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Publication numberCN101212959 A
Publication typeApplication
Application numberCN 200680024126
PCT numberPCT/US2006/025376
Publication date2 Jul 2008
Filing date29 Jun 2006
Priority date29 Jun 2005
Also published asCA2613221A1, EP1898896A2, US20070003585, WO2007002831A2, WO2007002831A3
Publication number200680024126.6, CN 101212959 A, CN 101212959A, CN 200680024126, CN-A-101212959, CN101212959 A, CN101212959A, CN200680024126, CN200680024126.6, PCT/2006/25376, PCT/US/2006/025376, PCT/US/2006/25376, PCT/US/6/025376, PCT/US/6/25376, PCT/US2006/025376, PCT/US2006/25376, PCT/US2006025376, PCT/US200625376, PCT/US6/025376, PCT/US6/25376, PCT/US6025376, PCT/US625376
Inventors凯思林L克拉克, 杰弗里S雷诺兹
Applicant史帝富大药厂公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Topical skin treating compositions
CN 101212959 A
Abstract  translated from Chinese
用于治疗各种皮肤病或症状的局部用组合物及其使用方法。 Or the treatment of various dermatological symptoms topical compositions and methods of use for. 在一个具体的方面,这些组合物包括含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,和类视色素或其药学上可接受的盐的储存稳定的混合物。 In a specific aspect, such compositions include benzoyl peroxide-containing composition, the antibiotic or a pharmaceutically acceptable salt or ester thereof, retinoids, and the mixture was storage stable pigment or a pharmaceutically acceptable salt thereof. 在一个任选的实施方案中,这些组合物包括类视色素或其药学上可接受盐以及或者含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯的储存稳定的混合物。 In one optional embodiment, these compositions comprise a retinoid or a pharmaceutically acceptable salt thereof and a pigment or a benzoyl peroxide-containing composition, the storage antibiotic or a pharmaceutically acceptable salt or ester of stable mixture.
Claims(38)  translated from Chinese
1.一种用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物最终pH为约3至约8,并且其中组合物具有比以前得到所述稳定贮存混合物更低的含过氧化苯甲酰组合物的粘度。 1. A method for the treatment of various skin diseases or symptoms topical composition, comprising: an over-the benzoyl peroxide containing composition, the antibiotic or a pharmaceutically acceptable salt or ester thereof, retinoids or stored thereon a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier stable mixture, wherein the pH of the final composition is from about 3 to about 8, and wherein the composition has obtained less than before the storage stability of the mixture containing had a viscosity of the benzoyl peroxide composition.
2.权利要求1的组合物,其中所述组合物配制用于每日一次或每日两次给药。 The composition of claim 1, wherein said composition is formulated for once daily or twice daily dosing.
3.权利要求1的组合物,其中所述组合物配制用于每日一次在夜晚给药。 The composition of claim 1, wherein said composition is formulated for administration once daily at night.
4.权利要求1的组合物,其中所述组合物最终pH为3.5到5.5。 The composition of claim 1, wherein the pH of the final composition is from 3.5 to 5.5.
5.权利要求1的组合物,其中所述组合物选自包含溶液、凝胶、油膏、洗液、悬浮液、乳状液、软膏、喷雾剂、泡沫、糊剂或其混合物。 The composition of claim 1, wherein said composition is selected from the group comprising a solution, gel, ointment, lotions, suspensions, emulsions, ointments, sprays, foams, pastes, or mixtures thereof.
6.权利要求1的组合物,其中所述组合物在高至25℃的温度下稳定贮存至少30天。 The composition of claim 1, wherein said composition is at a temperature of up to 25 ℃ storage stability of at least 30 days.
7.权利要求1的组合物,其中所述组合物最终粘度为20,000到1,000,000厘泊。 The composition of claim 1, wherein the viscosity of the final composition is from 20,000 to 1,000,000 centipoise.
8.权利要求7的组合物,其中所述组合物具有最终粘度为40,000到500,000厘泊。 The composition of claim 7, wherein the composition has a final viscosity of 40,000 to 500,000 cps.
9.权利要求1的组合物,其中所述含过氧化苯甲酰组合物粘度为25,000到1,250,000厘泊。 The composition of claim 1, wherein the benzoyl peroxide-containing composition having a viscosity of 25,000 to 1,250,000 centipoise.
10.权利要求1的组合物,其中所述混合物包含0.1%到10%重量计的所述过氧化苯甲酰。 10. The composition of claim 1, wherein said mixture comprises from 0.1% to 10% of the weight of benzoyl peroxide.
11.权利要求1的组合物,其中所述混合物包含0.5%到3%重量计的所述抗菌素。 11. The composition of claim 1, wherein said mixture comprises 0.5% of the antibiotic to 3% by weight.
12.权利要求1的组合物,其中所述混合物包含0.01%到1.5%重量计的所述类维生素A。 12. The composition of claim 1, wherein said mixture comprises from 0.01% to 1.5% by weight of the retinoid A.
13.权利要求1的组合物,其中所述类维生素A选自他佐罗汀、视黄酸、维甲酸、异维甲酸、阿达帕林、贝卡瑞特、9-顺式视黄酸、维生素A、视黄醇、视黄素、棕榈酸视黄酯、乙酸视黄酯、5-(2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基)噻吩-2-羧酸乙酯、6-(2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基)-3-吡啶甲醇、2-(2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基)-5-吡啶甲醛,其盐、其酯、其衍生物和其混合物。 The composition according to claim 1, wherein A is selected from the retinoid tazarotene, retinoic acid, tretinoin, isotretinoin, adapalene, Bekaa Reiter, 9-cis retinoic acid, Vitamin A, retinol, retinoids, retinyl palmitate, retinyl acetate, 5- (2- (4,4-dimethyl-thiochroman-6-yl) ethynyl) thiophene 2-carboxylate, 6- (2- (4,4-dimethyl-thiochroman-6-yl) ethynyl) -3-pyridine methanol, 2- (2- (4,4 - dimethyl-thiochroman-6-yl) ethynyl) -5-pyridinecarboxaldehyde, salts thereof, esters thereof, derivatives thereof, and mixtures thereof.
