TW200924782A - Prostaglandin analogues for implant devices and methods - Google Patents

Abstract

The present invention provides prostaglandins, compositions, and methods useful for sustained release of a therapeutic agent over an extended period of time. Exemplary prostaglandins are C4-C32 alkyl esters or amides of prostaglandins, for example, isobutyl esters and amides.

Description

</ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Medium β [Prior Art] - Patients and physicians face multiple problems in the field of ocular drug delivery. In particular, the repetitive treatment (multiple daily injections, multiple drops of eye drops), associated costs, and lack of patient compliance can significantly affect the efficacy of effective treatment, resulting in decreased vision and even blindness. Patient compliance with medications (eg, instilled eye drops) may be irregular and sometimes patients may not follow a targeted treatment regimen. Lack of compliance can include – no drops, no technical inefficiency (drinking less than needed), excessive use of drops (causing system side effects), and the use of non-specified drops or failure to follow treatment regimens that require multiple types of drops . Many drugs may require patients to instill up to 4 times a day. A promising approach to drug delivery in the eye is to place the drug-releasing implant in the group of G's close to the eye. Although this method may provide some improvements over eye drops, some potential problems with this approach may include implanting the implant at the desired tissue location, leaving the implant at the desired tissue location, and • Long-term sustained release of the drug, for example in glaucoma treatment

Under the condition of It, the detection of loss of implants and premature loss of the implant can lead to no drug delivery and the patient may increase to f j. This has reduced vision and may even be blind. In some cases, the current device may not provide an ideal continuous visit based on a daily average amount of drug, but the item is released and may need to be compared to the ideal situation. More than 134345.doc 200924782 Frequent visits to replace the implant. Prostaglandins have medicinal efficacy in the treatment of ocular conditions (eg, reduction of intraocular pressure (I〇p)), but existing prostaglandins administered by drops (eg, latan〇prost, ratio Bimat〇pr〇st and travoprost may cause irritation to the eyes of some patients and fill the eyes with gold. There is a need to develop other prostaglandins and provide improved drug delivery. SUMMARY OF THE INVENTION The present invention provides prostaglandins, compositions, methods, and implant devices for the sustained release of therapeutic agents into a patient (e.g., a human or a mammal). Although specifically mentioned for use in or near the nasolacrimal excretion system, the serotonin as described herein can be used in other tissue structures in or near the eye. Advantageously, the prostaglandins as described herein have a lower water solubility than latanoprost, bimatoprost and travoprost and are capable of sustained, effective and specific release of the therapeutic agent for a prolonged period of time at the desired therapeutic level. In some embodiments, the lower water solubility of the prostaglandin derivative allows for a more uniform or zero order release of the drug per ounce of time. In some embodiments, the metabolites and/or prodrugs of prostaglandins as described herein can have different penetration and/or dispensing characteristics that can affect the clinical endpoints described above. The different physical and chemical characteristics of the prostaglandin metabolites and/or prodrugs as described herein may also provide greater freedom in the formulation and loading of medical devices. Thus, medical devices of various durations and dosage ranges can be easily manufactured. The present invention provides a compound of formula I: 134345.doc 200924782

And a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein [I-〇- or -NRa_' wherein Ra4_H or C1_C8 alkyl; meaning 匕...alkyl; r2 is -H4Ci_C8_alkyl; X is - Ο- or -CH2·; a dashed bond as indicated by ...-- indicates an optional double bond; and a wavy line indicates that the stereoscopic configuration of the carbon to which it is attached may be R*s. In the aspect, the compounds have a water solubility of no greater than about 16 mg/ml. In another aspect, the compounds have a logarithm of the partition coefficient (1 〇 gP) greater than about 2.4 at a value of about 7.4 ipH. • The invention also provides a compound of formula II:

Wherein L is -Ο- or -NRa-, wherein Ra is -HSq-Cs alkyl; R is C4-32 alkyl; R2 is alkyl; X is -〇- or -CH2-; ..... An optional double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II has a water solubility of no greater than about 16 mg/mi or a logP greater than about 2.4 at a pH of about 7.4 . I34345.doc 200924782 In one embodiment, the compound of formula II is:

Wherein L is -Ο- or -NH- and R1 is isobutyl. In another embodiment, the compound of formula II is:

Ila, wherein L is -Ο- and R1 is isobutyl;

Ila, ❹ wherein L is -NH- and R1 is isobutyl;

Wherein L is -Ο- and R1 is isobutyl; 134345.doc 200924782

Ϊη lib, wherein L is -NH- and R1 is isobutyl;

Lie, wherein L is -〇· and R1 is isobutyl; or

Lie, wherein L is -NH- and R1 is isobutyl. In yet another embodiment, the compound of formula II has a water solubility of from about 4 ng/ml to about 16 mg/ml or an i〇gp of from about 2.5 to about 9.0 at a pH of about 7. In one embodiment, the compound of formula II is about 55 hours after topical administration to the eye at an average concentration of greater than about 5-7 ng/mi, or about 1 after topical administration at an average concentration of greater than about 丨8 7 ng/ml. Hours, or about 2 hours after topical administration at an average concentration of greater than about 32.6 ng/ml, or about 4 hours after topical administration at an average concentration of greater than about 29.0 ng/ml, or at greater than about 0.2 ng/ml The average concentration is present in the aqueous humor about 24 hours after topical administration or a combination thereof in the form of the free acid. 134345.doc -9- 200924782 In another embodiment, the compound of formula II can be hydrolyzed by an esterase. The invention further provides a composition comprising: a compound of formula II:

Wherein: ❹ L is -0- or -NRa-, wherein Ra is -H4Cl-C8 alkyl; R1 is C4_32 alkyl, • R2 is -H or Ci-Cg dentate; X is -Ο- or -CHa -, ..... represents an optional double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II has a no greater than about 16 mg/ml at a pH of about 7.4 Water soluble or greater than about 2.4 logP; and a pharmaceutically acceptable carrier. ® In one embodiment, the composition is used to treat an eye condition, an eye condition, or a cosmetically enhanced eyelash or eyebrow. In another embodiment, the eye disease 'is glaucoma. In yet another embodiment, the pharmaceutically acceptable carrier comprises * polydecyloxy. The present invention provides a method of treating glaucoma in an individual in need thereof. The method comprises administering to the individual an effective amount of a composition comprising: a compound of the formula: 134345.di -10- 200924782

Wherein: L is -Ο- or -NRa-, wherein Ra is -HSCVCs alkyl; R1 is C4_32 alkyl; R2 is alkyl; X is -〇- or -CH2-; ----- indicates an optional a double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II has a water solubility of no greater than about mg6 mg/ml or a logP greater than about 2.4 at a pH of about 7.4; A pharmaceutically acceptable carrier is optional. In one embodiment, the composition is administered to the eye of the individual. The invention also provides a method of delivering a therapeutic agent to an eye having associated tears. The method comprises administering a therapeutic agent to an eye in need thereof via an operation of a drug core comprising a therapeutic agent, wherein the therapeutic agent comprises a compound of formula II:

among them:

134345.doc • 11 - 200924782 R1 is C4-32 alkyl; R2 is -Η or CVC8 haloalkyl; X is -Ο- or -CH2·; , —...is an optional double bond; or its pharmacologically An acceptable salt, metabolite or prodrug wherein the hydrazine compound has a water solubility of no greater than about 16 mg/ml or a logp greater than about 2.4 at a pH of about 7.4. In one embodiment, the administering further comprises contacting the drug core with the eye and releasing the therapeutic agent to the tears of the eye. In another embodiment, the therapeutic agent and the polyoxyl group form a drug core. In yet another embodiment, the drug core is placed in the lacrimal canal of the eye. In one embodiment, the therapeutic agent dissolves into the polymethoxyl and the polymethoxyl remains filled with the therapeutic agent. The invention further provides the use of a compound of formula π or a pharmaceutically acceptable salt, metabolite or prodrug thereof:

Wherein: L is A· or -NRa_, where ... is -!! or Cl-C8 alkyl; R is C4-32 yard; R is -H or c--c8_ unified; X is -〇· or -CH2-; 134345.doc -12· 200924782 ―... denotes an optional double bond; wherein the hydrazine compound has a water solubility of no greater than about 16 mg/ml or greater than about 24 at a pH of about 7.4丨〇#, which is used in drug therapy. In one embodiment, the drug therapy enhances the eyelashes or eyebrows for treating an eye condition, an eye condition, or a cosmetic condition. In another embodiment, the eye disease is glaucoma. The invention also provides the use of a compound of formula II or a pharmaceutically acceptable salt, metabolite or prodrug thereof:

Wherein: L is -〇- or -NRa- ' wherein the alkyl group; R is a C4-32 building group; R2 is a -HSCVCs functional group; ❹ X is -0- or -CH2-; ..... An optional double bond; wherein the compound of formula II has a water solubility of no greater than about 16 mg/ml or a logP greater than about 2.4 at a pH of about 7,4; it is used to prepare a medicament for the treatment of glaucoma. In some embodiments, the change in kinetics of prostaglandin exiting the cornea can be adjusted, for example, by modulating the rate of cleavage of prostaglandin metabolites and/or prodrugs. For example, the R 丨 group can be altered to change the binding constant of the esterase that produces the free acid to 134345.doc •13·200924782. The present invention also provides a method of increasing the length, concentration, amount or twist of a warm hair or eyebrow. The method also comprises administering an effective amount of a compound of the formula π to a region in which the individual needs hair growth:

❹ where: L is -〇- or ·NRa-' wherein Ra is 4 or CVC8 alkyl; * R is C4-32 alkyl; R2 is # or c^-Cs alkyl; X is -〇- or - CH2-; ..... indicates an optional double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II has a ratio of no greater than about 16 at a pH of about 7,4 The water solubility of mg/ml ® or greater than about 2.4 logP. In one embodiment, the effective amount is administered to the individual as a liquid composition containing about 3% by weight of a compound of the formula Π '. In another embodiment, the liquid

* Body composition is applied to the edge of the eye or eyebrows. In yet another embodiment, the compound of formula II is administered to the eyelid edge or eyebrow. [Embodiment] I. Definitions Reference is now made in detail to certain claims of the subject matter disclosed, examples of which are described in the accompanying drawings. Although the disclosed subject matter will be described in connection with the recited claims, it is not difficult to understand that it is not intended to limit the disclosed subject matter. Rather, the invention is intended to cover all alternatives, modifications, and equivalents, which are included within the scope of the subject matter disclosed herein. The description refers to an embodiment, which indicates that the embodiment may include specific features, structures, or characteristics, but each embodiment may not necessarily include the specific feature, structure, or characteristic. In addition, the phrases are not necessarily the same. Example. In addition, it is to be understood that the specific features, structures, or characteristics are described in the context of the embodiments of the invention. Unless otherwise indicated, the words and phrases that are present in this document are of ordinary meaning as understood by those skilled in the art. Such general meanings can be obtained by reference to their use in the art and by reference to general and scientific dictionaries such as Webster's Third New International Dictionary, Merriam-Webster Inc., Springfield, MA, 1993 'The American Heritage Dictionary of the English

