Sustained-release drug delivery compositions for treating ocular diseases

Abstract

Disclosed herein are drug delivery compositions to treat ophthalmic diseases.

Description

[0001] SUSTAINED-RELEASE DRUG DELIVERY COMPOSITIONS FOR TREATING OCULAR DISEASES Inventors: Scott M. Whitcup, Sanjib K. Das and Michael E. Garst

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 555,836 filed February 20, 2024; this priority application is incorporated by reference herein in its entirety.

[0004] BACKGROUND

[0005] Alpha -2 adrenergic agonists are a class of compounds that may be useful to treat a number of conditions including hypertension, attention deficit disorders, certain pain conditions, and more recently as adjuncts to sedation in anesthesiology. In ophthalmology, some alpha-2 adrenergic agonists have been used to decrease intraocular pressure (IOP) in patients with glaucoma.

[0006] SUMMARY

[0007] Disclosed herein are drug delivery compositions and other sustained-release formations comprising [3-[(lS)-l-(lH-imidazole-5-yl)ethyl]-2-methylphenyl]methyl-2,2- dimethylpropanoate, (S)-(3-(l-(lH-imidazol-4-yl)ethyl)-2-methylphenyl)methanol, or a salt thereof; and polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), also called poly( lactide- co-glycolide) or poly(D,L-lactide-co-glycolide), or a combination thereof.

[0008] Typically, these drug delivery compositions are intended to deliver a drug over an extended period of time, e.g., to avoid daily dosing, such as at least two days, least one week, at least 2 weeks, at least one month, at least 3 months, at least 6 months, at least one year, or more, and / or up to one month, up to 3 months, up to one year, up to two years, up to five years, up to 10 years, or longer.

[0009] Some embodiments include a method of treating an ocular condition, comprising implanting a drug delivery sustained-release formulation described herein into or near an eye of a mammal in need thereof.

[0010] DETAILED DESCRIPTION

[0011] This disclosure generally relates to drug delivery compositions containing

[0012] [3-[(lS)-l-(lH-imidazole-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate

[0013] Compound 1; or

[0014] (S)-(3-(l-(lH-imidazol-4-yl)ethyl)-2-methylphenyl)methanol

[0015] Compound 2.

[0016] Unless otherwise indicated, any reference to a compound herein, such as Compound 1 or Compound 2, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; deuterium modified compounds, such as deuterium modified dextromethorphan; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

[0017] A pharmaceutically acceptable salt includes a salt that is acceptable for administration to an animal or a human being. Examples of suitable pharmaceutically acceptable salts of therapeutic compound include salts of an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; or an organic acid such as citric acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalene-sulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, etc.

[0018] In some embodiments, Compound 1 or Compound 2 is in an amorphous form when combined with the biodegradable polymers. In some embodiments, Compound 1 or Compound 2 is in a crystalline form when combined with the biodegradable polymers.

[0019] In addition to Compound 1 or Compound 2, or a salt thereof, the drug delivery composition includes a biodegradable polymer, or a mixture of biodegradable polymers, such as poly(D,L-lactide-co-glycolide) (PLGA), poly(D, L-lactide) (DL-PLA), poly( L-lactide) (L-PLA), or a combination thereof.

[0020] When used in a drug delivery composition, poly(D,L-lactide-co-glycolide) (PLGA) may have an acid end group, an ester end group, or a combination thereof. In some embodiments, the PLGA has an acid end group. In some embodiments, the PLGA has an esterend group. In some embodiments, the PLGA is about 5-100% of the mass of the polymers or about 5-50% of the mass of the drug delivery compositions. For drug delivery compositions containing only PLGA polymers, an acid terminated PLGA may be about 50-100%, about 60-70%, or about 66- 67% of the mass of the PLGA. For drug delivery compositions containing only PLGA polymers, an esterterminated PLGA may be about 0-50%, about 30-40%, or about 33-34% of the mass of the PLGA. For drug delivery compositions containing PLGA and DL-PLA or L-PLA, the PLGA may be about 5-50%, about 5-15%, or about 10% of the mass of the polymers.