14.权利要求1的组合物,其中所述混合物,其中所述抗菌素选自以下组分:氯洁霉素、四环素、红霉素、林肯霉素、阿奇霉素、卡包霉素、氯四环素、克拉霉素、脱甲四环素、强力霉素、庆大霉素、交沙霉素、卡那霉素、北里霉素、新霉素、甲烯土霉素、麦迪霉素、美欧卡霉素、竹桃霉素、土霉素、伯霉素、核糖霉素、罗他霉素、吡咯甲基四环素、蔷薇霉素、罗红霉素、大观霉素、螺旋霉素、链霉素、磺胺醋酰、苯酰磺胺、磺胺嘧啶、磺胺多辛、磺胺甲基嘧啶、磺胺二甲嘧啶、磺胺甲噻二唑、磺胺甲基异恶唑、托普霉素、三乙酰夹竹桃霉素、其盐、其酯、其衍生物和其混合物。 The composition of claim 1, wherein said mixture, wherein the antibiotic is selected from the following components: clindamycin, tetracycline, erythromycin, clindamycin, azithromycin, card pack neomycin, chlortetracycline, Carat ADM, from A tetracycline, doxycycline, gentamicin, josamycin, kanamycin, North, neomycin, methacycline, Midecamycin, US Oka adriamycin, oleandomycin, oxytetracycline, primycin, ribostamycin, rokitamycin, pyrrolylmethyl tetracycline, neomycin rose, Luo erythromycin, spectinomycin, spiramycin, streptomycin, sulfonamides vinegar acid, benzoyl sulfonamides, sulfadiazine, sulfadoxine, sulfamethyldiazine, sulfamethazine, sulfamethoxazole thiadiazole, sulfamethoxazole, tobramycin, triacetyl oleandomycin, its salt, ester derivatives and mixtures thereof.
15.权利要求1的组合物,其中所述组合物进一步包含赋形剂,其选自表面活性剂、防腐剂、软化剂、湿润剂、液体烷基醇、增稠剂、乳化剂、悬浮剂、pH调节剂/缓冲剂、螯合剂、防晒霜、其衍生物和其混合物。 15. The composition of claim 1, wherein said composition further comprises an excipient selected from surfactants, preservatives, emollients, humectants, fluid alkyl alcohol, thickening agents, emulsifying agents, suspending agents , pH modifiers / buffering agents, chelating agents, sunscreens, their derivatives and mixtures thereof.
16.权利要求1的组合物,其中所述组合物进一步包含赋形剂,其选自卡波姆、聚丙烯聚合物、甘油、氢氧化钠、硫代硫酸钠、培酸丙酯、烷基对羟苯甲酸、纯化水、二氧化钛、氧化锌及其混合物。 The composition of claim 1, wherein said composition further comprises an excipient selected from carbomers, polyacrylic polymer, glycerin, sodium hydroxide, sodium thiosulfate, propyl gallate culture, alkyl paraben, purified water, titanium dioxide, zinc oxide and mixtures thereof.
17.权利要求1的组合物,其中一种或多种所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐或酯和所述类维生素A或其药学上可接受的盐被包封或圈闭在固体或半固体的成分内。 Composition wherein one or more of said benzoyl peroxide, said antibiotic or a pharmaceutically acceptable salt or ester thereof and the A retinoid or a pharmaceutically acceptable salt thereof according to claim 17., encapsulated or trapped in the inner solid or semi-solid ingredients.
18.权利要求1的组合物,其中一种或多种所述过氧化苯甲酰、所述抗菌素或其药学上可接受的盐或酯和所述类维生素A或其药学上可接受盐可存在于溶液、悬浮液或在所述贮存稳定的混合物的分散液中。 18. The composition of claim 1, wherein one or more of said benzoyl peroxide, said antibiotic or a pharmaceutically acceptable acceptable salt or ester thereof and said retinoid or a pharmaceutically acceptable salt thereof can be A in solution, suspension or dispersion in said storage stable mixtures.
19.权利要求18的组合物,其中所述过氧化苯甲酰和所述类维生素A或其药学上可接受的盐存在于悬浮液中,所述抗菌素或药学上可接受的盐存在于溶液中。 19. The composition of claim 18, wherein said acceptable benzoyl peroxide and the retinoid or a pharmaceutically acceptable salt thereof A is present in the suspension, the antibiotic or a pharmaceutically acceptable salt thereof present in the solution in.
20.权利要求1的组合物,其中过氧化苯甲酰的颗粒大小通过处理或使用溶剂而得以减小。 20. The composition of claim 1, wherein the particle size of the benzoyl peroxide or by treatment using a solvent which can be reduced.
21.权利要求1的组合物,其中过氧化苯甲酰、抗菌素或其药学上可接受盐或酯和类维生素A或其药学上可接受盐的任意两种组合在室温下是稳定的。 21. The composition of claim 1, wherein the upper acceptable salt benzoyl peroxide, antibiotic or a pharmaceutically acceptable salt or ester thereof, and retinoid or a pharmaceutically A combination of any two are stable at room temperature.
22.权利要求1的组合物,其中过氧化苯甲酰、抗菌素或其药学上可接受盐或酯和类维生素A或其药学上可接受盐的至少两种需要冷藏。 22. The composition of claim 1, wherein the upper acceptable salt benzoyl peroxide, antibiotic or a pharmaceutically acceptable salt or ester thereof, and retinoid or a pharmaceutically least two of A need to be refrigerated.
23.一种用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物, 23. A method for the treatment of various skin diseases or symptoms topical composition, comprising: an over-the benzoyl peroxide containing composition, the antibiotic or a pharmaceutically acceptable salt or ester thereof, retinoids or storage-stable mixture of its pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
其中一种或多种所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐包封或圈闭在固体或半固体的成分内, Wherein one or more of the benzoyl peroxide, the antibiotic or a pharmaceutically acceptable salt thereof and a retinoid or a pharmaceutically acceptable salt thereof A encapsulated or trapped in a solid or semi-solid ingredients inside,
其中组合物最终pH为3至8。 Wherein the final pH of the composition is 3-8.
24.权利要求23的组合物,其中所述固体或半固体成分具有哺乳动物体温的熔点。 24. The composition of claim 23, wherein the solid or semi-solid component having a melting point temperature in mammals.
25.权利要求24的组合物,其中所述哺乳动物是人。 25. The composition of claim 24, wherein said mammal is a human.
26.一种用于治疗各种皮肤病或症状的局部用组合物,其包含:一种含过氧化苯甲酰组合物、一种抗菌素或其药学上可接受的盐或其酯,一种类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物, 26. A method for the treatment of various skin diseases or symptoms topical composition, comprising: A benzoyl peroxide-containing composition, an antibiotic or a pharmaceutically acceptable salt or ester thereof, a class The mixture was storage stable on the retinoid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
