WO2021010920A1 - A stable composition comprising tetracyclin and tretinoin for topical acne treatment - Google Patents
A stable composition comprising tetracyclin and tretinoin for topical acne treatment Download PDFInfo
- Publication number
- WO2021010920A1 WO2021010920A1 PCT/TR2020/050574 TR2020050574W WO2021010920A1 WO 2021010920 A1 WO2021010920 A1 WO 2021010920A1 TR 2020050574 W TR2020050574 W TR 2020050574W WO 2021010920 A1 WO2021010920 A1 WO 2021010920A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tretinoin
- weight
- amount
- pharmaceutical composition
- composition
- Prior art date
Links
- 206010000496 acne Diseases 0.000 title claims abstract description 27
- 208000002874 Acne Vulgaris Diseases 0.000 title claims abstract description 19
- 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 title claims abstract description 18
- 229960001727 tretinoin Drugs 0.000 title claims abstract description 18
- 229930101283 tetracycline Natural products 0.000 title claims abstract description 16
- 239000000203 mixture Substances 0.000 title claims description 27
- 230000000699 topical effect Effects 0.000 title description 12
- OFVLGDICTFRJMM-WESIUVDSSA-N tetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 title description 4
- 239000004098 Tetracycline Substances 0.000 claims abstract description 13
- 239000003883 ointment base Substances 0.000 claims abstract description 13
- 229960002180 tetracycline Drugs 0.000 claims abstract description 13
- 235000019364 tetracycline Nutrition 0.000 claims abstract description 13
- 150000003522 tetracyclines Chemical class 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 235000019271 petrolatum Nutrition 0.000 claims abstract description 8
- 239000003871 white petrolatum Substances 0.000 claims abstract description 7
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 8
- 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 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 229960005280 isotretinoin Drugs 0.000 claims description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000008311 hydrophilic ointment Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 208000031513 cyst Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 229940057917 medium chain triglycerides Drugs 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000004408 titanium dioxide Substances 0.000 description 3
- KTTKGQINVKPHLY-WPINSWFRSA-N (4r,4as,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-6-methyl-3,12-dioxo-4a,5-dihydro-4h-tetracene-2-carboxamide Chemical compound C1=CC(O)=C2C(O)=C(C(=O)[C@@]3(O)[C@H]([C@H](C(C(C(N)=O)=C3O)=O)N(C)C)C3)C3=C(C)C2=C1 KTTKGQINVKPHLY-WPINSWFRSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 239000004150 EU approved colour Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960002227 clindamycin Drugs 0.000 description 2
- 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 description 2
- 238000004040 coloring Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 235000013980 iron oxide Nutrition 0.000 description 2
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 2
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 description 1
- ZBCATMYQYDCTIZ-UHFFFAOYSA-N 4-methylcatechol Chemical compound CC1=CC=C(O)C(O)=C1 ZBCATMYQYDCTIZ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000186427 Cutibacterium acnes Species 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Chemical class CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 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
- 230000001464 adherent effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- STORWMDPIHOSMF-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O STORWMDPIHOSMF-UHFFFAOYSA-N 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000035618 desquamation Effects 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical class CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229960003128 mupirocin Drugs 0.000 description 1
- 229930187697 mupirocin Natural products 0.000 description 1
- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- -1 plastibase Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K31/65—Tetracyclines
-
- 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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
Definitions
- the present invention relates to the preparation of a stable topical composition effective in the treatment of acne containing the active substance of tetracycline and tretinoin.
- Said composition is characterized by being stable in water- free environments.
- Acne vulgaris also known as pimple, is a skin disease characterized by blisters, comedones (blackheads), inflammatory blisters in severe cases, inflammatory lesions, nodules and cysts located in the hair follicle. Symptoms related to acne vulgaris mostly occur on the face, upper part of the body and back, where the sebaceous glands are dense.
- Topical antibiotics are one of the most effective drugs against Propionibacterium acnes bacteria, which is one of the factors affecting acne formation. Erythromycin, tetracycline, doxycycline and clindamycin, which are among the topical antibiotics, are widely used in the treatment of acne and are especially effective in mild and moderate inflammatory acne. Apart from these, fucidic acid, mupirocin, oxytetracycline, nadifloxazin, polymycin are used.
