NZ712804B2 - Sustained release of bimatoprost, bimatoprost analogs, prostamides and prostaglandins for fat reduction - Google Patents
Sustained release of bimatoprost, bimatoprost analogs, prostamides and prostaglandins for fat reduction Download PDFInfo
- Publication number
- NZ712804B2 NZ712804B2 NZ712804A NZ71280414A NZ712804B2 NZ 712804 B2 NZ712804 B2 NZ 712804B2 NZ 712804 A NZ712804 A NZ 712804A NZ 71280414 A NZ71280414 A NZ 71280414A NZ 712804 B2 NZ712804 B2 NZ 712804B2
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- New Zealand
- Prior art keywords
- fat
- sustained release
- compound
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- formulation
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- 230000002459 sustained Effects 0.000 title claims abstract description 61
- AQOKCDNYWBIDND-FTOWTWDKSA-N Bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 title abstract description 62
- 229960002470 bimatoprost Drugs 0.000 title abstract description 54
- 150000003180 prostaglandins Chemical class 0.000 title description 17
- 229940082622 Prostaglandin cardiac therapy preparations Drugs 0.000 title description 6
- 229940077717 Prostaglandin drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD) Drugs 0.000 title description 6
- 229940094443 oxytocics Prostaglandins Drugs 0.000 title description 6
- 239000000203 mixture Substances 0.000 claims abstract description 100
- 239000007943 implant Substances 0.000 claims abstract description 40
- 239000002537 cosmetic Substances 0.000 claims abstract description 11
- 230000001225 therapeutic Effects 0.000 claims abstract description 9
- 238000009472 formulation Methods 0.000 claims description 58
- 150000001875 compounds Chemical class 0.000 claims description 54
- 239000003814 drug Substances 0.000 claims description 29
- 229920001244 Poly(D,L-lactide) Polymers 0.000 claims description 25
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 210000001596 Intra-Abdominal Fat Anatomy 0.000 claims description 7
- 210000004003 Subcutaneous Fat Anatomy 0.000 claims description 6
- 210000000579 Abdominal Fat Anatomy 0.000 claims description 5
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 5
- 229920000747 poly(lactic acid) polymer Polymers 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- -1 diethyl glycol dibenzoate Chemical compound 0.000 description 23
- 229920000642 polymer Polymers 0.000 description 18
- GGXICVAJURFBLW-CEYXHVGTSA-N Latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 17
- 239000000499 gel Substances 0.000 description 17
- 229960001160 latanoprost Drugs 0.000 description 17
- 229940079593 drugs Drugs 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 239000004005 microsphere Substances 0.000 description 12
- MAKUBRYLFHZREJ-JWBQXVCJSA-M sodium;(2S,3S,4R,5R,6R)-3-[(2S,3R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylate Chemical compound [Na+].CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@H](O)[C@H]1O MAKUBRYLFHZREJ-JWBQXVCJSA-M 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229920002674 hyaluronan Polymers 0.000 description 9
- 229960003160 hyaluronic acid Drugs 0.000 description 8
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 7
- MKPLKVHSHYCHOC-AHTXBMBWSA-N Travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229960002368 travoprost Drugs 0.000 description 6
- 210000000577 Adipose Tissue Anatomy 0.000 description 5
- 229910052688 Gadolinium Inorganic materials 0.000 description 5
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 description 5
- 238000011068 load Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 210000003205 Muscles Anatomy 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 229960005188 collagen Drugs 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 229920001610 polycaprolactone Polymers 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrugs Drugs 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 206010003694 Atrophy Diseases 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 229920001287 Chondroitin sulfate Polymers 0.000 description 2
- KXKPYJOVDUMHGS-OSRGNVMNSA-N Chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 2
- 229920000126 Latex Polymers 0.000 description 2
- 210000002027 Muscle, Skeletal Anatomy 0.000 description 2
- 229920001710 Polyorthoester Polymers 0.000 description 2
- 229940010747 Sodium Hyaluronate Drugs 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 229940059329 chondroitin sulfate Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 150000004676 glycans Polymers 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920000117 poly(dioxanone) Polymers 0.000 description 2