Language, Houghton Mifflin, Boston MA, 1981 and Hawley's Condensed Chemical Dictionary, 14th edition, Wiley Europe, 2002 ° The following explanations of certain terms are meant to be illustrative rather than exhaustive. These terms have the general meaning given by the use in the art and include the following explanation. The term &quot;about&quot; as used herein refers to a 10% change in the specified value, for example 134345.doc -15- 200924782 about 50% means 45°/. Up to 55°/. Change. The term &quot;and/or&quot; as used herein refers to any one of the items associated with the term, any combination of items, or all items. The singular form &quot;a&quot; as used herein, unless the context clearly dictates otherwise. And &quot;this&quot; includes plural references. The following specific and preferred values for groups, substituents and ranges are for illustrative purposes only; they do not exclude other specified values for groups and substituents or within specified ranges. Other values. As used herein, the term &quot;administration&quot; refers to a method of placing a device at a desired location. The placement of the device can be accomplished by any pharmaceutically acceptable method, such as by swallowing, Keeping it in the mouth until the drug has been dispensed, placed in the buccal cavity, inserted, implanted, attached, etc. These and other methods of administration are known in the art as β as used herein, alkane "Base" means a q-Ci8 hydrocarbon containing a normal, second, third or cyclic carbon atom. Examples are methyl, ethyl, decyl propyl, decyl propyl, 1-butyl, 2-methyl-1-propyl (isobutyl, _CH2CH(CH3)2), 2-butyl (second butyl , -CH(CH3)CH2CH3), 2-methylpropyl (t-butyl, -C(CH3)3), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2 · Butyl, 3-mercapto-2-butyl, 3-methylbutyl, 2-hydrazino-p-butyl, ^hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl , 3-mercapto-2_pentyl, 4-mercapto-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2 - butyl, 3,3-dimercapto-2-butyl. The hospital base may be a monovalent hydrocarbon group as described above and shown, or it may be a divalent nicotine group (i.e., an alkylene group). 134345.doc • 16 · 200924782 ❹ ❹ Alkyl groups may optionally be subjected to one or more alkoxy groups, dentyl groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, cycloalkyl groups, Alkyl fluorenyl, alkoxy group, amine group, imino group, alkylamino group, arylamino group, nitro group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, carboxyalkyl group, ketone group , thiol sulfhydryl, dazzle &gt; thiol, aryl aryl, decyl thio, cyano, ethoxylated, ethoxylated, ethinyl, benzoguanamine, phenyl Sulfonyl, benzoic acid, benzene, phenyl, phenyl, benzoyl, benzyloxy, benzyl, benzyloxy, benzyloxy Carbonyl, benzylthio, amine carbaryl, amino phthalate, isocyanate, amine sulfonyl, amine sulfinyl, sulfinate, sulfonate, sulfonate, thio acid a group, NRxRy& or COORx substituted, wherein each of rx and Ry is independently hydrazine, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl or hydroxy. The alkyl group may optionally be one or more of a non-peroxyoxy group (_〇-), a thio group (-S-), an imido group (-Ν(Η)-), a methylenedioxy group (·ochw-). ), carbonyl (-C(=0)·), buffer (-C(=〇)〇_), carbonyldioxy (_〇c(=〇)〇_), carboxy root (-〇C(= 0)-), imino group (c=NH), sulfinyl (s〇) or sulfonyl (S〇2). Alternatively, the alkyl group can be at least partially unsaturated, thereby providing an alkenyl group. The term &quot;aqueous medium&quot; as used herein refers to a liquid medium that is primarily, but not necessarily, only water. Other components such as salts, cosolvents, buffers, stabilizers, dispersants, colorants and the like may also be present. A combination comprising a specified amount of a specified ingredient, a carrier, a diluent, or a product, as the term &quot;composition&quot; is used herein, and any product, directly or indirectly, as specified. &quot;Pharmaceutically acceptable,, 134345.doc •17· 200924782 The agent must be compatible with the other ingredients of the formulation and unrecognized to its recipient. &quot;Compound&quot; as used herein refers to a chemical group of two or more elements that have an effect on any living system, such as cells, nerves or tissues. Also as used herein, the term &quot;compound&quot; refers not only to a specified molecular entity but also to its pharmaceutically acceptable pharmacologically active derivatives, including but not limited to salts, hydrates, solvates thereof and analog. As used herein, the term &quot;derivative&quot; refers to a chemically modified compound wherein the chemical modification is in one or more functional groups of the compound and/or an aromatic or aromatic structure, an alicyclic structure or a heterocyclic ring. The structure (when present) is performed. However, it is expected that bamboo organisms will retain the pharmacological activity of the compound from which they are derived. The term &quot;esterase, as used herein, refers to an enzyme that catalyzes the hydrolysis of an ester. Esterases as used herein can catalyze the hydrolysis of prostaglandins as described herein. In some embodiments, the enzyme includes an enzyme that catalyzes the hydrolysis of a prostaglandin (e.g., bimatoprost-derived). The term &quot;eye disease&quot; or &quot;eye condition&quot; as used herein refers to an abnormality of the eye. It may involve the retina, vitreous fluid, lens, cornea, sclera or other parts of the eye, or adversely affect the physiological abnormalities of the eye, • &lt;columns such as inappropriate tear production, allergic conjunctivitis, uveitis or corneal dislocation The term m as used herein refers to a fluoro group, a gas group, a desert group, and a cleavage group. Similarly, the term 'four' &quot; refers to fluorine, gas, and moth. The term &quot;fathoyl,&quot; as used herein, refers to an alkyl group, as defined herein, substituted by a radical which may be substituted by (i) or different t. The representative includes, for example, trifluoromethyl, 3; Twelve base, 12,12,12_three 134345.doc 200924782 gas dodecapine, 2-octyl, 3 · desert · 6_chloroheptyl and the like. About containing - or multiple substitutions Any of the groups as described herein should of course be understood that the groups do not contain any sterically impractical and/or "unfeasible substitution or substitution patterns." Further, the disclosed subject matter A compound includes all stereochemically isomeric forms derived from the substitution of such compounds. The selected substituents within a compound as described herein exist recursively. In this regard, "recursive substituent" means © Substitute the other examples of the base description itself. Due to the recursive nature of such substituents, it is theoretically possible to exist in large quantities in any given claim. Those skilled in the art & chemical and organic chemistry generally understand that the total number of such substituents is suitably limited by the desired properties of the desired compound. Such characteristics include, for example, but are not limited to, physical properties such as molecular weight, solubility or 1 〇 gp; application properties such as activity for a predetermined target; and practical properties such as ease of synthesis. The recursive substituent is a predetermined aspect of the disclosed subject matter. Those skilled in the art of pharmacy and organic chemistry should be aware of the versatility of such substituents. To the extent that recursive substituents are present in the claims of the disclosed subject matter, the total number will be determined as set forth above. The term &quot;mammal&quot; as used herein refers to humans, livestock (e.g., dogs or cats), farm animals (e.g., cows, horses or pigs), monkeys, rabbits, mice, and laboratory animals. The term &quot;metabolic product&quot; as used herein refers to any compound of formula (1) or formula (H) produced in vivo or ex vivo from a parent drug or a prodrug thereof. The term "molecular weight (MW·), as used herein, refers to the weight average molecular weight well known in the art as 134345.doc • 19·200924782. The term &quot;pharmaceutically acceptable&quot; as used herein refers to Compounds, substances, compositions and/or substances suitable for contact with human and animal tissues without toxic toxicity, allergic reactions or other problems or complications proportional to reasonable benefit/risk ratios within the scope of reliable medicine Formulations of pharmaceutically acceptable ingredients are disclosed in this and the art: The United States Pharmac.

The term &quot;pharmaceutically acceptable salt&quot; as used herein refers to an ion compound wherein the parent nonionic compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like Things. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids and the four-grade salt. Non-toxic salts can include salts derived from inorganic acids such as hydrogenates, hydrobromides, hydroiodides, sulfates, amine sulfonates, phosphates, nitrates, and the like. Salts prepared from organic acids may include such salts as, for example, acetate, 2-ethyloxybenzoate, ascorbate, benzoate, benzoate, citrate, ethanesulfonate, Ethane dihydrochloride, formate, fumarate, gentisate, glucuronate, gluconate, glutamate, glycolate, hydroxy maleate, Ethyl sulfonate, isonicotinic acid salt, lactate, maleate, frequency fruit acid salt, mesylate or decane sulfonate, oxalate, bis-naphthoic acid Salt (1,1'-arylene) bis-(2-hydroxy-3-naphthoate), pantothenate, benzene 134345.doc •20- 200924782 acetate, propionate, salicylate , p-aminobenzenesulfonate, toluenesulfonate, stearate, succinate, tartrate, ditartrate and the like. Certain compounds form pharmaceutically acceptable salts with various amino acids. For a review of pharmaceutically acceptable salts, see, for example, Berge et al., /. 19*77, 66(1), 1-19, which is incorporated herein by reference. The pharmaceutically acceptable salts of the compounds as described herein can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. The above salts can be prepared by reacting the free acid or the form of the compound with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two, usually such as diethyl ether or acetic acid. A non-aqueous medium of ethyl ester, ethanol, isopropanol or acetonitrile is preferred. A list of many suitable salts can be found in Remingt〇n, s

Pharmaceutical Sciences, 17th edition, Mack Publishing

Company, Easton, PA, (1985), 1418 and the disclosure of which is incorporated herein by reference. The term "patient" as used herein refers to all mammals including humans. Examples of patients include, but are not limited to, humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. The term &quot as used herein Preferred &quot;and &quot;preferred&quot; means an embodiment of the invention that provides certain benefits under certain circumstances. However, other embodiments may be preferred in the same or other circumstances. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not applicable and that no other embodiments are excluded from the scope of the invention. The term &quot;prodrug&quot; as used herein refers to any medicine of a compound. I can theoretically provide I34345.doc ^ 200924782 === This compound is provided after administration to a patient. It is pharmaceutically acceptable to metabolize in the host (for example, a compound that hydrolyzes a compound of (1) or (II). &amp; ^ A typical example of a music includes a compound that has a biological weight and a protective A on the g energy portion of the active substance. The chemical substance can be oxidized, reduced, or the like. Amination, deserification, warp base Compounds which are activated, chiralized, hydrolyzed, dehydrated, thiolated, defoamed, deuterated, de-branched, phosphorylated, dephosphorylated to produce active compounds.

The term &quot;individual&quot; as used herein refers to an animal such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, dogs, rabbits, rats, small Rats and their analogues. In certain embodiments, the individual is a human. The term &quot;substituted&quot; as used herein is intended to indicate that one or more of the hydrogens on the atom indicated in the expression &quot;substitution&quot; is replaced by a group selected from the indicated group, the restrictions In order not to exceed the normal valence of the indicated atom and the substitution results in a stable compound "suitable indicating groups include, for example, alkyl, alkenyl, alkylene, alkenylene, alkoxy, dentyl, _alkyl, hydroxy , hydroxyalkyl, aryl, heteroaryl, heterocyclic, cycloalkyl, alkanoyl, decyloxy, alkoxycarbonyl, amine, imido, alkylamino, decylamino, Nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioketo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamidine Amine, ethoxylated, ethoxylated, benzylamino, phenylsulfinyl, benzenesulfonylamino, phenylsulfonyl, phenylsulfonylamino, benzamidine, benzamidine Amino, benzyloxy, benzyl, benzyloxy, benzyloxycarbonyl 134345.doc • 22· 200924782 base, benzylthio, amine sulfhydryl, urethane , an isocyanate group, an amine sulfonyl group, an amine sulfinyl group, a sulfinic acid group, a sulfonic acid group, an sulfonic acid amine group, a thiosulfonic acid group, an NRXRy and/or a C00RX substitution, wherein each of An anthracene, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, a heterocyclic group, a cycloalkyl group or a thiol group. Although the substituent is a pendant oxy group (ie, 〇) or a thiol group (ie, when 'replaces two hydrogens on the atom. ❹ ❹ as used herein, the term &quot;therapeutic agent&quot; refers to any drug or Organic compounds such as therapeutic agents can include, for example, agents for treating and/or preventing eye conditions, eye diseases, or cosmetically enhancing eyelashes or eyebrows. As used herein, the term &quot;therapeutic composition&quot; refers to organic or inorganic A mixture of carriers or excipients and may be admixed, for example, with a conventional non-toxic, pharmaceutically acceptable carrier for use in lozenges, pills, capsules, suppositories, solutions, emulsions, suspensions or other suitable forms. The term &quot;therapeutically effective amount&quot; as used herein is intended to include a quantity of a compound as described herein or a combination of compounds as described herein, for example, for treating or preventing a disease or condition in a host, Or treating a symptom of a disease or condition. The combination of compounds is preferably a synergistic combination, such as (for example, (10) (10) and Talalay 'heart v. fine heart (10), 1984, 22:27, when the compound combination is administered, the effect is large. The synergistic effect of the compound when administered as a single agent alone is combined with a synergistic effect at the suboptimal concentration of the compound. Synergistic effects can be combined with lower cytotoxicity compared to individual components. For the purpose of increasing the activity or some other beneficial effects of physiotherapy, the term "treatment" as used herein refers to obtaining the desired drug 134345.doc -23· 200924782

Disease even if the disease subsides.

It also includes excipients that can be used by veterinary medicine and used in human medicine. As used herein, &gt;g&quot; means micrograms, "mg," means milligrams, &quot;g&quot; means 'grams', &gt;L&quot; means microliters &quot;mL&quot; means milliliters, &quot;L&quot; means liters: &quot "nM" means Nym, &quot;μΜ&quot; means micro-mole," means millimolar, &quot;M&quot; means Mohr &quot;nm&quot; means nano. Salty PGF2a&amp; The ester is filled with the current drug in the eye, wherein the ester or guanamine form administered is hydrolyzed by an endogenous ocular esterase to release the free acid of the PGFu analog as an active pharmacological agent. However, this also releases potentially toxic and potential An irritating small aliphatic alcohol (such as isobutanol) to the eye. In the case of bimatoprost, ethylamine is released into the eye. Although it is extremely effective in reducing intraocular pressure, all drugs currently used (including latanoprost, bimatoprost, and travoprost) can cause some patients to produce a significant degree of eye irritation. In addition to the above, isopropyl ester of PGF2 « analog compounds (eg, latano 134345.doc •24- 200924782 And fluorine (tetra) alcohol) are extremely viscous, glassy oils that are difficult to handle and difficult to formulate into ophthalmic solutions. In addition, these compounds can easily retain potentially toxic process solvents 〇A ^ F2&lt;x Ester or higher alkanelamines are easier to handle and may not release irritating alcohols or amines after hydrolysis. ❷ In addition to: the glandular hormone itself, and especially the currently available types of natural and oral glandular glands In addition to the irritations caused by the stimuli, it is known that most of the individuals in the ophthalmic solution are responsible for irritation. Therefore, although serotonin represents an important effective therapeutic agent for the treatment of glaucoma 'But improper side effects of these drugs, especially eye irritation and inflammation, may limit the use of the drug and may be associated with the patient's withdrawal from the use of such drugs. ^ As described herein, higher alkanol esters and higher alkanes of PGF^ The amine may be less irritating to the patient but still therapeutically effective. II. Compounds One embodiment provides a compound of formula J:

And pharmaceutically acceptable salts, metabolites or prodrugs thereof. The wavy line indicates that the stereo configuration of the carbon to which it is attached may be R or S. In the formula I, 'L is -Ο- or -NRa-, wherein alkyl. In one embodiment, -NRa is -NH. In Formula I, R1 is an alkyl group having more than 4 carbon atoms. In one embodiment 134345.doc •25·200924782, R1 is c4-c32 alkyl. In another embodiment, R1 is a C4-C20 alkyl group. In one embodiment, R1 is C4-C12 alkyl. In one embodiment 'R1 is an isobutyl group. In formula I, R2 is -H.CVCs haloalkyl. In one embodiment, R2 is -H. In one embodiment, R2 is -CF3. In the formula ’ 'X is -〇- or -CH2-. In one embodiment 'X is. In one embodiment, X is _CH2-. The dotted line indicated by '..... in Formula 1 indicates a selective double bond.

One embodiment provides a compound of formula II:

The dotted line of the table indicates that one of the substituents R1, R2, X, __ is selected as the alternative double bond.