- Creams with retinoids can be used alone or in combination with other acne medications.
- the first option in acne with comedones is topical retinoids such as retinoic acid, tretinoin, isotretinoin and adapalene.
- Tetracycline hydrochloride ointment is an antibiotic that acts against skin infections caused by bacteria. It prevents bacteria from growing and reproducing on the skin. It penetrates into acute pimples with red-pink blisters that have formed (purulent) or have just begun to form and dries the inflammation. 100 grams of ointment contains 3.0g Tetracycline hydrochloride.
- Tretinoin prevents the formation of acne lesions, stimulates the follicular epithelium and accelerates the proliferation of non-adherent keratinocytes. These free horn-like cells are discharged to the skin surface with sebum. These horn-like cells cannot cling together and form a plug. Thus, formation of new acne lesions is prevented.
- Tretinoin also helps in the expulsion of comedones, micro-cysts that cause retention in the follicle. Apart from the superficial desquamation of the epidermis, tretinoin also acts deep within the follicle. These free horn-like cells stimulate the proliferation of cells, preventing the adhesion of these cells and thus the formation of plugs, while also excreting micro-cysts and comedones.
- US2010029765 relates to the topical combination of tretinoin and lincomycins, lincomycin derivatives, erythromycin, erythromycin derivatives, tetracycline, tetracycline derivatives and their acceptable salts, esters or prodrugs.
- antibiotic is clindamycin or an acceptable salts thereof.
- composition prepared in oily ointment base is superior in terms of stability compared to the hydrophilic ointment base.
- the major degradation products of tetracycline are 4-epithetracycline (4-ETC), 4- epianhydrotetracycline (4-EATC) and anhydrotetracycline (ATC) compounds.
- Isotretinoin has been accepted as the critical impurity for tretinoin.
- Hydrocarbon-based ointment bases are intended as the oil phase in the composition of the composition of the invention.
- This group of ointment bases are not soluble in water, washed with water and do not contain water. They do not absorb water, they are emollient and occlusive. They are suitable for hydrolysis -prone drugs because they are oleaginosis (oily).
- Such oily ointment bases are petrolatum, solid paraffin, plastibase, beeswax, spermaceti, carnauba wax, and white petrolatum is chosen as oily ointment base for the composition.
- Medium chain triglycerides were chosen as the solvent in the composition.
- Medium chain triglycerides also known as "Caprylic/Capric Triglyceride, Octanoic/Decanoic Acid Triglyceride, MCT Coconut Oil" contains saturated fatty acids with C8 and CIO carbon.
- Medium chain triglycerides have a variety of commercial products that can be used as a solvent in topical preparations such as Kollisolv® MCT (formerly known as Myritol® 318 PH).
- the composition may contain colouring agents. Titanium dioxide is used as a colouring agent in the composition of the invention. Apart from titanium dioxide, iron oxides can be present in the composition.
- the present invention is an easily applicable combination of tetracycline and tretinoin that allows the active ingredients to be formulated without stability issues.
- the object of the invention is to obtain a stable tetracycline and tretinoin topical combined composition to be used in the treatment of acne.
- Tetracycline and tretinoin topical combined composition has been developed in oily ointment base in accordance with its intended use in the treatment of acne.
- the amount of tetracycline is approximately 3% by weight (w/w) and the amount of tretinoin is approximately 0.5% by weight (w/w).
- the amount of white petrolatum in the composition is 50 to 70%, preferably 60 to 70%, more preferably 65-70% by weight (w/w).
- the amount of medium chain triglyceride used as solvent in the composition is 20 to 40%, preferably 20 to 30% by weight (w/w).
- the amount of titanium dioxide used as a colouring agent in the composition is 4 to 8%, preferably 5 to 7%, more preferably approximately 6% by weight (w/w).
- iron oxides can be present in the composition in less than 1% by weight (w/w).
- composition comprises:
- compositions of the present invention can be formulated with one or more pharmaceutically acceptable excipients.
- the composition may comprise pharmaceutically acceptable excipients such as viscosity enhancers, penetration enhancers, surfactants, antimicrobial preservatives, antioxidants, chelate compounds, fragrances in addition to ointment bases, solvents and colouring agents.
- the topical combined composition of the stable tetracycline and tretinoin, which is the present invention, is for use in the treatment and prevention of acne.
