-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thioethylamidomethyl-(1-[1,2,3]-triazole-4- yl)-methoxy-(hexaethoxy)-methyl-(4-[1,2,3]-triazole-1-yl)-methylamidoethylthio-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-thioethylamidomethyl(1-[1,2,3]-triazole-4- yl)-methoxy-(hexaethoxy)-methyl-(4-(4-[1,2,3]-triazole-1-yl)-β-phenyl-1, N2-etheno)]-8-bromoguanosine- 3′, 5′-cyclic monophosphorothioate [Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1-(pentaethoxy)ethyl-1]-8- bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1-propylamidomethyl-(pentaethoxy)- propylamidopropyl-1]-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1-propylamidomethyl-(pentaethoxy)- propylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; 8-Bromoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[1-propylamidomethyl-(pentaethoxy)- propylamidomethylthio-8]-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; Guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8-(phenyl-4-thio)(pentaethoxy)-ethyl-(4- thiophenyl)-8]-guanosine-3′, 5′-cyclic monophosphorothioate[Rp]; β-(3-Thiophenyl)-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate[Rp]-[8- thiomethylamido-(PEG pd 2000)-amidomethylthio-8]-β-(3-thiophenyl)-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate[Rp]; or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 15. The microparticle according to claim 12, wherein the compound is selected from the group consisting of 8- Amidomethylthioguanosine- 3', 5'- cyclic monophosphate 8- (4- Boronatephenylthio)-guanosine- 3', 5'- cyclic monophosphate 8- (4- Cyanobenzylthio)guanosine- 3', 5'- cyclic monophosphate 8- (4- (2- Cyanophenyl)- benzylthio)guanosine- 3', 5'- cyclic monophosphate 8- Cyclohexylmethylthioguanosine- 3', 5'- cyclic monophosphate 8- (2, 4- Dichlorophenylthio)guanosine- 3', 5'- cyclic monophosphate 8- Diethylphosphonoethylthio-guanosine- 3', 5'- cyclic monophosphate 8- Ethylthioguanosine- 3', 5'- cyclic monophosphate 8^{- Hexylthioguanosine- 3', 5'- cyclic monophosphate} 8- (4- Isopropylphenylthio)guanosine- 3', 5'- cyclic monophosphate 8- (3- (2- Methyl)furanyl)thioguanosine- 3', 5'- cyclic monophosphate 8- (5- (1- Methyl)tetrazolyl)thioguanosine- 3', 5'- cyclic monophosphate 8- (4- Methoxybenzylthio)guanosine- 3', 5'- cyclic monophosphate 8- (7- (4- Methyl)coumarinyl)thio-guanosine- 3', 5'- cyclic monophosphate 8- Methylacetylthioguanosine- 3', 5'- cyclic monophosphate 8- (5- (1- Phenyl)tetrazolyl)thioguanosine- 3', 5'- cyclic monophosphate 8- (2- Phenylethyl)thioguanosine- 3', 5'- cyclic monophosphate 8- (2- (4- Phenyl)imidazolyl)thioguanosine- 3', 5'- cyclic monophosphate 8- (2- Thiophenyl)thioguanosine- 3', 5'- cyclic monophosphate 8- (1, 1, 2- Trifluoro- 1- butenthio)guanosine- 3', 5'- cyclic monophosphate 8- Amidopropylthioguanosine- 3', 5'- cyclic monophosphate 8- Amidoethylthioguanosine- 3', 5'- cyclic monophosphate 8- Amidobutylthioguanosine- 3', 5'- cyclic monophosphate 8- Acetamidoethylthioguanosine- 3', 5'- cyclic monophosphate 8- (2- Benzothiazolyl)thioguanosine- 3', 5'- cyclic monophosphate 8- (2- Boronatebenzylthio)guanosine- 3', 5'- cyclic monophosphate 8- (4- Boronatebutylthio)guanosine- 3', 5'- cyclic monophosphate 8- (4- Boronatebenzylthio)guanosine- 3', 5'- cyclic monophosphate 8- (3- Boronatebenzylthio)guanosine- 3', 5'- cyclic monophosphate 8- Azidomethylamidoethylthio-guanosine- 3', 5'- cyclic monophosphate 8- (3- Boronatephenyl)amidobutylthio-guanosine- 3', 5'- cyclic monophosphate 8- Benzylamidobutylthioguanosine- 3', 5'- cyclic monophosphate 8- Benzamidoethylthioguanosine- 3', 5'- cyclic monophosphate 8- (3- Boronatephenyl)amidomethyl-thioguanosine- 3', 5'- cyclic monophosphate 8- Benzylamidomethylthio-guanosine- 3', 5'- cyclic monophosphate 8- (3- Boronatephenyl)amidoethylthio-guanosine- 3', 5'- cyclic monophosphate 8- (3- Boronatephenyl)amidopropylthioguanosine- 3', 5'- cyclic monophosphate 8- Carboxypropylthioguanosine- 3', 5'- cyclic monophosphate 8- Carboxybutylthioguanosine- 3', 5'- cyclic monophosphate 8- (2, 6- Dichlorophenoxypropyl)thio-guanosine- 