US20060280715A1 - Retinoid solutions and formulations made therefrom - Google Patents
Retinoid solutions and formulations made therefrom Download PDFInfo
- Publication number
- US20060280715A1 US20060280715A1 US11/481,435 US48143506A US2006280715A1 US 20060280715 A1 US20060280715 A1 US 20060280715A1 US 48143506 A US48143506 A US 48143506A US 2006280715 A1 US2006280715 A1 US 2006280715A1
- Authority
- US
- United States
- Prior art keywords
- retinoid
- solution
- composition
- alcohol
- tretinoin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 63
- 150000004492 retinoid derivatives Chemical class 0.000 title claims abstract description 40
- 238000009472 formulation Methods 0.000 title description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 49
- 239000000839 emulsion Substances 0.000 claims abstract description 19
- 239000000725 suspension Substances 0.000 claims abstract description 18
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 11
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 9
- 206010000496 acne Diseases 0.000 claims abstract description 9
- 150000002148 esters Chemical class 0.000 claims abstract description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 20
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 239000008346 aqueous phase Substances 0.000 claims description 10
- 235000011187 glycerol Nutrition 0.000 claims description 10
- 229940088710 antibiotic agent Drugs 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 229920001296 polysiloxane Polymers 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 230000003381 solubilizing effect Effects 0.000 claims 2
- 229960002227 clindamycin Drugs 0.000 abstract description 21
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 abstract description 20
- 239000006184 cosolvent Substances 0.000 abstract description 17
- DLAHAXOYRFRPFQ-UHFFFAOYSA-N dodecyl benzoate Chemical compound CCCCCCCCCCCCOC(=O)C1=CC=CC=C1 DLAHAXOYRFRPFQ-UHFFFAOYSA-N 0.000 abstract description 15
- 239000000843 powder Substances 0.000 abstract description 9
- 239000007788 liquid Substances 0.000 abstract description 7
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 abstract description 6
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 abstract description 5
- 229940031578 diisopropyl adipate Drugs 0.000 abstract description 5
- 230000000699 topical effect Effects 0.000 abstract description 5
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 abstract description 4
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 208000017520 skin disease Diseases 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 45
- 229960001727 tretinoin Drugs 0.000 description 30
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 29
- 235000019441 ethanol Nutrition 0.000 description 26
- 239000004615 ingredient Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- 229920001213 Polysorbate 20 Polymers 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 6
- 239000003995 emulsifying agent Substances 0.000 description 5
- NUHSROFQTUXZQQ-UHFFFAOYSA-N isopentenyl diphosphate Chemical compound CC(=C)CCO[P@](O)(=O)OP(O)(O)=O NUHSROFQTUXZQQ-UHFFFAOYSA-N 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- -1 alkyl benzoates Chemical class 0.000 description 4
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 4
- 229940074928 isopropyl myristate Drugs 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 235000010199 sorbic acid Nutrition 0.000 description 4
- 239000004334 sorbic acid Substances 0.000 description 4
- 229940075582 sorbic acid Drugs 0.000 description 4
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229960002291 clindamycin phosphate Drugs 0.000 description 3
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- OVGORFFCBUIFIA-UHFFFAOYSA-N Fenipentol Chemical compound CCCCC(O)C1=CC=CC=C1 OVGORFFCBUIFIA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 229940100460 peg-100 stearate Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229930002330 retinoic acid Natural products 0.000 description 2
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- JKXYOQDLERSFPT-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-octadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO JKXYOQDLERSFPT-UHFFFAOYSA-N 0.000 description 1
- SBMYBOVJMOVVQW-UHFFFAOYSA-N 2-[3-[[4-(2,2-difluoroethyl)piperazin-1-yl]methyl]-4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound FC(CN1CCN(CC1)CC1=NN(C=C1C=1C=NC(=NC=1)NC1CC2=CC=CC=C2C1)CC(=O)N1CC2=C(CC1)NN=N2)F SBMYBOVJMOVVQW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BKCJZNIZRWYHBN-UHFFFAOYSA-N Isophosphamide mustard Chemical compound ClCCNP(=O)(O)NCCCl BKCJZNIZRWYHBN-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920002509 Poloxamer 182 Polymers 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- PLGPSDNOLCVGSS-UHFFFAOYSA-N Tetraphenylcyclopentadienone Chemical compound O=C1C(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)=C1C1=CC=CC=C1 PLGPSDNOLCVGSS-UHFFFAOYSA-N 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 description 1
- 229960002916 adapalene Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 229960002255 azelaic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- ZCTXEAQXZGPWFG-UHFFFAOYSA-N imidurea Chemical compound O=C1NC(=O)N(CO)C1NC(=O)NCNC(=O)NC1C(=O)NC(=O)N1CO ZCTXEAQXZGPWFG-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 239000003410 keratolytic agent Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- CBKLICUQYUTWQL-XWGBWKJCSA-N methyl (3s,4r)-3-methyl-1-(2-phenylethyl)-4-(n-propanoylanilino)piperidine-4-carboxylate;oxalic acid Chemical compound OC(=O)C(O)=O.CCC(=O)N([C@]1([C@H](CN(CCC=2C=CC=CC=2)CC1)C)C(=O)OC)C1=CC=CC=C1 CBKLICUQYUTWQL-XWGBWKJCSA-N 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- IYIYMCASGKQOCZ-DJRRULDNSA-N motretinide Chemical compound CCNC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C IYIYMCASGKQOCZ-DJRRULDNSA-N 0.000 description 1
- 229960005406 motretinide Drugs 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- KPWVFNOPNOTYNJ-UHFFFAOYSA-N octadecyl benzoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)C1=CC=CC=C1 KPWVFNOPNOTYNJ-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229940093426 poloxamer 182 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940096958 ppg-15 stearyl ether benzoate Drugs 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
Definitions
- retinoids are powerful keratolytic agents and antibiotics provide anti-bacterial activity for treating acne.