- the clinical study of the composition is foreseen in the treatment of acne vulgaris under conditions of Good Clinical Practices (GCPs).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pharmaceutical composition topically used for the treatment of acne, the amount of tetracycline is approximately 3% by weight (w/w), the amount of tretinoin is approximately 0.5% by weight (w/w) and it comprises white petrolatum as oily ointment base, medium chain triglyceride as a solvent.
Description
A STABLE COMPOSITION COMPRISING TETRACYCLIN AND TRETINOIN FOR
TOPICAL ACNE TREATMENT
Technical Field
The present invention relates to the preparation of a stable topical composition effective in the treatment of acne containing the active substance of tetracycline and tretinoin. Said composition is characterized by being stable in water- free environments.
Prior Art
Acne (acne vulgaris), also known as pimple, is a skin disease characterized by blisters, comedones (blackheads), inflammatory blisters in severe cases, inflammatory lesions, nodules and cysts located in the hair follicle. Symptoms related to acne vulgaris mostly occur on the face, upper part of the body and back, where the sebaceous glands are dense.
Retinoids and antibiotics can be applied topically in the treatment of acne. Topical antibiotics are one of the most effective drugs against Propionibacterium acnes bacteria, which is one of the factors affecting acne formation. Erythromycin, tetracycline, doxycycline and clindamycin, which are among the topical antibiotics, are widely used in the treatment of acne and are especially effective in mild and moderate inflammatory acne. Apart from these, fucidic acid, mupirocin, oxytetracycline, nadifloxazin, polymycin are used.
Creams with retinoids can be used alone or in combination with other acne medications. The first option in acne with comedones is topical retinoids such as retinoic acid, tretinoin, isotretinoin and adapalene.
Tetracycline hydrochloride ointment is an antibiotic that acts against skin infections caused by bacteria. It prevents bacteria from growing and reproducing on the skin. It penetrates into acute pimples with red-pink blisters that have formed (purulent) or have just begun to form and dries the inflammation. 100 grams of ointment contains 3.0g Tetracycline hydrochloride.
Tretinoin prevents the formation of acne lesions, stimulates the follicular epithelium and accelerates the proliferation of non-adherent keratinocytes. These free horn-like cells are
discharged to the skin surface with sebum. These horn-like cells cannot cling together and form a plug. Thus, formation of new acne lesions is prevented.
Tretinoin also helps in the expulsion of comedones, micro-cysts that cause retention in the follicle. Apart from the superficial desquamation of the epidermis, tretinoin also acts deep within the follicle. These free horn-like cells stimulate the proliferation of cells, preventing the adhesion of these cells and thus the formation of plugs, while also excreting micro-cysts and comedones.
US2010029765 relates to the topical combination of tretinoin and lincomycins, lincomycin derivatives, erythromycin, erythromycin derivatives, tetracycline, tetracycline derivatives and their acceptable salts, esters or prodrugs. Specifically indicated antibiotic is clindamycin or an acceptable salts thereof.
Description of the Invention
The suitability of oily or hydrophilic ointment base has been investigated as the carrier matrix that will preserve the combined topical preparations containing Tetracycline approximately 3% by weight (w/w) and tretinoin approximately 0,5% by weight, in a stable way during the shelf life under room conditions.
As a result of the researches, it has been seen that the composition prepared in oily ointment base is superior in terms of stability compared to the hydrophilic ointment base.
The major degradation products of tetracycline are 4-epithetracycline (4-ETC), 4- epianhydrotetracycline (4-EATC) and anhydrotetracycline (ATC) compounds. Isotretinoin has been accepted as the critical impurity for tretinoin.
Detailed Description of the Invention
Hydrocarbon-based ointment bases are intended as the oil phase in the composition of the composition of the invention. This group of ointment bases are not soluble in water, washed with water and do not contain water. They do not absorb water, they are emollient and occlusive. They are suitable for hydrolysis -prone drugs because they are oleaginosis (oily).
Such oily ointment bases are petrolatum, solid paraffin, plastibase, beeswax, spermaceti, carnauba wax, and white petrolatum is chosen as oily ointment base for the composition.