In the examples in which the group has a compound of the formula π, [is also seven or -ch2. In one example, R丨 is a c4 2 group, for example, _CK 1 , -c6Hi3 , -C7Hi5 , -C8Hi7 , _C9Hi9 , _CigH2 , _c&quot;h= -Cl2H25, -Cl3H27, -C14h2...Ci5h3i ' Ci6H33, c"Heart, _c18H37, _Cl9H39 or -c2QH4l and isomers thereof. In another example, R2 is -Η or Cl-C8 haloalkyl, such as _CF3, _CH2CF3, _CF and the like. In another embodiment, L is ·NRa and χ is _ or even. In the example, R1 is C4_20 alkyl, for example _C4H9, _11 _l6H13, _c7H15 134345.doc -26- 200924782 '-CsHi7 ' C9H19 '-C10H21 '-C11H23 ' -C12H25 ' -C13H27 ' -C14H29 ' -C15H3I ' -C16H33 ' -C17H35 ' -Ci8H37 ' -C19H39 or -CmH4 and its isomers. In another example, R2 is ^ Or a 匕-仏-alkyl group, such as -CF3, -CH2CF3, -CF2CF3, -CC13, and the like. In one embodiment, L is -NH. In one embodiment, the compound as described herein is Low water solubility at 25 ° C, pH between about 7.0 and about 7.2, for example, the compound has no more than about 0.03 wt%, such as 0.03 wt%, 〇, 〇 2 wt%, 0.01 wt 〇 〇 / 〇, 0.005 Weight %, 0.003 by weight. Λ, 0.002% by weight, 0.001% by weight of 〇/〇 or 0.0001% by weight of water solubility. In one embodiment, the compound has a water solubility of no greater than about 16 mg/ml. In another embodiment, The compound has a water solubility of from about 4 ng/ml to about 16 mg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 8 mg/ml. In another embodiment The compound has a water solubility of from about 4 ng/ml to about 300 pg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 50 pg/ml. In yet another embodiment, the compound has Water solubility of from about 4 ng/ml to about 40 pg/ml. In some embodiments, the compound has a water solubility of less than about a value selected independently from the group consisting of: 4 ' * 4.1, 4.2, 4.3 ' .4.4, 4.5, 4.6, 4.7, • 4.8, 4.9, 5, 5, 1 ' 5.2, 5.3, 5.4, 5.5, 5.6 ' 5.7 ' 5.8 ' 5.9 , 6.0 6.1, 6.2, 6.3 ' 6.4, 6.5, 6.6, 6.7 ' 6.8 ' 6.9 ' 7.0 7.1, 7.2 ' 7.3 ' 7.4, 7.5, 7.6, 7.7 ' 7.8 ' 7.9 ' 8.0 8.1 ' 8.2, 8.3 ' 8.4, 8.5, 8. 6, 8.7, 8.8 '8.9 ' 9.0 % 9.1, 9.2 ' 9.3, 9.4, 9.5, 134345.doc -27· 200924782 9.6 ' 9.7, 9.8, 9·9, 10, 11, 12, 13, 14, 15, 16 , 17, 18 ' 19, 20 ' 21, 22 ' 23 ' 24, 25, 26, 27, 28, 29 ' 30, 31, 32, 33 ' 34, 35, 36, 37, 38, 39, 40, 41 , 42 ' 43, 44 ' 45 '46 , 47 , 48 , 49 , 50 , 51 , 52 &gt; 53 ' 54 , 55 ' 56 ' 57 '58 , 59 , 60 ' 61 , 62 ' 63 '64 , 65 , 66, 67 '68, 69 '70, 71, 72 &gt; 73 &gt; 74, 75 '76 , 77, 78 &gt; 79, 80, 81 '82 ' 83 ' 84, 85 ' 90 ' 91 '92 , 93 , 94, 95, 96 &gt; 97, 99 '100, 200, 250, 300, 350 '400 &gt; ❹ 450 , 500 , 550 , 600 , 650 , 700 , 750 , 800 , 850 , 900 , 1000 , 1500 ' 2000, 2500 '3000 ' 3500 ' 4000 ' 4500 ' 5000 ' 5500, 6000, 6500, 7000, 7500, 8000, 8500 ' 9000, 9500, 10,000, 10,500, 1 1,000, 1 1,500, 12,000 ' 12.500 &gt; 15.500 &gt; 18.500 &gt; 21.500, 〇^ 24,500 &gt; 27.500 ' * 30,500 &gt; 33.500, 36.500, 39.500, 42.500 ' 45.500, 134345.doc 13.000 ' 16.000 ' 19.000, 22,000 ' 25.000 &gt; 28.000 ' 31.000, 34.000 &gt; 37.000 ' 40.000 ' 43.000 , 46.000 &gt; 135,00 ' 16.500 ' 19.500 , 22.500 ' 25.500 , 28.500 ' 31.500 ' 34.500, 37.500 ' 40.500 ' 43.500 , 46.500 , 14.000 , 17.000 ' 20.000 ' 23.000 ' 26,000 , 29.000 ' 32.000 ' 35.000 , 38.000 , 41.000 , 44.000 , 47.000 , 14.500 ' 17.500 &gt; 20.500, 23.500 , 26.500 &gt; 29.500 &gt; 32.500 35.500, 38.500, 41.500 &gt; 44.500 &gt; 47.500 ' 15.000, 18.000, 21,000 ' 24.000 ' 27.000 ' 30.000 ' 33.000 ' 36.000, 39.000 ' 42.000 , 45.000 , 48.000 , -28 - 200924782 48 , 500 &gt; 49,000 χ 49,500 &gt; 50,000 '60,000' 70,000 χ 80,000, 9 〇, 〇〇〇, 100,000, 200,000 and 300,000 ng/m Bu In certain embodiments, the compound has a water solubility of from about 10 ng/ml to about 50 pg/ml. An embodiment provides a compound of formula IIa:

❹ In some instances, L is -〇_ or _NH_. In some other instances, 'R is C4_2. Alkyl group 'e.g. _c4H9, _C6Hi3, _C7Hl5, -C8Ht7^-C9H19 '-C, 〇H21 &gt; -CnH23 '-C12H25 ' -Ci3H27 ' -C,4H29 ' -C15H31 &gt; -C16H33 ' -C17H35 ' - C,8H37 '-Ci9H39^-C2()H41 and its isomers. An embodiment provides a compound of formula 11 &amp;

OH lla-l

R1 is C4·20 alkyl, such as -c4h9, -c5h&quot;, -C6H13, -C7H15, -C8H17, -C9Hi9, _Cl°H21, -CuH23, -c12h25, -c13h27, -c14h29, -C15H31, -C16H33, _Ci7h35, _Ci8H37, _Ci9H39 or · C2GH41 and its isomers. In one embodiment, r1 is isobutyl. 134345.doc • 29. 200924782 In one embodiment, the compound of Formula 11a or IIa-1 has a water solubility of less than about 8 mg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 8 mg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 300 pg/ml. In another embodiment, the compound has about 50 pg/ml, or in one embodiment, from about 4 ng/ml to about 10 pg/m b or in one embodiment from about 4 ng/ml to about 1 pg/ Or even in an embodiment, from about 4 ng/ml to about 100 ng/ml, and even or in one embodiment, from about 4 ng/ml to about 10 ng/ml. © - The embodiment provides a compound of formula lib: R1

In certain instances, L is -〇- or -NH-. In certain other examples, r1 is c4_20 alkyl such as -C4li9, _C5Hu, C6Hi3, ©-C8H17, -C9H19, -C1()H21, -C&quot;H23, _Ci2H25, -C&quot;H, -C14H29, -C15H31 ^ -C16H33 ^ -C17H35 ^ -c18H37 ^ -C19H395t - -GgHw and its isomers. An embodiment provides a compound of formula lib-1:

134345.doc •30· 200924782 R is a C4-20 yard base, for example -C4H9, -CsHii ' -C6H13, -C7H15, -CgHi? -C9H19 ' -C10H21 ' -C11H23 ' ~Cj2H25 ' ~Ci3H27 ' -C14H29 ' - Ci5H3i, -C16H33, _C17H35, -C18H37, -Ci9H39 or -C2〇H4i and its isomers. In one embodiment, R1 is isobutyl. In one embodiment, the compound of formula lib or IIb-oxime has a water solubility of less than about 300 Å/ml. In another embodiment, the compound has from about 4 ng/ml to about 40 pg/ml' or, in one embodiment, from about 4 ng/ml to about 1 〇gg/ml' or in an embodiment about 4 ng /mi to about! The με/ϊη Bu is even water-soluble from about 4 ng/ml to about 100 ng/ml, and even or in the embodiment, from about 4 ng/ml to about 10 ng/ml. An embodiment provides a compound of the formula lie:

某些 In some instances, L is -Ο- or -NH-. It is c4.2G alkyl' such as _C4il9, -C5Hii, _. In some other examples, R1

•C6H

, -c9h19, -c1()h21, -ChHu, -c12h25 -C15H31, -C16H

Its isomers.

- Example provides a compound of formula lie-1: 134345.doc -31- 200924782

R1 is C4-2. Alkyl groups, for example, -C4H9, -C5Hn, ·ί:6Η13, _c7H15, -C8H17 '-C9H19 ' -Ci〇H2, &gt; -C11H23 ' -C12H25 ' -C13H27 ' -C14H29 ' -Ci5H31, _C16H33, _c17H35,- C18H37, -C19H3d-C2〇H4j isomers thereof. In one embodiment, R1 is isobutyl. In some embodiments, the compound of formula lie or lie-1 has a water solubility of less than about j 6 mg/ml. In another embodiment the compound has a water solubility of from about 4 ng/ml to about 8 mg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 300 pg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 100 pg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 10 pg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 1 pg/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 100 ng/ml. In another embodiment, the compound has a water solubility of from about 4 ng/ml to about 1 ng/ml. In one embodiment, the compound has a logP greater than about 2.4 at a pH of about 7.4. In one embodiment, the compound has a logP greater than a value selected from the group consisting of: 5.9, 2.6, 2. 7, 2.8, 2.9, 3.0, 3.1, 3.2 at a pH of about 7.4. , 3.3, 3·4, 3.5, 3.6, 3.7, 3.8, 3·9, 4.0, 4.1, 4.2, 4·3, 4.4, 4.5, 134345.doc ·32· 200924782 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 '5.2, 5.3, 5.4, 5_5, 5.6, 5.7 ' 5.8, 5.9, 6.0, 6.1, 6.2 ' 6.3, 6.4 ' 6.5 &gt; 6.6, 6.7 &gt; 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5 &gt; 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8·3, 8.4 '8.5 &gt; 8.6, 8.7, 8.8, 8.9 and 9.0. A compound as described herein may include, for example, a prodrug that is hydrolyzable to form an active free acid compound. Thus, when a prodrug of Formula I is administered in vivo to a mammalian individual, the cleavable ester or guanamine is modified to release the parent compound of the formula m.

The symbols have the same definitions as the above formulas. In certain embodiments the compound can be cleaved by an esterase. Esterases naturally occurring in body tissues of cleavable compounds as described herein may include, but are not limited to, lipases, such as carboxylesterases, such as arylesterase, triglyceride lipase, phospholipase A2 , lysophospholipase, acetamyl esterase, acetylcholine acetylase, biliary acetamase, tropinesterase, pectin vinegar, sterol vinegar, chlorophyllase, L-arabinolide Enzyme (L&gt;&gt; arabinonolactonase) &gt;gluconolactamase, uronolactonase, tannase, palmitic acid retinase, hydroxybutyrate dimer hydrolase, deuteration Glycerol lipase, 3-oxoadipate enolactonease, 4-lactone lipase, galactolipidase, 4·pyridinol endoacetase, 134345.doc -33· 200924782 Hydrolysis of mercaptocarnitine Enzyme, Amine 醯-tRNA^Kolytic enzyme, D_arabinic acid S曰 enzyme, linoleic acid gluconate lactonase, squamous lipase Ai, 6-acetylglucose deacetylase, lipoprotein lipase , dihydrocoumarin hydrolase, limonin _D_cycloesterase, steroid lactase, triacetate, actinomycin lactone, color Depsipeptide hydrolase, cephalosporin_c deacetylase, gas orthohydrolase, alpha-amino esterase, 4_mercaptoacetate, carboxymethylene butyrate Lactonease, deoxy citrate bismuth ring enzyme, cyano-2, ❹ ❹ 醯 醯 醯 醯 醯 镰 镰 镰 镰 镰 镰 镰 镰 镰 镰 鸟 鸟 鸟 水解 水解 水解 水解 水解Enzyme, phorbol alcohol diacetate hydrolase, spleen inositol dehydrogenase, sialic acid 0_ acetamidine series, ethoxylated butyne hydrazide dehydroethylation enzyme, acetamidine salicylate Base enzyme, coumarin acetate vinegar dehydrogenase, 2-pyrone-4,6-dicarboxylate lactase, indole galactosamine deacetylase, hormone vinegar, Bis(2-ethylhexyl)phthalic acid brewing enzyme protein glutamic acid methyl vinegar,!卜顺_Brown acid reflux yellow vinegar hydrolase, all anti-dong pick acid vinegar hydrolase, L-rhamnose-α endogenous enzyme, % (3,4-diethoxy butyl butyl acetylene) )_2,2··Break-removing enzyme, fat-branched ethyl vinegar synthase, wood ", internal vinegar, citric acid vinegar base lysine, ethyl glyceryl glycerol, hydrolase, B Xylan vinegar, ferulic acid (tetra), horn (tetra), poly (3' butyl (tetra)) depolymerase, poly (3 • thiocyanate) depolymerase '醯 ethoxylate hydrolase and poly brain Amine-producing enzymes. Preparation of the compound = text = = compound can be used with readily available starting materials or known intermediates obtained from commercial suppliers, limited to serotonin, such as latanoprost (仁 刖 刖 及 及 及 134 345345.doc -34- 200924782 The free acid of the compound and the above compound; and 2-diethylaminomethyl 4-hydroxy-2-cyclopentenone. Analogs of prostaglandins, bimatoprost, and travoprost prodrugs can be prepared according to the procedure described in Martynow et al, Ewro Chew. 2007, 689-703. Scheme 1 illustrates the preparation of a compound as disclosed herein Exemplary Synthesis process. Process 1

❹ In Scheme 1, the compounds of Structures 1, 2 and 3 are hydrolyzed in the presence of a hydrolysis reagent to produce the corresponding buffer acid as shown in General Structure 4. Where appropriate, • Certain Structure 4 compounds are available from commercial sources. Compound 4 can then be converted to the ester of structure 5 or the guanamine. Examples of suitable reagents and conditions for hydrolyzing the ester include, but are not limited to, TMSC1, Nal, CH3CN, reflux; and aqueous NaOH, DMF, HC1 (see, for example, Martinez et al.