3', 5'- cyclic monophosphate 8- (4- Dimethylaminophenyl)amido-methylthioguanosine- 3', 5'- cyclic monophosphate 8- (4- Dimethylaminophenyl)amido-butylthioguanosine- 3', 5'- cyclic monophosphate 8- Ethylbutyrylthioguanosine- 3', 5'- cyclic monophosphate 8- Methylpropionylthioguanosine- 3', 5'- cyclic monophosphate 8- Methylvalerianylthioguanosine- 3', 5'- cyclic monophosphate ^{8- Methoxyethylamidobutylthio-guanosine- 3', 5'- cyclic monophosphate} 8- Methoxyethylamidomethylthio-guanosine- 3', 5'- cyclic monophosphate 8- Methoxyethylamidoethylthio-guanosine- 3', 5'- cyclic monophosphate 8- Phenylamidomethylthio-guanosine- 3', 5'- cyclic monophosphate 8- Phenylpropylthioguanosine- 3', 5'- cyclic monophosphate 8- (3- Butynylthio)guanosine- 3', 5'- cyclic monophosphate 8- (4- Acetamidophenylthio)guanosine- 3', 5'- cyclic monophosphate 8- (4- Chlorophenylsulfonyl)guanosine- 3', 5'- cyclic monophosphate 8- (4- Chlorophenylsulfoxide)-guanosine- 3', 5'- cyclic monophosphate 8- ((2- Ethoxyethyl)- 4- thiophenylthio)guanosine- 3', 5'- cyclic monophosphat 8- (4- Thiophenyl- 4''- thiophenylthio)guanosine- 3', 5'- cyclic monophosphate 8- (2- Azidoethylthio)guanosine- 3', 5'- cyclic monophosphate 8- (3- Aminopropyl)- (pentaethoxy)- methylamidomethylthio-guanosine- 3', 5'- cyclic monophosphate 8- (2- Aminoethyl)- (octaethoxy)- amidomethylthioguanosine- 3', 5'- cyclic monophosphate 8- (2- Bromoethyl)- (pentaethoxy)- (4- thiophenylthio)guanosine- 3', 5'- cyclic monophosphate 8- (4- (Propargyloxy- (hexaethoxy)- methyl)- [1, 2, 3]- triazole- 1- yl)- methylamidoethylthio guanosine- 3', 5'- cyclic monophosphate 8- (4- Carboxyphenylthio)guanosine- 3', 5'- cyclic monophosphate 8- (4- Hydroxyphenylsulfonyl)-guanosine- 3', 5'- cyclic monophosphate 8- (4- Isopropylphenylsulfonyl)-guanosine- 3', 5'- cyclic monophosphate 8- (4- Methylcarboxyphenylthio)-guanosine- 3', 5'- cyclic monophosphate 8- Methylsulfonylguanosine- 3', 5'- cyclic monophosphate 8- (1- Bromo- 2- naphthyl)methylthioguanosine- 3', 5'- cyclic monophosphate 8- (2- (1- Benzyl- [1, 2, 3]- triazole- 4- yl)- ethylthio)guanosine- 3', 5'-cyclic monophosphate 8- (3- Fluoro- 5- methoxybenzylthio)guanosine- 3', 5'- cyclic monophosphate 8- Pentafluorobenzylthioguanosine- 3', 5'- cyclic monophosphate 8- Triphenyliminophosphoranyl-guanosine- 3', 5'- cyclic monophosphate 8- (4- Chlorophenyl)guanosine- 3', 5'- cyclic monophosphate 8- (4- Fluorophenyl)guanosine- 3', 5'- cyclic monophosphate 8- (2- Furyl)guanosine- 3', 5'- cyclic monophosphate 8- (4- Hydroxyphenyl)guanosine- 3', 5'- cyclic monophosphate 8- (4- Isopropylphenyl)guanosine- 3', 5'- cyclic monophosphate 8- Phenylguanosine- 3', 5'- cyclic monophosphate β- Phenyl- 1, N²- etheno- 8- thioguanosine- 3', 5'- cyclic monophosphate 8- (2- Aminophenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- Cyclohexylthio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- Cyclopentylthio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate ^{8- (4- Methylphenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate} 8- (4- Methoxyphenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (3- (2- Methyl)furanyl)thio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (7- (4- Methyl)coumarinyl)thio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (2- Naphthyl)thio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate ß- Phenyl- 1, N²-etheno- 8- (2- thiophenyl)thioguanosine- 3', 5'-cyclic monophosphate ß- Phenyl- 1, N²-etheno- 8- (2- phenylethyl)thioguanosine- 3', 5'- cyclic monophosphate 8- Amidomethylthio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'-cyclic monophosphate 8- Carboxymethylthio- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (4- Boronatephenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- Ethylthio- ß- phenyl- 1, N2- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (4- Fluorophenylthio)- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- Methylthio- ß- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate ß- Phenyl- 1, N²- etheno- 8- propylthio- guanosine- 