WO2014179295A1 - Controlled release pharmaceutical formulations - Google Patents
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- C07—ORGANIC CHEMISTRY
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- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
Definitions
- the present invention relates to controlled release formulations of self- polymerizing drug moieties comprising one or more carboxylic acid groups and one or more hydroxy 1 groups.
- U.S. Patent No. 7,417,070 discloses certain esters, salts, and sustained release oral compositions comprising treprostinil.
- compositions some of which include treprostinil.
- a drug release polymer wherein the polymer includes an active pharmaceutical moiety which comprises at least one carboxylic acid group and at least one hydroxyl group.
- the active pharmaceutical moieties form monomeric units covalently bonded to each other to form a polymer backbone, and the active pharmaceutical moieties are capable of being released at a rate that is dependent on the extent of biodegradation of the polymer backbone.
- the active pharmaceutical or drug moiety is a prostacyclin compound.
- the prostacyclin compound is selected from epoprostenol, treprostinil, beraprost, iloprost, cicaprost, or a prostaglandin 12.
- the prostacyclin compound is treprostinil.
- the prostacyclin compound has the following structure (I)
- Z 1 and Z 2 each independently represents an O or C3 ⁇ 4;
- n l, 2, or 3;
- R 1 represents a H or an acid protective group
- R 2 and R 3 each independently represents a H or a hydroxyl protective group
- R 4 represents H and the other represents a C e alkyl
- R 5 represents a Ci_6 alkyl group or C2-8 alkynylene group.
- the prostacyclin compound forms various configurations of drug release polymers via formation of ester bonds between the carboxylic acid group on one prostacyclin molecule and the hydroxyl group on the other prostacyclin molecule.
- the polymer in addition to the prostacyclin compound, also includes a co-monomer covalently bonded to the carboxylic acid group of one drug moiety and the hydroxyl group of a second drug moiety.
- the co-monomer is 6-hydroxyhexanoic acid or hydroxyl-polyethylene glycol-carboxylic acid.
- the recurring unit in the polymer has a structure selected from the group consisting of Formula (Ha), (lib) and (lie):
- a pharmaceutical composition comprising the drug release polymer and a pharmaceutically acceptable excipient.
- the drug release polymer upon administration of the pharmaceutical composition to a patient, degrades initially into inert polymer fragments, which thereafter give rise to active drug only after a time interval.
- the pharmaceutical composition exhibits accelerating release of the drug moiety.
- the pharmaceutical composition is used as a medicament for injection, preferably subcutaneous or intramuscular injection. In other embodiments, the pharmaceutical composition is used as a medicament for implant.
- a method for producing a drug release polymer comprising esterifying a drug moiety which comprises at least one carboxylic acid group and at least one hydroxyl group prostacyclin compound in the presence of a coupling agent and a catalyst.
- the coupling agent is N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide or ⁇ , ⁇ '-Dicyclohexylcarbodiimide.
- the catalyst is 4-(Dimethylamino)pyridine.
- the method further comprises blocking one or more carboxylic acid groups in excess of one carboxylic group, prior to esterification.
- the method further comprises blocking one or more hydroxyl groups, in excess of one hydroxyl group, prior to esterification.
- the one or more hydroxyl groups are blocked using trimethylsilyl chloride or ?-butyldimethylsilyl chloride.
- a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions comprising administering to said patient a diagnostically and/or therapeutically effective amount of the drug release polymer or a pharmaceutical composition containing the drug release polymer.
- the drug moiety is treprostinil
- the method is a method for treating pulmonary hypertension in a patient in need thereof.
- Figure 1 shows one embodiment of the structure of a drug moiety forming a repeating unit in the polymer.
- Figure 2 shows one embodiment of the polymer of the invention, wherein both the ring hydroxyl and the chain hydroxyl of treprostinil are involved in backbone bonds of the polymer leading to a branched structure.
- Figure 3 shows one embodiment of a linear polymer formed by utilizing a 'ring- hydroxyl-b locked' form of treprostinil and involving only the chain hydroxyl and not the ring hydroxyl.
- Figure 4 shows another embodiment of a linear polymer formed by utilizing a 'chain-hydroxyl-blocked' form of treprostinil and involving only the ring hydroxyl and not the chain hydroxyl.
- Figure 5 shows one embodiment of a heteropolymer of treprostinil formed in the presence of 6-hydroxyhexanoic acid as a co-monomer.
- Figure 6 shows one embodiment of a heteropolymer of treprostinil formed in the presence of a hydroxyl-PEG-carboxylic acid co-monomer.
- C m - n such as Ci-u, Ci-s, or Ci-6 when used before a group refers to that group containing m to n carbon atoms.
- alkoxy refers to -O-alkyl
- halo or “halogen” or even “halide” can refer to fluoro, chloro, bromo, and iodo.
- alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms (i.e., C1-C12 alkyl) or 1 to 8 carbon atoms (i.e., Ci-Cs alkyl), or 1 to 4 carbon atoms.
- This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), w-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), w-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), ?-butyl ((CH 3 ) 3 C-), «-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
- linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), w-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-),
- aryl refers to a monovalent, aromatic mono- or bicyclic ring having 6- 10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom.
- prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound.
- prodrugs include, but are not limited to, derivatives of a compound that include biohydrolyzable groups such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues (e.g., monophosphate, diphosphate or triphosphate).
- hydrate is a form of a compound wherein water molecules are combined in a certain ratio as an integral part of the structure complex of the compound.
- solvate is a form of a compound where solvent molecules are combined in a certain ratio as an integral part of the structure complex of the compound.
- “Pharmaceutically acceptable” means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
- “Pharmaceutically acceptable salts” mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
- organic and inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic
- Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like. Included are pharmaceutically acceptable salts or compounds of any of the Formulae herein.
- the phrase "pharmaceutically acceptable salt,” as used herein, refers to a pharmaceutically acceptable organic or inorganic acid or base salt of a compound.
- Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 -disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate,
- phosphate/diphosphate picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, subsalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.
- protecting group or “protective group” is used as known in the art and as demonstrated in Greene, Protective Groups in Organic Synthesis.
- hydroxyl protective group or “hydroxyl protecting group” or “hydroxyl blocking group” refers to the generally understood definition of an alcohol or hydroxyl protecting group as defined in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991 (hereinafter “Greene, Protective Groups in Organic Synthesis”).
- acid protective group or “acid protecting group” or “carboxylic acid blocking group” refers to the generally understood definition of protection for the carboxylic acid group as defined in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991 (hereinafter “Greene, Protective Groups in Organic Synthesis ' ").
- drug polymers are provided for sustained release of an injected or implanted drug in order to achieve favorable pharmacokinetics with minimal peak-to- trough variation of drug concentration in the blood.
- the drug polymers are designed to achieve a better approximation of the ideal continuous, steady, blood concentration profile which is approached most closely by continuous drug infusion, and which is difficult to achieve with current sustained release methodologies.
