阅读说明：本技术 用于减脂的比马前列素、比马前列素类似物、***酰胺和***素的持续释放 (Sustained release of bimatoprost, bimatoprost analogs, prostamides and prostaglandins for fat reduction ) 是由 S·M·惠特卡普 D·F·伍德沃 P·M·休斯 于 2014-04-09 设计创作，主要内容包括：本发明涉及用于注射到脂肪沉积体中以持续释放导致局部减脂的化合物的组合物和方法。因此,本申请提供一种非治疗目的的减脂的方法,其包括将化合物#1的持续释放制剂注射到脂肪沉积体中,其中所述持续释放制剂为具有8.0％化合物#1和92.0％R202H的制剂的植入物,具有8.0％化合物#1和92.0％R203H的制剂的植入物,具有8.0％化合物#1、51.7％R203S、23.0％RG752S、11.5％R202H和5.8％十六醇的制剂的植入物,或具有8.0％化合物#1、18.4％R203S和73.6％R203H的制剂的植入物。<Image he="357" wi="620" file="RE-DDA0002368110560000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to compositions and methods for injection into fat deposits for sustained release of compounds that result in localized fat loss. Accordingly, the present application provides a method of fat reduction for non-therapeutic purposes comprising injecting a sustained release formulation of compound #1 into a fat deposit, wherein the sustained release formulation is an implant having a formulation of 8.0% compound #1 and 92.0% R202H, an implant having a formulation of 8.0% compound #1 and 92.0% R203H, an implant having 8.0% compound #1, 51.7% R203S, 23.0% RG752S, 11.An implant of 5% R202H and 5.8% cetyl alcohol formulation, or an implant of 8.0% compound #1, 18.4% R203S and 73.6% R203H formulation.)

1. A method of fat reduction for non-therapeutic purposes comprising administering compound # 1:

the sustained release formulation of (a) is injected into a fat deposit, wherein the sustained release formulation is an implant of a formulation having 8.0% compound #1 and 92.0% R202H, an implant of a formulation having 8.0% compound #1 and 92.0% R203H, an implant of a formulation having 8.0% compound #1, 51.7% R203S, 23.0% RG752S, 11.5% R202H, and 5.8% cetyl alcohol, or an implant of a formulation having 8.0% compound #1, 18.4% R203S, and 73.6% R203H, wherein the sustained release formulation is injected into a location that allows for reduction of abdominal fat deposits, visceral fat deposits, epicardial fat deposits, subcutaneous fat deposits, or ectopic fat deposits.

2. The method of claim 1, wherein the sustained release formulation is selected from the group consisting of an injectable depot, a gel suspension, a ReGel delivery system, a hyaluronic acid release platform, an implant, a microsphere, a macrosphere, and an injectable solvent.

3. The method of claim 1, wherein the sustained release formulation is injected directly into the fat deposit.

4. The method of claim 1, wherein the fat reduction is local fat reduction at and around the injection site.

5. The method of claim 1, wherein the method results in atrophy of both brown and white adipocytes and in local fat reduction.

6. The method of claim 1, wherein the implant with a formulation of 8.0% compound #1 and 92.0% R202H releases compound #1 into the fat deposit over a period of 100 days.

7. The method of claim 1, wherein the sustained release formulation releases the compound systemically to target a fat deposit in the body not at the location of the sustained release formulation.

8. The method of claim 1 or 7, wherein the sustained release formulation is injected or implanted at a location that allows for reduction of abdominal fat deposits, visceral fat deposits, epicardial fat deposits, subcutaneous fat deposits, and ectopic fat deposits.

9. A composition for topical lipid reduction, wherein the composition is a sustained release composition selected from the group consisting of an injectable depot, a gel suspension, a ReGel delivery system, a hyaluronic acid-based platform, an implant, a microsphere, a macrocphere, and an injectable solvent, wherein the composition further comprises compound # 1:

wherein the sustained release composition is an implant consisting of 8.0% compound #1 and 92.0% R202H, an implant consisting of 8.0% compound #1 and 92.0% R203H, an implant consisting of 8.0% compound #1, 51.7% R203S, 23.0% RG752S, 11.5% R202H, and 5.8% cetyl alcohol, or an implant consisting of 8.0% compound #1, 18.4% R203S, and 73.6% R203H.