Le&quot;, 1991, 32, 5931; Khurana et al., Corpse/Price, 1994, 580). Examples of suitable reagents and conditions for the hydrolysis of guanamine 134345.doc -35- 200924782 include, but are not limited to, NO + BF4_ (see, for example, Olah et al., */· Og. C; 2ew., 1965, 30 , 2386). Examples of reagents for forming esters include, but are not limited to, DCC/DMAP and TMSC1 (see, for example, Nakao et al, Bw//. C/zew. Soc. 1981, 54, 1267; and Gibson et al., / .0 Guanghou·CTiew., 1994, 59, 7503). Examples of reagents for forming indoleamine include, but are not limited to, DCC (see, for example, Sheehan et al, 乂 Jw. C/zew., 1955, 77, 1067). Modifications and selections of specific reaction conditions are within the skill of those skilled in the art. Hydrolysis, esterification, and guanamine formation in the reaction pathways identified in Scheme 1 are suitable for alkyl groups having any number of carbons, such as c4-c2 alkyl. One set - the choice of specific reaction conditions is within the skill of those skilled in the art (see, for example, March J, Advanced. Organic Chemistry, 6th Edition, Wiley, 2007; Sandler SR, Karo W, Organic Functional Group Preparations, 2nd Edition, Academic Press, Inc., 1986; Wade LG, Compendium of Organic Synthetic Methods, John Wiley and Sons, 1980; and Larock, R. Comprehensive ❿

Organic Transformations: A Guide to Functional Group Preparations; 2nd Edition, Wiley, 2000). Purification techniques commonly known to those skilled in the art include crystallization, steam distillation, flash chromatography, gas chromatography, size exclusion chromatography, and the like. The compounds of formula I can be synthesized by the methods disclosed in U.S. Patent Nos. 6,740,772, 6,313,341 and 7,163,959. The choice of protecting group and leaving group for a particular set of reaction conditions is well within the capabilities of those skilled in the art. 134345.doc -36- 200924782 III. Compositions ❹ 实施 Examples provide compositions comprising the compounds described herein. In certain embodiments, the composition comprises a compound of formula j or II, and a pharmaceutically acceptable carrier 'excipient or diluent. In some embodiments, the composition comprises a compound of formula Ila-IIc. In one embodiment, the composition is a pharmaceutical composition for sputum treatment of an ocular condition or an ocular condition. Non-limiting exemplary ocular conditions or diseases which may be treated with the composition include age-related macular degeneration, septic keratoconjunctivitis, allergic conjunctivitis, allergic keratosis, uveitis, Behcet's disease ( Behcetis disease), orbital inflammation, rupture of aqueous humor barrier, choroiditis, chronic uveitis, conjunctivitis, keratoconjunctivitis induced by spectacles, corneal abrasion, corneal injury, corneal ulcer, morphological disease, cystoid macular edema , dacryocystitis, diabetes, lesions, urinary macular edema, diabetic retinopathy, dry disease, age-related macular degeneration, eosinophilic granuloma, epithelial inflammatory disease, exudative macular edema, Fu Ke Dystrophic i Dystrophy), giant cell arteritis, giant papillary conjunctivitis, lunar eye, glaucoma surgery failure, transplant rejection, banded therapy, inflammation after cataract surgery, iris corneal endothelium syndrome, iritis, dryness Good cornea, 'membrane inflammation, keratoconjunctival inflammatory disease, keratoconus, lattice-shaped malnutrition' map - point strong Buckle-like spleen-like dystrophy, necrotizing cornea; raw! = neovascular disease of the membrane, uvea or cornea (eg tubular lupus, corneal neovascularization, vitrectomy and 1 verrucous) Neovascularization of the resection combination, neovascularization of the optic nerve, and neovascularization due to ocular penetration or contusive ocular damage), 134345.doc •37· 200924782 Neuroparalytic keratitis, non-infectious uveal Inflammatory eye herpes, ocular lymphoma, ocular rosacea, eye infection, ocular pemphigus, optic neuritis, total uveitis, optic nerve papillitis, ciliary flat inflammation, persistent macular edema, lens Allergies, posterior uveitis, postoperative inflammation, proliferative diabetic retinopathy, proliferative sickle cell retinopathy, vitreoretinopathy, retinal artery occlusion, retinal detachment, retinal vein occlusion, retinitis pigmentosa, early Retinopathy of the child, iris redness, scleritis, Stevens-Johnson syndrome, sympathetic ophthalmia, incitement Vein, thyroid-associated ophthalmopathy, uveitis, spring conjunctivitis, corneal softening induced by vitamin A deficiency, vitreitis, and wet age-related macular degeneration. In one embodiment, a pharmaceutically acceptable carrier can include A polymeric matrix, such as a polyoxyl. Pharmaceutical compositions for administration of a compound as described herein are conveniently presented in unit dosage form and may be prepared by any methods well known in the pharmaceutical and pharmaceutical delivery techniques. The method comprises the steps of bringing into association the active ingredient with a carrier which comprises one or more compounding agents. In general, the pharmaceutical composition is prepared by uniformly and intimately bringing the active ingredient together with a liquid carrier or a fine powdery solid carrier or two The combination is, and then, if necessary, shaped into a desired formulation. In a pharmaceutical composition, the active ingredient is included in an amount sufficient to produce the desired effect on the course or condition of the disease. The pharmaceutical composition containing the active ingredient may be in a form suitable for topical administration. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as carboxymethylcellulose 134345.doc -38- 200924782 nano, methylcellulose, propylmethylcellulose, sodium alginate, polyethylene glycol, scutellaria and Acacia gum; dispersant or wetting agent may be a naturally occurring fat-filling compound such as (tetra) lipid; or a condensation product of oxygen (iv) with a fatty acid, such as polyethylene oxide hard fat (tetra); or a condensation product of alkylene oxide and long-chain aliphatic: ' For example, 17#乙美堇其+&gt;结。. butyl hexaethyloxy decyl, alcohol, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol Sugar alcohol monooleic acid 6; or ethylene oxide and derived from fatty acid and hexitol

A condensation product of acetal anhydride, such as polyethylene sorbitol oleic acid vinegar. Aqueous suspensions may also contain - or a plurality of preservatives (for example, lyophilic acetoacetate or n-propyl hydroxybenzoate), or a plurality of coloring agents, one or more flavoring agents, and one or more sweeteners (eg, sucrose) Or saccharin). The oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or suspended in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents such as those described above may be added to provide a palatable oral preparation. The compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide active ingredients in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the dispersing or wetting agents and suspending agents which have been mentioned above. Additional excipients such as sweeteners, flavoring agents, and coloring agents may also be present. The pharmaceutical compositions as described herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil) or a mineral oil (e.g., liquid stone 134345.doc-39-200924782 butterfly) or a mixture of such materials. Suitable emulsifiers may be naturally occurring gums such as acacia or tragacanth; naturally occurring phospholipids such as soy, (iv), and vinegar or glycerol derived from fatty acids and hexitols. Alcoholic liver monooleic acid; and these partial s are intended to be oxidized sigma condensation products, such as polyoxyethylene sorbitan monooleic acid vinegar. The lotion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with, for example, glycerin, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent, a preservative, and a flavoring agent and a coloring agent. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, and surfactants. The pharmaceutical compositions as described herein may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the known art using the appropriate dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in u-butanediol. ◎ The acceptable vehicles and solvents used are water, Ringer's solution (8) nger, s 3〇1 'η) and isotonic gasification solution. In addition, sterile, non-volatile oils are known for use as a solvent or suspending medium. For this purpose, any warm volatile oil may be used, including synthetic glycerol mono- or diglyceride. In addition, fatty acids such as oleic acid are suitable for the preparation of injectables. Drug Cores In some embodiments, a pharmaceutical composition can include a drug core. The drug core includes therapeutic agents and provides sustained release of (4). The therapeutic agent migrates from the drug core to the target tissue, such as the ciliary body of the eye. The therapeutic agent can be 134345.doc 200924782 It is only slightly soluble in the matrix, as the case may be, so that a small amount of the therapeutic agent is dissolved in the matrix and is effectively released from the surface of the drug core. When the therapeutic agent diffuses from the exposed surface of the core to the tear or tear film, the rate of migration from the core to the tear or tear film may be related to the concentration of the therapeutic agent dissolved in the matrix. Additionally or in combination, the rate at which the therapeutic agent migrates from the core to the tear or tear film may be related to the nature of the matrix in which the therapeutic agent is dissolved. In a particular embodiment, the rate of migration from the drug core to the tear or tear film can be based on a polyoxic acid formulation. In some embodiments, the concentration of the therapeutic agent in the drug core can be adjusted to provide a release rate of the therapeutic agent. The therapeutic agent included in the core towel can include liquid, solid, solid gel, solid crystal, solid non- Crystalline, solid particles and/or dissolved-form therapeutic agents. In an embodiment, the drug core comprises a therapeutic agent comprising an oxygen species. The therapeutic agent can include a liquid or oral inclusion that is dispersed in the polyoxylated hydroxy group. In some embodiments, prostaglandin metabolites and/or prodrugs as described herein can crystallize prostaglandins in the polymethoxyl group and alter the dissolution rate, dissolution rate, and bioavailability of the avidin.药物 The drug core may include one or more biological phase materials that provide sustained release of the therapeutic agent. Although the core of the music is as described above for the inclusion of a substrate, w is described as having a substantially inviable compound in which the drug inclusions are dissolved, but the drug core may comprise a structure that provides sustained release of the therapeutic agent, For example, biodegradable matrices, porous drug cores, liquid drug cores, and solid drug cores. The matrix containing the therapeutic agent can be formed from a biodegradable or non-biodegradable polymer. Non-biodegradable drug cores - may include polyphthalamides, acrylates, polyethylenes, polyurethanes, polyamine phthalic acid sulphur, water condensate, poly vinegar (eg, obtained from E-Du Du) Nt ^ 134345.doc 200924782

Nemours and Company, DACRON of Wilmington, DE, USA), Polypropylene, Polytetrafluoroethylene (PTFE), Expanded PTFE (ePTFE), Polyetheretherketone (PEEK), Nylon, Extrusion Collagen, Polymer Foam, polyoxyethylene rubber, polyethylene terephthalate, very high molecular weight polyethylene, polycarbonate amino phthalate, polyurethane, polyimine, stainless steel, recorded - Titanium alloy (for example, Nitinol), Chin, stainless steel, Ming-chromium alloy (for example, ELGILOY from Elgin Specialty Metals, Elgin, IL, USA; available from Carpenter Metals 〇 Corp., Wyomissing, PA , USA's CONICHROME). The biodegradable drug core may include one or more biodegradable polymers such as proteinaceous, hydrogel, polyglycolic acid (PGA), polylactic acid (PLA), poly(L-lactonic acid) (PLLA), Poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acid), polydioxanone, polyhexanoic acid Lactone, polygluconic acid ester, polylactic acid-polyoxyethylene copolymer, modified cellulose, collagen, polyorthoester, polyhydroxybutyrate, polyanhydride, polyphosphate, poly(α-hydroxy acid ) and its combination. In some embodiments, the drug core can include at least one hydrogel polymer. In a particular embodiment, the drug core matrix comprises a solid material comprising a drug inclusion, such as polyoxin. The drug includes molecules that are extremely insoluble in water and slightly soluble in the core matrix of the drug. The inclusions in the drug core can be microparticles having a diameter of from about 1 μm to about 100 μm. Drug inclusions can include, for example, small droplets of solids and/or oils having the esters or guanamines described herein. The drug inclusions are soluble in the solid drug core matrix and substantially fill the drug core matrix with the drug (e.g., to dissolve the prodrug oil to the solid drug core 134345.doc -42- ❹

200924782 Pre-drugs from the drug core matrix are usually delivered to the tear film by diffusion, X-exposed surfaces. When the drug core is substantially charged&apos; In many embodiments, the rate limiting step of drug delivery is the delivery of drug = exposed drug core group f to (d). # Drug core matrix is generally filled with Muller ^ ^ ~ , , when the object, the gradient of the concentration of the music in the matrix is very small and does not significantly affect the rate of music transfer. The rate of drug delivery from the drug core to the tear film can be substantially constant when the surface area of the drug core exposed to the tear film is nearly heart. Studies relating to the present disclosure indicate that the solubility of the therapeutic agent in water and the molecular weight of the drug t can affect the transport of the drug from the solid substrate to the tears. In many embodiments, the therapeutic agent is substantially insoluble in water and has a weight of about 0.03. /〇 to about 0.0001% by weight, for example from about 0.03 wt% to about G G1 wt%, from about 〇〇1 wt% to about 0.002 wt%, from about 0 002 wt% to about 〇〇〇〇5 wt%, about 0.0005 The weight percent to about 〇. 〇〇〇 1% by weight of the solubility in water and a molecular weight of from about 400 g/m to about 12 g/m. The drug core can also be modified to utilize a carrier vehicle, for example, using nanoparticles or microparticles depending on the size of the molecule to be delivered, such as a latent reactive nanofiber composition for the composite and nanotexture surface ( Inn〇vative Surface Technologies, LLC, St. Paul, MN, USA), a nanostructured porous crucible called Bi〇Silicon (including micron-sized particles, films, woven fibers, or micromechanical implants) (pSividia, Umited, UK) and dry-selective cells to deliver drugs to the protein nanocage system (Chimeracore, Santa Barbara, CA, USA) » Formulation of therapeutic agents 134345.doc -43- 200924782

The above method of preparation contains a compound II xu. A regular derivative of the formula) will be used directly as a 'vacuum to prepare a therapeutic agent. A therapeutic agent with a_c is also used. Non-limiting examples of compounds of the formula Ila-c include latanoprost and the acetoprost and the ratio of the acetoprost.