- 239000002745 poly(ortho ester) Substances 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Polymers 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 229920000428 triblock copolymer Polymers 0.000 description 2
- YZWRNSARCRTXDS-UHFFFAOYSA-N 1,3-di(propanoyloxy)propan-2-yl propanoate Chemical compound CCC(=O)OCC(OC(=O)CC)COC(=O)CC YZWRNSARCRTXDS-UHFFFAOYSA-N 0.000 description 1
- 210000001593 Adipocytes, Brown Anatomy 0.000 description 1
- 210000000636 Adipocytes, White Anatomy 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N Ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- SOFLHPFCJKLSJL-BUDFFRDRSA-N [(2S,3S,4R,5R)-2-(acetyloxymethyl)-4-hydroxy-5-(hydroxymethyl)-2-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-3-yl] 2-methylpropanoate Chemical compound CC(C)C(=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 SOFLHPFCJKLSJL-BUDFFRDRSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- JJTUDXZGHPGLLC-UHFFFAOYSA-N dilactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003628 erosive Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920001888 polyacrylic acid Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 231100000803 sterility Toxicity 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000010983 sucrose acetate isobutyrate Nutrition 0.000 description 1
- 239000001797 sucrose acetate isobutyrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001248 thermal gelation Methods 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/559—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing hetero atoms other than oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61P3/04—Anorexiants; Antiobesity agents
Abstract
The present invention is directed to sustained release compositions comprising polylactides and bimatoprost or a bimatoprost analogue. The compositions may be in the form of an implant and are useful for localized fat reduction in both cosmetic and therapeutic applications. The active agent may be released from the compositions into a fat deposit over a duration exceeding 100 days. eleased from the compositions into a fat deposit over a duration exceeding 100 days.
Description
SUSTAINED RELEASE OF BIMATOPROST, BIMATOPROST ANALOGS,
PROSTAMIDES AND PROSTAGLANDINS FOR FAT REDUCTION
CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of United States Provisional Patent Application Serial No.
61/811,682, filed April 12, 2013, the entire disclosure of which is incorporated herein by reference.
SUMMARY OF THE INVENTION
The present disclosure is directed to compositions and methods for the sustained release of
bimatoprost, bimatoprost analogs, bimatoprost prodrugs, prostamides, prostaglandins, prostaglandin
analogs and prostaglandin derivatives from injectable and implantable depots for the purpose of fat
reduction including localized fat reduction.
Topical bimatoprost has been shown to effectively prevent apidocyte formation and maturation
and to atrophy adipocytes in animal models after topical administration. Furthermore, clinical evidence
of fat reduction after topical administration of bimatoprost has been reported. The present disclosure is
directed to sustained release methods and formulations of bimatoprost, bimatoprost analogs, bimatoprost
prodrugs, prostamides, prostaglandins, prostaglandin analogs and derivatives and prostaglandin analogs
such as latanoprost and travoprost for localized fat reduction.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows in vitro release profiles of brimatoprost with injectable PLGA implants;
Figure 2 shows in vitro release profiles of brimatoprost with injectable SynBiosys implants;
Figures 3A and 3B show 100 day ReGel 100 or ReGel B release data;
Figures 4A – 4C show a comparison of latanoprost release data of ReGel 100 or ReGel B delivery
systems;
Figure 5 shows a 2-D MR image 40 minutes post-injection oriented longitudinal through the
gastrocnemius muscle to show the MGL and MGM muscle groups in each leg. The right leg was injected
with HA/Albumin-Gadolinium, the left leg with Albumin-Gadolinium alone;
Figure 6A shows the release rate of bimatoprost in a formulation of 20% Bimatoprost, 45% R203s, 20%
RG752s 10% R202H, 5% PEG-3350;
Figure 6B shows the release rate of bimatoprost in a formulation shown at the bottom of Figure 6B;
Figure 6C shows the release rate of Compound #1 of the formulations of Table I;
Figure 7A shows bimatoprost microspheres which can be used for sustained release of bimatoprost for
localized fat reduction;
Figure 7B shows the release rate of bimatoprost from the latanoprost microspheres;
Figures 8A and 8B show shows 10% bimatoprost in diethyl glycol dibenzoate (gel); and,
Figure 8C shows an example of bimatoprost release from a 10% Bimatoprost in Diethyl Glycol
Dibenzoate depot (gel).