- the present technology is adaptable to any drug containing one or more carboxylate groups and additionally one or more hydroxyl groups (i.e., primary or secondary alcohols).
- the drug itself acts as a monomer. Therefore, in one embodiment, the only ingredient in the polymer is the drug molecule, minus abstracted water molecules generated in the formation of ester bonds during polymer formation.
- the ester bonds being metastable, will hydrolyse in the presence of water in body fluids following administration, causing breakdown of the polymer, resulting in the re-generation of monomeric drug molecule from the inactive polymer prodrug, in a staged manner, via oligomeric, inactive, intermediates.
- Prostacyclin compounds are an example of a drug containing one or more carboxylate groups and one or more hydroxyl moieties. These include both stable prostacyclin compounds such as treprostinil and beraprost (and the 314d active isomer of beraprost) and less-stable prostacyclin compounds such as prostacyclin (prostaglandin- ⁇ ) itself.
- the significant peak-to-trough variation in blood concentration that remains may not be markedly better than other alternative modes of sustained delivery of the free compound (such as sustained release oral tablet formulations), resulting in periods of inadequate efficacy or undesirable toxicity of the drug, when blood concentrations are in 'trough' or 'peak' zones (respectively).
- the new drug polymers of the present technology provide solutions to the problem of residual peak-to-trough variation inherent in existing drug-polymer conjugate systems.
- a drug release polymer is provided, wherein the polymer includes a drug moiety which comprises at least one carboxylic acid group and at least one hydroxyl group.
- the drug moiety is a prostacyclin compound.
- the drug release polymer is a controlled release polymer.
- the drug moieties form monomeric units that are covalently bonded to each other to form the polymer backbone, and wherein the drug moieties are capable of being released in a manner dependent upon the extent of breakdown of the polymer backbone.
- the drug moiety is an integral part of the polymeric chain and is embedded and comprises the fabric of the polymer.
- the drug release polymer includes linear and branched homopolymers and heteropolymers of a prostacyclin compound.
- Any prostacyclin which has one or more carboxylic acid group and one or more hydroxyl group can be utilized for the drug release polymer.
- Examples of such prostacyclin compounds include, but are not limited to, epoprostenol, treprostinil, beraprost, iloprost, cicaprost, prostaglandin 12.
- the prostacyclin compound is treprostinil.
- the prostacyclin compound is beraprost.
- the prostacyclin compound has the following structure (I)
- Z 1 and Z 2 each independently represents an O or CH 2 ;
- n l, 2, or 3;
- R 1 represents a H or an acid protective group
- R 2 and R 3 each independently represents a H or a hydroxyl protective group
- R 4 represents H and the other represents a C e alkyl
- R 5 represents a Ci-6 alkyl group or C2-8 alkynylene group.
- Z 1 is a O and Z 2 is CH 2 . In some embodiments, Z 1 is CH 2 and Z 2 is O.
- R 1 is H. In other embodiments, R 1 is an acid protective group.
- Suitable carboxylic acid protective groups R 1 are known in the art and include the ester derivatives of a carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Exemplary groups for the protection of the carboxylate group include allyl, methyl, ethyl, nitrobenzyl, dinitrobenzyl, tetrahydropyranyl, methoxybenzyl,
- R 1 is a benzyl, tertiary-butyl, dime
- R 2 and R 3 each independently is a H. In other words, R 2 and R 3 each independently is a H.
- R 2 and R 3 each independently is a hydroxyl protective group.
- Suitable groups for the protection of the hydroxyl groups are known in the art and include, but are not limited to, methyl, ?-butyl, tetrahydropyranyl, benzyl, methoxybenzyl, nitrobenzyl, tertiary butyl dimethyl silyl (TBDMS), trimethylsilyl (TMS), tertiary methyl dimethyl silyl group, methoxymethyl, methoxyethoxymethyl, allyl, trityl, ethoxy ethyl, 1 -methyl- 1-methoxy ethyl, tetrahydropyranyl, or tetrahydrothiopyranyl group.
- the hydroxy protective group is tetrahydropyranyl (THP).
- R 2 and R 3 each independently is a tetrahydropyranyl, benzyl, methoxybenzyl, nitrobenzyl, tertiary butyl dimethyl silyl or a tertiary methyl dimethyl silyl group.
- n is 1 and p is 1. In other embodiments, m is 3 and p is 0.
- the prostacyclin compound forms various configurations of drug release polymers via formation of ester bonds between the carboxylic acid group on one prostacyclin compound and the hydroxyl group on the other prostacyclin compound.
- the drug can be designed to be a homopolymer in three basic forms, or a number of heteropolymer variants made with different co-monomers.
- Treprostinil is the active ingredient in Remodulin ® , and is described in Moriarty, et al in J. Org. Chem. 2004, 69, 1890-1902, U.S. Pat. Nos. 6,441,245, 6,528,688, 6,700,025, and 6,809,223, which are incorporated by reference in their entirety.
- Treprostinil has the following structure (II):
- Treprostinil has one carboxylic acid group and two hydroxyl groups- one ring hydroxyl group and one chain hydroxyl group.
- Various homopolymers and heteropolymers can result from the reaction between the carboxylic group with either the ring hydroxyl or the chain hydroxyl group of various treprostinil moiety to form esters.
- Blocking agents can be used to selectively block either the ring hydroxyl or the chain hydroxyl group resulting in the formation of various linear or branched homopolymers.
- Fig. 1 shows a structure of a preferred drug moiety forming a repeating unit in the polymer, wherein the letter variables of the formula have the same meaning set forth in paragraph 6.
- Exemplary homopolymers and heteropolymers of treprostinil are depicted in Figs. 2-6, wherein all inter-monomer bonds are ester bonds.
- the drug release polymers of the present technology function as prodrugs, whereby they release the pharmacologically active form of the drug moiety by cleavage of the temporary ester group linkages formed between the drug moieties.
- the drug release polymers of the present technology have a polarity, just like important biopolymers such as DNA, RNA and protein. Whereas nucleic acids have a 5 ' and a 3 ' end, and proteins have an N-terminus and a C-terminus, which dictate their direction of growth during biosynthesis, so the present polymers have a 'carboxylate end' and a 'hydroxyl end.
- Polymer chain length can be controlled by various methods known in the art, e.g., by incorporating various amounts of chain terminating reagents.
- a drug moiety with carboxylate protection methyl, nitrile
- Increasing amounts of such chain terminating agents incorporated into a polymerization mixture would give rise to shorter polymer lengths on average.
- a drug moiety with two blocked hydroxyls and a free carboxylate can be used to limit the length of the polymer.
- incorporation of methanol or ethanol (or other primary, secondary or tertiary alcohols) into the reaction mixture after an interval can be used to stop the polymerization reaction. The time at which the reaction is stopped can be altered to create polymers of different lengths. In general, longer reaction times will result in longer polymers. It may or may not be appropriate or necessary to remove the chain terminating groups.
- a methyl ester blocking group on a carboxylate could be left on, whereas a tertiarybutyldimethylsilane, which can be toxic if liberated, can be removed before administration to humans.