其中所述组合物维持在所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐成分的浓缩,即要求所述各个成分标注要求为至少90%。 Wherein the composition is maintained in the benzoyl peroxide, concentrated acceptable salt thereof and a retinoid or a pharmaceutically acceptable salt thereof A composition of the antibiotic or a pharmaceutically acceptable, which requires the respective components labeling requirements for at least 90%.
27.一种用于治疗患者皮肤病或症状的方法,包含对患者局部给药,所需局部用组合物为治疗所述皮肤病症有效量,其中所述组合物包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中一种或多种所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐包封或圈闭在固体或半固体的成分内,其中组合物具有最终pH为3至8,并且其中组合物具有比以前得到所述稳定贮存混合物更低的含过氧化苯甲酰组合物的粘度。 27. A method for treating skin diseases or symptoms of a patient, comprising topical administration to the patient, the desired topical compositions for the treatment of an effective amount of the skin disorder, wherein said composition comprises: one containing benzoyl peroxide The mixture was storage stable compositions upper formyloxy, antibiotic or a pharmaceutically acceptable salt or ester thereof, a retinoid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein one or more of the said benzoyl peroxide, said antibiotic or a pharmaceutically acceptable salt thereof and a retinoid A or a pharmaceutically acceptable salt thereof encapsulated or trapped in the solid or semi-solid composition, wherein the composition has The final pH of 3-8, and wherein the composition has obtained less than the storage stability of the mixture before the viscosity of the benzoyl peroxide-containing composition.
28.权利要求27的方法,其中所述皮肤病症或症状包括细菌引起的感染。 28. The method of claim 27, wherein said skin disorder or condition, including bacterial infections.
29.权利要求27的方法,其中所述皮肤病症选自痤疮、脓疱病、红斑痤疮、牛皮癣、皮炎、继发性的皮肤感染、响应性皮肤病及其结合。 29. The method of claim 27, wherein the skin disorder is selected from acne, impetigo, rosacea, psoriasis, dermatitis, secondary skin infections, responsive dermatoses, and combinations thereof.
30.权利要求27的方法,其中局部用组合物伴随或连续地将其它药物剂型给药以治疗所述皮肤病症或症状。 30. The method of claim 27, wherein the topical composition or continuously along the other of said pharmaceutical dosage form to treat a skin disorder or condition.
31.用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、一种抗菌素或其药学上可接受的盐或其酯,一种类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物最终pH为3至8以有助于所述局部用组合物稳定性的。 31. A method for the treatment of various skin diseases or symptoms topical composition, comprising: a composition containing benzoyl peroxide, an antibiotic or a pharmaceutically acceptable salt or ester thereof, a retinoid or a storage-stable mixture of a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is a final pH of 3-8 to aid in stability of the topical composition used.
32.权利要求31的组合物,其中所述局部用组合物可以在选自低于0℃、2℃到8℃,8℃到15℃,23℃到27℃,直到约25℃,15℃到30℃的冷藏条件下保持稳定贮存。 32. The composition of claim 31, wherein the topical composition can be selected from less than 0 ℃, 2 ℃ to 8 ℃, 8 ℃ to 15 ℃, 23 ℃ to 27 ℃, up to about 25 ℃, 15 ℃ 30 ℃ under refrigerated conditions to the stable storage.
33.一种用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、一种抗菌素或其药学上可接受的盐或其酯,一种类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物在不超过15℃下的冷藏温度下稳定贮存至少60天。 33. A method for the treatment of various skin diseases or symptoms topical composition, comprising: a composition containing benzoyl peroxide, an antibiotic or a pharmaceutically acceptable salt or ester thereof, a class The mixture was storage stable the retinoid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is at a refrigerated temperature of not more than 15 ℃ stable under storage for at least 60 days.
34.权利要求33的组合物,其中所述组合物在2℃到8℃的冷藏温度下稳定贮存至少60天。 34. The composition of claim 33, wherein said composition is at a refrigerated temperature of 2 ℃ to 8 ℃ storage stability of at least 60 days.
35.局部用组合物在制备用于治疗病人的皮肤病症或症状的药物方法中的用途,其中所述组合物包含:一种包含过氧化苯甲酰组合物、一种抗菌素或其药学上可接受的盐或其酯,一种类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物具有最终pH为3至8,并且其中组合物粘度低于得到所述稳定贮存混合物以前的粘度。 35. The topical pharmaceutical composition for the treatment of disorders or symptoms of the patient's skin in use, wherein said composition comprises: a composition containing benzoyl peroxide, an antibiotic or a pharmaceutically acceptable salt or ester thereof, storage-stable mixture of a retinoid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition has a final pH of 3-8, and wherein the low viscosity of the composition The resulting mixture was stored in the previous stable viscosity.
36.权利要求35的用途,其中所述皮肤病症或症状包括细菌引起的传染。 36. The use of claim 35, wherein said skin disorder or condition includes infection caused by bacteria.
37.权利要求35的用途,其中所述皮肤病症选自痤疮、脓疱病、红斑痤疮、牛皮癣、皮炎、继发性的皮肤感染、响应性皮肤病及其结合。 37. The use of claim 35, wherein the skin disorder is selected from acne, impetigo, rosacea, psoriasis, dermatitis, secondary skin infections, responsive dermatoses, and combinations thereof.
38.权利要求35的用途,其中局部用组合物可以伴随或连续地同其它药物剂型一起给药以治疗所述皮肤病症或症状。 38. The use of claim 35, wherein the topical composition may be accompanied or continuously administered together with other pharmaceutical dosage forms to treat said skin disorder or condition.
Description  translated from Chinese
局部皮肤治疗用组合物 Topical skin treatment composition