Summary of the Invention
In a first aspect the invention provides a use of compound #1:
in the manufacture of a medicament for therapeutic fat reduction, wherein the medicament is in the form
of an injectable sustained release formula suitable for injecting into a fat deposit in a subject in need
thereof, wherein the sustained release formulation is an implant with the formulation of about 8%
Compound #1, and about 92% R202H poly(D,L-lactide).
In a second aspect the present invention provides a use of compound #1:
in the manufacture of a medicament for therapeutic fat reduction, wherein the medicament is in the form
of an injectable sustained release formula suitable for injecting into a fat deposit in a subject in need
thereof, wherein the sustained release formulation is an implant with the formulation of about 8%
Compound #1, and about 92% R203H poly(D,L-lactide).
In a third aspect the present invention provides a use of compound #1:
in the manufacture of a medicament for therapeutic fat reduction, wherein the medicament is in the form
of an injectable sustained release formula suitable for injecting into a fat deposit in a subject in need
thereof, wherein the sustained release formulation is an implant with the formulation of about 8%
Compound #1, about 52% R203S poly(D,L-lactide), about 23% RG752S poly(D,L-lactide-co-glycolide),
about 11% R202H poly(D,L-lactide), and about 6% hexadecanol.
In a fourth aspect the present invention provides a use of compound #1:
in the manufacture of a medicament for therapeutic fat reduction, wherein the medicament is in the form
of an injectable sustained release formula suitable for injecting into a fat deposit in a subject in need
thereof, wherein the sustained release formulation is an implant with the formulation of about 8%
Compound #1, about 18% R203S poly(D,L-lactide), and about 74% R203H poly(D,L-lactide).
In a fifth aspect the present invention provides a cosmetic method of fat reduction wherein a sustained
release formulation of Compound #1:
is to be injected into a fat deposit, wherein the sustained release formulation is an implant with the
formulation of about 8% Compound #1 and about 92% R202H poly(D,L-lactide).
In a sixth aspect the present invention provides a cosmetic method of fat reduction, wherein a sustained
release formulation of Compound #1:
is to be injected into a fat deposit, wherein the sustained release formulation is an implant with the
formulation of about 8% Compound #1 and about 92% R203H poly(D,L-lactide).
In a seventh aspect the present invention provides a cosmetic method of fat reduction, wherein a sustained
release formulation of Compound #1:
is to be injected into a fat deposit, wherein the sustained release formulation is an implant with the
formulation of about 8% Compound #1, about 52% R203S poly(D,L-lactide), about 23% RG752S
poly(D,L-lactide-co-glycolide), about 11% R202H poly(D,L-lactide), and about 6% hexadecanol.
In an eighth aspect the present invention provides a cosmetic method of fat reduction, wherein a sustained
release formulation of Compound #1:
is to be injected into a fat deposit, wherein the sustained release formulation is an implant with the
formulation of about 8% Compound #1, about 18% R203S poly(D,L-lactide), and about 74% R203H
poly(D,L-lactide.
Some additional embodiments described herein are included in the following paragraphs:
1) A method of fat reduction 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 the group consisting of
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 injectable depots, gel suspensions, a ReGel delivery system, a hyaluronic acid release
platform, implants, microspheres, macrospheres and injectable solvents.
4) The method of paragraphs 2 or 3 wherein the compound is bimatoprost.
) 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 localized fat reduction at and around the
injection site.
7) The method of paragraphs 1 or 3 wherein the sustained release formulation is an implant with the
formulation of about 20% bimatoprost, about 45% R203s, about 20% RG752s, about 10% R202H
and about 5% PEG-3350.
8) The method of paragraphs 1 or 3 wherein the method results in atrophy of both brown and white
adipocytes and results in localized fat reduction.
9) The method of paragraph 7 wherein the implant releases bimatoprost in the fat deposit for over a
period of 100 days.
) The method of paragraph 1 wherein the sustained release formulation releases the compound
systemically to target a fat deposit at a location in the body that is not at the location of the sustained
released formulation or at difficult to reach areas.
11) The method of paragraphs 1 or 10 wherein the sustained release formulations are injected or
implanted at a location that permits reduction of abdominal fat deposits, visceral fat deposits,
epicardial fat deposits, subcutaneous fat deposits and ectopic fat deposits as non-limiting examples.