- Antibiotics such as erythromycin and clindamycin are soluble in aqueous media.
- Retinoids are insoluble in water.
- retinoids alone in formulations have been known to be quite unstable.
- the stabilization of retinoids by dissolving in alcohols has been proposed.
- U.S. Pat. No. 5,721,275 discloses a topical composition containing a retinoid as a single active ingredient wherein in large concentrations of alcohol are used to dissolve the retinoids in solution.
- the stability of the composition containing high levels of alcohol is limited and high levels of alcohol will irritate the skin.
- Retinoids have also been formulated in aqueous vehicles using surfactants.
- U.S. Pat. No. 5,690,923 discloses the use of surfactants such as ethoxylated alcohol, ethers, and block polymers to solubilize retinoids in water without using any alcohol.
- compositions containing both retinoids and antibiotics there exists room for improvement in the area of formulating, packaging, storing and dispensing compositions containing both retinoids and antibiotics to satisfactorily provide a full two year expiration date. Specifically, a need exists for a composition containing a retinoid and an antibiotic in complete solution, in which both active are chemically and physically stable.
- Solutions of retinoic acid, tretinoin and other retinoids that are not completely soluble in alcohol are provided.
- the solutions include anhydrous alcohol in an amount insufficient alone to solubilize the retinoid and an ester co-solvent.
- the solutions can be used alone or to formulate topical compositions, such as emulsions or suspensions.
- the formulations contain a water-soluble active in an aqueous phase and the retinoid solution in a non-aqueous phase.
- the present retinoid solutions are dispersed via a chamber in chamber pump delivery system.
- the present compositions do not use any surfactants or emulsifiers to solubilize retinoids. Rather, the present retinoid solutions employ cosolvents, (such as alkyl benzoate, isopropyl palmitate (“IPP”), isopropylmyristate (“IPM”), diisopropyl adipate, or their derivatives) in conjunction with a small amount of alcohol.
- cosolvents such as alkyl benzoate, isopropyl palmitate (“IPP”), isopropylmyristate (“IPM”), diisopropyl adipate, or their derivatives
- a benefit of the present solutions is that the amount of alcohol employed in the emulsion or suspension is so insignificant that the alcohol induced skin irritation is eliminated.
- FIG. 1 shows one type of dispenser suitable for packaging and delivering formulations containing the present retinoid solutions.
- Solutions of retinoids in accordance with this disclosure contain anhydrous alcohol in an amount insufficient alone to solubilize the retinoid, and an ester co-solvent.
- the retinoid can be any retinoid that provides a benefit to a user upon topical application and is not completely soluble in alcohol. Suitable materials include, but are not limited to retinoic acid, retinyl palmitate, retinyl propionate, retinyl acetate, tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid as well as synthetic retinoid mimetics.
- the anhydrous alcohol is present in an amount insufficient alone to solubilize the retinoid. At such low levels, the amount of alcohol present is less likely to be sufficient to irritate the skin of a user.
- Suitable anhydrous alcohols include anhydrous ethanol and anhydrous isopropanol.
- the cosolvent can be any material which, when combined with the small amount of anhydrous alcohol, completely solubilizes the retinoid.
- Particularly useful cosolvents include esters, such as alkyl benzoates, isopropyl palmitate (“IPP”), isopropyl myristate (“IPM”), diisopropyl adipate and their derivatives.
- Long chain alkylbenzoates are one type of benzoic acid ester useful as a co-solvent in preparing the present retinoid solutions.
- the alkyl group of the alkyl benzoate preferably contains from 12 to 15 carbon atoms.
- Suitable alkyl benzoates are commercially available, for example, under the tradename FINSOLV (Finetex, Inc., Elmwood Park, N.J.) such as FINSOLV-TN and FINSOLV-P (PPG-15 stearyl ether benzoate).
- Other suitable benzoate esters include Poloxamer 182 Dibenzoate, Poloxamer 105 benzoate and stearyl benzoate.