Preparation of Polyfluorene Polyoxymethylene, such as NuSil 6385 (NuSil Technology LLC, Carpinteria, CA, USA), can be supplied by the manufacturer in a sealed container. An appropriate amount of polyoxane can be weighed based on the constructed batch size. Combination Therapeutic Agents and Polyoxoxime A therapeutic agent, e.g., a prodrug of Formula Ila (e.g., isobutyl ester), can be combined with polyoxoxime based on the expected and/or measured percentage of the therapeutic agent in the drug core matrix. The percentage of compound to polyoxyl oxide can be determined by the total weight of the drug matrix. A therapeutic agent such as Compound 11a is incorporated into polyoxoxime by weighing an appropriate amount of the component. The following formula can be used to determine the percentage of therapeutic agent in the drug core matrix: percent drug = (weight of drug) / (weight of drug + weight of polyoxyn) χΐοο. The percentage of prodrugs in polyoxoxime is given by: (20 mg prodrug) / (20 mg prodrug + 8 〇 氧 oxi) χ 100 = 20%. IV. Manufacture of Implants 134345.doc • 44- 200924782 Figure 1 shows a method 60 of manufacturing an implant in accordance with embodiments described herein. Sub-method 610 manufactures a punctuai plug e sub-method 65 to produce a drug core insert&apos; such as described above. Sub-method 69 装配 assembles the components into an integrated drug delivery system. 2 shows a method 620 of fabricating a hydrogel stem for a punctal plug in accordance with the method 600 of FIG. In some embodiments, method 62A includes a sub-method or sub-step of method 610. Step 622 will be 4 〇 weight. /. The hydrogel is combined with an organic solvent. Step 624 mixes the hydrogel with the solvent. In some embodiments, the hydrogel can be dissolved in an organic solvent. Step 626 injects the hydrogel into the polysulfide tube. In many embodiments, the polyfluorene tube can be infiltrated with an organic solvent. The polyfluorene tube includes a mold that forms a hydrogel. Step 628 cures the hydrogel. At least one of heat or pressure may be used, and in many embodiments, two are used, such as via a permeable mold to drive off the solvent to cure the hydrogel. Step 629 cuts the cured hydrogel to the desired length. Experimental process/validation studies can be used to optimize curing with appropriate sample sizes (e.g., hydrazine cured hydrogel samples) to determine material variability and/or process variability over time. Process variables that can be optimized include curing time, pressure, and temperature. Process-related tolerance analysis can also be performed. Figure 3 shows a method of molding a polyoxygen oxide plug 637 according to the method of Figure i. 630 Step 632 winds a filament comprising a solid material (e.g., coil 6) and heat sets the filament. Step 634 places the filaments including the heat set coil 632c in the mold. Step 636 molds plug body 637 with coil 632C therein. The plug body may comprise a sleeve, f, a retaining structure and/or at least one cavity i as described above, and the heat setting of the filament may be based on a product from a heat-set filament sample 134345.doc -45- 200924782 (eg '10 The empirical data of the filaments are optimized to properly control the time and/or temperature of the heated filaments. The molding of the plug in step 636 can be optimized in a number of ways, such as suitable time and temperature, hard upper mold of the mold, multi-cavity mold, and mold equipment parameters. 4 shows a method 64 of assembling a tearpipe plug component in accordance with the method 600 of FIG. Step 630 molds the tear duct plug 637 with a coil 632C. Step 620 molds the hydraulic gel. Step 642 inserts the hydrogel rod component into the trough of the plug component. Step 644 extends the winding of coil 632c on the hydrogel rod and step 648 wets the coated hydrogel rod and plug body. Step 646 can prepare a hydrogel coating solution 646 comprising, for example, a 5% by weight hydrogel solution. When the hydrogel rod and the plug body are immersed in the solution, the needle 648N can be placed in the groove of the plug body to hold the plug body. Figure 5 shows a method 650 of making a drug core insert in accordance with the method 6 of Figure 1. Step 661 prepares a syringe assembly for injecting a drug matrix into a polyimine tube. Step 662 prepares a polyimine tube for injection. Step 670 prepares a drug core matrix for use in the injection tube. Step 672 injects the drug core matrix into the polyimide tube. Step 680 cures the substrate to the interior of the polyimide tube. Step 682 cuts the polyimide tube and the cured substrate to a length and coats the adhesive. Step 661 can use a known commercially available syringe in the syringe assembly. The syringe assembly can include a syringe barrel and a cartridge assembly. The syringe assembly can be used to inject a drug core mixture and/or substance into a polyimide tube. Step 662 can be prepared for injection of a polyimide tube by attaching a 15 cm long polyimide tube to a luer. The flow interface can be connected to a syringe for the core mixture and/or substance of the 134345.doc • 46 - 200924782. In some embodiments, the tube attached to the syringe may comprise PMMA and/or PET. In many embodiments, the sputum comprises inhibiting the therapeutic agent from the drug core via a tube release, such as a substance that is substantially infiltrated by the flow of the therapeutic agent via the tube to direct the flow of therapeutic agent to the exposed end of the drug core. Step 670 can produce a drug core comprising a therapeutic agent and a matrix material (e.g., polyoxyl). In some embodiments, the therapeutic agent can include at least one formula. Chemical. For example, latanoprost is a free acid form of isobutyl or isobutamine of trazoprost and travodine. The examples may use polyfluorene oxide including dimethyloxane, such as Med_4011, Med 6385, and Med_6380 (NuSil Technology LLC, Carpinteria, CA, USA). In a particular embodiment, step 670 can produce a pharmaceutical core mixture comprising the latanoprost isobutyl ester oily inclusions in the polyoxoxime. The therapeutic agent and the drug core matrix material can be prepared, after which the therapeutic agent is mixed with the drug core matrix material. Step 672 can inject a mixture of therapeutic agent and polyoxoxime into the tube. A syringe, such as a 1 ml syringe, can be attached to the syringe barrel and cartridge assembly. A drop of a catalyst suitable for polyfluorene (for example, MED-6385 curing agent) can be placed in / in the main shot and the syringe can be filled with the uncured mixture of polyoxyl and the therapeutic agent or the polyoxo drug matrix. Inject into the polyamid tube until the tube is full. The open end of the polyimine tube can be closed until the polysulfide begins to solidify. Step 680 cures the core of the drug comprising mixing the polyoxygen and the therapeutic agent. 134345.doc • 47- 200924782 The compound is cured by oxygen (for example) for 12 hours. The time and temperature of curing can be controlled and empirical data can be generated to determine the desired time and temperature for curing. Studies relating to the embodiments as described herein indicate that the core polyoxo substance and drug loading (e.g., the percentage of therapeutic agent in the core) can affect the optimal time and temperature of curing. In some embodiments, empirical data can be generated for each polymethoxyl material and the percentage of each therapeutic agent to determine the optimal time to cure the injected mixture. Table 1 shows the drug inserts that can be used in accordance with the embodiments described herein and the related cure characteristics. The drug core insert matrix material can include a base polymer containing a sulfhydryl group, such as MED-4011, MED 63 85 and MED-6380 (NuSil Technology LLC, Carpinteria, CA, USA) *The base polymer can be used, for example, in a platinum/vinyl hydride curing system and/or a tin-alkoxy curing system (both available from NuSil) The curing system is cured. In many embodiments, the curing system can include commercially available known curing systems for known materials, such as the known platinum ethylene hydride curing system with respect to known MED-4011. In one particular embodiment shown in Table 1, 90 parts of MED-4011 can be combined with 10 parts of crosslinker such that the crosslinker constitutes 10% of the mixture. A mixture having MED-6385 may include 2.5% of a crosslinking agent, and a mixture having MED-6380 may include 2.5% or 5% of a crosslinking agent. 134345.doc -48- 200924782 Table 1 Drug Inserts Polylithium Oxygen Selective Material Raw Material Polymer Curing System Crosslinking % MED-4011 Dimethyloxane Ceria Filling Material Initial Vinyl Hydride System 10% MED -6385 Dimethyl oxyhydrogenated diatomaceous earth filler tin - alkoxy 2.5% MED-6380 dimethyl methoxy oxane unfilled tin-alkoxy 2.5 to 5% as described herein, relevant to the examples Studies have shown that curing systems and types of polyoxyxides can affect the solidification characteristics of solid drug core inserts and can potentially affect the yield of therapeutic agents from drug core matrix materials. In a particular embodiment, curing of the MED-4011 via a platinum vinyl hydride system can be inhibited by a high concentration of prodrug (e.g., more than 20% of the prodrug) such that a solid drug core may not form. In a particular embodiment, the curing of the MED-6385 and/or MED © 630 via the tin alkoxy system can be slightly inhibited by a high concentration (e.g., 20%) of the previous drug. This slight suppression of curing can be compensated for by increasing the time and/or temperature of the curing process. For example, the examples described herein can be prepared using a tin alkoxy system using a suitable cure time and temperature, including 40% prodrug and 60% MED- 6385 drug core. Similar results were obtained with the MED-6380 system, tin-alkoxy system and suitable cure time and/or temperature. Even for the best results of the tin alkoxy cure system, as described herein, studies related to the examples indicate that there may be an upper limit, such as 50% of the previous drug or more, at the upper limit of tin - 134345.doc -49 - 200924782 The oxycure system may not produce a solid drug core. In many embodiments, the therapeutic agent comprising a serotonin analog (e.g., a prodrug) in the drug solid drug may be at least about 5% by weight of the drug core, such as from about 5% to 50% by weight. /. Within the range, and may range from about 2% by weight to about % by weight. In some embodiments, a therapeutic agent can include a functional group that can (at least potentially) react with a curing system. In some embodiments, the therapeutic agent can include a prostaglandin analog, such as latanoprost, bimatoprost or tverprost in the free acid form of isobutyl or isobutylamine, each of which Unsaturated carbon-carbon double bonds that can potentially react with the platinum vinyl hydride curing system can be included. The unsaturated carbon-carbon double bonds can be similar to the ethylene groups in the Turning County hydride solidification system and can potentially react with the ethylene hydride cure system via a hydrogeno-sintering reaction. The isobutyl ester of the free acid form of latanoprost includes an unsaturated carbon-carbon double bond in one side chain. The free acid form of the isobutyramine in the acid form and the isobutyric acid in the form of the free acid form of travoprost each comprise two unsaturated carbon-carbon double bonds, one in each side chain. Studies relating to the examples as described herein indicate that the hydrogeno-sintering reaction of the unsaturated double-bonded ethylene hydride curing system in prostaglandin analogs does not significantly reduce prostaglandin analogs that are effective from drug core release. the amount. In some embodiments, the therapeutic agent can include a prostaglandin analog, which can include a hydroxyl group that can potentially react with the tin alkoxy cure system. The (d) group can potentially react with the alkoxy group via an alkoxy condensation reaction. The esters of latanopyrene and travoprost and the guanamine each include a hydroxy group having three hydroxyl groups which are potentially reactive via alkoxy condensation reaction. 134345.doc -50- 200924782 Studies relating to the examples as described herein indicate that the alkoxy condensation reaction of the hydroxyl group with the tin alkoxy cure system in the prostaglandin analog does not significantly reduce the amount of prostaglandin analog that can be effectively released from the drug core. In some embodiments, the polyoxymethylene material can include an inert filler to increase the stiffness of the cured matrix. Studies relating to the embodiments as described herein indicate that the filler material can increase the rate of release of the therapeutic agent. MED-4011 and MED-6385 materials having a filler content can be constructed. MED-4011 substances can include