3', 5'- cyclic monophosphate 8- Azidoethylthio- β- phenyl- 1, N²- ethenoguanosine- 3', 5'-cyclic monophosphate ß- Phenyl- 1, N²- etheno- 8- (4- trifluoromethylphenylthio)guanosine- 3', 5'- cyclic monophosphate 8- (4- Chlorophenylsulfonyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (4- Isopropylphenylthio)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (4- Isopropylphenylsulfonyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (4- Chlorophenyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (4- Hydroxyphenyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- (4- Isopropylphenyl)- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphate 8- Bromo- (4- methoxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (4- methyl- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate alpha- Benzoyl- beta- phenyl- 1, N2- etheno- 8- bromoguanosine- 3', 5'- cyclic monophosphate 8- Bromo- (4- chloro- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (3- nitro- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (ß- tert.- butyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (2- methoxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (3- methoxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (2, 4- dimethoxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (4- pyridinyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (3- thiophen- yl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (4- fluoro- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- 1, N2- ethenoguanosine- 3', 5'- cyclic monophosphate 8- Bromo- (3- hydroxy- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (4- hydroxy- ß- phenyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate ^{8- Bromo- (ß- (2, 3- dihydro-1, 4- benzodioxin)- 1, N2- etheno)guanosine- 3', 5'- cyclic} monophosphate 8- Bromo- (4- methylsulfonamido- ß- phenyl- 1, N2- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (4- cyano- β- phenyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (α- phenyl- β- methyl- 1, N²- etheno)guanosine- 3', 5'-cyclic monophosphate β- (4- Aminophenyl)- 1, N²- etheno- 8- bromoguanosine- 3', 5'- cyclic monophosphate 8- Bromo- (6- methoxy- 2- naphthyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (9- phenanthrenyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate 8- Bromo- (4- trifluoromethyl- β- phenyl- 1, N²- etheno)guanosine- 3', 5'- cyclic monophosphate (4- Fluoro- ß- phenyl- 1, N2- etheno)- 8- methylthioguanosine- 3', 5'- cyclic monophosphate (4- Methoxy- ß- phenyl- 1, N2- etheno)- 8- methylthioguanosine- 3', 5'- cyclic monophosphate 1, N²- Etheno- 8- (2- phenylethyl)thioguanosine- 3', 5'- cyclic monophosphate (4- Methoxy- ß- phenyl- 1, N2- etheno)- 8- propylthioguanosine- 3', 5'- cyclic monophosphate β- 1, N²- Acetyl- 8- bromoguanosine- 3', 5'-cyclic monophosphate 8- Bromo-δ- 1, N²- butyrylguanosine- 3', 5'-cyclic monophosphate 8- Bromo- 1- (3- carboxypropyl)guanosine- 3', 5'-cyclic monophosphate 1-[Aminomethyl- (pentaethoxy)- propylamidopropyl]- 8- bromoguanosine- 3', 5'-cyclic monophosphate 1-Benzyl- 8- bromoguanosine- 3', 5'-cyclic monophosphate 2'- O- (2- Azidoacetyl)- 8- bromo- β- phenyl- 1, N²- ethenoguanosine- 3', 5'-cyclic monophosphate; or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 16. The microparticle according to claim 12, wherein the compound is selected from the group consisting of β-1, N2-Acetyl-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-(4-methyl-β-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-(3-thiophen-yl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-(2-naphthyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-(α-methyl-β-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 1-Benzyl-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Thioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Isopropylphenylthio)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Carboxymethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(2-Aminophenylthio)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Phenylamidomethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Carboxymethylthio-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; β-Phenyl-1, N2-etheno-8-phenylamidomethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp- ^isomer; 