- chain terminating compounds can be used, including those that stop chain elongation at the 'carboxylate end,' and those that stop chain elongation at the 'hydroxyl end,' or a mixture of the two can be used if needed. Chain length can also be controlled by controlling the esterification reaction time.
- the drug release polymer can have any suitable length depending on the desired physiochemical property or the mode of administration.
- DM dimer, where all molecules have two monomeric moieties and there is no dispersity
- DM may conveniently be in the range 1.1-1.3. Where it is particularly important to have a rather uniform distribution of polymer lengths, e.g. for an accelerating release soluble polymer designed to form a circulating depot in the bloodstream, this may be controlled during polymerization by the timed addition of suitable terminating agents, such as those described herein, to achieve values of D M in the range 1.01-1.1
- a method for producing a drug release polymer comprises esterifying a monomeric drug moiety which has one or more carboxylic acid groups and one or more hydroxyl groups.
- the method comprises esterifying a prostacyclin compound.
- Suitable drug candidates for polymer formation by ester bond formation include drugs which have at least one alcohol (hydroxyl) group, and at least one carboxylate group.
- the drug has two or more hydroxyl groups.
- the drug has more than one hydroxyl group, most favorably it does not have more than one carboxylate because this may result in the formation of non-extendible dimers rather than the desired polymeric product.
- the drug has more than one carboxylate groups and one hydroxyl group. In such cases, protection of the additional carboxylate groups is required in order to allow for productive polymer formation.
- the various polymer types described herein can have differing degrees of polymerization, from dimer to trimer and beyond, to potentially contain hundreds of monomeric moieties per polymer. All of these polymers, including small oligomers, such as dimer and trimer, can be useful for drug delivery purposes. In their simplest form, where the only monomeric ingredient is drug molecule, these polymers or prodrugs have the unique quality of having no additional chemical moieties over and above the original drug substance. Therefore, their toxicological properties would not vary significantly from the original drug substance. In the case of prostacyclin compounds, such as those described herein, their dose- limiting toxicity would be the pharmacological toxicity of the prostacyclin class of compounds. Such adverse effects, if any, can be managed more effectively by sustained or accelerating release of the drug from the polymer.
- the esterification process is conducted using the Steglich esterification reaction.
- the method comprises esterifying a prostacyclin compound in the presence of a coupling agent and a catalyst.
- the coupling agent is N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide or ⁇ , ⁇ '-Dicyclohexylcarbodiimide.
- the catalyst is 4-(Dimethylamino)pyridine.
- the polymerization reaction is conducted using a Steglich esterification process as described by H5fle, G., W. Steglich, et al.
- An alternative method of polymer formation is to conduct the polymerizing esterification reaction using acidic alumina and methanesulfonic acid (A ⁇ Os/MeSOsH (AMA)) as described in detail by Sharghi et al. (H. Sharghi, Babak Kaboudin, J.Chem. Research (S), 1998, pp. 628-629).
- a ⁇ Os/MeSOsH AMA
- This method is particularly suited to creating monoesters from a carboxylate compound and a diol, such as ethylene glycol, however it should be recognized in the present invention that prostacyclin drugs such as treprostinil and beraprost, having both carboxylate and diol functionalities in the same molecule, in the absence of other extraneous diol compound, and unlike the compounds studied by Sharghi, will polymerize. Unlike Steglich esterification, which can be conducted at room temperature, the Sharghi method requires heating at about 80 °C.
- AI 2 SO 3 (a solid) and MeSOsH (a liquid) are used in molar ratio of 1 :5 at 80 °C for between 7 and 120 mins, or until an acceptable yield of product is obtained.
- the method further comprises blocking one or more of the additional carboxylic acid and/or hydroxyl groups. In some embodiments, the method further comprises blocking one or more of the additional carboxylic acid groups. In other embodiments, the method further comprises blocking one or more of the additional hydroxyl groups.
- the polymer can be prepared by ester bond formation methods known in the art.
- the drug can be acidified in aqueous solution using a strong acid such as, e.g., para-toluenesulfonic acid or sulfuric acid, upon which it will undergo Fischer esterification (Emil Fischer, Arthur Speier, Chemische Berichte 1895, 28: 3252- 3258).
- para-Toluenesulfonic acid a solid
- sulfuric acid a liquid
- the acidification is conducted in aqueous medium at a pH less than 2.0, e.g., pH approx 1.0 in aqueous para-Toluenesulfonic acid at a concentration of 0.5 M..
- aqueous medium at a pH less than 2.0, e.g., pH approx 1.0 in aqueous para-Toluenesulfonic acid at a concentration of 0.5 M..
- non-polymerizing reactants e.g., ethanol and acetic acid to form ethyl acetate
- the resulting drug homopolymer (or heteropolymer formed from 6-hydroxy-hexanoic acid and drug) is likely to be insoluble, it will be removed from the aqueous reaction mixture by spontaneous precipitation while forming, which will inhibit the reverse reaction, tending to drive the reaction towards completion.
- the precipitated polymer may be recovered by filtration and washing with water to remove para-Toluenesulfonic acid. Heating, up to about 80 °C, may be required to drive the reaction, which may require from 1 to 8 hours to give acceptable yield.
- OH-R' represents either the ring or chain hydroxyl of a prostacyclin drug molecule, with R' representing the remainder of the molecule.
- the other reactant represents the carboxylate end of a second prostacyclin molecule.
- 'R' represents the moiety of a prostacyclin molecule except for the carboxylate.
- the polymer forming esterification reactions can be conducted at or near room temperature in order to avoid damage to the monomer and polymeric material.
- the esterification reactions are conducted at suitable temperature, e.g., at about 100 °C or below, at about 80 °C or below, at about 70 °C or below, at about 60 °C or below, at about 50 °C or below, at about 40 °C or below, at about 30 °C or below, or at about 25 °C or below.
- the esterification reaction is conducted at room temperature. In some embodiments, the esterification reaction is conducted at about 25 °C.
- a linear polymer can be formed is using a 'ring-hydroxyl- blocked' form of prostacyclin. This is because the ring hydroxyl is the more reactive of the two hydroxyls, and its selective blockade is easier to achieve.
- the carboxylate must be temporarily protected, in order to prevent reaction of the carboxylate with the hydroxyl- blocking reagent.
- Fig. 3 depicts a linear polymer formed by utilizing a 'ring-hydroxyl- blocked' form of treprostinil and involving only the chain hydroxyl and not the ring hydroxyl. The lesser reactivity of the available chain-hydroxyl groups (compared to the ring hydroxyl groups) will lead to slower reaction rates for this type of polymer.
- the chain-hydroxyl group can be blocked following the temporary protection of the carboxylate group, leading to the formation of another linear polymer depicted in Fig. 4.
- the rate and extent of polymerization of this form is anticipated to be greater than for the other homopolymers.
- the blocking or protective group can either be removed or retained on the polymer.