The inert dioxide filler is added to increase the rigidity of the cured polysulfide. MED-63 85 may include an inert diatomaceous earth filler to increase the rigidity of the cured polyoxyl. The inert filler material increases the concentration of the drug in the matrix of the component because the filler material may not substantially absorb the therapeutic agent and the inert filler material may reduce the polyoxane fraction in the drug drug core matrix. In some embodiments, MED_6385 comprises about 25% of the earth sulphate filler and about 75% of the methyl oxyhydrogen. In a particular embodiment, the drug core can comprise 4 〇〇 / ° of the therapeutic agent and 6% by weight of the substance. 60% of the material (eg MED_ 6385) phase is 45% of the p-based 11 oxo-forming base polymer and i5% of the inert diatomaceous earth filler. Assuming that the inert filler material absorbs very little of the therapeutic agent, the therapeutic agent of the peach is contained in 45% of the dimethyl oxalate base polymer to have a concentration of the therapeutic agent in the base polymer of 47% or about hop. So, ...therapy! The rate of release of the exposed surface from the core of the polyoxymethylene drug may be due to the concentration of the therapeutic agent in the polyoxo 4 of the matrix material due to the presence of the filler material. Step _ Cut the polyimide tube with the solidified matrix mixture into a length of 134345.doc • 51· 200924782 and apply the adhesive to one end of the tube of the cut length. The polyimide tube can be inserted into a fixture and cut into segments of a specified length. In some embodiments, the cut fragments of the polyimide tube can be placed in a vacuum for 30 minutes. The cut = segment polyimine tube including the drug insert can be inspected and weighed after vacuum processing and the weight can be recorded. An adhesive can be applied to one end of the drug core insert. The adhesive can be applied in liquid form and cured under UV light, for example, under UV light for 5 seconds. In a particular embodiment, the adhesion agent can include a Loctite 4305 uv adhesive (Henkel Corporation, R0cky, CT, USA). In many embodiments, the substance applied to one end of the drug core insert comprises a substance that is substantially non-permeable to the therapeutic agent to inhibit release of the therapeutic agent via the covered end. This inhibition of drug release from the drug core via the covered end allows efficient and/or efficient delivery of the drug via the exposed surface of the drug core on the opposite end to selectively release the drug into the target tissue and/or body fluid, such as tears. In the middle. In some embodiments, the exposed end opposite the closed end can be shaped to increase the surface area of the exposed end as described above. In some embodiments, a cone having a sharp tip similar to a sharp pencil tip can be inserted into the exposed surface to indent the exposed surface to have an inverted taper that increases the surface area. In some embodiments, the exposed ends can be crimped to reduce the surface area. Figure ό shows a method 69 final assembly according to the method 600 of Figure 1. Step 692 inserts the core component of the drug into the trough in the punctal plug. Step 694 encapsulates the punctal plug with a drug core insert in the trough. Step 696 sterilizes the encapsulated plug 134345.doc -52- 200924782 and the drug core insert. Step 698 releases the product. ❹ ❹ Step 692 inserts the musical item core into the implant (eg, a punctal plug). The drug core can be examined prior to insertion and it can be part of the insertion step. The inspection may include visual inspection to ensure that the sleeve including the cutting tube is completely filled without voids or foreign particles in the polyoxin, and the polyoxo oxygen is flush with the polyaniline tube and has the same length, including cyanopropyl The adhesion of the acid esterate completely covers one end of the tube and the length of the tube is appropriate. The drug insert and implant including the punctal plug can be loaded onto the drug insertion tool and the holding fixture. The drug insert can be loaded into the implant hole or slot using a plunger on the drug insertion tool. The removable drug insert insertion tool. The implant including the punctal plug can be examined to verify that the drug core insert is fully secured in the well' the drug core insert is beneath the surface of the lacrimal plug rim and has no visible damage to the implant/drug core assembly. The step 'inserts the punctal plug with the drug core inserted into the trough. The punctal plug can be packaged in a known package and method, such as an inner bag of the Myra outer bag ((10) plus Μ-), a bag sealer, argon, and an inflatable needle. In a particular embodiment, two complete music delivery systems, each comprising a punctal plug implant and a drug core insert, are placed in the inner bag and sealed in the inner bag. Place the sealed inner bag in the outer bag. The recognition -r Ψ outer k can extend over about 1/4 of the enveloper element. A 25 gauge needle can be inserted into the pocket φ Β — 玟 and under the sealing element, argon flows. The back seal element can be clamped and the seal can be sealed and sealed. The package can be inspected by = = argon flow needle removal and repeating this. If the oxygen filled bag is to be checked for money leaking into the new Myra (4), the inner bag can be removed and resealed in step 696 using known sterilization methods, such as with commercially available electron beam devices 134345. Doc • 53” 200924782 (Nutek Corporation of Hayward, CA, USA) sterilizes the encapsulated plug and drug core insert. Step 698 can release the product according to the final test and release procedure. It should be noted in Figures 1 to 6 The particular steps provide a particular method of making a plug having a drug core insert in accordance with some embodiments described herein. Other sequences of steps may also be implemented in accordance with alternative embodiments, for example, alternative embodiments as described herein may be implemented in a different order In addition, the individual steps illustrated in Figures 1 through 6 may include a plurality of sub-steps that may be implemented in different orders for individual steps, and may be added or removed depending on the particular application. Among other steps, many variations, modifications, and alternatives will occur to those skilled in the art. V. Methods of Delivery and Treatment One embodiment provides a treatment A method of glaucoma in an individual in need thereof. The method comprises administering to the individual an effective amount of a compound or composition thereof, for example, administering the compound to the eye of the individual. In some embodiments φ, the compound has the formula IIa-c In certain embodiments, the compound is isobutyrate in the free acid form of latanoprost or travoprost. In other embodiments, the compound is isobutyramine in the free acid form of bimatoprost An embodiment provides a method of delivering a therapeutic agent to an eye associated with tears, the method comprising administering a therapeutic agent to a desired eye HW, the method comprising: contacting the therapeutic agent with the eye; and releasing the therapeutic agent to the tears of the eye In certain instances, the therapeutic agent and the matrix forming drug core are in some other examples, the therapeutic agent is placed in the canalic canal 134345.doc 54. 200924782. The therapeutic agent is soluble in the matrix and the matrix Maintaining a substantially full therapeutic agent. The therapeutic agent includes a compound of the formula or Ha-c. Non-limiting examples of the compound include latanoprost, bimatoprost, and trovopros The amount of the drug in the free acid form of isobutyl amide and isobutyl amide may vary depending on the particular agent, the benefit to be treated, and the time over which the device is intended to deliver the treatment. Because of the presence of the device as described herein A variety of shapes, sizes, and delivery mechanisms, so the amount of drug associated with the device will depend on the particular disease or condition being treated, and the dose and duration desired to achieve a therapeutic effect. Typically, the amount of drug is at least the device. An amount of a drug effective to achieve a desired physiological or pharmacological local or systemic effect upon release. Embodiments of the drug delivery device as described herein can be adapted to provide delivery of the drug at a rate that is substantially lower than the therapeutically effective drip form of the treatment so that A large therapeutic range with a wide range of safety is provided, for example, many embodiments treat the eye for a prolonged period of time with a therapeutic amount no greater than 5% or 1% of the dose per minute. Thus, during an initial bolus or rinse period of about 1 to 3 days, the implant can be substantially free of the sustained release amount and suitably at a rate lower than the daily drip form dose, for example, per sputum The average sustained release of 〇ng and the initial release rate of 1000 to 1500 ng per day dissolve the therapeutic agent, and the amount of the initially released drug is less than 2500 ng of the drug that can be present in the drug droplets delivered to the eye. This use, which is substantially lower than the sustained release amount of one dose per day and/or multiple doses of the drug, allows the device to release a therapeutically beneficial amount of the drug to achieve the desired therapeutic benefit over a wide safe range while avoiding pre-positioning Inappropriate or excessive amounts of drugs at points or areas. 134345.doc -55- 200924782 Long time can mean relatively short periods of time, such as minutes or hours (eg 'use of anesthesia') to days or weeks (eg, pre- or post-operative antibiotics, steroids, NSAIDs) And its analogs) or longer (for example, in the case of glaucoma treatment), such as months or years (based on repeated use of the device). A drop of xalatan (pfizer, Groton „, USA) contains about 25 Kg of latanoprost, assuming a volume of 50, so assuming that there is about 8% of 2.5 5 5 minutes after the instillation, then only about 2 The snoring drug is retained in the eye. Based on the latanoprost clinical trial, this amount is effective to reduce Ι〇ρ for at least 24 hours. Pfizer/Pharmacia performs several dose-response studies to support the NDA» dose at 12.5 §/ 1^ to 115 pg/mL of latanoprost. The current dose of latanoprost is 5 〇pg/mL (administered once a day) is optimal. However, 'even ΐ25 μ§/πιί QD or The lowest dose of 15 pg/mL BID still gives a reduction of K〇P of 5〇^/mL QD dose of about 60-75%. Based on the above assumption, the concentration of 12.5 pg/mL in 5〇吣 is 0.625. Latanoprost, which causes only about 50 ng (8%) of the drug to remain in the eye after 5 minutes. In many embodiments, the compound 17-phenyl-13,14-dihydro-tri-pGF2a C4·32 alkane The concentration of the ester or (:4·32 alkanoin (formula na) is about 0.0001%, 0.001%, 0,01%, 0.1% or 1% of the concentration of latanoprost, And in a particular embodiment, the concentration of 17-phenyl-dihydrotrisodium PGF2aC4 32 alkane vinegar or C4 32 alkyl decylamine may be about 0.0001%, 〇QQ1%, 0.002%, 0.01% of the concentration of latanoprost, 0.02% or 2%, for example, a commercially available latanoprost solution formulation can be purchased at a concentration of 0.005%, usually delivered in a single drop. As described herein, 134345.doc • 56- 200924782 17·phenyl q 3,14• Dihydrogenated pGp^Cm alkyl ester or C4...alkylamine can deliver one drop every 2, 3, 4 or 5 days. In many embodiments, the therapeutically effective concentration of the drug released per device from the device can be Latan About 0.01%, 0.1%, 〇2%, 1% of prostaglandins, about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 to 1 50 ng 'eg, about 8 ng, assuming that tear irrigation and bioavailability are similar to latanoprost, for example, the amount of drug on the implantable device can be significantly less.

〇.0〇〇1%_〇〇〇1%, 〇〇〇1% 〇〇1% of latanoprost, bimatoprost or travoprost (eg, about 2.7 to 13.5 μ8) 〇〇1%_0.1% or 1% to 2% and for 17_phenyl_13,14-dihydrotris-lowering pGF2a a ” alkyl ester or C4_32 alkyl decylamine, may also be about 1〇〇ng l called, about i pg or about 3 pg to 20 pg. Although the daily release of ι7_phenyl _η, 14_diazotriazine PGF ^ Cm alkyl ester or C4 · 32 alkyl decylamine sustained release can change , but a sustained release of 10 ng per day is equivalent to about 0.5% of a solution of 2.5-phenyl-13,14 dihydrogen three-down π, C432 vinegar or c(9) guanamine by a drop of 5% solution. For example, in the case of a synthetic prostaglandin prostaglandin analog 17_stuppyral PGF2a C4_32 alkyl ester or C4-32 alkylguanamine (a compound of formula lib), the glaucoma drug may have bimatoprost Concentration of _1%, 0.001%, 0.002%, 0.01%, 〇〇2%, 2% or 5% of concentration. Therefore, depending on the availability of the organism, it is added to the extended release device for 3 to 6 months. The amount of drug that can be prolonged release can be lacked by Gu Ji, Bu #, _ , « Li J significantly 'About 5 gg-30 pg for bimatoprost and usually 1 〇| υ Pg-2〇μ§ and for compound IIb of formula IIb is called 〇 〇gg and usually 100 ng to 1, a, δ for example 17- Phenyl tris-lowering PGF2a Ibuprofen 134345.doc -57- 200924782 may have a concentration of 0.5% of the concentration of bimatoprost. In many embodiments, the implant may have more drugs for longer. Time-sustained release, for example 20-40 bimatoprost for 6 to 12 months of sustained release, whereas ι 〇 or 100 ng-Ι its hydrophobic ester or guanamine derivative such as "phenyl trisodium PGF^ C: 4,32 alkyl ester or C: 4.32 alkyl decylamine. This reduction in drug concentration can also be reflected as a device that is less than the device required for beta blocker delivery. The concentration of the commercially available bimatoprost solution is 〇 〇 3% by weight, usually once per ounce. Although the sustained release of bimatoprost released daily may vary, a sustained release of 300 ng per day is equivalent to about 2 〇/〇 of 15 pg of bimatoprost administered via a drop of 3% solution. Studies relating to the present disclosure indicate even lower sustained release doses of the formula lib compounds (eg, 17•phenyltrisodium pGF22a C4 32 ester or guanamine, including 17-phenyl trisodium pgf^isobutyl or isobutyl sulfonate) The amine, for example, from about 2 Torr to about 200 ng of the formula lib, and a daily sustained release dose of from about 2% to about 2% of the daily drip dose still provides at least a slight reduction in intraocular pressure. In some instances, a sustained release dose of from about 4 ng to about 1 ng of the formula lib compound and from about 0.04% to about 0.1% per day of the daily drip dose can be achieved. For example, 'in the case of prostaglandin F2a analog 16_m-trifluorodecyl phenyloxytetraclinal PGFh (: 4-32 alkyl ester or c4 32 alkyl decylamine (formula nc compound)' glaucoma drug may have The concentration of voproprost is 0.0001%, 0-0011⁄4, 0.002%, 〇〇1%, 〇〇2〇/〇 or 2〇/, such as the concentration of commercially available travoprost solution is 〇.〇〇4 %, usually delivered once daily. In many embodiments, the therapeutically effective concentration of the drug released from the device per day may be about 10, 15, 20, 25, 30, 35, 40, 50, 55, 60 or 65 134345 .doc • 58 - 200924782 ng 'Assume that tear washing and bioavailability are similar to travoprost. Therefore, the amount of drug on the implantable device will be significantly less depending on bioavailability. This is also reflected in the device being smaller than beta resistance. The device required for delivery of the drug may be capable of containing more drug for longer release, for example, 2.7 pg to 13.5 pg for travoprost and typically about 3 pg to 20 pg, on the implantable device The amount can be significantly less - about 1% of travoprost, for example 3〇ng_ 100 ng, 100 ng-300 n g or 300 ng-130 gg. Use the compound lie as described herein, for example 16_m-trifluoromethylphenoxytetrahydrop(}F2a Gw © alkyl ester or C4-32 alkyl decylamine (including isobutyl) The amount of the drug on the implantable device may be 0. 01%, 〇.1%, 〇2% of travoprost. Despite the daily release of 16-m-trifluoromethylphenoxy 4 The sustained release of pGF2a C4·32 alkyl ester or hazinium-amine can be varied, but a sustained release of 10 ng per day is equivalent to the application of a 0.004% solution to a solution of 2·〇16_m-trifluoromethylbenzene. The oxytetradecene PGF2a C4-32 alkyl ester or the C4_32 alkyl decylamine is about 〇5〇/〇. Since the solubility of the formula iic compound is low, the φ node can be easily adjusted by adjusting the ester or guanamine functional group, thus the formula IIcMb The compound allows a sustained release of 10 ng per day, which is equivalent to a drop of 0·〇〇4% solution applied to 2·〇16_m-trimethoxymethylphenoxy. IV PGF2« alkyl ester or C4 -0.5 alkalamine about 0.5 〇 / 〇. In some embodiments 'the therapeutic agent may include a corticosteroid such as fluocmolone acetonide to treat the target ocular tissue. In a particular embodiment' The ketonated fluocinolone can be released from the lacrimal canal and delivered to the retina as a treatment for diabetic macular edema. 4 Changing or adapting the device to deliver a high release rate, a low release rate, a large dose release, a burst release or a combination thereof is also in the present invention. High dose 134345.doc -59- 200924782 The drug can be released by forming a polymer cap that dissolves immediately in the tears or tear film. When the polymer cap is in contact with tears or tears, the solubility characteristics of the polymer allow the cap to erode and release the drug immediately. The burst release of the drug can be carried out using a polymer that is also abraded in the tear or tear film based on the solubility of the polymer. In this example, the drug and polymer can be layered along the length of the device so that when the outer polymer layer dissolves, the drug is released immediately. A high or low drug release rate can be achieved by varying the solubility of the erodible polymer layer to allow rapid or slow release of the drug layer. The other side of the drug release 2 ® 4 depends on the size of the drug molecule via a porous membrane, a soluble gel (for example, a gel in a typical ophthalmic solution), a microparticle encapsulation of the drug, or encapsulation of the nanoparticles. The release rate of the therapeutic agent in an effective amount to release the therapeutic agent can be related to the concentration of the therapeutic agent dissolved in the drug core. In many embodiments, the drug core comprises a non-therapeutic agent selected to provide the desired solubility of the therapeutic agent in the drug core. Drug Cores Non-therapeutic agents can include polymers and additives as described herein. The polymer of the core can be selected to provide the desired solubility of the therapeutic agent in the base f, e.g., the core - can include a hydrogel that increases the solubility of the hydrophilic therapeutic agent. In a second embodiment, a functional group can be added to the polymer to provide the desired solubility of the therapeutic agent in the mass, for example, to link the functional group to the polyvalent polymer. 0: In some embodiments, an additive can be used. To control the release of the therapeutic agent = for example, an additive can be used to control the concentration of the therapeutic agent by increasing or decreasing the solubility of the therapeutic agent in drug A in order to control the release of the therapeutic agent 134345.doc 200924782.囍, ☆ for increasing and / or reducing the dissolution of the therapeutic agent in the matrix to dissolve the appropriate molecules and / or substances to control the solubility. The therapeutic agent may have a degree of solubility with respect to the hydrophobicity and/or hydrophilicity of the matrix and the therapeutic agent. The surfactant, salt and water may be added to the matrix and the solubility of the therapeutic agent in the matrix may be increased. In addition, oil and hydrophobicity can be added to the matrix and it can increase the solubility of the hydrophobic therapeutic agent in the matrix.