Medium chain triglycerides were chosen as the solvent in the composition. Medium chain triglycerides, also known as "Caprylic/Capric Triglyceride, Octanoic/Decanoic Acid Triglyceride, MCT Coconut Oil", contains saturated fatty acids with C8 and CIO carbon. Medium chain triglycerides have a variety of commercial products that can be used as a solvent in topical preparations such as Kollisolv® MCT (formerly known as Myritol® 318 PH).
The composition may contain colouring agents. Titanium dioxide is used as a colouring agent in the composition of the invention. Apart from titanium dioxide, iron oxides can be present in the composition.
The present invention is an easily applicable combination of tetracycline and tretinoin that allows the active ingredients to be formulated without stability issues.
The object of the invention is to obtain a stable tetracycline and tretinoin topical combined composition to be used in the treatment of acne.
Tetracycline and tretinoin topical combined composition has been developed in oily ointment base in accordance with its intended use in the treatment of acne.
In a preferred embodiment of the invention, the amount of tetracycline is approximately 3% by weight (w/w) and the amount of tretinoin is approximately 0.5% by weight (w/w).
In a preferred embodiment of the invention, the amount of white petrolatum in the composition is 50 to 70%, preferably 60 to 70%, more preferably 65-70% by weight (w/w).
In another preferred embodiment of the invention, the amount of medium chain triglyceride used as solvent in the composition is 20 to 40%, preferably 20 to 30% by weight (w/w).
In another preferred embodiment of the invention, the amount of titanium dioxide used as a colouring agent in the composition is 4 to 8%, preferably 5 to 7%, more preferably approximately 6% by weight (w/w). In addition, iron oxides can be present in the composition in less than 1% by weight (w/w).
In another preferred embodiment of the invention, the composition comprises:
The compositions of the present invention can be formulated with one or more pharmaceutically acceptable excipients. The composition may comprise pharmaceutically acceptable excipients such as viscosity enhancers, penetration enhancers, surfactants, antimicrobial preservatives, antioxidants, chelate compounds, fragrances in addition to ointment bases, solvents and colouring agents. The topical combined composition of the stable tetracycline and tretinoin, which is the present invention, is for use in the treatment and prevention of acne. The clinical study of the composition is foreseen in the treatment of acne vulgaris under conditions of Good Clinical Practices (GCPs). It has been confirmed by accelerated stability studies that the composition containing the oily ointment base subject to the invention is more stable than the water based ointment base. The stability results of the compositions containing hydrophilic ointment base and oily ointment base are presented below.
Table 1. Oily Ointment Based Unit Formula:
Table 2. Stability Study of Oil Based Unit Formula at 25°C,60% RH
Table 3. Hydrophilic Ointment Based Unit Formula:
Table 4. Stability Study of Water Based Unit Formula at 25°C,60% RH
Clinical study of the developed stable oil-based composition is planned for products containing two mono active ingredients.
Claims
1) A pharmaceutical composition topically used for the treatment of acne, wherein the amount of tetracycline is approximately 3% by weight (w/w), and the amount of tretinoin is approximately 0.5% by weight (w/w), and it comprises white petrolatum as an oily ointment base.
2) Pharmaceutical composition according to Claim 1, wherein the amount of white petrolatum is 50 to 70% by weight (w/w).
3) Pharmaceutical composition according to Claim 2, wherein the amount of white petrolatum is 60 to 70% by weight (w/w).
4) Pharmaceutical composition according to any of the preceding claims, comprising medium chain triglyceride as a solvent.
5) Pharmaceutical composition according to Claim 4, wherein the amount of medium chain triglyceride as solvent is 20 to 40% by weight (w/w). 6) Pharmaceutical composition according to Claim 5, wherein the amount of medium chain triglyceride as a solvent is 20 to 30% by weight (w/w).