12) A composition for use in localized fat reduction wherein the composition is a sustained release
composition selected from the group consisting of injectable depots, gel suspensions, a ReGel
delivery system, a hyaluronic acid based platform, implants, microspheres, macrospheres and
injectable solvents.
13) The composition of paragraph 12 wherein the composition further comprises a compound selected
from the group consisting of bimatoprost, bimatoprost analogs, bimatoprost prodrugs, prostamides,
prostaglandins, prostaglandin analogs, latanoprost and travoprost and prostaglandin derivatives.
14) The composition of paragraph 12 and 13 wherein the sustained release composition is a Regel
delivery system and the compound is bimatoprost.
) 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 at multiple injection sites into a
single localized fat deposit.
17) The composition of paragraph 15 wherein the composition releases bimatoprost into the localized fat
deposit for over a period of 100 days.
18) The composition of paragraph 12 or 13 wherein the sustained release formulation is an implant
comprised 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 abdominal fat deposits, visceral fat deposits, epicardial fat deposits,
subcutaneous fat deposits and ectopic fat deposits.
) The composition of paragraph 18 wherein injection of the composition results in atrophy of
adipocytes in the localized fat deposit and reduction of localized fat.
21) The composition of paragraph 12 or 13 wherein the sustained release formulation is an implant
comprised of at least one polymer selected from the group consisting of poly(d,l-lactide-co-
glycolide), poly (d,l-lactide), poly(caprolactone), poly(dioxanone), poly(ethylene glycol), poly(ortho-
ester), polyesters, poly(phosphazine), poly (phosphate ester), polycaprolactone, silicone, natural
polymers such as latex, gelatin or collagen, or polymeric blends and the compound is selected from
the group consisting of bimatoprost, latanoprost, travoprost and mixtures thereof.
22) The composition of paragraph 12 or 13 wherein the sustained release formulation is a gel suspension
comprised of at least one compound selected from the group consisting of sodium hyaluronate,
crosslinked hyaluronic acid, chondroitin sulfate, cellulosics, gelatin, collagen, glycosaminoclycans, or
other synthetic or naturally occurring polysaccharides and the compound is selected from the group
consisting 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 is comprised of solutions of A–
B-A or B-A-B triblock copolymers or B-A block copolymers.
) The composition of paragraph 12 or 13 wherein the sustained release formulation is an injectable
depot with biocompatible solvents selected from the group consisting of DMSO, NMP and DMAC or
mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION
Bimatoprost and other compounds can be dissolved or dispersed in a gel, in a biodegradable solid
implant, or biocompatible solvents containing solvated polymers, which can form solid depots upon
injection. Additionally, thermal gelling delivery systems of bimatoprost may also be utilized. Solid
implants for sustained release may be comprised of poly(d,l-lactide-co-glycolide), poly (d,l-lactide),
poly(caprolactone), poly(dioxanone), poly(ethylene glycol), poly(ortho-ester), polyesters,
poly(phosphazine), poly (phosphate ester), polycaprolactone, silicone, natural polymers such as latex,
gelatin or collagen, or polymeric blends. Gel suspensions could contain sodium hyaluronate, crosslinked
hyaluronic acid, chondroitin sulfate, cellulosics, gelatin, collagen, glycosaminoclycans, or other synthetic
or naturally occurring polysaccharides. Biocompatible solvents for injection of in situ forming depots
include DMSO (dimethyl sulfoxide), NMP (N-methylpyrrolidone), DMAC (dimethylacetamide), or other
non-aqueous solvents for injection.
Bimatoprost delivery systems and delivery systems for other compounds can be administered for
reduction of adipose tissue through the injection or implantation of implants or injectable depots. Such
delivery systems may be used for reduction of local adipose tissue, e.g subcutaneous fat, and/or as a
method for sustained systemic delivery to achieve reduction of visceral fat and other fat pad depositions
that are not easily reached by local administration of the implant or injection such as pericardial fat
depositions. . Bimatoprost is a low melting compound and the ability to sustain its release from multiple
delivery platforms is surprising. Specific delivery platforms include but are not limited to injectable
bimatoprost delivery depots, in situ forming bimatoprost depots, hyaluronic acid depots, solid form
bimatoprost implants, bimatoprost microspheres and injectable solvent depots.