10. The composition of claim 9, wherein the sustained release composition is a Regel delivery system.

11. The composition of claim 10, wherein the composition is injected into a localized fat deposit.

12. The composition of claim 11, wherein the composition is injected into a single localized fat deposit at multiple injection sites.

13. The composition of claim 11, wherein the composition releases compound #1 into the localized fat deposit over a period of more than 100 days.

14. The composition of claim 9, wherein injection of the composition consisting of 8.0% compound #1 and 92.0% R202H results in atrophy of adipocytes and reduction of local fat in the localized fat deposit.

15. Compound # 1:

use in the preparation of a sustained release formulation for fat reduction, wherein the sustained release formulation is injected into a fat deposit, wherein the sustained release formulation is an implant of a formulation having 8.0% compound #1 and 92.0% R202H, an implant of a formulation having 8.0% compound #1 and 92.0% R203H, an implant of a formulation having 8.0% compound #1, 51.7% R203S, 23.0% RG752S, 11.5% R202H, and 5.8% cetyl alcohol, or an implant of a formulation having 8.0% compound #1, 18.4% R203S, and 73.6% R203H, wherein the sustained release formulation is injected into a location that allows for reduction of abdominal fat bodies, visceral fat bodies, epicardial fat deposits, subcutaneous fat deposits, or ectopic fat bodies.

16. The use according to claim 15, wherein the sustained release formulation is selected from the group consisting of injectable depot, gel suspension, ReGel delivery system, hyaluronic acid release platform, implant, microsphere, macrosphere and injectable solvent.

17. The use of claim 15, wherein the sustained release formulation is injected directly into the fat deposit.

18. The use of claim 15, wherein the fat reduction is local fat reduction at and around the injection site.

19. The use of claim 15, wherein injection of the sustained release formulation into a fat deposit results in atrophy of both brown and white adipocytes and results in local fat reduction.

20. The use of claim 15, wherein the implant with a formulation of 8.0% compound #1 and 92.0% R202H releases compound #1 into the fat deposit over a period of 100 days.

21. The use of claim 15, wherein the sustained release formulation releases the compound systemically to target a fat deposit in the body not at the location of the sustained release formulation.

Summary of The Invention

The present invention relates to compositions and methods for sustained release of bimatoprost, bimatoprost analogs, bimatoprost prodrugs, prostamides, prostaglandins, prostaglandin analogs and prostaglandin derivatives from injectable and implantable reservoirs for the purpose of lipid reduction, including local lipid reduction.

Topical bimatoprost has been shown to be effective in preventing adipocyte formation and maturation and atrophy of adipocytes in animal models after topical administration. In addition, clinical evidence of fat reduction following topical bimatoprost administration has been reported. The present invention relates to sustained release methods and formulations of bimatoprost, bimatoprost analogs, bimatoprost prodrugs, prostamides, prostaglandins, prostaglandin analogs and derivatives, and prostaglandin analogs (e.g., latanoprost and travoprost) for topical lipid reduction.

Brief Description of Drawings

Fig. 1 shows the in vitro release profile of bimatoprost using an injectable PLGA implant;

fig. 2 shows an in vitro release profile of bimatoprost using an injectable SynBiosys implant;

FIGS. 3A and 3B show Release data for either ReGel 100 or ReGel B over 100 days;

FIGS. 4A-4C show a comparison of Latanoprost release data for ReGel 100 or ReGel B delivery systems;

fig. 5 shows a 2-D MR image 40 minutes after injection, oriented longitudinally through the gastrocnemius muscle to show MGL and MGM muscle groups for each leg. Injecting HA/albumin-gadolinium into the right leg, and injecting albumin-gadolinium only into the left leg;

FIG. 6A shows the rate of bimatoprost release in a formulation containing 20% bimatoprost, 45% R203s, 20% RG752s 10% R202H, 5% PEG-3350;

FIG. 6B shows the release rate of bimatoprost from the formulation shown at the bottom of FIG. 6B;

figure 6C shows the release rate of compound #1 from the formulation in table I;

FIG. 7A shows bimatoprost microspheres that can be used for sustained release of bimatoprost for local fat reduction;

FIG. 7B shows the release rate of bimatoprost from latanoprost microspheres;

figures 8A and 8B show diethylene glycol dibenzoate (gel) containing 10% bimatoprost; and the number of the first and second groups,

fig. 8C shows an example of bimatoprost release from a diethylene glycol dibenzoate depot (gel) containing 10% bimatoprost.