- Suitable benzoic acid esters are described for example in U.S. Pat. Nos. 4,275,222; 4,278,655; 4,293,544; 4,322,545; and 4,323,694.
- retinoid solutions in accordance with this disclosure may contain from 0.001 to 10 percent by weight retinoid, 0.003 to 40 percent by weight anhydrous alcohol and 50 to 99 percent by weight cosolvent.
- the method of preparing the solution is not critical. Typically, the cosolvents are combined and the retinoid is added with stirring at room temperature until completely solubilized.
- the retinoid solution can be used to formulate topical compositions, such as emulsions or suspensions.
- the topical formulations contain a second active ingredient.
- the second active ingredient can be useful in treating acne, such as antibiotics (e.g., clindamycin, tetracyclone or erythromycin).
- retinoid solutions in accordance with this disclosure are included in the non-aqueous phase of an emulsion or suspension, the aqueous phase of which contains a water-soluble active that is incompatible with the retinoid.
- thermal stability of an emulsion or suspension formulation containing both a retinoid and clindamycin in combination is achieved using the present retinoid solutions.
- retinoid solutions The formulation of oil-in-water emulsions or powder suspensions using the present retinoid solutions is within the purities of one skilled in the art given the present disclosure. Typically, an emulsion or suspension is prepared, and a retinoid solution in accordance with this disclosure is added with adequate stirring to provide homogenous incorporation of the solution. Exemplary formulations are provided in the working examples, infra.
- Examples 1-4 are clear yellow solutions of tretinoin.
- Isopropyl myristate (“IPM”) can be replaced with alkyl benzoate, isopropyl palmitate (“IPP”) or diisopropyl adipate to achieve the same results.
- Example E F G H I J Tretinoin 0.1 0.05 0.025 0.01 0.05 0.025 Alkyl benzoate 9.90 — — 9.90 — — IPM — 4.95 — — — — IPM — — 2.475 — — — Diisopropyl Adipate — — — — — 4.95 2.475
- the retinoids are not soluble in the esters alone. This further confirms the present finding that retinoids can be solubilized in a small amount of alcohol by using specific cosolvents.
- Examples 5-9 Further exemplary formulations made using retinoid solutions in accordance with this disclosure are presented in Examples 5-9: Examples Ingredient 5 6 7 8 9 Dionized water QS QS QS QS QS Disodium EDTA 0.40 0.4 0.4 0.4 0.4 Carbopol 980 0.20 0.2 0.2 0.2 0.2 Steareth S-2 1.22 1.22 1.22 1.22 1.22 Stearate (and) PEG-100 0.896 .896 .896 .896 .896 stearate Cetyl stearyl alcohol 1.22 1.22 1.22 1.22 1.22 Emulsifier 10 0.80 .80 .80 .80 .80 Glycerin 13.79 13.79 13.79 13.79 13.79 Butyl hydroxyl toluene 0.05 .05 .05 .05 .05 Sorbic acid 0.10 .10 .10 .10 .10 Clindamycin phosphate 1.00 1.00 1.00 100% active) Tretinoic acid 0.05 0.05 0.025 0.
- IPM can be replaced with alkyl benzoate (C 12 -C 15 alkyl benzoate) or IPP.
- the emulsions of Example 10 and 11 is prepared as follows: Carbopol 980 is dispersed in water at 70-80° C. Then, dissolve EDTA and mix well.
- the oil phase is prepared by combining steareth S-2, steareth S-21, tween 20 stearate and PEG-100 stearate, cetyl stearyl alcohol, emulsifier 10 , Fluilan butyl hydroxy toluene and sorbic acid in the amounts indicated.
- the oil phase is heated to 75° C. Add the oil phase to the aqueous phase at 70-80° C. with high shear mixing until a white emulsion is produced. Then cool the batch to room temperature.
- Example 10 The elevated temperature stability of the actives in the oil in water emulsion of Example 10 was determined using techniques within the purview of those skilled in the art. The results were as follows: 25° C. 30° C. Clindamycin Initial 0.975% — — 1 month — 0.958% 2 months 0.975% 0.958% 3 months 0.975% 0.958% Tretinoin Initial 0.0497% — — 1 month — 0.0490 2 months 0.0497 0.0490 3 months 0.0497 0.0490
- Liquid to powder suspension systems are prepared having the following compositions: Example 12 13 Ingredient % % Clindamycin phosphate 1.00 1.00 Water 15.8 15.15 Glycerin 13.80 13.80 Propylene glycol 14.50 14.50 Volatile silicone 35.0 35.00 Modified starch 15.0 15.00 Tretinoin 0.05 0.05 Alcohol 0.80 1.50 Alkyl benzoate 3.50 3.50 BHT 0.05 — Tween 20 0.50 0.50
- Tretinoin is in a solution using a very small amount of alcohol and cosolvent, alkyl benzoate, IPM, IPP.