The delivery systems described herein can be injected or implanted at a location to achieve
reduction of 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 Depots
PLGA and multiblock polymers have been shown to release bimatoprost upon depot formation.
The polymers and drug are dissolved in a biocompatible solvent for both, such as N-methypyrrolidinone,
di-methyl acetamide or DMSO. The formulation is sterile filtered, autoclaved, or irradiated for sterility.
The solution is filled into a sterile vial or a unit dose syringe. After injection, the biocompatible solvent
diffuses away from the depot, leaving behind a firm prostamide or prostaglandin loaded implant. The
depot releases bimatoprost, prostamide or prostaglandin for days, weeks, or months, as the polymer
bioerodes. Drug loading in solution could range from 0.1% to 50%. Polymer loading in solution could
range from 15% to 50%. Excipients could include poly(ethylene glycol), short chain fatty acids, waxes,
cholesterol, aliphatic alcohols, co-solvents, or other compounds which would adjust the hydrophobicity of
the depot.
With both PLGA and SynBiosys bimatoprost containing injectable depots, the drug was
continuously released for at least one month as shown in figures 1 and 2 . It is possible to further
optimize the release kinetics by varying drug load, polymer concentration, polymer properties,
formulation excipients or DMSO volume used for implant preparation.
Example II
ReGel Delivery System
Polymer systems that undergo phase transitions in response to various stimuli can also be used.
This phase transition results in a significant volume and or viscosity change in the system. The system
can respond to pH, ionic environment, temperature, biologic triggers as well as other chemical and
physical triggers. The system comprises one or more polymers capable of interacting to cause a phase-
transition resulting in the volume or viscosity increases. Examples of polymers include polyacrylic acid
and polyethylene oxide copolymers. Other components of the system include excipients known to those
experienced in the art.
The system has the further advantage of offering controlled and sustained release of
therapeutically active agents to local tissues. The drug may be physically entrapped or chemically bound
via covalent linkages, hydrogen binding, ionic interactions, van der Waals forces or hydrophobic
interactions. Release of the drug can be controlled by physical entrapment of the active compound in the
transitioned gel. Compounds can also be physically or chemically bound to the polymers comprising the
phase transition gel. The phase transition of the gel serves to create a depot for drug delivery.
A specific example of this invention teaches the use of thermal gelling bimatoprost deliver
delivery systems comprised of solutions of A–B-A or B-A-B triblock copolymers or B-A block
copolymers where A = polylactide-co-glycolide (PLGA/ PLA) and B = polyethylene oxide (PEO) and
latanoprost. These polymers make up the Regel in situ gelling delivery system. Its aqueous solutions
have shown to have sol-to-gel transition behavior as temperature increases. For drug delivery
applications, gelation at physiologically relevant temperature (e.g., 37°C) is particularly important and
forms the basis for the utility of the systems for medical and drug delivery purposes.
In the specific example, latanoprost was loaded at 3% loading into ReGel 100 or ReGel B i.e. 3
mg drug in 100ul gel. The system displayed sustained release after thermal gelation with no burst of
latanoprost. This is very surprising given the relative low melting point and solubility of latanoprost. i.e.,
slow release, no burst. The gel remained for longer than 100 days as shown in Figures 3A and 3B.
Additional modifications can be made by adding other polymers to the system, e.g., CMC, agarose and
starch.
Example III
Hyaluronic Acids
Crosslinked hyaluronic acid has been shown to localize upon injection providing a potential
sustained release platform. Drug can either be incorporated into the crosslinked hyaluronic acid or
conjugated to the vehicle for sustained release. In the case of the former, release and erosion of the
platform can be controlled by porosity of the gel, length of the crosslinkers and crosslinking density.
Alternatively, in the latter case, bimatoprost or a prostamide analog can be covalently or ionically bonded
to the hyaluronic backbone through one of several linkers known to the art. Finally, drug may be
incorporated into another sustained release modality, such as microspheres, then incorporated into the
hyaluronic acid (crosslinked or non-crosslinked) and injected as a delivery platform.