- removal of the blocking or protective group after polymerization, under conditions that do not hydrolyze or otherwise break the ester bonds, will give rise to different forms of regular (i.e., linear or unbranched) drug homopolymer.
- the protective group is not toxic, it can be left on, and the protected drug polymer used as a therapeutic agent.
- the protective group will likely undergo a slow spontaneous aqueous hydrolysis in vivo. In cases where the protective group is toxic, it must first be removed before the polymer can be used as a therapeutic agent.
- linear polymers may be formed by the use of protecting groups to temporarily block the reactivity of particular target groups in the prostacyclin or prostacyclin-drug molecule.
- the linear polymers are prepared by creating prostacyclin structures wherein only one of the two hydroxyl (alcohol) groups is blocked (i.e., the ring hydroxyl and the chain hydroxyl), leaving a molecule in which there are exposed a single reactive carboxylate and a single reactive hydroxyl.
- Suitable groups for the protection or blocking of hydroxyl and carboxylate group are known in the art and are disclosed herein.
- particular ester groups that allow selective removal of carboxylate-protecting groups by enzymatic methods are known in the art, and include, but are not limited to heptyl esters (C 7 Hi 5 0 2 CR), 2-N-(morpholino)ethyl esters, choline esters (Me 3 N CH 2 CH 2 0 2 Br ⁇ ) (Sander, J. and H.
- the hydroxyl blocking or protective group is a silyl ether group.
- Suitable silyl ether blocking groups include, e.g., trimethylsilyl (TMS), i-butyldimethylsilyl (TBDMS), introduced as the chlorides TMSC1, TBDMSCl, which are spontaneously and selectively reactive towards hydroxyl groups.
- the chloride forms react under mild conditions conducive to stability of the drug molecule e.g., TBDMSCl, imidazole, dimethylformamide, 25 °C, lOh.
- the differential reactivity of different hydroxyl groups in a compound can be utilized to achieve selective blockade of one hydroxyl as opposed to other hydroxyl groups in the compound (Wuts 2007).
- the blocking groups can be utilized to selectively block the more-reactive ring hydroxyl compared.
- the blocking groups can be utilized to selectively block the chain hydroxyl of a prostacyclin compound.
- Suitable groups for the blocking or protecting the carboxylic acid groups include, but are not limited to, allyl, methyl, ethyl, nitrobenzyl, dinitrobenzyl, tetrahydropyranyl, methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl, trimethylbenzyl, pentamethylbenzyl, methylenedioxybenzyl, benzhydryl, 4,4'
- methoxytrityl 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenyl-prop-2-yl,
- the carboxylic acid blocking or protective group is the 2-N-(morpholino)ethyl ester, which is removable enzymatically.
- Selective blockade can be achieved as follows, using treprostinil as an example.
- carboxylate-protected treprostinil with TBDMS or TMS under gentle conditions (e.g., TBDMSC1, DMAP, Et 3 N, DMF, 25 °C, 12h), using stoichiometric amounts or modest molar excess of blocking agent, it will be possible to obtain selective derivatization of the ring hydroxyl. Enzymatic removal of the carboxylate protection would then yield a treprostinil derivative with free chain hydroxyl but with a blocked ring-hydroxyl and having a free carboxylate.
- Such a process would be conducive to producing a linear polyester polymer (or co-polymer), wherein only the chain hydroxyl is involved in formation of the backbone ester bonds. Subsequent deprotection would yield a linear polymer devoid of protecting groups.
- selective blockade of the chain hydroxyl group can also be achieved by taking advantage of the differential base lability of TBDMS and TMS ethers.
- TBDMS ether groups are known to be 10 4 times more stable to basic hydrolysis than the TMS ether groups. Reaction of carboxylate-blocked treprostinil under the gentle conditions with TMSC1, as discussed herein, will yield a treprostinil molecule with a TMS ether on the ring hydroxyl. Further reaction with TBDMS will produce a double-blocked molecule wherein the chain hydroxyl is blocked with TBDMS.
- TBDMS group Subsequent removal of the remaining TBDMS group will give rise to a polymer wherein the only constituents are treprostinil moieties.
- Various strategies for the selective protection and deprotection of multiple hydroxyls using silyl ethers are known in the art (e.g., Crouch, 2013), some which are suitable for the removal of protective groups such as TBDMS groups from the polymer.
- Suitable mild conditions for deprotection of the linear homopolymers include those which avoid breakage of the inter-monomer ester bonds.
- acid and base hydrolysis are commonly used to remove silyl ether protecting groups, such conditions are also liable to hydrolyze the desirable inter-monomer ester bonds. Therefore, in some embodiments, mildly acid or mildly base hydrolysis conditions may be appropriate for the removal of the protecting groups from the polymer.
- methods for the deprotection of silyl-ether protected hydroxyls are those which do not use acid or base conditions for removal of the protecting group, and which are more conducive to deprotection of the polymers while preserving their backbone ester bonds.
- Examples of such methods include those which utilize catalytic fluoride under neutral conditions (DiLauro, et ah, Journal of Organic Chemistry, 2011 76(18), 7352-7358.). This method will particularly be suitable for the deprotection of the polymers, i.e., removal of TMS or TDBMS, since it will likely preserve the inter-monomer ester bonds.
- Other examples include use of sulfated Sn02 (Bhure et ah Synthetic Communications 2008, 38(3), 346-353) and Selectflour (Shah, S. T. A., S. Singh, et al. (2009), Journal of Organic Chemistry, 2009, 74(5), 2179-2182) for the removal of silyl ether protecting groups from polymers described herein, without risk of hydrolysis of inter-monomer ester bonds.
- the physical form and characteristics of the polymer can be adapted to resemble the properties of other known polymers by polymer formation in the presence of excess amounts, in molar terms, of co-monomers to form a heteropolymer.
- the polymer in addition to the drug moiety, also includes one or more co-monomers.
- the co-monomer is covalently bonded to the carboxylic acid group of one drug moiety and the hydroxyl group of a second drug moiety.
- the co-monomers are selected so as to modify the properties of the drug release polymer in a desired manner.
- co-monomers examples include, but are not limited to, 6-hydroxyhexanoic acid, hydroxyl-polyethyleneglycol- carboxylic acid, lactic acid, glycolic acid and beta-hydroxybutyrate.
- the polymer is designed to adapt to properties of a Polycaprolactone containing composition.
- Fig. 5 shows a heteropolymer of treprostinil formed in the presence of 6-hydroxyhexanoic acid as a co-monomer.
- 6-hydroxyhexanoic acid is the open form of caprolactone (a cyclic ester) which is used to form the polymer polycaprolactone using catalyzed ring-opening polymerization method.
- the 6-hydroxyhexanoic acid is incorporated as a co-monomer during the Steglich esterification of unblocked treprostinil or blocked treprostinil. Incorporation of a molar excess (e.g., lOx) of the 6-hydroxyhexanoic acid gives rise to a polymer whose predominating characteristic resembles that of polycaprolactone.