Some embodiments of the invention are included in the following paragraphs:

1) a method of reducing fat comprising injecting a sustained release formulation of a compound selected from the group consisting of bimatoprost, bimatoprost analogs, bimatoprost prodrugs, prostamides, prostaglandins, prostaglandin analogs, latanoprost and travoprost, and prostaglandin derivatives and mixtures thereof into a fat deposit.

2) The method of paragraph 1, wherein the compound is selected from bimatoprost, latanoprost, travoprost and compound #1 and mixtures thereof.

3) The method of paragraph 1, wherein the sustained release formulation is selected from the group consisting of an injectable depot, a gel suspension, a ReGel delivery system, a hyaluronic acid release platform, an implant, a microsphere, a macrosphere, and an injectable solvent.

4) The method of paragraph 2 or 3, wherein the compound is bimatoprost.

5) The method of paragraphs 1-4, wherein the sustained release formulation is injected directly into the fat deposit.

6) The method of paragraph 1, wherein the fat reduction is local fat reduction at and around the injection site.

7) The method of paragraph 1 or 3, wherein the sustained release formulation is an implant having a formulation of about 20% bimatoprost, about 45% R203s, about 20% RG752s, about 10% R202H, and about 5% PEG-3350.

8) The method of paragraph 1 or 3, wherein the method results in atrophy of both brown and white adipocytes and in local fat reduction.

9) The method of paragraph 7, wherein the implant releases bimatoprost into the fat deposit over a period of 100 days.

10) The method of paragraph 1, wherein the sustained release formulation releases the compound systemically to target a fat deposit in the body that is not in the location of the sustained release formulation or in a hard-to-reach area.

11) The method according to paragraph 1 or 10, wherein the sustained release formulation is injected or implanted, as non-limiting examples, allowing for reduction of abdominal fat deposits, visceral fat deposits, epicardial fat deposits, subcutaneous fat deposits and ectopic fat deposits.

12) A composition for topical lipid reduction, wherein the composition is a sustained release composition selected from the group consisting of an injectable depot, a gel suspension, a ReGel delivery system, a hyaluronic acid-based platform, an implant, a microsphere, a macrocphere, and an injectable solvent.

13) The composition of paragraph 12, wherein the composition further comprises a compound selected from bimatoprost, bimatoprost analogs, bimatoprost prodrugs, prostamides, prostaglandins, prostaglandin analogs, latanoprost and travoprost, and prostaglandin derivatives.

14) The composition of paragraphs 12 and 13, wherein the sustained release composition is a Regel delivery system and the compound is bimatoprost.

15) The composition of paragraph 14, wherein the composition is injected into a localized fat deposit.

16) The composition of paragraph 15, wherein the composition is injected into a single localized fat deposit at multiple injection sites.

17) The composition of paragraph 15, wherein the composition releases bimatoprost into the localized fat deposit over a period of more than 100 days.

18) The composition of paragraph 12 or 13, wherein the sustained release formulation is an implant consisting of about 20% bimatoprost, about 45% R203s, about 20% RG752s, about 10% R202H, and about 5% PEG-3350.

19) The composition of paragraph 18, wherein the composition is injected into at least one selected from the group consisting of an abdominal fat deposit, a visceral fat deposit, an epicardial fat deposit, a subcutaneous fat deposit, and an ectopic fat deposit.

20) The composition of paragraph 18, wherein injection of the composition results in atrophy of adipocytes and reduction of local fat in the localized fat deposits.

21) The composition according to paragraph 12 or 13, wherein the sustained release formulation is an implant consisting of at least one polymer selected from poly (d, l-lactide-co-glycolide), poly (d, l-lactide), poly (caprolactone), poly (p-dioxanone), poly (ethylene glycol), poly (orthoester), polyester, poly (phosphazene), poly (phosphate ester), polycaprolactone, silicone, natural polymers such as latex, gelatin or collagen, or polymer blends, and the compound is selected from bimatoprost, latanoprost, travoprost and mixtures thereof.