- Clindamycin will be in a clear solution in aqueous media with glycerin and propylene glycol. Both the clindamycin aqueous solution and the ester solution of tretinoin are suspended in the volatile silicone and starch. Both actives stay in one composition without interacting. Upon shaking, the composition delivers a therapeutic amount of the two actives for treating acne.
- Starch and volatile silicone provide excellent aesthetic vehicles, which upon application to the skin provide aesthetically acceptable liquid powder without any stickiness or tackiness. Furthermore, volatile silicone will evaporate from the skin surface, making the active easily available for acne treatment.
- the liquid to powder suspension containing clindamycin and tretinoin is prepared as follows: Prepare a clear solution of tretinoin in alcohol and cosolvent. Prepare a clear solution of clindamycin in water and glycerin. Mix the volatile silicone and starch with a high shear mixer. Add polysorbate 20 and propylene glycol to the oil phase. Add clindamycin solution to the oil phase and continue mixing at high speed (shear). Add tretinoic solution to oil phase and continue mixing with a high shear mixer, until a smooth liquid to powder suspension is produced
- Example 13 The elevated temperature stability of the actives in the liquid to powder suspension system of Example 13 was determined using techniques known to those skilled in the art. The results were as follows: 25° C. 30° C. Clindamycin Initial 1.00% — — 1 month 0.999% 0.991% 2 months 0.990% 0.977% 3 months 1.02% 1.01% Tretinoin Initial 0.0517% — — 1 month 0.0508 0.051 2 months 0.0499 0.0498 3 months 0.0497 0.0488
- the elevated temperature drug incompatibility is entirely overcome.
- One of the chambers may include a retinoid solution made in accordance with this disclosure using low levels of alcohol and one or more cosolvents.
- the small chamber 14 which has a small capacity, contains a composition (A) containing one of the active ingredients, such as antibiotics or retinoid.
- the composition in the small chamber could be either a solution or a powder blend.
- This chamber is inserted into a main chamber 2 , which contains a composition (B) such as a thin lotion, suspension or emulsion, containing the other active ingredient.
- a composition (B) such as a thin lotion, suspension or emulsion, containing the other active ingredient.
- the small chamber is locked inside the main chamber.
- the two active drugs never come in contact with each other until the consumer activates the system before use.
- the consumer twists the main container to release the composition from the small chamber into the main chamber.
- the consumer then will shake the package to blend both products, which are specially formulated with low viscosity to facilitate quick and uniform blending.
- the consumer can then use the pump delivery mechanism (as shown in FIG. 3 ) to dispense the blended compositions to deliver the combination of both actives for treating the skin.
- the ratio of both actives is calculated for this system to deliver the combination of retinoid and antibiotics at a concentration that has already been established as acceptable by the FDA.
- shelf life or expiration date for such products from the time of manufacturing to the time of patient's total consumption of the dispensed product, will be well over two years since the combined drugs are never exposed to elevated temperatures. Furthermore, this system does not require any overage. The long shelf life and elimination of overage are big advantages from both the FDA perspective as well as the marketing viewpoint.
- the present disclosure teaches how to prepare higher concentrations of tretinoin in solution for the small chamber by using lower concentrations of alcohol by means of cosolvents such a alkyl benzoate, isopropyl myristate, and isopropyl palmitate.
- cosolvents such as alkyl benzoate, isopropyl myristate, and isopropyl palmitate.
- 1 gram of tretinoin can be completely dissolved in only 3 grams of alcohol (33.3 percent solution) by using alkyl benzoate, isopropyl mystirate, isopropyl palmitate, or other esters as cosolvent.
- the inner smaller chamber of a chamber in a chamber package is filled with tretinoin solution composition and the larger, main chamber is filled with a clindamycin emulsion.
- the formulation for each composition is as follows: Small chamber composition Ingredient % Tretinoin 100% 1.00 Anhydrous alcohol 30.00 Alkyl benzoate 69.00
- composition in the main (large) chamber (Clindamycin Emulsion)
- composition provides clindamycin at 1.0% and tretinoin at 0.05%
- the inner, smaller chamber of a chamber in a chamber package is filled with tretinoin solution composition and the larger, main chamber is filled with a clindamycin suspension.
- the formulation for each composition is as follows:
- composition B Main Chamber Composition—Clindamycin Suspension Ingredient % Clindamycin PO 4 (82.7%) 1.28 H 2 O 16.60 Glycerin 99% 15.46 Propylene glycol 16.16 Volatile silicone 35.00 Dry flo 15.00 Tween 20 0.50 Ratio of composition A & B Composition A: 5.00 Composition B: 95.00
- composition provides Clindamycin at 1.00% and tretinoin at 0.05%.
Abstract
Compositions for topical application for treating a skin disorder (e.g., acne) include a retinoid, which is solubilized completely in alcohol only with the aid of cosolvents such as esters (e.g., alkyl benzoate, isopropyl palmitate, isopropyl myristate, diisopropyl adipate and their derivatives). This completely solubilized retinoid can be used to formulate an emulsion system or liquid to powder suspension containing a second active, such as an antibiotic (e.g., clindamycin).