7) Pharmaceutical composition according to any of the preceding claims, comprising white petrolatum as oily ointment base, medium chain triglyceride as a solvent, wherein said composition has impurities of 4-ETC less than 3.0%, 4-EATC less than 1.0%, ATC less than 1.0% and impurity of isotretinoin less than 3.0% after being stored under 25°C60% conditions for at least 6 months.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2019/10426A TR201910426A2 (en) | 2019-07-12 | 2019-07-12 | STABILITY FORMULATION WITH TETRASYCLIN AND TRETINOIN FOR TOPICAL ACNE TREATMENT |
| TR2019/10426 | 2019-07-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2021010920A1 true WO2021010920A1 (en) | 2021-01-21 |
Family
ID=67902190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2020/050574 WO2021010920A1 (en) | 2019-07-12 | 2020-07-03 | A stable composition comprising tetracyclin and tretinoin for topical acne treatment |
Country Status (2)
| Country | Link |
|---|---|
| TR (1) | TR201910426A2 (en) |
| WO (1) | WO2021010920A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5037655A (en) * | 1990-04-18 | 1991-08-06 | Giovanoni Richard L | Method of stabilizing tretinoin |
| US20100029765A1 (en) * | 2008-07-30 | 2010-02-04 | Ranbaxy Labortories Limited | Topical aqueous composition comprising tretinoin |
| US20160287614A1 (en) * | 2013-11-20 | 2016-10-06 | Lupin Limited | Stable Pharmaceutical Formulation(s) of Tetracycline Antibiotic |
-
2019
- 2019-07-12 TR TR2019/10426A patent/TR201910426A2/en unknown
-
2020
- 2020-07-03 WO PCT/TR2020/050574 patent/WO2021010920A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5037655A (en) * | 1990-04-18 | 1991-08-06 | Giovanoni Richard L | Method of stabilizing tretinoin |
| US20100029765A1 (en) * | 2008-07-30 | 2010-02-04 | Ranbaxy Labortories Limited | Topical aqueous composition comprising tretinoin |
| US20160287614A1 (en) * | 2013-11-20 | 2016-10-06 | Lupin Limited | Stable Pharmaceutical Formulation(s) of Tetracycline Antibiotic |
Non-Patent Citations (1)
| Title |
|---|
| IPEK EROGLU ET AL.: "Liposome Based Combination Therapy for Acne Treatment", JOURNAL OF LIPOSOME RESEARCH, 26 June 2019 (2019-06-26), DOI: 10.1080/08982104.2019.1630646 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TR201910426A2 (en) | 2019-08-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3947215B2 (en) | Stable topical retinoid composition | |
| US8313782B2 (en) | Acne vulgaris treatment regimen | |
| JP2003526595A (en) | Treatment of cell-mediated immune disease | |
| KR20110027838A (en) | Topical composition for the treatment of actinic keratosis | |
| JP2013500984A (en) | Combination of dapsone and adapalen | |
| CA2902977A1 (en) | Acne solution | |
| US5843998A (en) | Skin blemish treatment | |
| JP2023061951A (en) | Treatment of cutaneous disorders | |
| US20140199413A1 (en) | Melatonin and an antimicrobial or antibacterial agent for the treatment of acne | |
| EP1965872A2 (en) | Compositions including at least one retinoid compound and at least one anti-irritant compound and uses thereof | |
| WO2021010920A1 (en) | A stable composition comprising tetracyclin and tretinoin for topical acne treatment | |
| JPH01311014A (en) | Antimicrobial skin drug for external use | |
| WO2014042604A1 (en) | Clindamycin phosphate, salicylic acid and tea tree oil combinations | |
| JP5275811B2 (en) | Composition comprising at least one retinoid compound and at least one anti-irritant compound and use thereof | |
| US10123970B2 (en) | Topical retinoid solutions | |
| US10022348B2 (en) | Topical solution of isotretinoin | |
| EP1633374B1 (en) | Composition consisting of alkane dicarboxylic acids and a pharmaceutically active ingredient | |
| JPH05271052A (en) | Lotion for improving acne vulgaris | |
| WO2022140467A1 (en) | Topical compositions and methods of treating skin diseases and conditions with such compositions | |
| SK18652000A3 (en) | PHARMACEUTICAL COMPOSITION ON THE BASIS OF ERYTHROMYCIN FATTYì (54) ACID SALTS FOR THE TOPICAL TREATMENT OF SKIN DISEASES | |
| MX2008009364A (en) | Use of alkanedicarboxylic acids and retinoids for treatment of rosacea and other inflammatory skin diseases | |
| ITMI20010971A1 (en) | PHARMACEUTICAL AND / OR DIETETIC FORMULATIONS CONTAINING COLOSTRUM AND USE OF COLOSTRUM FOR ACNE TREATMENT |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20841055 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20841055 Country of ref document: EP Kind code of ref document: A1 |