22) The composition according to paragraph 12 or 13, wherein the sustained release formulation is a gel suspension consisting of at least one compound selected from sodium hyaluronate, cross-linked hyaluronic acid, chondroitin sulfate, a cellulosic material, gelatin, collagen, glycosaminoglycan or other synthetic or naturally occurring polysaccharides, and the compound is selected from bimatoprost, latanoprost, travoprost and mixtures thereof.

23) The composition of paragraph 22, wherein the gel suspension is a thermal gelling delivery system.

24) The composition of paragraph 22, wherein the thermal gelling system consists of a solution of an A-B-A or B-A-B triblock copolymer or a B-A block copolymer.

25) The composition according to paragraphs 12 or 13, wherein the sustained release formulation is an injectable depot comprising a biocompatible solvent selected from DMSO, NMP, and DMAC, or mixtures thereof.

Detailed Description

Bimatoprost and other compounds may be dissolved or dispersed in a gel, a biodegradable solid implant, or a biocompatible solvent containing a solvating polymer, which upon injection may form a solid reservoir. In addition, a thermogelling delivery system for bimatoprost may also be utilized. Solid implants for sustained release may be composed of poly (d, l-lactide-co-glycolide), poly (d, l-lactide), poly (caprolactone), poly (p-dioxanone), poly (ethylene glycol), poly (orthoester), polyester, poly (phosphazene), poly (phosphate ester), polycaprolactone, silicone, natural polymers such as latex, gelatin, or collagen, or polymer blends. The gel suspension may contain sodium hyaluronate, cross-linked hyaluronic acid, chondroitin sulfate, cellulosic materials, gelatin, collagen, glycosaminoglycans or other synthetic or naturally occurring polysaccharides. Biocompatible solvents for injection of in situ-forming depots include DMSO (dimethyl sulfoxide), NMP (N-methyl pyrrolidone), DMAC (dimethylacetamide), or other non-aqueous solvents for injection.

Bimatoprost delivery systems and delivery systems for other compounds may be administered by injection or implantation of an implant or injectable depot to reduce adipose tissue. Such delivery systems can be used to reduce local adipose tissue (e.g., subcutaneous fat) and/or as a means for sustained systemic delivery to achieve reduction of visceral fat and other fat pad deposits (e.g., pericardial fat deposits) that are not readily accessible by local administration of implants or injections. Bimatoprost is a low melting compound whose ability to sustain release from a variety of delivery platforms is surprising. Specific delivery platforms include, but are not limited to, injectable bimatoprost delivery reservoirs, in situ formed bimatoprost reservoirs, hyaluronic acid reservoirs, bimatoprost implants in solid form, bimatoprost microspheres, and injectable solvent reservoirs.

The delivery system of the present invention may be injected or implanted into a site to achieve a reduction in subcutaneous fat deposits and adipose tissue such as abdominal fat, visceral fat, epicardial fat, submental fat, periorbital fat, and ectopic fat pads.

Example I

Injectable depot

PLGA and multi-block polymers have been shown to release bimatoprost upon depot formation. The polymer and drug are dissolved in a biocompatible solvent such as N-methylpyrrolidone, dimethylacetamide or DMSO. The formulation is sterile filtered, autoclaved or irradiated for sterilization.

The solution is filled into sterile vials or unit dose syringes. After injection, the biocompatible solvent diffuses from the reservoir, leaving a stable implant loaded with prostamide or prostaglandin. As the polymer bioerodes, the depot releases bimatoprost, prostamide, or prostaglandin for days, weeks, or months. The drug loading in the solution may range from 0.1% to 50%. The polymer loading in the solution may be in the range of 15% to 50%. Excipients may include poly (ethylene glycol), short chain fatty acids, waxes, cholesterol, fatty alcohols, co-solvents, or other compounds that may modulate reservoir hydrophobicity.

The drug was released continuously for at least one month using an injectable depot containing both PLGA and SynBiosys bimatoprost, as shown in fig. 1 and 2. Release kinetics can be further optimized by varying drug loading, polymer concentration, polymer properties, formulation excipients, or DMSO volume for implant preparation.