Figure 5 shows a 2-D MR image 40 minutes post-injection oriented longitudinal through the
gastrocnemius muscle to show the MGL (tripennate gastrocnemius lateralis) and MGM
(unipennate gastrocnemius medialis) muscle groups in each leg. The right leg was injected with
HA/Albumin-Gadolinium, the left leg with Albumin-Gadolinium alone. The left leg shows
diffuse spread of the Albumin-Gadolinium (blue color) throughout the MGL muscle and
crossover to the adjacent MGM muscle. This data shows that cross-linked HA depots can be
localized and provide a platform for the local sustained release of a prostaglandin or prostamide
for fat reduction.
Example IV
Implants
Bimatoprost has been formulated into implants that can be injected or implanted subcutaneously,
into visceral fat or in direct apposition to an organ. An example is the following formulation : 20%
Bimatoprost, 45% R203s, 20% RG752s 10% R202H, 5% PEG-3350 and Figure 6A shows the release
rate of bimatoprost from this formulation (R203S is an ester end-capped PLA, R202H is an acid end
group PLA, RG752S is a 75:25 PLGA with an ester end group and PEG_3350 is polyethylene glycol with
a molecular weight of 3350). Other implant formulations and their release rates are shown in Fig 6B.
Another compound (Compound #1) which may be useful for fat reduction is disclosed below:
Implant formulations with Compound #1 and their properties are in Table I below:
Examples Lot # compositions implant implant in vitro estimated
dimension wt (µg) release release
rate duration
(µg/d) (month)
1 10524-101 8.0% API. 92.0% 150µm x 1.5 mm 36 29 3
R202H
2 10810-061 8.0% API, 92.0% 200µm x 1.5 mm 64 26 6
R203H
3 10810-080 8.0% API, 51.7% 200µm x 1.5 mm 64 34 4-5
R203S, 23.0%
RG752S, 11.5%
R202H, 5.8%
hexadecanol
4 10810-116 8.0% API, 18.4% 200µm x 1.5 mm 64 28 6
R203S, 73.6% R203H
Example V
Microspheres
Bimatoprost and latanoprost can also be sustained through the use of PLGA microspheres and
macrospheres as shown in Figures 7A -7B for latanoprost. Latanoprost microspheres were manufactured
from the PLA and PLGA polymers as shown in the table below. The microspheres were manufactured by
dissolving 20 mg of latanoprost and 100 mg polymer in 0.8 ml ethyl acetate. A minimum amount of
dichloromethane may be added to complete dissolution of the polymer. This solution is added to 40 mL
1% polyvinyl alcohol aqueous solution via a micro-pipette while mixing at high sheer, 3000 rpm, for 5
minutes with a homogenizer.
After shearing, a milky white emulsion is formed, and it is mildly agitated in a fume hood for 3-5
hours to allow solvent evaporation. This dispersion is then centrifuged at 2000 rpm for 15 min to remove
supernatant, and then 10 mL water is added to reconstitute the microspheres. The final reconstituted
micropsheres are lyophilized. The release of latanoprost from the microspheres into isotonic phosphate
buffered saline is shown in Figure 7B
Lot Polymer drug entrap PS before freeze drying,
number load efficiency um
d10 d90 Mean
13.5% 81.0% 15.4 59.2 31.9
MP-5 203H
12.2% 73.3% 15.8 64.5 34.7
MP-8 R203S
11.9% 71.3% 17.4 66.3 35.6
MP-11 RG755
Example VI
Injectable solvents
Other excipients such as sucrose acetate isobutyrate, ethyl benzoate, benzyl benzoate.
tripropionin, diethyl Gglycol dibenzoate among others can be used for direct injection subcutaneously or
into the fat. Figures 8A- 8B shows 10% bimatoprost in Diethyl Glycol Dibenzoate (gel) and Figure 8C
shows an example of bimatoprost release from 10% Bimatoprost in Diethyl Glycol Dibenzoate (gel).
The term “comprising” as used in this specification and claims means “consisting at least in part
of”. When interpreting statements in this specification, and claims which include the term “comprising”,
it is to be understood that other features that are additional to the features prefaced by this term in each
statement or claim may also be present. Related terms such as “comprise” and “comprised” are to be
interpreted in similar manner.
In this specification where reference has been made to patent specifications, other external
documents, or other sources of information, this is generally for the purpose of providing a context for
discussing the features of the invention. Unless specifically stated otherwise, reference to such external
documents is not to be construed as an admission that such documents, or such sources of information, in
any jurisdiction, are prior art, or form part of the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within
the scope of the claims of the current application. That subject matter should be readily identifiable by a
person skilled in the art and may assist in putting into practice the invention as defined in the claims of
this application.