[0001] 技术领域 [0001] Technical Field

[0002] 本发明主题涉及通常用于治疗各种皮肤病或症状的局部用组合物及其使用方法。 [0002] The subject of the present invention relates to topical compositions and methods typically used to treat various skin diseases or symptoms. 在一个具体的方面,这些组合物包括含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,和类视色素或其药学上可接受的盐的储存稳定的混合物。 In a specific aspect, such compositions include benzoyl peroxide-containing composition, the antibiotic or a pharmaceutically acceptable salt or ester thereof, retinoids, and the mixture was storage stable pigment or a pharmaceutically acceptable salt thereof. 在一个任选的实施方案中,这些组合物包括类视色素或其药学上可接受盐以及或者含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯的储存稳定的混合物。 In one optional embodiment, these compositions comprise a retinoid or a pharmaceutically acceptable salt thereof and a pigment or a benzoyl peroxide-containing composition, the storage antibiotic or a pharmaceutically acceptable salt or ester of stable mixture.

[0003] 背景技术 [0003] BACKGROUND

[0004] 皮肤病涉及人体内皮脂腺和毛囊包括如痤疮和红斑痤疮症状,以及其它非感染性的皮肤疾病包括微生物。 [0004] Skin Diseases involving the human body including the hair follicles and sebaceous glands such as acne and rosacea symptoms, as well as other non-infectious skin diseases include microorganisms. 这些病症常常伴有炎症。 These disorders are often accompanied by inflammation.

[0005] 痤疮是一种常见的皮肤失调,其特征表现为黑头粉刺,白头粉刺,丘疹,脓疱,囊肿及大小不同的小结和疤痕,在发炎部位被细菌,如丙酸杆菌属痤疮菌(Propionibacterium,acnes),所感染。 [0005] Acne is a common skin disorder, which is characterized by blackheads, whiteheads different, papules, pustules, cysts and nodules and scar sizes at inflammatory sites by bacteria, such as Propionibacterium acne bacteria ( Propionibacterium, acnes), infection. 这种失调累及皮脂腺最活跃的皮肤区域,并且细菌感染能够在皮脂毛囊内发生。 This disorder involving the sebaceous glands of the most active areas of the skin, and bacterial infections can occur in the sebaceous hair follicles.