Description
- This application is a divisional application of pending U.S. application Ser. No. 10/984,630 filed Nov. 9, 2004, which claims priority to U.S. Provisional application Ser. No. 60/569,809 filed May 11, 2004. The entire disclosure of each of these priority applications is incorporated herein by this reference.
- The combination of retinoids and antibiotics is of great interest in dermatology, due to the established synergistic efficacy of the two actives in treating acne. Retinoids are powerful keratolytic agents and antibiotics provide anti-bacterial activity for treating acne. Antibiotics such as erythromycin and clindamycin are soluble in aqueous media. Retinoids are insoluble in water. When formulating combination actives for treating acne, it is important to keep the retinoids in complete solution as well as antibiotics in solution. For example, aqueous retinoid acid formulations containing no alcohol and no fats have not shown to be clinically efficacious because the active ingredients are not dissolved in solution, and therefore not available for effectively treating the skin. See, U.S. Pat. No. 5,690,923.
- Unfortunately, retinoids alone in formulations have been known to be quite unstable. The stabilization of retinoids by dissolving in alcohols has been proposed. For example, U.S. Pat. No. 5,721,275 discloses a topical composition containing a retinoid as a single active ingredient wherein in large concentrations of alcohol are used to dissolve the retinoids in solution. However, the stability of the composition containing high levels of alcohol is limited and high levels of alcohol will irritate the skin. Retinoids have also been formulated in aqueous vehicles using surfactants. For example, U.S. Pat. No. 5,690,923 discloses the use of surfactants such as ethoxylated alcohol, ethers, and block polymers to solubilize retinoids in water without using any alcohol.
- There exists room for improvement in the area of formulating, packaging, storing and dispensing compositions containing both retinoids and antibiotics to satisfactorily provide a full two year expiration date. Specifically, a need exists for a composition containing a retinoid and an antibiotic in complete solution, in which both active are chemically and physically stable.
- Solutions of retinoic acid, tretinoin and other retinoids that are not completely soluble in alcohol are provided. The solutions include anhydrous alcohol in an amount insufficient alone to solubilize the retinoid and an ester co-solvent. The solutions can be used alone or to formulate topical compositions, such as emulsions or suspensions. In particularly useful embodiments, the formulations contain a water-soluble active in an aqueous phase and the retinoid solution in a non-aqueous phase.
- In some embodiments, the present retinoid solutions are dispersed via a chamber in chamber pump delivery system.
- The present compositions do not use any surfactants or emulsifiers to solubilize retinoids. Rather, the present retinoid solutions employ cosolvents, (such as alkyl benzoate, isopropyl palmitate (“IPP”), isopropylmyristate (“IPM”), diisopropyl adipate, or their derivatives) in conjunction with a small amount of alcohol. A benefit of the present solutions is that the amount of alcohol employed in the emulsion or suspension is so insignificant that the alcohol induced skin irritation is eliminated.
-
FIG. 1 shows one type of dispenser suitable for packaging and delivering formulations containing the present retinoid solutions. - Solutions of retinoids in accordance with this disclosure contain anhydrous alcohol in an amount insufficient alone to solubilize the retinoid, and an ester co-solvent.
- The retinoid can be any retinoid that provides a benefit to a user upon topical application and is not completely soluble in alcohol. Suitable materials include, but are not limited to retinoic acid, retinyl palmitate, retinyl propionate, retinyl acetate, tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid as well as synthetic retinoid mimetics.
- The anhydrous alcohol is present in an amount insufficient alone to solubilize the retinoid. At such low levels, the amount of alcohol present is less likely to be sufficient to irritate the skin of a user. Suitable anhydrous alcohols include anhydrous ethanol and anhydrous isopropanol.
- The cosolvent can be any material which, when combined with the small amount of anhydrous alcohol, completely solubilizes the retinoid. Particularly useful cosolvents include esters, such as alkyl benzoates, isopropyl palmitate (“IPP”), isopropyl myristate (“IPM”), diisopropyl adipate and their derivatives. Long chain alkylbenzoates are one type of benzoic acid ester useful as a co-solvent in preparing the present retinoid solutions. The alkyl group of the alkyl benzoate preferably contains from 12 to 15 carbon atoms. Suitable alkyl benzoates are commercially available, for example, under the tradename FINSOLV (Finetex, Inc., Elmwood Park, N.J.) such as FINSOLV-TN and FINSOLV-P (PPG-15 stearyl ether benzoate). Other suitable benzoate esters include Poloxamer 182 Dibenzoate, Poloxamer 105 benzoate and stearyl benzoate. Suitable benzoic acid esters are described for example in U.S. Pat. Nos. 4,275,222; 4,278,655; 4,293,544; 4,322,545; and 4,323,694.