- Polycaprolactone can be melted at 60 °C allowing it to be molded into diverse shapes for drug delivery (e.g., for a solid macro-implant delivered subcutaneously or as a stent).
- the caprolactone-like heteropolymer e.g., as depicted in Fig. 5
- the caprolactone-like heteropolymer can be formed from emulsions as a nano- or micro-particlate suspension, if required, without recourse to heat- melting, which imposes a finite risk of damaging the drug substance.
- Other biologically compatible hydroxyl-containing carboxylic acid co-monomers, such as lactic acid and others mentioned herein, would also be suitable for the purpose.
- Polycaprolactone solid macro-implants have a longevity of up to three years in vivo and are the basis of several FDA approved products (Woodruff, M. A. and D. W.
- the polycaprolactone-like treprostinil heteropolymer (and the poly-lactide-like treprostinil hetropolymer) could be used to achieve a very steady rate of release (achieving classic zero order pharmacokinetics) determined by its surface area.
- the polycaprolactone-like treprostinil polymer can be administered as a solid implant.
- the polymer is designed to adapt to properties of a PEG- containing composition, thereby resulting in a water soluble linear polymer.
- Fig. 6 shows the result of co-polymerization of treprostinil in the presence of a hydroxyl- PEG-carboxylic acid co-monomer.
- the PEG co-monomers have an average molecular weight of from about 500 to about 20000, about 800 to about 10000 or about 1000 to about 5000 daltons. In some embodiments, the PEG co-monomers would be in the range of about 1 to about 5 kDa.
- the PEG-heteropolymer can be administered using suitable methods discussed herein.
- the PEG-heteropolymer would be most amenable to be administered as a subcutaneous injection, with the aim of avoiding injection-site reactions and achieving 'accelerating release' in the bloodstream to counteract the exponential decay of the drug-polymer conjugate in circulation.
- the drug release heteropolymers so formed can have an average molecular weight of from about 10,000 to about 200,000 daltons.
- the PEG heteropolymers have an average molecular weight of from about 15,000 to 150,000, about 20,000 to 100,000, about 25,000 to 75,000, from about 30,000 to 50,000.
- polymers such as monomethoxy-PEG-OH or monomethoxy-PEG-COOH can be used as chain termini individually or collectively, as well as chain terminating reagents.
- Such polymers when used in chain termination, can be added in excess after a timed interval of reaction progress. In this manner it will be possible to achieve polymers with narrow dispersity i.e. >M in the range 1.01-1.1. Incorporation of these PEG moieties depends on their relative concentration in the reaction mixture and can impart solubility to the resulting polymer.
- the PEG moieties When used as chain termini, the PEG moieties have a suitable average molecular weight in the range of about 5,000 to about 100,000 daltons, about 10,000 to about 60,000 daltons, about 20,000 to about 40,000 daltons, or about 25,000 to about 30,000 daltons.
- the use of a monomethoxy-PEG-OH in the Steglich esterification would result in a drug homopolymer with a PEG on the carboxylate end of the polymer.
- Analogous use of a monomethoxy-PEG-COOH would result in a drug homopolymer with a PEG on the other end.
- di-hydroxy PEG forms i.e., having a hydroxyl group at both ends of a linker PEG chain
- prostacyclin drug molecules having protected or unprotected groups. This would produce symmetrical polymer structures in which the PEG is located centrally, and flanked by homopolymers of the drug moiety either side, oriented in the 'carboxylate-in' orientation as described below: - prostacyclin homopolymers
- PEG-prostacyclin polymers prepared by these methods will have unusually high drug loading capabilities compared to multi-arm PEGs which have a maximum loading capacity of one drug molecule per arm (e.g., 4). No such limit applies to these polymer forms.
- the polymers prepared using the methods described herein can be suitably characterized by methods known in the art.
- the detailed physicochemical properties of the drug release polymers disclosed herein, e.g., solubility, rates of hydrolysis in vivo, can be experimentally determined.
- suitable qualities can be selected for a given drug delivery method, e.g., for subcutaneous administration, for incorporation into stents, etc..
- the rate of drug release can be controlled by manipulating the surface area of the drug-polymer solid.
- the drug release polymers can be designed to be in a nanoparticle, microparticle or macro form.
- the rate of release of the drug will be maximal when it is made in nanoparticle form (e.g., 1 nm to 999 nm diameter). In microparticle form (e.g., 10 ⁇ diameter) it will be at least an order of magnitude slower, and in macro-implant form (e.g., as a mesh, sheet or cylinder), it will be slower still.
- the release kinetic can be manipulated by choosing the shape of the implant (e.g., a mesh or sheet instead of a cylinder) in order to achieve an optimal surface area matched to the needs of drug release rate.
- the rate of drug release is generally proportional to the surface area of the implant and independent of the mass of the implant.
- the rate of drug release in these macro implementations is determined predominantly by the surface area, and not by the rate of aqueous or enzymatic hydrolysis of the ester bonds.
- the intrinsic rate of bond hydrolysis which determines release rate
- the intrinsic rate of bond hydrolysis can be adjusted only in a quantal manner by changing the chemical composition of the polymer-drug conjugate, namely the drug-linker element.
- the present drug release polymers are, therefore, more adjustable.
- the drug release polymer of the present technology may be administered conveniently in a small volume by bolus injection of a dose lasting one or more days.
- it may be made as an implant with duration of action up to three years, with no risk of potentially dangerous bolus release of drug.
- This approach avoids concerns over the toxicity of polymers, such as PEG in chronic high dosage use, but is also amenable to use with PEG and similar polymers where appropriate. It allows much higher loading in terms of moles of drug per mole of polymer than can be achieved with existing polymer systems.
- the drug polymer of the present technology is, in one aspect, a polyester, although it is designed to be biodegradable and resorbable by the body and can be manufactured under mild conditions conducive to stability of the monomeric drug molecules and their polymerized moieties.
- the physical properties of the polymer differ from that of the parent drug molecule which is water soluble. This is because the major hydrogen bonding elements, i.e., the hydroxyl groups, are engaged in covalent ester bonds and as such, the drug release polymer is likely to be less water soluble than the parent drug molecule.
- the drug release polymer if rendered in nanoparticulate or microparticulate form, the drug release polymer will be suitable for subcutaneous injection. In other embodiments, in
- nanoparticulate form it will also be suitable for intravenous injection.
- the drug undergoes a slow spontaneous hydrolysis by water molecules in the body which accelerates as more bonds are broken. Because cleavage into monomeric forms is not required for solubility, soluble oligomers will escape the injection site at the site of injection sparing injection site pain and inflammatory reactions. Due to the higher reactivity of the ring hydroxyl, it is anticipated that most of the bonds in the polyester homopolymer will involve the ring hydroxyl as opposed to the chain hydroxyl group.
- compositions comprising any of the drug release polymers described herein.
- the composition may include a pharmaceutically acceptable excipient.
- Pharmaceutically acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention.
- excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, a gaseous excipient that is generally available to one of skill in the art.