[0006] 过去,通过口服和/或局部抗菌剂治疗皮肤病症。 [0006] In the past, the treatment of skin disorders by oral and / or topical antibacterial agents. 使用的口服抗生素包括四环素、红霉素和二甲胺四环素。 Use of oral antibiotics, including tetracycline, erythromycin and minocycline. 使用的局部用组合物分别包含抗生素四环素、红霉素和林大霉素;类维生素A例如视黄酸或维甲酸;以及过氧化苯甲酰,其通过有效的氧化特性发挥其抗菌作用。 Use of topical compositions contain the antibiotic tetracycline, erythromycin and neomycin Lin; Vitamin A class such as retinoic acid or retinoic acid; and benzoyl peroxide, which exert their antibacterial effect through effective oxidation characteristics. 然而,过氧化物强的氧化特性可以常常导致非稳定组合物。 However, peroxide strong oxidizing properties can often lead to non-stable compositions. 过氧化苯甲酰还可以作为一种sebosuppressant、刺激剂和消除粉刺剂。 Benzoyl peroxide can also be used as a sebosuppressant, stimulators and eliminate acne agent.

[0007] 目前一种使用的产品,Kalamazoo的Pharmacia&Upjohn公司氯洁霉素外用溶液商品名为Cleocin T,Ml,是包含1%氯洁霉素的外用溶液。 [0007] A method of using the product currently, Kalamazoo's Pharmacia & Upjohn Company Clindamycin Topical Solution tradename Cleocin T, Ml, is a topical solution containing 1% of clindamycin. 然而,Cleocin T有某些缺点。 However, Cleocin T have certain disadvantages. 其一,该制剂包含50%异丙醇和水。 First, the formulation containing 50% isopropanol and water. 同样地,该制剂常常被证明对皮肤过于干燥和刺激。 Likewise, the formulation often proved to be too dry and irritate the skin. 第二,药剂师配制的组合物缺乏进一步储存在室温下的所需稳定性。 Second, pharmacists formulated composition lacks the required stability is further stored at room temperature.

[0008] [6]联合至少两种活性抗菌剂的局部用组合物已经用于治疗这些病症。 [0008] [6] United topical composition of at least two active antibacterial agents have been used to treat these disorders. 这些组合物一般需要通过药剂师混合并必须冷冻。 These compositions generally require a pharmacist mixing and must be frozen. 冷冻三个月后,组合物丢失效力和疗效,必须用新的一批替换。 Three months after freezing, the compositions lose potency and efficacy, it must be replaced with a new batch.

[0009] 例如,目前一种使用的产品是商品名为Benzamycin外用凝胶(Dermik Laboratories,Berwyn,PA),其包含3%的红霉素和5%的过氧化苯甲酰。 [0009] For example, the current method of using the product is under the tradename Benzamycin topical gel (Dermik Laboratories, Berwyn, PA), which contains 3% of erythromycin and 5% benzoyl peroxide. 然而,Benzamycin有某些缺点。 However, Benzamycin have certain disadvantages. 第一,该产品作为在第一容器中的过氧化苯甲酰凝胶和在第二容器中的红霉素粉剂,由药房供应。 First, the product as the first container of benzoyl peroxide and erythromycin gel powder in a second container, supplied by pharmacies. 因此该产品需要由药剂师混合,必须(1)将红霉素溶解在酒精中,(2)将红霉素溶液加入到凝胶中,和(3)搅拌直到表面均匀。 Therefore, the product needs to be mixed by the pharmacist must (1) of erythromycin is soluble in alcohol, (2) erythromycin was added to the gel, and (3) stirring until a uniform surface. 第二,存在于组合物中的乙醇占组合物配制总量的16%,其被证明对皮肤过于干燥和刺激,特别是与过氧化苯甲酰结合使用。 Second, the presence of ethanol in the composition of 16% of the total formulated composition, which proved to be too dry and irritated skin, in particular in combination with benzoyl peroxide. 第三,药剂师配制的组合物(即重新配制或混合之后)缺乏进一步储存在室温下的所需稳定性。 Third, pharmacists formulated composition (i.e., after reconstitution or mixing) lack the desired stability and further stored at room temperature. 该组合产品可以在冷冻条件下储存三(3)个月。 The combination product can be stored for three (3) months under refrigeration.

[0010] 类似地,目前一种使用的组合产品BenzaClin是包含1%氯洁霉素和5%过氧化苯甲酰的外用凝胶。 [0010] Similarly, a combination product for use BenzaClin currently containing 1% clindamycin and 5% benzoyl peroxide topical gel. 然而,BenzaClin也有某些缺点。 However, BenzaClin have certain disadvantages. 例如,由于只能储存三(3)个月,该产品缺乏进一步储存在室温下的所需稳定性。 For example, since only store three (3) months, the product lacks the required stability is further stored at room temperature. 因此,由于它作为在第一容器中的过氧化苯甲酰凝胶和在第二容器中的氯洁霉素粉剂,需要由药房供应,因此必须由药剂师混合。 Therefore, since it is the first container as benzoyl peroxide and clindamycin gel powder in a second container, it is necessary from the pharmacy supply, and therefore must be mixed by a pharmacist. 由于需要通过药剂师混合,该产品还具有易变性/掺杂杂质的问题,结果该药物生成部分溶解或不溶的集料。 Due to the need by a pharmacist mixing, the product also has variability / impurity-doped, and the result of the drug to generate partially dissolve or insoluble aggregates. 有报道说这导致一些病人在该产品接触皮肤时有时感觉“有砂砾感”,进一步由于皮肤磨损导致加重炎症和刺激的问题。 There are reports that this resulted in some patients in contact with the skin when the product sometimes feels "gritty feel" and further aggravated due to the abrasion of the skin inflammation and irritation problems. 最后,根据说明书指导必须将该组合物每天至少进行两次局部涂敷。 Finally, according to the instructions to guide the composition to be applied topically at least twice a day.