[0021] When used in a drug delivery composition, a PLGA may have any suitable ratio of lactide and glycolide repeating units, such as a mole ratio of about 40%-90% lactide (and the corresponding amount of glycolide to make 100 mole %), about 40-60% lactide (and the corresponding amount of glycolide to make 100 mole %), about 60-70% lactide (and the corresponding amount of glycolide to make 100 mole %), about 70-80% lactide (and the corresponding amount of glycolide to make 100 mole %), about 80-90% lactide (and the corresponding amount of glycolide to make 100 mole %), about 50% lactide (and about 50% glycolide), about 65% lactide (and about 35% glycolide), about 75% lactide (and about 25% glycolide), or about 85% lactide (and about 15% glycolide).

[0022] When used in a drug delivery composition, a PLGA may have any suitable molecular weight, such as about 3,000-500,000 Da, about 3,000-50,000 Da, about 50,000-100,000 Da, about 100,000-200,000 Da, about 200,000-300,000 Da, about 300,000-500,000 Da, about 7,000-17,000 Da, about 24,000-38,000 Da, or about 7,000-240,000 Da.

[0023] When used in a drug delivery composition, a PLGA may have any suitable viscosity, such as about 0.05-3 dL / g, about 0.05-0.1 dL / g, about 0.08-0.16 dL / g, about 0.14-0.22 dL / g, about 0.16-0.24 dL / g, about 0.24-0.32 dL / g, about 0.32-0.44 dL / g, about 0.44-0.6 dL / g, about 0.5-0.7 dL / g, about 0.6-0.74 dL / g, about 0.74-0.8 dL / g, about 0.8-1.2 dL / g, about 0.9-1.3 dL / g, about 1.3-1.7 dL / g, or about 1.7-3 dL / g.

[0024] A polylactide or polylactic acid (PLA) may include a poly(D, L-lactide) (DL-PLA) and / or a poly(L-lactide) (L-PLA). When used in a drug delivery composition, DL-PLA may have an acid end group, an esterend group, or a combination thereof. In some embodiments, the DL-PLA has an acid end group. In some embodiments, the DL-PLA has an ester end group.

[0025] When used in a drug delivery composition, a DL-PLA may have any suitable molecular weight, such as about 5,000-50,000 Da, about 5,000-10,000 Da, about 10,000-20,000 Da, about 20,000-30,000 Da, about 30,000-40,000 Da, about 40,000-50,000 Da, or about 10, ODO- 28, 000 Da.

[0026] When used in a drug delivery composition, a DL-PLA may have any suitable viscosity, such as about 0.07-1.5 dL / g, about 0.05-0.16 dL / g, 1.3-1.7 dL / g, about 0.16-0.24 dL / g, about 0.24-0.35 dL / g, about 0.35-0.55 dL / g, about 0.55-0.75 dL / g, about 0.8-1.2 dL / g, or about 0.75- 1.5 dL / g.

[0027] When used in a drug delivery composition, L-PLA may have an acid end group, an ester end group, or a combination thereof. In some embodiments, the L-PLA has an acid end group. In some embodiments, the L-PLA has an ester end group.

[0028] When used in a drug delivery composition, an L-PLA may have any suitable molecular weight, such as about 5,000-50,000 Da, about 5,000-10,000 Da, about 10,000-20,000 Da, about 20,000-30,000 Da, about 30,000-40,000 Da, about 40,000-50,000 Da, or about 10, DOO- 28, 000 Da.

[0029] When used in a drug delivery composition, a L-PLA may have any suitable viscosity, such as about 0.07-1.5 dL / g, about 0.05-0.16 dL / g, about 0.16-0.24 dL / g, about 0.24-0.35 dL / g, about 0.35-0.55 dL / g, about 0.55-0.75 dL / g, about 0.8-1.2 dL / g, or about 0.75-1.5 dL / g.

[0030] In some embodiments, the composition is a polyglycolic acid (PLGA) copolymer having about 0-100% polylactic acid, about 15-85% polylactic acid, or about 35-65% polylactic acid. In some compositions, a copolymer having about 50% polylactic acid is used.