- While the amounts of each component of the present solutions will depend on the particular ingredients chosen, generally retinoid solutions in accordance with this disclosure may contain from 0.001 to 10 percent by weight retinoid, 0.003 to 40 percent by weight anhydrous alcohol and 50 to 99 percent by weight cosolvent.
- The method of preparing the solution is not critical. Typically, the cosolvents are combined and the retinoid is added with stirring at room temperature until completely solubilized.
- The retinoid solution can be used to formulate topical compositions, such as emulsions or suspensions. In particularly useful embodiments, the topical formulations contain a second active ingredient. The second active ingredient can be useful in treating acne, such as antibiotics (e.g., clindamycin, tetracyclone or erythromycin). In particularly preferred embodiments, retinoid solutions in accordance with this disclosure are included in the non-aqueous phase of an emulsion or suspension, the aqueous phase of which contains a water-soluble active that is incompatible with the retinoid. In certain embodiments, thermal stability of an emulsion or suspension formulation containing both a retinoid and clindamycin in combination is achieved using the present retinoid solutions.
- The formulation of oil-in-water emulsions or powder suspensions using the present retinoid solutions is within the purities of one skilled in the art given the present disclosure. Typically, an emulsion or suspension is prepared, and a retinoid solution in accordance with this disclosure is added with adequate stirring to provide homogenous incorporation of the solution. Exemplary formulations are provided in the working examples, infra.
- In order that those skilled in the art may be better able to practice the compositions and methods described herein in connection with the retinoid solution embodiments, the following examples are given as an illustration of the preparation of the present retinoid solutions and compositions containing them. It should be noted that the invention is not limited to the specific details embodied in the examples.
- It has been experimentally determined that tretinoin is not soluble in ethanol in the ratios set forth in Examples A-D:
Example A B C D Tretinoin 0.025 0.05 0.01 0.1 Ethanol 0.750 0.80 0.30 3.0 - However, it has now been surprisingly found that when a cosolvent is added to compositions containing the same ratios of tretinoin to ethanol, the tretinoin will completely dissolve into a clear solution:
Example 1 2 3 4 Tretinoin 0.05 0.025 0.01 0.1 Ethanol 0.80 0.750 0.01 3.0 IPM 3.50 1.72 0.70 7.00 - Examples 1-4 are clear yellow solutions of tretinoin. Isopropyl myristate (“IPM”) can be replaced with alkyl benzoate, isopropyl palmitate (“IPP”) or diisopropyl adipate to achieve the same results.
Example E F G H I J Tretinoin 0.1 0.05 0.025 0.01 0.05 0.025 Alkyl benzoate 9.90 — — 9.90 — — IPM — 4.95 — — — — IPM — — 2.475 — — — Diisopropyl Adipate — — — — 4.95 2.475 - In Examples E-J where alcohol is not present, the retinoids are not soluble in the esters alone. This further confirms the present finding that retinoids can be solubilized in a small amount of alcohol by using specific cosolvents.
- Further exemplary formulations made using retinoid solutions in accordance with this disclosure are presented in Examples 5-9:
Examples Ingredient 5 6 7 8 9 Dionized water QS QS QS QS QS Disodium EDTA 0.40 0.4 0.4 0.4 0.4 Carbopol 980 0.20 0.2 0.2 0.2 0.2 Steareth S-2 1.22 1.22 1.22 1.22 1.22 Stearate (and) PEG-100 0.896 .896 .896 .896 .896 stearate Cetyl stearyl alcohol 1.22 1.22 1.22 1.22 1.22 Emulsifier 100.80 .80 .80 .80 .80 Glycerin 13.79 13.79 13.79 13.79 13.79 Butyl hydroxyl toluene 0.05 .05 .05 .05 .05 Sorbic acid 0.10 .10 .10 .10 .10 Clindamycin phosphate 1.00 1.00 1.00 1.00 1.00 (100% active) Tretinoic acid 0.05 0.05 0.025 0.01 0.1 Ethyl alcohol, anhydrous 0.80 0.80 0.750 0.30 3.00 IPM 6.40 3.50 1.72 0.70 7.00 - In examples 5-9 above, IPM can be replaced with alkyl benzoate (C12-C15 alkyl benzoate) or IPP.