Claims (14)
1. A use of compound #1: 5 in the manufacture of a medicament for therapeutic fat reduction, wherein the medicament is in the form of an injectable sustained release formula suitable for injecting into a fat deposit in a subject in need thereof, wherein the sustained release formulation is an implant with the formulation of about 8% Compound #1, and about 92% R202H poly(D,L-lactide).
2. The use of claim 1, wherein the implant releases compound #1 in the fat deposit for over a period 10 of 100 days.
3. A use of compound #1: in the manufacture of a medicament for therapeutic fat reduction, wherein the medicament is in the form of an injectable sustained release formula suitable for injecting into a fat deposit in a subject in need 15 thereof, wherein the sustained release formulation is an implant with the formulation of about 8% Compound #1, and about 92% R203H poly(D,L-lactide).
4. A use of compound #1: in the manufacture of a medicament for therapeutic fat reduction, wherein the medicament is in the form 5 of an injectable sustained release formula suitable for injecting into a fat deposit in a subject in need thereof, wherein the sustained release formulation is an implant with the formulation of about 8% Compound #1, about 52% R203S poly(D,L-lactide), about 23% RG752S poly(D,L-lactide-co-glycolide), about 11% R202H poly(D,L-lactide), and about 6% hexadecanol.
5. A use of compound #1: in the manufacture of a medicament for therapeutic fat reduction, wherein the medicament is in the form of an injectable sustained release formula suitable for injecting into a fat deposit in a subject in need thereof, wherein the sustained release formulation is an implant with the formulation of about 8% Compound #1, about 18% R203S poly(D,L-lactide), and about 74% R203H poly(D,L-lactide). 15
6. The use of any one of claims 1-5, wherein the sustained release formulations are to be injected or implanted at a location that permits reduction of abdominal fat deposits, visceral fat deposits, epicardial fat deposits, subcutaneous fat deposits and ectopic fat deposits.
7. A use as claimed in any one of claims 1-6, substantially as herein described and exemplified.
8. A cosmetic method of fat reduction wherein a sustained release formulation of Compound #1: is to be injected into a fat deposit, wherein the sustained release formulation is an implant with the formulation of about 8% Compound #1 and about 92% R202H poly(D,L-lactide).
9. The method of claim 8, wherein the implant releases compound #1 in the fat deposit for over a 5 period of 100 days.
10. A cosmetic method of fat reduction, wherein a sustained release formulation of Compound #1: is to be injected into a fat deposit, wherein the sustained release formulation is an implant with the formulation of about 8% Compound #1 and about 92% R203H poly(D,L-lactide). 10
11. A cosmetic method of fat reduction, wherein a sustained release formulation of Compound #1: is to be injected into a fat deposit, wherein the sustained release formulation is an implant with the formulation of about 8% Compound #1, about 52% R203S poly(D,L-lactide), about 23% RG752S poly(D,L-lactide-co-glycolide), about 11% R202H poly(D,L-lactide), and about 6% hexadecanol. 15
12. A cosmetic method of fat reduction, wherein a sustained release formulation of Compound #1: is to be injected into a fat deposit, wherein the sustained release formulation is an implant with the formulation of about 8% Compound #1, about 18% R203S poly(D,L-lactide), and about 74% R203H poly(D,L-lactide). 5
13. The cosmetic method of any one of claims 8-12, wherein the fat deposit into which the formulation is to be injected is selected from the group consisting of abdominal fat deposits, visceral fat deposits, epicardial fat deposits, subcutaneous fat deposits, and ectopic fat deposits.
14. A cosmetic method as claimed in any one of claims 8-13 substantially as herein described and exemplified.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361811682P | 2013-04-12 | 2013-04-12 | |
US61/811,682 | 2013-04-12 | ||
PCT/US2014/033558 WO2014169075A1 (en) | 2013-04-12 | 2014-04-09 | Sustained release of bimatoprost, bimatoprost analogs, prostamides and prostaglandins for fat reduction |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ712804A NZ712804A (en) | 2021-02-26 |
NZ712804B2 true NZ712804B2 (en) | 2021-05-27 |
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