[0011] 美国专利6,117,843描述了用于治疗痤疮的另一种已知局部组合物。 [0011] U.S. Patent No. 6,117,843 describes another known topical composition for treating acne. 该专利描述了含有过氧化苯甲酰和氯洁霉素组合物,用于治疗痤疮的局部治疗组合物。 This patent describes containing benzoyl peroxide and clindamycin composition for topical treatment composition for the treatment of acne. 用于该公开组合物的氯洁霉素具有前组合pH5.9-6.9。 The disclosed compositions for clindamycin combination with a front pH5.9-6.9. 另外,该公开组合物必须至少进行两次给药以有效治疗痤疮。 In addition, the disclosed compositions must be administered at least two effective to treat acne.

[0012] 这些目前用于治疗痤疮配制的已知组合物对患者每天两次给药,已报道说对患者每天两次给药的顺从性趋向不规律,特别是具有男性第一性征十几岁的青少年患有痤疮的人群。 [0012] These known compositions currently formulated for the treatment of acne patients twice daily dosing, has reported that the patient compliance tends twice daily dosing irregular, especially those with more than a dozen male primary symptoms Teenagers suffering from acne-year-old crowd.

[0013] 最后,这些目前治疗选择造成有害副作用的显著危险。 [0013] Finally, the current treatment options cause a significant risk of harmful side effects. 通过皮肤有效吸收的氯洁霉素与结肠炎、腹泻和带血丝腹泻相关。 Effective absorption through the skin of clindamycin and colitis, diarrhea, and diarrhea associated with bloodshot. 同样地,过氧化苯甲酰是一种不能有效被皮肤吸收的已知皮肤刺激物。 Likewise, benzoyl peroxide is not effectively absorbed by a known skin irritant skin. 类似地,类维生素A通常也是刺激性的,特别是对具有敏感皮肤的人。 Similarly, retinoids A usually irritating, especially for people with sensitive skin. 因此,需要通过减少每天所需暴露的数量来减少这些前组合物潜在的副作用。 Therefore, by reducing the number of daily exposure needed to reduce potential side effects of these former composition.

[0014] 如所预期的,制备含有三种活性成分的组合已证明比含有两种活性成分的组合更难。 Composition [0014] As expected, the preparation containing the three active ingredients than compositions has proven more difficult to contain two active ingredients. 尽管该三种活性成分的组合具有固有的优点,迄今为止,在配制稳定产品的困难阻止了含有全部三种抗生素、类维生素A和过氧化苯甲酰产品的发展。 Although the combination of the three active ingredients have inherent advantages, so far, in the preparation of stable difficulties prevented the full development of three antibiotics, vitamins A and benzoyl peroxide containing products. 类似地,已经在配制含有类视色素和至少一种过氧化苯甲酰和抗生素产品中出现许多困难。 Similarly, it has been many difficulties arise in the preparation containing retinoids and benzoyl peroxide and at least one antibiotic products. 因此,为了治疗各种皮肤病如痤疮,仍然需要这样的产品。 Therefore, in order to treat various skin diseases such as acne, still a need for products and services.

[0015] 在改善组合产品稳定性的其它努力特别依赖于使用新的包装,保持活性剂分离以维持稳定性直到有用期结束。 [0015] In other efforts to improve the stability of the combination product is particularly dependent on the use of new packaging, to maintain the active agent in order to maintain the stability of the separation until the end of useful life. 然而,在配制的时候还需要混和,稳定性留下一个问题,即由于制备产品时必须立即使用。 However, the time required in the preparation of the mixture, leaving a stability problem, i.e., since the preparation of the product must be used immediately.

[0016] 由于这些原因,希望提供配制组合物改善的组合物和方法用于治疗痤疮。 [0016] For these reasons, it is desirable to provide compositions and methods for formulating compositions for the treatment of acne improved. 具体的,希望提供抗菌素化合物如氯洁霉素的活性与过氧化苯甲酰和类维生素A的活性结合的产品,几乎没有或很少如上所述缺点。 Specifically, it is desirable to provide the antibiotic compound as the active clindamycin activity and benzoyl peroxide and retinoids A combination of product, almost no or very little disadvantage as described above. 这些组合物应当克服制剂和与以前组合物相联系的稳定性问题,并提供具有较小刺激、便于配制、在配制后具有平滑稠度的改善组合物,其足够地稳定,足以长期贮存而无需冷藏。 Such compositions should overcome the formulation and stability problems associated with the prior compositions, and provide a small stimulus, to facilitate the preparation, with a smooth consistency after formulation improvement composition is sufficiently stable, sufficient long-term storage without refrigeration .

[0017] 类似地,同样地希望提供类维生素A与抗菌素化合物如氯洁霉素活性或者过氧化苯甲酰活性结合的产品,几乎没有或很少如上所述缺点。 [0017] Similarly, in the same manner desirable to provide a class of compounds such as vitamin A and clindamycin antibiotic activity or binding activity of the benzoyl peroxide product, almost no or very little disadvantage as described above. 这些组合物应当克服制剂和与以前组合物相联系的稳定性问题,并提供具有较小刺激、便于配制、在配制后具有平滑稠度的改善组合物,其足够地稳定,足以长期贮存而无需冷藏。 Such compositions should overcome the formulation and stability problems associated with the prior compositions, and provide a small stimulus, to facilitate the preparation, with a smooth consistency after formulation improvement composition is sufficiently stable, sufficient long-term storage without refrigeration .