Instead of controlling the migration rate based on the concentration of the therapeutic agent dissolved in the matrix or in addition to the eight, it can also control the surface area of the drug core to achieve the desired content of the drug from the core target site, such as the larger area of the heart. The rate at which the South therapeutic agent migrates from the drug core to the target site, and the drug core J exposed surface area will reduce the rate at which the therapeutic agent migrates from the drug core to the target site. The exposed surface area of the drug core can be increased in a number of ways, for example by making the exposed surface tooth-shaped, having a porous surface with a storm channel connected to the tear or tear film, making the exposed surface misaligned, making the exposed surface large The role of the beginning - the way to increase. The exposed surface can be made porous by the addition of a salt that is soluble and leaves the porous chamber upon dissolution. It is also possible to use water to condense and it can expand in size to provide a larger exposed surface area. The water can also be made porous to further increase the rate of migration of the therapeutic agent. In addition, implants capable of releasing two or more drugs in combination may be used, for example, the structure disclosed in U.S. Patent No. 4,281,654 (Shell), for example, in the case of glaucoma treatment, may be required a variety of prostaglandins or a prostaglandin and a cholinergic agent or an adrenaline 134345.doc -61 - 200924782 anti-agent (beta blocker) (eg Alphagan, Allegan, Irvine, CA, USA) Or a prostaglandin and a carbonic acid liver enzyme inhibitor to treat the patient. In addition, a drug-impregnated screen may be used, such as those disclosed in U.S. Patent Application Publication No. 2002/0055701, or as described in U.S. Patent Application Serial No. 2005/0129731. Biostable polymer. Certain polymers may be used to incorporate the drug into a device as described herein, such as the so-called "self-delivering drug" or Polymer Drugs (Polymerix O Corporation, Piscataway, NJ, US A) designed to degrade only to be therapeutically useful. Compounds and physiologically inert linker molecules are further described in detail in U.S. Patent Application Publication No. 2005/0048121 (East), which is incorporated herein in its entirety by reference. The device is provided to provide a release rate equal to the rate of polymer erosion and degradation and throughout the course of treatment. The transfer polymers can be used as device coatings or for drug reservoir injections (eg, as described herein) The use of the microspheres of the reservoirs. Another polymer delivery technique may also be suitable for use in the apparatus described herein, for example, in the technique described in U.S. Patent Application Publication No. 2004/0170685 (Carpenter). And techniques available from Medivas (San Diego, CA, USA). In many embodiments, the therapeutic agent has an extremely low level of, for example, from about 0.03 wt% to about 0.0001 wt% in water. Solubility, molecular weight of from about 400 g/mol to about 1200 g/mol and soluble in organic solvents. Cyclosporin A (CsA) has a water solubility of 27.67 pg/mL or about 0.0027% by weight at 25 ° C and 1202.6 g/mol molecular weight (MW) of solid. Latanoprost (Applied) 134345.doc -62- 200924782 is a prostaglandin Fh analogue which is a liquid oil at room temperature and at 25 ° C It has a water solubility of 50 pg/mL or about 0.005 wt% and a molecular weight of 432.6 g/mol in water. Lumigan is a synthetic prostaglandin analog which is solid at room temperature at 25 &lt; t It has a water solubility of 3 〇〇Hg/mL or 〇.〇3 wt% in water and has a molecular weight of 4156 g/m〇i. Studies related to the present disclosure indicate naturally occurring surfactants in the tear film (eg Surfactant D and phospholipids can affect the transport of the drug dissolved in the solid matrix from the core to the tear film. The surfactant can be modulated in response to the surfactant in the tear film to provide sustained delivery of the drug to the therapeutic volume to the tear film. For example, empirical data collection can be generated by a patient population of, for example, 10 patients The patient's tears are analyzed and the surfactant content is analyzed. The dissolution profile of the slightly water-soluble drug (eg cyclosporine) in the collected tears can also be measured and compared with the dissolution profile in buffers and surfactants. In contrast to establishing an in vitro model of a tear surfactant, an in vitro solution with a surfactant based on this empirical data can be used to modulate the drug core in response to the surfactant of the tear film. In many embodiments, the drug insert comprises a thin-walled polyimide sheath outer sheath = a compound of formula I or II comprising dispersing in Nusil 6385 (MAF) (used as a drug delivery matrix = graded solid polyoxime) For example, the drug core of the compound Ila). The end of the drug insert is sealed with a solid medium of Loctite 4305 Medicine (4). The drug insert can be placed in the hole of the punctal plug. Loctne 4305 adhesive does not come into contact with tissue or tear film. The pinch of the drug insert may be 〇.32_ : and the length may be 〇 95 mm. Three concentrations in the final drug can be tested clinically: the drug core can include 3.5, 7 or 134345.doc -63· 200924782 14 latanoprost isobutyl vinegar with a concentration of 5, 1 〇 and 2% by weight, respectively . Assuming a total dissolution rate of about 1 ng per day, the drug core comprising the prodrug is suitable for delivery of the drug for at least about 1 day, for example 12 days. The total weight of the drug core including the prodrug may be about 70 Μ. The drug insert comprising the polyimide sleeve can have a weight of about 100 materials. In many embodiments, the drug core can be dissolved at an initially high therapeutic agent level, followed by substantially constant dissolution of the therapeutic agent. The high level of dissolved therapeutic agent can produce residual effects of the residual therapeutic agent and/or therapeutic agent in combination with the therapeutic agent to provide relief to the patient. In the embodiment where the therapeutic amount is about 80 ng per ounce, the device delivers about 1 ng per day during the initial delivery time. An additional 20% delivered daily can have beneficial effects. Since the amount of drug delivered can be controlled, the initial high dose may not cause complications and/or adverse events to the patient. Throughout the disclosure, the concentrations, amounts, etc. of the various components are usually in the form of ranges. The description in the form of a bracket is for convenience and short-term purposes only and should not be considered as a fixed limitation to the invention. Therefore, the description of the scope should be considered as not to disclose all possible sub-ranges and individual values within the scope, such as the description of the range (for example, to 8.) should be regarded as a specific disclosure sub-scope. % to 7%, 2% to 8%, 2% to 6%, 3% to 6%, 4% to 8%, 3% to 8%, etc. 'and individual quantities within the range, such as 2%, 5 / 〇, 7 /〇, etc. This structure applies and applies to all cases of the entire disclosure, regardless of the width of the scope. In the scope of the patent application provided herein, unless the terms of the patent application clearly specify the time or sequence of operations, The steps specified in the claimed method or in the process of 134345.doc -64 - 200924782 can be performed in the same way as in the present invention without departing from the invention. In the request, the general steps are increased, and other steps are performed. The description material V; / silk step after the implementation of the step, but unless further refers to: other: what other steps before the implementation of the first step in the other steps, no = any order of execution, such as narrative &quot; first A, Subsequent to the 2nd request element should be regarded as meaning that the step must be the first - , 2 is the last-step, but steps B, c, and D can be performed in any order between the steps of reading and (10) is over (4) within the scope of the request. ^ 'In the scope of this article, please patent scope Unless the explicit range of terms requires a specified step to be performed separately or as a different processing operation, 'otherwise, the specified (4) can be executed simultaneously, for example, the step of the claimed = and the claimed step is within the single-operation. Simultaneously and the process is covered by the request. Therefore, the step of performing step Y and the step of performing z can be the same in the single H step or in two separate processing steps or in three independent processing steps. Zhongjin~ and the process is still within the scope of the request for the three steps. 仃 Similarly 'unless the language of the patent application clearly requires, the quality or component may meet more than one functional requirement, the restriction is the single :Quality meets as specified in the terms of the patent scope - the function of the heart is to be an example 1 17-phenyl] 3,14_ dihydrogen lower prostaglandin F2a (pGi^)

A round bottom flask containing a magnetic rod was filled with 195 MW 134345.doc • 65·200924782 mmol) 17-phenyl-13,14-dihydrotrisodium PGF2a (Cayman Chemical Company, Ann Arbor, MI, USA)' 5 ml CH2C12 ' 30.2 mg (0.23 mmol) diisopropylethylamine. This solution was stirred at a temperature of 0 to 10 ° C and 13.5 mg (0.07 mmol) of isobutyl trifluoroformate was added. The solution was allowed to stand at 0-10 ° C for 15 min and slowly warmed to room temperature. When fully esterified according to TLC (usually after 3-4 h at room temperature), the solvent is removed in vacuo. The residue was diluted with 20 mL of ethyl acetate and washed with 2×10 mL 5% The organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel flash column chromatography using ethyl acetate: acetone as solvent. A compound is obtained in the form of a colorless oil. Example 2 Preparation of (+)-16-m-trifluoromethylphenoxytetraclide (PGF2a) isobutyl ester A round bottom flask equipped with a magnetic stir bar was filled with 23 mg (0.05 mmol) (+)- 16-m-Trifluorodecylphenoxytetrahydroprostaglandin F2a (Cayman Chemical Company, Ann Arbor, MI, USA), 6 1111 C-, 39.2 ❹ mg (0.25 mmol) DBU and 42.5 mg (0.25 mmol) Butyl moth. The solution was allowed to stand at room temperature for 24 h, the solvent was removed in vacuo and the residue was diluted with 30 ml of ethyl acetate and washed twice with 10 ml of 5% sodium bicarbonate and 10 ml of 3% citric acid. The solvent was removed in vacuo and the crude product was purified by flash chromatography using silica gel: acetone as solvent. An oily compound is obtained. Example 3 Hydrolysis of 17-phenyl-dihydrotris-prostaglandin F2a (PGF2a) isobutyl ester 134345.doc -66- 200924782 Will 17-phenyl-13,14-dihydrotris-prostaglandin? 2 〇 1 (?0? 2 (1) isopropyl ester (43 mg, 0.1 mmol) was diluted with THF (1.0 mL) and lithium hydroxide (0.4 mL of 0.5 N solution in H20, 0.2 mmol) was added. The reaction was then acidified with 1N EtOAc (EtOAc) eluted eluted with EtOAc EtOAc (EtOAc) 90% yield). Example 4 Preparation of 17-phenyltrisole-20 from an ester (isobutylamine) 17-phenyl-13,14-dioxintris PGF2a isopropyl vinegar (43.3 mg, 0.1 mmol And a solution of isobutylamine (1. 〇mL, 10.1 mmol) in MeOH (4.0 mL) was warmed to <RTI ID=0.0></RTI> </RTI> <RTIgt; The residue was purified by flash chromatography using CH.sub.2Cl.sub.2.sub.sub.sub.sub.sub.sub.sub.sub.sub. 14-Dihydrogen tris(R) 〇卩2 (1 Isobutylamine was added to a flask equipped with a magnetic stir bar under an argon atmosphere to add 17_phenyl_13,14-dihydrogen to pGF2a (39.1 mg, 0.1) Mm〇l) and a solution of isobutylamine (12 pL, 0.12 mmol) in THF (1.0 mL) The solution was added with DCC (24.8 mg, 0.12 mmol) eluting Purification by column chromatography using ethyl acetate / hexanes as a solvent to afford &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&& Pressure Effect Study The intraocular pressure (IOP) of an animal was measured using a pneumatic tonometer (Digilab Modular One, Bio Rad, Cambridge, MA, USA) to perform specific calibrations for the eyes of a particular species. Prior to each XOP measurement The cornea was anesthetized with 1-2 drops of oxybuprocain. The IOP of healthy human volunteers was measured by applanation tonometry or Keeler puls air. For example, a pressure tonometer (Digilab) or a Goldmann's applanation tonometer mounted on a slit lamp microscope was used before each measurement with the applanation tonometry. Oucarba anesthesia of the cornea. Using a non-contact tonometer (p Ulsajr tonometer) Measurement. Local anesthesia was not used before. Example 7 Comparison of 17-phenyl-13,14-dihydrotrisodium PGF2a ester and guanamine and latanoprost ocular hypotensive effect This example illustrates the use of the monkey eye IOP test, which will be approximately 1% clinically The dose of 17-phenyl-13,14-dihydrotrisodium PGF2a- or guanamine was compared to the IOP reduction caused by the same dose of latanoprost. Compare the ratio of 17_phenyl_13,14_ dihydrogen to PGF2 «isobutyl ester 0.0005 ° /. 5% solution of solution and 13,14-dihydro-17-phenyl-18,19,20-tris-PGF2a·isopropyl ester (latanoprost) in a single partial to wolf The intraocular pressure reduction effect after the eye is dripped. Preparation of the drug solution: The following vehicle was used to prepare a hydrazine containing 17-phenyl-13,14-dihydro-17-phenyl- 18,19,20-tris-butanol or latanoprost. 〇〇〇5% soluble 134345, doc-68 - 200924782 solution. Composition of the vehicle (/mL): NaCl (4.1 mg), NaH2P04-H20 (4.6 mg), Na2HP04-2H20 (5.94 mg), benzalkonium chloride (0.2 mg) and water for injection. Animal: Five male macaques (Kasyo Co., Ltd., Tokyo, Japan) were used. The monkeys were housed in indoor monkey cages, and the room was maintained at 24 °C: room temperature, 55 ± 10% relative humidity, about 12 times/hour air exchange rate and 12 hours light-darkness Cycle (fluorescent lighting: 8:00 am to 8:00 pm). These animals were given granular foods (PS, Oriental Yeast Co., Ltd., Tokyo, Japan), vegetables and fruits for consumption by monkeys and were free to use tap water from an automatic dispenser. Healthy animals with no abnormalities in the front of the eye were used for this study. Test group and administration method: group administration method administration volume N 17-phenyl-13,14-dihydro three drop PGF2a isobutyl ester dropped into 35 μl/eye 5 0.0005% latanoprost dropped into 35 μl/eye 5 0.005% Five monkeys were divided into two groups: group 1 (3 monkeys) and group 2 (2 monkeys). Will 0.0005% 17-phenyl-13,14-dihydrogen drop? 0? 2 (1 isobutyl ester and 0.0005% latanoprost were dropped into the right eye of monkeys of group 1 and group 2, respectively. After one week, 0.0005% latanoprost and 0.0005% 15-keto-latanoprost Instilled into the right eye of the monkeys in Groups 1 and 2, respectively, using a micro-absorption 134345.doc -69- 200924782 liquid tube (Pipetman P 100, Gilson) to inject 35 吣 each test solution. With the same volume of vehicle. The intraocular pressure of each group (measured in mmHg, mean standard error) was measured before instillation. Measurement of intraocular pressure: by intramuscular injection of 5 mg/kg hydrochloric acid amide Ketone (Ketalar 5〇, Sanky〇Co·, Ltd” Tokyo, japan) General anesthesia of animals and by instillation of 奥4〇/〇 oxybuprocaine hydrochloride (Bino Camp. 4% solution, Santen pharmaceutical)