8-(4-Hydroxyphenylthio)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; 8-(4-Isopropylphenylthio)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; 8-(2-Aminophenylthio)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; β-Phenyl-1, N2-etheno-8-thioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Isopropylphenylthio)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; β-(4-Azidophenyl)-1, N2-etheno-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(2-Aminoethyl)-(octaethoxy)-amidomethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp- isomer; 8-(3-Aminopropyl)-(pentaethoxy)-methylamidomethylthio-guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Azidomethylamidoethylthioguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-(Propargyloxy-(hexaethoxy)-methyl)-[1,2,3]-triazole-1-yl)-methylamidoethylthioguanosine-3′, 5′- cyclic monophosphorothioate, Rp-isomer; 8-Bromo-1-(3-carboxypropyl)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Bromo-δ-1, N2-butyrylguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 1-[Aminomethyl-(pentaethoxy)-propylamidopropyl]-8-bromoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Phenylguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(2-Furyl)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenyl)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-Phenyl-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenyl)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenylsulfoxide)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenylsulfonyl)guanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; 8-(4-Chlorophenylsulfonyl)-β-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphorothioate, Rp-isomer; or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 17. The microparticle according to claim 12 comprising a compound selected from:

or a pharmaceutically acceptable salt thereof, including for example a pharmaceutically acceptable lipophilic salt thereof. 18. The microparticle according to any of claims 10-17, wherein the microparticle is an aggregating surface- treated microparticle.

19. The microparticle according to claim 18, wherein the surface-modified solid aggregating microparticle: (i) has a modified surface which has been treated under mild conditions to partially remove surfactant; (ii) is sufficiently small to be injected in vivo; (iii) aggregates in vivo to form at least one aggregated microparticle depot of at least 500 μm in vivo in a manner that provides sustained drug delivery in vivo for at least one month; and (iv) has a weight loading of about 40% or greater of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof, including pharmaceutically acceptable lipophilic salt thereof. 20. A pharmaceutical composition comprising an implant according to any of claims 2-9 or a microparticle according to any of claims 10-19. 21. A pharmaceutical composition comprising an implant according to any of claims 2-9 and a microparticle according to any of claims 10-19. 22. A method of treating a disease or disorder selected from the group consisting of cancer, cardiovascular disease or disorder, or autoimmune disease or disorder, ocular disorder or disease, or neurodegenerative disease or disorder comprising administering an implant according to any of claims 2-9 to a patient in need thereof. 23. A method of treating a disease or disorder selected from the group consisting of cancer, cardiovascular disease or disorder, or autoimmune disease or disorder, ocular disorder or disease, or neurodegenerative disease or disorder comprising administering a microparticle according to any of claims 10-18 to a patient in need thereof. 24. A method of treating a disease or disorder selected from the group consisting of cancer, cardiovascular disease or disorder, or autoimmune disease or disorder, ocular disorder or disease, or neurodegenerative disease or disorder comprising administering a pharmaceutical composition according to any of claims 20-21 to a patient in need thereof. 