[0031] Some drug delivery compositions may have a composition within the following ranges: Some drug delivery compositions may have a composition within the following ranges:

[0032] A drug delivery composition may have any suitable physical form for administration, such as an implant, e.g. a cylindrical implant, fibers, rods, sheets, films, circular disc implant and the like.

[0033] Adjusting the diameter of implants, such as cylindrical implants, fibers, rods, or circula r disc implants, may be used to control the release of a drug to adapt to the patient needs. As water permeates the polymer matrix, it gradually forms water-filled pores. Over time, these pores enlarge, ultimately facilitating drug release. Thicker implants tend to release drugs more slowly compared to thinner ones. This delay occurs because thicker implants take longer to hydrate and create the necessary pores, thus extending the overall duration of drug release. The implant may have any diameter that is suitable for the need, such as about 100- 500 pm, about 100-200 pm, about 200-250 pm, about 250-300 pm, about 300-350 pm, about 350-400 pm, or about 400-500 pm.

[0034] For implants with a shape that does not include a radius, the square root of the smallest cross sectional area of the implant may be about 100-500 pm, about 100-200 pm, about 200-250 pm, about 250-300 pm, about 300-350 pm, about 350-400 pm, or about 400- 500 pm.

[0035] The composition, such as in the form of an implant, may be of any suitable mass. A larger mass may allow for longer delivery, and a smaller mass may be less noticeable to the patient or may be used for shorter delivery. In some embodiments, the mass of the implant is about 100-1000 pg, about 100-300 pg, about 300-400 pg, about 400-500 pm, about 500- 600 pg, about 600-700 pg, about 700-800 pg, or about 800-1000 pg.

[0036] The drug delivery composition is delivered into or near an eye of a mammal, such as a human being, e.g., by intravitreal injection, by intracameral injection, by suprachoroidal injection, by subretinal injection, by subconjunctival injection, by subtenon injection, by periorbital injection, or in other locations in or around the eye.

[0037] In some embodiments, the drug delivery composition is delivered by intravitreal injection.

[0038] In some embodiments, the drug delivery composition is delivered by intracameral injection.

[0039] In some embodiments, the drug delivery composition is delivered by suprachoroidal injection.

[0040] In some embodiments, the drug delivery composition is delivered by subretinal injection.

[0041] In some embodiments, the drug delivery composition is delivered by subconjunctival injection.

[0042] In some embodiments, the drug delivery composition is delivered by subtenon injection.

[0043] In some embodiments, the drug delivery composition is delivered by periorbital injection.

[0044] The patient may be a non-human mammal or a human being. In some embodiments, the mammal is a human being. In some embodiments, the patient is a human being. In some embodiments, the patient is a non-human mammal, such as a dog, a cat, a mouse, a rat, a rabbit, a monkey, a horse, a pig, etc.

[0045] The drug delivery composition may be implanted to treat an ocular condition in a mammal, such as a human being, such as glaucoma or ocular hypertension; age-related macular degeneration, or other forms of macular degeneration, such as geographic atrophy; diabetic retinopathy; a retinal degeneration, including inherited retinal diseases like retinitis pigmentosa; radiation retinopathy; retinal disease caused by toxic medications, light or other insults; retinopathy of prematurity; an ischemic retinal disease, including central retinal vein occlusions; branch retinal vein occlusions; central retinal artery occlusion; sickle cell retinopathy; myopia and myopia related retinal degeneration; uveitis or other inflammatory retinal diseases; decreased vision associated with ocular surgery; decreased vision associated with Alzheimer's disease or other neurologic diseases including stroke or cerebral ischemia; decreased visual acuity from ocular surgery or an other acute even such as radiation, drug related toxicity, or trauma ; etc.

[0046] The terms "treating" or "treatment" broadly includes any kind of treatment activity, including the diagnosis, cure, mitigation, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.

[0047] In some embodiments, a human patient has an age of 0-18 years, 18-30 years, 30-50 years, 50-65 years, or 65-100 years. In some embodiments, a human patient is female. In some embodiments, a human patient is male.

[0048] Example 1

[0049] Drug delivery implants were prepared having the compositions of Formulations 1-5 in Table 1 and Table 2 below.

[0050] Compound 1 or Compound 2 and the polymers were micronized together and then heat extruded by a ram extruder to form cylindrical implants. The cylindrical implants were then cut and weighed.