[0018] 因此,仍有需要治疗皮肤病有效的局部用组合物,其可以稳定贮存一段延长的时间,便于配制且大体上是均匀的。 [0018] Thus, there is still need for an effective topical treatment of dermatological compositions, which can be stably stored for a prolonged period of time, and to facilitate the preparation of substantially uniform.

[0019] 发明内容 [0019] SUMMARY

[0020] 本发明主题涉及通常用于治疗各种皮肤病或症状的局部用组合物。 [0020] The present invention relates to a theme commonly used to treat various skin diseases or symptoms topical composition.

[0021] 在一个优选实施方案中,本发明涉及通常用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物具有最终pH为约3至约8,并且其中组合物具有比得到所述稳定贮存混合物以前更低的含过氧化苯甲酰组合物的粘度。 [0021] In a preferred embodiment, the present invention relates generally used to treat various skin diseases or symptoms topical composition, comprising: a composition comprising benzoyl peroxide, antibiotic or a pharmaceutically acceptable salt or ester thereof, retinoids storage stable pigment mixture, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition has a final pH of from about 3 to about 8, and wherein the composition has a ratio of The resulting mixture was storage stable over previous lower viscosity benzoyl peroxide-containing composition.

[0022] 在一个进一步优选实施方案中,本发明主题涉及通常用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中一种或多种所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐包封或圈闭在固体或半固体的成分内,其中组合物具有最终pH为约3至约8。 [0022] In a further preferred embodiment, the present invention relates to a theme commonly used to treat various skin diseases or symptoms topical composition, comprising: a composition comprising benzoyl peroxide, antibiotic or a pharmaceutically acceptable salt or ester thereof, retinoids mixture was storage stable pigment or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein one or more of the benzoyl peroxide, the antibiotic or a pharmaceutically acceptable salt thereof and the type of vitamin A or a pharmaceutically acceptable salt or traps encapsulated in solid or semi-solid composition, wherein the composition has a final pH of from about 3 to about 8.

[0023] 在另一个优选实施方案中,本发明主题涉及通常用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中所述组合物维持在所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐成分的各个浓度内,即要求所述各个成分标注要求为至少90%。 [0023] In another preferred embodiment, the present invention relates to a theme commonly used to treat various skin diseases or symptoms topical composition, comprising: a composition comprising benzoyl peroxide, the antibiotic or a pharmaceutically acceptable salt or ester thereof, retinoids storage-stable mixture of a pigment or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said composition is maintained in the benzoyl peroxide, the within each concentration of the antibiotic or a pharmaceutically acceptable salt thereof and a retinoid or a pharmaceutically acceptable salt thereof A composition, which requires the labeling requirements for the respective components of at least 90%.

[0024] 在另一个优选实施方案中,本发明主题还涉及通常用于治疗患者皮肤病或症状的方法,包含对患者局部给药,所需局部用组合物为治疗所述皮肤病症有效量,其中所述组合物包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中一种或多种所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐包封或圈闭在固体或半固体的成分内,其中组合物具有最终pH为约3至约8,并且其中组合物具有比得到所述稳定贮存混合物以前更低的含过氧化苯甲酰组合物的粘度。 [0024] In another preferred embodiment, the subject of the present invention also relates to methods commonly used to treat skin diseases or symptoms of a patient, comprising topical administration to the patient, the desired topical compositions for the treatment of disorders of the skin an effective amount, wherein said composition comprises: one containing benzoyl peroxide compositions had the antibiotic or a pharmaceutically acceptable salt or ester thereof, depending on the type of pigment, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier storage stable mixture, wherein one or more of said benzoyl peroxide, said antibiotic or a pharmaceutically acceptable salt thereof and a retinoid or a pharmaceutically acceptable salt thereof A encapsulated or trap in solid or semi-solid composition, wherein the composition has a final pH of from about 3 to about 8, and wherein the composition has a viscosity before storage stability than that of the mixture obtained containing less benzoyl peroxide compositions.

[0025] 在进一步优选实施方案中,本发明主题涉及通常用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物具有有助于所述局部用组合物稳定性的最终pH为约3至约8。 [0025] In a further preferred embodiment, the present invention relates to a theme commonly used to treat various skin diseases or symptoms topical composition, comprising: a composition of the benzoyl peroxide, antibiotic or a pharmaceutically too may contain acceptable salt or ester thereof, a retinoid acceptable pigment, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier storage stable mixture, wherein the composition has a topical composition helps the stability of the final pH from about 3 to about 8.

[0026] 在还有另一个优选实施方案中,本发明主题涉及通常用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物在不超过15℃下的冷冻温度下稳定贮存至少60天。 [0026] In yet another preferred embodiment, the present invention relates to a theme commonly used to treat various skin diseases or symptoms topical composition, comprising: a composition comprising benzoyl peroxide, antibiotic or a pharmaceutically acceptable salt or ester, retinoid acceptable dye or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier storage stable mixture, wherein the freezing temperature of the composition does not exceed 15 ℃ storage stability under at least 60 days.