-
Active combination: clindamycin 1.00% w/w; tretinoin 0.05% w/w Ingredient % Ex. 10 % Ex. 11 Dionized water 71.5626 75.6824 Disodium EDTA 0.4 0.5 NaOH (10%) — 0.35 Carbopol 980 0.20 0.65 Steareth S-2 1.216 1.9 Stearate (and) PEG-100 stearate 0.896 2.5 Cetyl stearyl alcohol 1.216 3.0 Emulsifier 100.800 2.3 Tween 200.80 — Fluilan — 0.36 Glycerin 13.79 1.9 Butyl hydroxyl toluene 0.040 0.05 Stearaths-21 — 1.40 Sorbic acid 0.08 0.10 Clindamycin phosphate 1.00 1.255 (100% active) Tretinoic acid 0.0504 0.526 Ethyl alcohol, anhydrous 0.80 1.0 Alkyl benzoate 7.149 — IPM — 7.0 - The emulsions of Example 10 and 11 is prepared as follows: Carbopol 980 is dispersed in water at 70-80° C. Then, dissolve EDTA and mix well. The oil phase is prepared by combining steareth S-2, steareth S-21,
tween 20 stearate and PEG-100 stearate, cetyl stearyl alcohol,emulsifier 10, Fluilan butyl hydroxy toluene and sorbic acid in the amounts indicated. The oil phase is heated to 75° C. Add the oil phase to the aqueous phase at 70-80° C. with high shear mixing until a white emulsion is produced. Then cool the batch to room temperature. Dissolve the clindamycin in water and glycerin and add to the emulsion. Prepare a clear solution of tretinoin in alcohol and cosolvent. Add the tretinoin solution to the emulsion phase and continue mixing at high shear until uniform creamy emulsion is produced. - The elevated temperature stability of the actives in the oil in water emulsion of Example 10 was determined using techniques within the purview of those skilled in the art. The results were as follows:
25° C. 30° C. Clindamycin Initial 0.975% — — 1 month — 0.958% 2 months 0.975% 0.958% 3 months 0.975% 0.958% Tretinoin Initial 0.0497% — — 1 month — 0.0490 2 months 0.0497 0.0490 3 months 0.0497 0.0490 - Liquid to powder suspension systems are prepared having the following compositions:
Example 12 13 Ingredient % % Clindamycin phosphate 1.00 1.00 Water 15.8 15.15 Glycerin 13.80 13.80 Propylene glycol 14.50 14.50 Volatile silicone 35.0 35.00 Modified starch 15.0 15.00 Tretinoin 0.05 0.05 Alcohol 0.80 1.50 Alkyl benzoate 3.50 3.50 BHT 0.05 — Tween 200.50 0.50 - Tretinoin is in a solution using a very small amount of alcohol and cosolvent, alkyl benzoate, IPM, IPP. Clindamycin will be in a clear solution in aqueous media with glycerin and propylene glycol. Both the clindamycin aqueous solution and the ester solution of tretinoin are suspended in the volatile silicone and starch. Both actives stay in one composition without interacting. Upon shaking, the composition delivers a therapeutic amount of the two actives for treating acne. Starch and volatile silicone provide excellent aesthetic vehicles, which upon application to the skin provide aesthetically acceptable liquid powder without any stickiness or tackiness. Furthermore, volatile silicone will evaporate from the skin surface, making the active easily available for acne treatment.
- The liquid to powder suspension containing clindamycin and tretinoin is prepared as follows: Prepare a clear solution of tretinoin in alcohol and cosolvent. Prepare a clear solution of clindamycin in water and glycerin. Mix the volatile silicone and starch with a high shear mixer. Add
polysorbate 20 and propylene glycol to the oil phase. Add clindamycin solution to the oil phase and continue mixing at high speed (shear). Add tretinoic solution to oil phase and continue mixing with a high shear mixer, until a smooth liquid to powder suspension is produced - The elevated temperature stability of the actives in the liquid to powder suspension system of Example 13 was determined using techniques known to those skilled in the art. The results were as follows:
25° C. 30° C. Clindamycin Initial 1.00% — — 1 month 0.999% 0.991% 2 months 0.990% 0.977% 3 months 1.02% 1.01% Tretinoin Initial 0.0517% — — 1 month 0.0508 0.051 2 months 0.0499 0.0498 3 months 0.0497 0.0488 - In another embodiment of this disclosure, by utilizing a chamber in a chamber single pump delivery system of the type disclosed in WO 03/082703A1, the disclosure of which is incorporated herein in its entirety, the elevated temperature drug incompatibility is entirely overcome. One of the chambers may include a retinoid solution made in accordance with this disclosure using low levels of alcohol and one or more cosolvents. As seen in
FIG. 1 , thesmall chamber 14, which has a small capacity, contains a composition (A) containing one of the active ingredients, such as antibiotics or retinoid. The composition in the small chamber could be either a solution or a powder blend. This chamber is inserted into amain chamber 2, which contains a composition (B) such as a thin lotion, suspension or emulsion, containing the other active ingredient. The small chamber is locked inside the main chamber. The two active drugs never come in contact with each other until the consumer activates the system before use. As shown inFIG. 2 , the consumer twists the main container to release the composition from the small chamber into the main chamber. The consumer then will shake the package to blend both products, which are specially formulated with low viscosity to facilitate quick and uniform blending. The consumer can then use the pump delivery mechanism (as shown inFIG. 3 ) to dispense the blended compositions to deliver the combination of both actives for treating the skin. The ratio of both actives is calculated for this system to deliver the combination of retinoid and antibiotics at a concentration that has already been established as acceptable by the FDA. - The shelf life or expiration date for such products, from the time of manufacturing to the time of patient's total consumption of the dispensed product, will be well over two years since the combined drugs are never exposed to elevated temperatures. Furthermore, this system does not require any overage. The long shelf life and elimination of overage are big advantages from both the FDA perspective as well as the marketing viewpoint.