25. The method according to any one of claims 22-24, wherein the ocular disorder or disease is retinal dystrophy. 26. The method of claim 25, wherein retinal dystrophy is retinitis pigmentosa. 27. A method of treating a disorder comprising administering an implant according to any of claims 2-9; a microparticle according to any of claims 10-19; or a pharmaceutical composition according to any of claims 20-21 to a patient in need thereof, wherein the disorder is selected from: a) retinitis pigmentosa or another hereditary disease of the retina; b) secondary pigmentary retinal degeneration as results of a metabolic or neurodegenerative disease, a syndrome or an eye disease; c) diseases of the retina comprising diabetic retinopathy, age related macular degeneration, macular Hole/Pucker, ocular malignancies, retinoblastoma, retinal d^{etachment and river blindness;} d) neuronal or neurodegenerative disorders, stroke, anosmia, inflammatory and neuropathic pain, axonal regrowth and recovery after spinal cord injury, e) parasitic diseases such as malaria, African trypanosomiasis, and Chagas disease, and f) cardiovascular diseases, hypotension, cancer, or acute shock. ^{28. The method of any one of claims 22-27, wherein the neurodegenerative disorder is selected from} stroke, anosmia, inflammatory and neuropathic pain, axonal regrowth, and spinal cord injury. 29. The method of claim 28, wherein the neurodegenerative disorder is a stroke. 30. The method of claim 28, wherein the neurodegenerative disorder is anosmia. 31. The method of claim 28, wherein the neurodegenerative disorder is inflammatory and neuropathic pain. 32. The method of claim 28, wherein the neurodegenerative disorder is axonal regrowth. 33. The method of claim 28, wherein the neurodegenerative disorder is a spinal cord injury. 34. The microparticle according to claim 1, wherein the cGMP analogue is: 8-bromo-(4-methyl-β-phenyl-1,N2-etheno)guanosine-3’,5’- cyclic monophosphorothioate, Rp- isomer, N-benzyl-2-(benzylamino)ethan-1-aminium salt (compound 188-BEZ); or 8-bromo-(4-methyl-β-phenyl-1,N2-etheno)guanosine-3',5'- cyclic monophosphorothioate, Rp- isomer, N-benzyl-2-phenylethan-1-aminium salt (compound 188-BEN); or 8-bromo-(β-phenyl-1,N2-etheno)guanosine-3',5'-cyclic monophosphorothioate, Rp-isomer which is N-benzyl-2-(benzylamino)ethan-1-aminium salt (compound 221-BEZ); or 8-bromo-(β-phenyl-1,N2-etheno)guanosine-3',5'-cyclic 20 monophosphorothioate, Rp-isomer, N-benzyl-2-phenylethan-1-aminium salt (compound 221-BEN), preferably 188-BEZ or 221-BEZ, more preferably 188-BEZ. 35. The microparticle according to claim 1 or 34, wherein the microparticle comprises about 15-25 wt.- % of the cGMP analogue, preferably about 18-22 wt.-%.

36. The microparticle according to claim 1 or 34 or 35, wherein the PLGA is PLGA₄₀₀₀₀ to PLGA₁₀₀₀₀₀, preferably PLGA₆₅₀₀₀ to PLGA₈₅₀₀₀₀, more preferably PLGA₇₅₁₂₅. 37. The microparticle according to claim 1 or 34-36, wherein the PLGA-PEG comprises a PEG block that is PEG_2k to PEG_10k, preferably PEG_3k to PEG_8k such as PEG_5k, and/or wherein the PLGA-PEG comprises a PLGA block that is PLGA₃₀₀₀ to PLGA₈₀₀₀ such as PLGA₅₀₅₀. 38. The microparticle according to claim 1 or 34-37, wherein the polymer composition comprises about 98-95.5 wt.% PLGA and about 0.5-2 wt.-% PLGA-PEG. 39. The microparticle according to claim 1 or 34-38, wherein the polymer composition comprises about 99 wt.% PLGA and about 1 wt.-% PLGA-PEG. 40. The microparticle according to claim 1 or 34-39, wherein the PLGA comprises terminal carboxylic acid moieties, or is acid capped. 41. The microparticle according to claim 1 or 34-40, wherein the cGMP analogue is covalently linked to the PLGA, preferably to terminal carboxylic acid moieties in the PLGA. 42. Use of 188-BEZ or 188-BEN or 221-BEZ or 221-BEN in the manufacture of a microparticle, preferably a polymeric microparticle.