[0051] Table 1

[0052] In Table 1, Resomer® 203 is a DL-PLA with an ester end group with a molecular weight of 18,000-28,000 Da and a viscosity of 0.25-0.35 dL / g. Resomer® 207 is a L-PLAwith an ester end group and a viscosity of 1.3-1.7 dL / g. Resomer® 503 is an ester terminated PLGA with a mole ratio of 50% lactic acid and 50% glycolic acid, a molecular weight range of about 24, ODO- 38, 000 Da, and a viscosity of 0.32-0.44 dL / g.

[0053] Table 2

[0054] In Table 2, Resomer® 502 is an esterterminated PLGA with a mole ratio of 50% lactic acid and 50% glycolic acid and a molecular weight of 7,000-17,000 Da and a viscosity of 0.16- 0.24 dL / g. Resomer® 502H is acid terminated PLGA with a mole ratio of 50% lactic acid and 50% glycolic acid and a molecular weight of 7,000-17,000 Da and a viscosity of 0.16-0.24 dL / g Drug delivery implants having the compositions of Formulations 1-5 were tested in vitro and found to release Compound 1 or Compound 2 over time.

[0055] Additional in vitro testing is planned, to be followed by animal and / or human release studies with similar implants in one or more of the conditions described herein.

[0056] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as amounts, percentage, and so forth used in the specification and claims are to be understood in all instances as indicating both the exact values as shown and as being modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Rounding any value to fewer significant digits is specifically contemplated herein. For example, the term "about 1.1" is intended to contemplate a value of "about 1." Similarly, a value such as "about 100" is intended to contemplate a value of "about 1 x 102," indicating only a single significant digit, and that values should be rounded so that there is only a single significant digit.

[0057] The terms "a," "an," "the" and similar referents used in the context of describing the embodiments (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims.

[0058] Any use of the terms "comprising," "comprises," "having," "includes," "including," or the like is intended to also contemplate use of "consisting essentially of," "consists essentially of," "consisting of," or "consists of."

Claims

CLAIMS1. A drug delivery composition comprising [3-[(15)-l-(lH-imidazole-5-yl)ethyl]-2- methylphenyl]methyl-2,2-dimethylpropanoate, (S)-(3-( l-( lH-imidazol-4-yl)ethyl)-2- methylphenyljmethanol, or a salt thereof; and polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), or a combination thereof.

2. The drug delivery composition of claim 1, comprising [3-[(15)-l-(lH-imidazole-5- yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate ora salt thereof.

3. The drug delivery composition of claim 1, comprising (S)-(3-(l-(lH-imidazol-4- yl)ethyl)-2-methylphenyl)methanol.

4. The drug delivery composition of claim 1, 2, or 3, comprising polylactic acid.

5. The drug delivery composition of claim 4, wherein the polylactic acid comprises poly(D,L-lactide).

6. The drug delivery composition of claim 4 or 5, wherein the polylactic acid comprises poly(L-lactide).

7. The drug delivery composition of claim 1, 2, 3, 4, 5, or 6, comprising poly(lactic-co- glycolic acid).

8. The drug delivery composition of claim 1, 2, 3, 4, 5, 6, or 7, having a diameter of about200 pm to about 500 pm.

9. A method of treating an ocular condition, comprising implanting the drug delivery composition of any preceding claim into or near an eye of a mammal in need thereof.

10. The method of claim 9, wherein the mammal is a human being.

11. The method of claim 9 or 10, wherein the drug delivery composition is delivered by intravitreal injection.

12. The method of claim 9 or 10, wherein the drug delivery composition is delivered by intracameral injection.

13. The method of claim 9 or 10, wherein the drug delivery composition is delivered by suprachoroidal injection.

14. The method of claim 9 or 10, wherein the drug delivery composition is delivered by subretinal injection.

15. The method of claim 9 or 10, wherein the drug delivery composition is delivered by subconjunctival injection.

16. The method of claim 9 or 10, wherein the drug delivery composition is delivered by subtenon injection.

17. The method of claim 9 or 10, wherein the drug delivery composition is delivered by periorbital injection.

Images