- To effectively utilize the chamber in a chamber delivery system, one must balance the concentration of the actives in both chambers. This is necessary to achieve the final, active concentration, which is efficacious as well as compliant with the FDA. The present disclosure teaches how to prepare higher concentrations of tretinoin in solution for the small chamber by using lower concentrations of alcohol by means of cosolvents such a alkyl benzoate, isopropyl myristate, and isopropyl palmitate. For example, in accordance with the
present methods 1 gram of tretinoin can be completely dissolved in only 3 grams of alcohol (33.3 percent solution) by using alkyl benzoate, isopropyl mystirate, isopropyl palmitate, or other esters as cosolvent. - In order that those skilled in the art may be better able to practice the compositions and methods described herein in connection with the chamber in chamber embodiment, the following examples are given as an illustration of the preparation of the present dispensing compositions and system. It should be noted that the invention is not limited to the specific details embodied in the examples.
- The inner smaller chamber of a chamber in a chamber package is filled with tretinoin solution composition and the larger, main chamber is filled with a clindamycin emulsion. The formulation for each composition is as follows:
Small chamber composition Ingredient % Tretinoin 100% 1.00 Anhydrous alcohol 30.00 Alkyl benzoate 69.00 - A. Composition in the main (large) chamber (Clindamycin Emulsion)
Ingredient % carbopol 980 0.25 glycerin 96% 2.00 disodium EDTA 0.50 Di H2O 78.92 Brij 721 1.12 Brij 72 1.52 CS-50 1.52 Arlacel 165 1.52 Emulsifier 1.84 Fluilan 0.38 Tween 201.75 Alkyl benzoate ester 7.00 Clindamycin PO4 1.28 Sorbic acid 0.10 Germall 115 0.30 Ratio of composition A & B Composition A 5.00 Composition B 95.00 - Once blended, the composition provides clindamycin at 1.0% and tretinoin at 0.05%
- The inner, smaller chamber of a chamber in a chamber package is filled with tretinoin solution composition and the larger, main chamber is filled with a clindamycin suspension. The formulation for each composition is as follows:
- A. Small Chamber Composition—Tretinoin Solution
Ingredient % Tretinoin 100% 1.00 Anhydrous alcohol 30.00 Alkyl benzoate 69.00 - B. Main Chamber Composition—Clindamycin Suspension
Ingredient % Clindamycin PO4 (82.7%) 1.28 H2O 16.60 Glycerin 99% 15.46 Propylene glycol 16.16 Volatile silicone 35.00 Dry flo 15.00 Tween 200.50 Ratio of composition A & B Composition A: 5.00 Composition B: 95.00 - Once blended, the composition provides Clindamycin at 1.00% and tretinoin at 0.05%.
- It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. Those skilled in art will envision other modifications within the scope and spirit of the claims appended hereto.
Claims (6)
1. A method of treating acne comprising applying to the skin of a subject afflicted with acne a composition comprising a solution, the solution comprising a retinoid, an anhydrous alcohol and an ester capable of solubilizing the retinoid in the presence of the anhydrous alcohol, wherein the amount of anhydrous alcohol is insufficient alone to solubilize the retinoid.
2. A method as in claim 1 wherein the composition is an emulsion comprising an aqueous phase containing a water soluble active ingredient and a non-aqueous phase containing the solution.
3. A method as in claim 1 wherein the composition is an emulsion comprising an aqueous phase containing clyndamycin, water and glycerine and a non-aqueous phase containing the solution.
4. A method as in claim 1 wherein the composition is a suspension comprising a mixture of volatile silicone and starch and the solution.
5. A method as in claim 1 wherein the composition is a suspension comprising a mixture of volatile silicone and starch, the solution and an aqueous phase containing clyndamycin, water, propylene glycol and glycerine.
6. An apparatus comprising:
a first chamber containing a first composition, the first composition comprising a solution, the solution comprising retinoid, an anhydrous alcohol and an ester capable of solubilizing the retinoid in the presence of the anhydrous alcohol, wherein the amount of anhydrous alcohol is insufficient alone to solubilize the retinoid;
a second chamber containing a second composition comprising an active ingredient selected from the group consisting of antibiotics;
means for selectively interconnecting the first and second chambers to allow mixing of the first and second compositions; and
at least one outlet for dispensing a mixture of the first and second compositions.
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US10/984,630 US7662855B2 (en) | 2004-05-11 | 2004-11-09 | Retinoid solutions and formulations made therefrom |
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US20180088614A1 (en) * | 2016-09-26 | 2018-03-29 | Maxim Integrated Products, Inc. | System and method for output voltage overshoot suppression |
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