- Pharmaceutical compositions in accordance with the invention are prepared by conventional means using methods known in the art.
- the drug release polymer is such that the monomeric prostacylin molecular moieties form the entirety of the backbone of the polymer (in the case of a drug
- the drug moieties of the polymer are tethered into the polymer by covalent ester bonds at both ends of the drug molecule moiety, as distinct from being pendant moieties on the end of a polymer chain.
- insoluble polymers of the present invention such as drug homopolymers or heteropolymers made with 6-hydroxyhexanoic acid, being less solvated than PEG-prostacyclin heteropolymers
- the 'fully hydrated' arrangement of the PEG-prostacyclin heteropolymer will not obtain and surface area of solvent exposure to extracellular fluids of the subcutaneous space, or other body compartment and fluid, will be the determining factor in rates of hydrolysis and drug release).
- the hydrolytic behaviour of a soluble polymer of the present invention such as the PEG-prostacyclin heteropolymer and the probabilistic nature of its hydrolysis favouring release of pharmacologically inert fragments in the first instance can best be conceived by reference to the figure below.
- a drug homopolymer of the present invention having 1 1 monomeric units (circles) and 10 inter- monomer bonds (A), at time zero (A) and at linear time intervals (B-H) after exposure to an aqueous environment, such as the extracellular fluid following a subcutaneous injection, whereupon a stochastic process of aqueous hydrolysis will ensue. Numbers to the right indicate number of free drug molecules; numbers to the left indicate number of ends. Initially (A) at time zero, there are only two monomeric moieties in the polymer that can give rise to free drug following a single hydrolytic aqueous hydrolysis event (a 'cut'). These are the end moieties (bold circles).
- the probability that a first cut will give rise to free drug is low therefore (1/5 in the instance of a short polymer such as ' ⁇ '. Following the first cut, which most likely (therefore) takes place at an internal bond, the abundance of end groups capable of giving rise to free drug upon a new cut, has doubled (B), as has the probability that a new cut will give rise to free drug. However, the probability that a new cut will occur at an internal bond is still higher than the probability that a cut will take place at an end bond. Following the next cut, the products are 'C, but still (in this particular stochastic instance) there is no free drug released.
- the probability of an initial cleavage event giving rise to free drug is 1/50, such that the lag phase in release of free drug from such a polymer is longer, per unit mass of polymer, than is the case for shorter polymers such as 'A' which have a greater abundance of ends (expressed as ends per unit mass of polymer, or per mole of monomer).
- ends per unit mass of polymer or per mole of monomer.
- the behaviour of the drug homopolymer may be contrasted to that of pendant polymer constructs (as described in the Ascendis patents cited earlier) wherein there is a fixed rate of drug release, and every cleavage event gives rise to liberation of a free drug molecule.
- the principle of accelerating drug release (with an initial lag phase) will apply to soluble forms of the polymers of the present invention, particularly those made as heteropolymers with PEG moieties as co-monomers.
- This 'lag' in the generation of free drug has two important effects. First, it allows the drug-polymer to escape the injection site (in the case of a PEG- prostacyclin polymer) before free drug is released. Secondly, as the concentration of polymer in the bloodstream declines, so its rate of drug liberation increases. These factors act firstly to avoid local injection site reaction, due to the action of free drug at the injection site, and secondly to counteract the exponential decline in drug concentration that would normally follow a the administration of a conventional drug-covalent-release polymer. By preventing, substantially, the initiation of drug release at the injection site, the pain, inflammation or other adverse reactions at the administration site can be prevented or reduced.
- the inert polymer fragments must first reach the bloodstream before they can begin to release drug to a significant extent, adequate to elicit the desired effects of the drug.
- the drug release polymers and their pharmaceutical compositions can be formulated for different routes of administration. These include, but are not limited to, oral, transdermal, intravenous, intraarterial, pulmonary, rectal, nasal, vaginal, lingual, inhalation, injection or infusion, including intradermal, subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneal.
- Other sustained release dosage forms may include, for example, in depot, an implant, a stent or a transdermal patch form.
- the pharmaceutical composition is administered as an injection, e.g., subcutaneous or intramuscular injection. In other embodiments, the pharmaceutical composition is administered as an implant.
- Various dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
- a reconstituted or liquid pharmaceutical composition comprising the drug release polymer is administered via a first method of administration and a second reconstituted or liquid pharmaceutical composition comprising drug release polymer is administered via a second method of administration, either simultaneously or
- Said first and second method of administration can be any combination of topical, enteral administration, parenteral administration, inhalation, injection, or infusion, intraarticular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneal, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal,
- the polymer is administered as an injection. Unlike the free drug molecule, the drug release polymers of the present technology can be injected without causing injection site pain, since they diffuse from the injection site, in prodrug- oligomeric form, entering the blood and lymphatic systems, before release of free drug by further aqueous hydrolysis.
- the polymer is administered via inhalation. In other embodiments, the polymer is administered orally. Upon inhaled or oral administration, the oligomeric forms would undergo a gradual sustained release of free drug avoiding the dose-limiting 'spike' or 'peak' in blood concentration that generally ensues following oral or inhaled delivery of free drug.
- the drug release polymer of the present technology may be administered conveniently in a small volume by bolus injection of a dose lasting one or more days. In alternative embodiments, it may be made as an implant with duration of action up to three years, with no risk of potentially dangerous bolus release of drug.
- This approach avoids concerns over the toxicity of polymers, such as PEG in chronic high dosage use, but is also amenable to use with PEG and similar polymers where appropriate. It allows much higher loading in terms of moles of drug per mole of polymer than can be achieved with existing polymer systems.
- the drug polymer of the present technology is, in one aspect, a polyester, although it is designed to be biodegradable and resorbable by the body and can be manufactured under mild conditions conducive to stability of the monomeric drug molecules and their polymerized moieties.
- the drug release polymers of the present technology can be administered as a subcutaneous injection or to inhaled delivery.
- the polymer, in a nanoparticle or soluble form can be administered intravenously.
- the polymer can be administered could be used in the formation or coating of plastic stents for slow sustained release of drug at suitable anatomical sites (e.g., within the arterial vessels of the pulmonary circulation) effecting localized drug delivery to the target tissue (e.g., in the case of pulmonary hypertension) while sparing systemic side effects.
- Such stents are known in the art, for example bioresorbable coronary stents for the sustained release of anti-proliferative drugs such as paclitaxel and everoliumus, to prevent restenosis after balloon angioplasty, and have recently been reviewed by Ormiston, J. A. and P. W. Serruys, Circulation.
- polylactide polylactic acid, PLA
- polylactide-glycolide PLA
- PLGA polylactide-glycolide
- a pro-inflammatory drugs such as prostacyclins, e.g., treprostinil, iloprost, cicaprost and beraprost.
- Covalent incorporation, as part of a homopolymer or heteropolymer allows desorption of the drug from the site as a transient covalent prodrug form, which may then be hydrolyzed to the active form during circulation.