Co·,Ltd·’ Tokyo, japan) anesthetized the two segments before. Fix the animal in the sitting position and measure the eye by using the flattening air pressure method (Alc〇n Japan Ltd:) before the instillation and at the 2nd, 4th, 8th, 12th and 24th hours after the instillation? ° Keep the animals in the cage in addition to the time of intraocular pressure measurement. Data were statistically analyzed using Student's t-test. The p value less than 〇.〇5 is considered to be significant on the sj·. Example 8 Evaluation of eye irritation 3 〇 albino rabbits were arbitrarily divided into 5 groups. 5〇 pL was used in 〇.9% physiological saline solution, 〇%, 0.396%, 0.5. /〇, 1·〇%, and 2% of the compound were administered topically to the conjunctival sac of the right eye of each rabbit for 1 hour (6 administrations) every 10 minutes. The indications for eye irritation of the treated eye of each rabbit are as follows: swelling 'excretion' redness' conjunctiva, eyelids, iris iritis, and turbidity and involvement of keratin. Individual scores are added to determine the extent of mild, moderate, or severe stimuli. Slit lamp for ocular observation 1 hour before and 1 , 2, 3, 4 and 7 days after the first and sixth infusions 0 134345.doc 200924782 Example 9 Corneal anesthesia measurement in a single After dropping into the conjunctival sac of the right eye of an albino rabbit (N = 5), the Cochet's esthesiometer (Nylon thread: 0.12 mm in diameter, length 10 mm) was used to measure PGF2a_ or proguanamine. 0.3% of the drug, 〇·5%, 1.0%, and a 50% single instillation of 2.0% solution for corneal anesthesia. Evaluation of corneal anesthesia by the number of corneal mechanical stimuli necessary to induce blinking response The effect was compared to animals treated with sterile 0.9% NaCl (control) and 0.4% oxybuproca (eg, Novesine). Example 10 Stability Test Accelerated stability testing of PGFh isobutyl ester or isobutylamine 0.253⁄4 solution at 40 ° C for 1, 2, 3, 4, 8 and 12 weeks and monitoring of prodrugs by hplc analysis The disappearance and the appearance of the parent compound. The individual compounds were dissolved in an acetate buffer of pH 3.5 (0.018% sodium acetate, 〇135% acetic acid, 〇9 〇/〇 sodium sulphate in water for injection) to obtain a 0.25% solution. The stability of the compound was measured at 1, 4, 3, 4, 8 and 12 weeks at 40 °C. The concentration of the parent compound and the concentrations of the prodrug compounds 6, 7, and 8 were determined by HPLC at each time point. Example 11 Measurement of octanol·water partition coefficient Test method PGF2„C4·32 vinegar or C:4·32 alkanoguanidine was dissolved in mM anhydrous sodium dihydrogen phosphate buffer (pH 7,8) in a certain manner. So that the ester or guanamine is 134345.doc - 71 - 200924782 0.1 wt/volume (w/v)% of this solution and 5 mL of water-saturated octanol is poured into a 20 mL glass ampoule. The ampoule is sealed and Oscillation at 100 rpm and 25 ° C for 18 hours. After shaking, the glass ampoule was allowed to stand at room temperature. The octanol phase (upper phase) and the aqueous phase (lower phase) were respectively separated by Pasteur pipette. Take the glass tube and centrifuge the mixture for 10 minutes at 2000 rpm to completely separate the octanol phase and the aqueous phase. Each 1 mL of the separated octanol phase and the aqueous phase are diluted with water (water/acetonitrile = 50/50 vol/v (v/v) diluted to a precise volume of 50 mL and serving as a HPLC sample. PGF2a C4.32 alkyl ester or C4_32 alkane oxime amine in each phase by high performance liquid chromatography Method determination (Shimadzu

Co., type: LC-10AD; detector: ultraviolet spectrophotometer (measuring wavelength: 266 nm); column: using 8 μιη for liquid chromatography, 18-base basestone. A tubular string, wherein the tubular string is a stainless steel tube having an inner diameter of about 4.6 mm and a length of about 25 cm (CAPCELL PAK C18, SG120 5 μιη, 4.6 mm ID x 250 mm, Shiseido Co., Ltd., Tokyo, Japan) ; guard column: ODS 80TS (TOSOH Co., Tokyo Japan); _ column temperature: constant temperature of about 40 ° C; mobile phase: 1.98 g of diammonium hydrogen phosphate dissolved in 750 mL of water. Phosphoric acid was added thereto to adjust the pH to 7.3 and 250 mL of acetonitrile was mixed therewith; flow rate: 1.1 mL/min; injection amount: 10 μ! As a control, only latanoprost was dissolved in 10 mM NaH2P04 dihydrate buffer (pH 7.8) to be a solution of 0.1 w/v%. Calculation of octanol-water partition coefficient The octanol-water partition coefficient (P) is calculated by the following equation. Octanol water-partition coefficient = (concentration of PGF2a C4.32 alkyl ester or C4_32 alkylguanamine in octanol phase 134345.doc -72- 200924782 degrees) / (PGF2a C4·32 burnt ester or c; 4.32 Concentration in the aqueous phase). will

LogP is defined as the logarithm of the ratio of the concentration of solute to octanol and water. Latanoprost has a logP value of 4.027 at a pH of about 7.4. The piranol has a logP value of 2.4 at a pH of about 7.4. Travoprost has a value of 3.725 to 1 at a pH of about 7.4. The pGF2a C4·32^ ester and C4·32 saponin as described herein have a logP ° greater than 2.4 at a pH of about 7.4. Example 12 Penetration test into aqueous humor The penetration test of PGF^C4·32 alkyl ester or c:4_32 alkylamine and latanoprost to aqueous humor was performed as follows. Albino rabbits without abnormal cornea were selected (n = 5) And 1.5 μM of each test substance (formulations. 1 to 3 eye drops) was administered to the rabbit once by using a pipette. Rabbits were administered by excessive administration of sodium pentobarbital solution 2 hours after intraocular administration. After euthanization, after washing the extraocular segment with physiological saline, the aqueous humor was collected by using a syringe having a 27G injection needle. The collected aqueous humor of 16 与 was mixed with the 160 吣 mobile phase to carry out the following Pretreatment/concentration, and the mixture was filtered through membrane filtration (0.45 μηη). The filtrate was used as a sample for HPLC measurement and the concentration of free acid was determined using high performance liquid chromatography. A drop of eye drops usually contains a Κ5肫 prodrug, for example PGF2a haalkyl ester or C4_32 alkanoylamine. Small in 0.5, i, 2, 4 and 24 The eye drops were administered and 20 rabbits of each group were studied. The average concentration was measured relative to latanoprost at about 5, 1, 2, 4 and 24 hours after topical administration of the prodrug. Doc •73· 200924782 The mean concentrations at 5, 1, 2, 4, and 24 hours after latanoprost administration were 5.7, 18.7, 32.6, 29.0, and 0.2 ng/ml, respectively. The maximum concentration of free acid of latanoprost in aqueous humor was obtained at 2.5 h after 丨.5 latanoprost, 33_34 ng/ml. 1.5 gg PGF2a C4-32 alkyl ester or C4_32 was administered locally to the eye. The maximum concentration of latanoprost acid in aqueous humor was obtained at 2.5 h after the alkalamine, 30-50 ng/ml. As shown, 'PGF2a C4-32 alkyl ester or C4_32 alkane oxime compared to latanoprost The penetration of amine to aqueous water is significantly increased. Although the exemplary embodiments have been described in considerable detail by way of example and for ease of understanding, it will be appreciated by those skilled in the art that various modifications, <RTIgt; A variety of delivery mechanisms can be employed and each device embodiment can be adapted to include other A variety of other features may be used or more materials or material features of the embodiment and a single device is set. Accordingly, the scope of the present invention is only limited by the scope of the appended patent.

All of the patents, patent applications, publications, scientific papers, websites, and other documents and materials referred to and referred to herein are intended to be familiar with the skill of those skilled in the art, and each of the references and materials are cited herein. In this document, the degree of citation is as it is hereby incorporated by reference in its entirety in its entirety herein in its entirety herein. In addition, all of the patent claims and all priority applications (including (but only limited to) the scope of the patent application) are incorporated herein by reference in their entirety to the extent in part. Applicants retain any and all materials and information entities from any such patents, applications, publications, scientific papers, websites, electronically available information, and other 134345.doc •74· 200924782 reference materials or literature. The right to this manual. Applicants reserve the right to physically incorporate the scope of the patent application referred to above (including but not limited to any original patent application scope) into any part of this document, including any part of the written specification. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a method of making a punctal plug according to embodiments described herein. Figure 2 shows a method of making a hydrogel rod according to the method of Figure 1. Figure 3 shows a method of molding a polyoxygen oxide plug according to the method of Figure 1. Figure 4 shows a method of assembling a punctal plug component in accordance with the method of Figure 1. Figure 5 shows a method of making a drug core insert according to the method of Figure 1. FIG. 6 shows a method 690 of final assembly in accordance with the method 600 of FIG. ❹ 134345.doc -75·

Claims (1)

200924782 X. Patent application scope: !· A formula compound: Ly among them: L is _〇- or _NRa-, wherein Ra is ·丨_C8 alkyl; R is C4.32 alkyl; R is haloalkyl; X is -0- or -CH2-; ..... A selective double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II has a water solubility of no greater than about 16 mg/ml or a log P of greater than about 2.4 at a pH of about 7.4. 〇 2, The compound of claim 1, wherein the hydrazine compound is: Ila 3. The compound of claim 2, wherein the compound of formula 134345.doc Ila, 200924782 wherein L is -Ο- and R1 is isobutyl; Ila wherein L is -NH- and R1 is isobutyl Lib where L is -Ο- and R1 is isobutyl; Lib, where L is ·NH- and R1 is isobutyl; He ❹ wherein L is -Ο- and R1 is isobutyl; or Lie, wherein L is -NH- and R1 is isobutyl. 4. The compound of claim 1 which has a water solubility of from about 4 ng/ml to about 16 134345.doc 200924782 mg/ml or a pH of from about 25 to about 9 在 at a pH of about 7. A compound of the formula 1 which is about 55 hours after topical administration at an average concentration of greater than about 5 7 ng/ml, or about 1 hour after administration to the eye at an average concentration of greater than about 18.7 ng/ml. Hours, or about 2 hours after topical administration at an average concentration of greater than about 32.6 ng/ml, or about 4 hours after topical administration at an average concentration of greater than about 29.0 ng/mi, or at greater than about 0.2 ng/ml The average concentration is present in aqueous humor (aqUe〇us humor) about 24 hours after topical administration or Aa as free acid. ® 6. The compound of claim 1, which can be hydrolyzed by an esterase. 7. A composition comprising: - a compound of formula II: Where: Ο [为为〇- or -NRa- ' where 1^ is -11 or (: 1-(:8 alkyl; R is C4.32 alkyl; • R2 is alkyl; X is -0- or -ch2-; ..... represents a selective double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II has a pH of no greater than about 16 mg/ml at a pH of about 7.4 a water-soluble or greater than about 2.4 logP; and 134345.doc 200924782 pharmaceutically acceptable carrier. 8' Πί 7 composition 'is used to treat eye conditions, eye diseases or cosmetic enhancement eyelashes or eyebrows 9. The composition of claim 8, wherein the eye disease is glaucoma. The composition of claim 7, wherein the pharmaceutically acceptable plant comprises a silicone matrix. 11. A method of treating glaucoma in an individual in need thereof, the method comprising administering to the individual an effective amount of a composition comprising: ° a compound of formula II: Wherein: L is -〇· or -NRa-, wherein alkyl; R is C4.32 alkyl; R is -H or Ci-Cg haloalkyl; X is -〇· or -CH2-; ..... represents a selective double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, Wherein the compound of formula II has a water solubility of no greater than about 16 !ng/ml or a log P of greater than about 2.4 at a pH of about 7.4; and a selective pharmaceutically acceptable carrier. 12. The method of claim 11, wherein the composition is administered to the eye of the individual 134345.doc 200924782. 13. A method of delivering a therapeutic agent to an eye associated with tears, the method comprising: administering the therapeutic agent to an eye in need thereof by a drug core comprising the therapeutic agent, wherein the therapeutic agent comprises Formula II Compound ❹ Wherein: L is ·〇- or _NRa-, wherein alkyl; R is C4-32 alkyl; r2 is ·Η or C--C8 haloalkyl; X is -〇- or -CH2-; .. means a selective double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II has a water solubility of no greater than about 16 mg/ml at a pH of about 7.4 or greater than about 2.4. The logP. 14. The method of claim 13, wherein the administering further comprises: contacting the drug core with the eye; and releasing the therapeutic agent into the tears of the eye. The method of claim 13, wherein the therapeutic agent and the polyoxyl group form the core of the drug. 16. The method of claim 15, wherein the drug core is placed in a canaliculus of the eye. 17. The method of claim 13, wherein the therapeutic agent is dissolved in the polymethoxyl group and the polymethoxyl group maintains saturation of the therapeutic agent. 18. - Compound of formula II Wherein: ❹ L is or _NRa- 'wherein Ra is -H4Ci_c8 alkyl; R is C4-32 alkyl; R2 is -H or Ci-C8_alkyl; X is -0- or -CH2-; ...indicating a selective double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II has a water solubility of no greater than about 16 mg / such as greater than about 7.4 2.4 logP, which is used in drug therapy. 19. The use of claim 18, wherein the drug therapy enhances eyelashes or eyebrows for treating an eye condition, an eye condition, or a cosmetic condition. 20. The use of claim 19, wherein the eye disease is glaucoma. 21. Use of the compound of formula II: 134345.doc -6 - 200924782 where: L is -〇_ or -nr, where Ra is seven or 匕-^ alkyl; R is C4-32 alkyl; R is -1^ or 01-€8 X is -〇- or -ch2-; ..... represents a selective double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein the compound of formula II is at a pH of about 7.4 It has a water solubility of no greater than about 16 mg/ml or a logP of greater than about 2.4 for the preparation of a medicament for the treatment of glaucoma. 22. A method of increasing the length, thickness, quantity or density of an eyelash or eyebrow. The method comprises administering to a subject in an area where hair growth is desired an effective amount of a compound of formula II: Wherein: 1 is _〇- or -NRa-, wherein Ra is -H or CrC8 alkyl; R is C4.32 alkyl; R is a halogen group; X is ·〇- or -CH2-; a selective double bond; or a pharmaceutically acceptable salt, metabolite or prodrug thereof 134345.doc 200924782 wherein the compound of formula II has a water solubility of no greater than about 16 mg/ml at a pH of about 7.4 or Greater than about 2.4 logP. 134345.doc