- Depot arrangements such as stents, can also be utilized to administer drugs which have very short pharmacokinetics for conventional modes of drug administration and delivery (e.g., intravenous) due to their inherent chemical instability.
- drugs include, e.g., natural prostacyclin molecule, i.e., prostaglandin-12.
- These drugs when utilized as the drug release polymer of the present technology, can be released locally into the pulmonary arterial circulation and will have a lesser availability in the general circulation outside of the pulmonary system, thereby avoiding systemic side effects and allowing higher doses to be administered locally to the affected vascular (arterial) tissues of the lung to achieve a more favorable therapeutic ratio.
- Administration by subcutaneous injection is most suitable for soluble forms of the drug release polymer, such as the linear PEG-prostacyclin co-polymer.
- the drug release polymer such as the linear PEG-prostacyclin co-polymer.
- a vial of polymer solution can be lyophilized from water or dried from solvent by evaporation under vacuum.
- the dry drug release polymer can then be reconstituted just before use as a solution or suspension in a medium suitable for subcutaneous injection.
- a medium suitable for subcutaneous injection include, e.g., phosphate-buffered physiological saline of pH, or buffers such as succinate, or citrate could be used to administer saline solutions buffered at pH's more conducive to polymer stability, e.g., pH 6.0.
- the polymer is, in one embodiment, at least a homodimer (for administration in liquid aerosol form).
- the polymer has sufficient length and particle size so that it can be administered as a solid form in a metered dose dry powder inhaler.
- the drug release polymer can have particles having mean or median size of about 3 micrometres, favoring deposition in the alveoli of the lung for optimal access to pulmonary arterioles.
- Low oligomer forms (such as a dimer or a trimer) would be less amenable to uptake than the monomer drug molecule such that lung administration of polymer forms would form a local depot which would gradually elute free drug from the alveoli into the pulmonary arterioles.
- the polymeric forms of drug (dimer, trimer and polymers) would be 'captive' in the alveoli, forming a local, inert, sustained release reservoir.
- the present polymers need to undergo hydrolysis before absorption can occur, they avoid the spike in blood concentration that occurs immediately following inhalation of non- polymerized drugs, thereby avoiding the dose limiting side effects associated with inhaled drug formulations.
- the polymeric formulations provide a more constant level of free drug in the vicinity of the pulmonary arterioles than the inhaled forms of free drugs.
- co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time.
- co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time.
- co-administration will be accomplished most conveniently by the same dosage form and the same route of
- the present technology is different in a number of respects from conventional drug release solutions known in the art.
- many sustained release strategies are known to use covalent ester bonds.
- the bond is not to a polymer carrier (as in classical drug-polymer covalent release conjugates) or to a substituent group (as in classical prodrug strategies for non-polymer drugs), but rather to another molecule of the drug itself.
- it eliminates concerns about the toxicology of the polymer or substituent element, since the polymer dissolves, upon aqueous hydrolysis, to release only the drug, such that the chemical toxicology of the new polymer is virtually identical to that of the parent drug molecule, which generally is known.
- the cleavage of the drug release polymers of the present technology does not inevitably result in release of free drug. This is because, initially, random cleavage of the new polymer results predominantly in the release of polymer fragments which are, as yet, inactive. Therefore, premature cleavage of the polymer, e.g., upon storage, before administration, does not give rise to significant amounts of free drug that might lead to contamination and adverse reactions, e.g., causing injection site reaction in case of an injectable formulation.
- the present drug release polymers exhibit flexibility in control of drug release properties.
- the rate of release of the drug is dictated by the fixed rate of hydrolysis of the bond attaching the drug to the polymer (e.g., an ester bonded PEG-drug prodrug conjugate)
- the rate of release of free drug is a complex function of the rate of ester bond hydrolysis and the length of the polymer.
- the drug release polymers which have shorter lengths and have a greater abundance of ends per unit mass will give rise to more rapid liberation of free drug.
- drug release polymers with longer lengths will result in slower release of free drug, such that drug release rates can be controlled by controlling the length or average length of the drug during polymer synthesis.
- the rate of release of the drug for such a polymer is more of an analog function less restricted by the quantal variation between different chemistries of attachment and can be 'tuned' to maximum effect.
- the rate of drug release can be controlled by manipulating the surface area of the implant or the stent.
- the polymer would be insoluble or soluble in aqueous solutions.
- the drug release polymer can be administered as a local depot (subcutaneous or by dry powder inhalation), or incorporated into stents. Shorter polymer chain lengths, e.g., dimmers and trimers, would likely result in soluble forms.
- the rate of active drug release is more likely to be 'analog' in character and could be tuned by adjustment of polymer length. This is advantageous for avoiding adverse reactions, for example, to avoid the spike in blood concentration following inhalation, possibly avoiding dose limiting systemic side effects.
- a method of diagnosing, treating, controlling, delaying or preventing in a mammalian patient, e.g., in a human, in need of the treatment of one or more conditions, diseases or disorders comprising administering to said patient a therapeutically effective amount of a drug release polymer of the present technology or a pharmaceutical composition comprising the drug release polymer or a pharmaceutically acceptable salt thereof, is provided.
- a drug release polymer of the present technology or a pharmaceutical composition comprising the drug release polymer or a pharmaceutically acceptable salt thereof.
- the drug moiety has anti-cancer activity, it will be administered to a cancer patient; if the drug moiety has an anti-inflammatory activity, it will be administered to a patient who suffers from an inflammatory disease, like rheumatoid arthritis, inflammatory bowel disease or Crohn's disease; a drug moiety which has neurological activity will be administered to a patient suffering from a neurological disease like Alzheimer's disease or Parkinson's disease, and so on and so forth.
- an inflammatory disease like rheumatoid arthritis, inflammatory bowel disease or Crohn's disease
- a drug moiety which has neurological activity will be administered to a patient suffering from a neurological disease like Alzheimer's disease or Parkinson's disease, and so on and so forth.
- Exemplary conditions, diseases or disorders that can be prevented and/or treated with the drug release polymer of the present technology include, but are not limited to, pulmonary hypertension, ischemic diseases (e.g., peripheral vascular disease including peripheral arterial disease, Raynaud's phenomenon including Raynaud's disease and
- Raynaud's syndrome scleroderma including systemic sclerosis, myocardial ischemia, ischemic stroke, renal insufficiency), ischemic ulcers including digital ulcers, heart failure (including congestive heart failure), portopulmonary hypertension, interstitial lung disease, idiopathic pulmonary fibrosis, conditions requiring anticoagulation (e.g., post MI, post cardiac surgery), thrombotic microangiopathy, extracorporeal circulation, central retinal vein occlusion, atherosclerosis, inflammatory diseases (e.g., COPD, psoriasis), hypertension (e.g., preeclampsia), reproduction and parturition, cancer or other conditions of unregulated cell growth, cell/tissue preservation.
- inflammatory diseases e.g., COPD, psoriasis
- hypertension e.g., preeclampsia
- reproduction and parturition cancer or other conditions of unregulated cell growth, cell/tissue preservation.
- the present technology relates to a treprostinil controlled release polymer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in a method of treating or preventing a disease or disorder which can be treated and/or prevented by treprostinil.
- the disease or disorder is pulmonary arterial hypertension.
- Non-small-cell lung cancer is another indication to which the present invention is applicable, wherein treprostinil (or other prostacyclin drug such as iloprost) can be used as an agonist of the Wnt signalling pathway, arresting the growth of lung cancer cells and inhibiting new tumour formation (Tennis, M. A., et al, Neoplasia, 2010, 12(3): 244-253.).
- the polymer forming reaction is achieved most favorably by a modification of the well known Steglich esterification (H5fle, G., W. Steglich, et al. 1978) as here described for the drug homopolymer of Fig. 2. Dissolve 30.5 mg 0.78 mmol of treprostinil in
- dichloromethane in a rotary evaporator Recover the particulate polymer by filtration, and wash with water to remove excess EDC and by-products, and any unreacted treprostinil. Further purification can be effected by dissolving the dried polymer in DCM and conducting gel permeation chromatography in DCM according to methods known in the art. The first (broad) peak to elute in such chromatography will be treprostinil polymers, later eluting peaks are residual contaminants and may be discarded.
- An alternative method to achieve the drug homopolymer of Fig. 2 is to apply the esterification method of Sharghi, Babak et al. 1998, as here described.
- MeSOsH 1.0 mL, 15 mmol
- AI2O 3 0.27 g, 3.0 mmol
- 2.0 mmol of treprostinil is added.
- the mixture is stirred and heated in an oil bath at 80 °C for 7-120 min.
- the mixture is poured into water, at which time the polymer precipitates, and is recovered by filtration along with the AI2O 3 , and washing with water (to remove free treprostinil).
- the recovered polymer and AI2O 3 mixture is then resuspended in water and the suspension is extracted twice with ethyl acetate or chloroform (20 mL) to dissolve the polymer leaving behind the alumina. The organic layer is then washed with a saturated solution of sodium bicarbonate (20 mL).
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4851432A (en) * | 1987-05-21 | 1989-07-25 | Devlin Thomas M | Therapeutic uses of oligomers of 15-dehydroprostaglandin B1 and oligomers of derivatives of 15-dehydroprostaglandin B1 |
WO2013024052A1 (en) * | 2011-08-12 | 2013-02-21 | Ascendis Pharma A/S | Carrier-linked treprostinil prodrugs |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2696481A (en) | 1951-06-05 | 1954-12-07 | Du Pont | Preparation of linear polymers from disalicylide and the like, and the fiber-forming polymers so prepared |
US6441245B1 (en) | 1997-10-24 | 2002-08-27 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
US20020164374A1 (en) * | 1997-10-29 | 2002-11-07 | John Jackson | Polymeric systems for drug delivery and uses thereof |
US6242482B1 (en) | 2000-06-05 | 2001-06-05 | United Therapeutics Corporation | Prostaglandin compounds and derivatives thereof, compositions containing the same and method of using the same for the treatment of congestive heart failure |
US6700025B2 (en) | 2001-01-05 | 2004-03-02 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
US6770248B2 (en) | 2001-05-04 | 2004-08-03 | Her Majesty The Queen In Right Of Canada, As Represented By The Minister Of National Defence Of Her Majesty's Canadian Government | Flowthrough device for the ultrasonic destruction of microorganisms in fluids |
ES2622471T5 (en) | 2003-05-22 | 2020-07-23 | United Therapeutics Corp | Compounds and procedures for the administration of prostacyclin analogs |
WO2005039489A2 (en) * | 2003-09-24 | 2005-05-06 | Polymerix Corporation | Compositions and methods for the inhibition of bone growth and resorption |
US8383092B2 (en) * | 2007-02-16 | 2013-02-26 | Knc Ner Acquisition Sub, Inc. | Bioadhesive constructs |
CA2723540C (en) * | 2008-05-08 | 2016-01-05 | United Therapeutics Corporation | Treprostinil monohydrate |
JP5780775B2 (en) * | 2011-02-18 | 2015-09-16 | 株式会社Lttバイオファーマ | Nanoparticles containing prostaglandin I2 derivatives |
US20140120058A1 (en) * | 2011-04-12 | 2014-05-01 | Polyactiva Pty Ltd | Polymer conjugated prostaglandin analogues |
AU2012296955B2 (en) | 2011-08-12 | 2016-12-15 | Ascendis Pharma A/S | Carrier-linked prodrugs having reversible carboxylic ester linkages |
JP2014522878A (en) * | 2011-08-12 | 2014-09-08 | アセンディス ファーマ エー/エス | Prostacyclin sustained release composition |
EP2991639A4 (en) * | 2013-04-30 | 2016-11-30 | United Therapeutics Corp | Controlled release pharmaceutical formulations |
-
2014
- 2014-04-29 EP EP14792255.3A patent/EP2991639A4/en not_active Withdrawn
- 2014-04-29 JP JP2016511799A patent/JP6594857B2/en active Active
- 2014-04-29 US US14/264,392 patent/US9758465B2/en active Active
- 2014-04-29 WO PCT/US2014/035849 patent/WO2014179295A1/en active Application Filing
- 2014-04-29 CA CA2911172A patent/CA2911172C/en active Active
- 2014-04-29 CN CN201480035102.5A patent/CN105407883A/en active Pending
-
2017
- 2017-09-08 US US15/698,852 patent/US10494327B2/en active Active
-
2019
- 2019-10-29 US US16/667,159 patent/US11001551B2/en active Active
-
2021
- 2021-05-10 US US17/316,094 patent/US20210317066A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4851432A (en) * | 1987-05-21 | 1989-07-25 | Devlin Thomas M | Therapeutic uses of oligomers of 15-dehydroprostaglandin B1 and oligomers of derivatives of 15-dehydroprostaglandin B1 |
WO2013024052A1 (en) * | 2011-08-12 | 2013-02-21 | Ascendis Pharma A/S | Carrier-linked treprostinil prodrugs |
Non-Patent Citations (1)
Title |
---|
See also references of EP2991639A4 * |
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Also Published As
Publication number | Publication date |
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US10494327B2 (en) | 2019-12-03 |
EP2991639A1 (en) | 2016-03-09 |
US9758465B2 (en) | 2017-09-12 |
US20140323567A1 (en) | 2014-10-30 |
JP2016518390A (en) | 2016-06-23 |
US20200062691A1 (en) | 2020-02-27 |
JP6594857B2 (en) | 2019-10-23 |
CN105407883A (en) | 2016-03-16 |
EP2991639A4 (en) | 2016-11-30 |
US11001551B2 (en) | 2021-05-11 |
CA2911172A1 (en) | 2014-11-06 |
US20170369416A1 (en) | 2017-12-28 |
US20210317066A1 (en) | 2021-10-14 |
CA2911172C (en) | 2021-10-19 |
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