[0027] 在进一步优选实施方案中,在进一步优选实施方案中,本发明主题还涉及用于治疗各种皮肤病或症状的局部用组合物,其包含:1)类维生素A或其药学上可接受的盐,2)或含过氧化苯甲酰组合物或抗菌素或其药学上可接受的盐或其酯,和3)一种药学上可接受载体的储存稳定的混合物,其中一种或多种所述类维生素A或其药学上可接受的盐、所述过氧化苯甲酰和所述抗生素或其药学上可接受盐包封或圈闭在固体或半固体的成分内,其中组合物具有最终pH为约3至约8。 [0027] In a further preferred embodiment, in a further preferred embodiment, the subject of the present invention also relates to the treatment of various skin diseases or symptoms of the topical composition, comprising: 1) A retinoid or a pharmaceutically acceptable salt thereof, 2) or through a benzoyl peroxide-containing composition or the antibiotic or a pharmaceutically acceptable salt or ester thereof, and 3) a pharmaceutically acceptable carrier storage stable mixture, wherein one or more A species on the retinoid or a pharmaceutically acceptable salt thereof, said benzoyl peroxide and acceptable salts encapsulated or trapped in the solid or semi-solid composition, wherein the composition of the antibiotic or a pharmaceutically having a final pH of from about 3 to about 8.

[0028] 在另一个优选实施方案中,本发明主题还涉及用于治疗各种皮肤病或症状的局部用组合物,其包含:1)类维生素A或其药学上可接受的盐,2)或含过氧化苯甲酰组合物或抗菌素或其药学上可接受的盐或其酯,和3)一种药学上可接受载体的储存稳定的混合物,其中所述组合物维持在所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐成分浓缩状态,即要求所述各个成分标注要求为至少90%。 [0028] In another preferred embodiment, the subject of the present invention also relates to the treatment of various skin diseases or symptoms topical composition, comprising: 1) A retinoid or a pharmaceutically acceptable salt thereof, 2) or a benzoyl peroxide-containing composition over the antibiotic or a pharmaceutically acceptable salt or ester thereof, and 3) a pharmaceutically acceptable carrier storage stable mixture, wherein the composition is maintained in the peroxide the benzoyl, the antibiotic or a pharmaceutically acceptable salt thereof and a retinoid or a pharmaceutically acceptable salt thereof A composition condensed state, which requires the various components of labeling requirements for at least 90%.

[0029] 在一个进一步优选实施方案中,本发明主题还涉及用于治疗各种皮肤病或症状的局部用组合物,其包含:1)类维生素A或其药学上可接受的盐,2)或含过氧化苯甲酰组合物或抗菌素或其药学上可接受的盐或其酯,和3)一种药学上可接受载体的储存稳定的混合物,其中组合物具有有助于所述局部用组合物稳定性的最终pH为约3至约8。 [0029] In a further preferred embodiment, the subject of the present invention also relates to the treatment of various skin diseases or symptoms topical composition, comprising: 1) the class of vitamin A or a pharmaceutically acceptable salt thereof, 2) or a benzoyl peroxide-containing composition or the antibiotic or a pharmaceutically acceptable salt or ester thereof, and 3) a pharmaceutically acceptable carrier storage stable mixture, wherein the composition has the topical helpful The final pH stability of the composition is from about 3 to about 8.

[0030] 在又一个优选实施方案中,本发明主题还涉及用于治疗各种皮肤病或症状的局部用组合物,其包含:1)类维生素A或其药学上可接受的盐,2)或含过氧化苯甲酰组合物或抗菌素或其药学上可接受的盐或其酯,和3)一种药学上可接受载体的储存稳定的混合物,其中组合物在不超过15℃下的冷藏温度下稳定贮存至少60天。 [0030] In a further preferred embodiment, the subject of the present invention also relates to the treatment of various skin diseases or symptoms topical composition, comprising: 1) the class of vitamin A or a pharmaceutically acceptable salt thereof, 2) or an over-the benzoyl peroxide composition or antibiotic or a pharmaceutically acceptable salt or ester thereof, and 3) a pharmaceutically acceptable carrier storage stable mixture, wherein the composition is not more than 15 ℃ under refrigeration The shelf-stable at a temperature of at least 60 days.

[0031] 具体实施方式 [0031] DETAILED DESCRIPTION

[0032] 定义 [0032] defines

[0033] 如这里使用的术语“痤疮”意指毛支脂腺的一种常见的炎性疾病,其特征为粉刺、丘疹、脓疱、发炎小结、表面充满脓的囊肿,和(在极个别情况下)是开裂和深处、发炎的,有时是化脓的液囊。 [0033] As used herein the term "acne" refers to bronchiolitis sebaceous glands of a common inflammatory disease, characterized by acne, pimples, pustules, inflamed nodules, cysts surface full of pus, and (in rare case) is cracking and deep, inflamed, and sometimes purulent sacs. 本发明范围内的痤疮包括寻常痤疮或局部痤疮。 Acne within the scope of the present invention include topical acne or acne vulgaris. “痤疮”由激素、角蛋白、皮脂和细菌之间相互作用引起。 "Acne" by the hormones, keratin, caused by the interaction between sebum and bacteria. 一种常见的细菌病原体是疮疱丙酸杆菌。 A common bacterial pathogen is Propionibacterium acnes.

[0034] 如这里使用的术语″给药″、“施药”和类似术语意指以可靠的医学或化妆实验释放组合物至患者的方法,用这样的方式以提供皮肤病症、症状或外观积极的影响。 [0034] As used herein, the term "administration", "administration" and similar terms is meant to sound medical or cosmetic experimental release composition to a patient way, in such a manner to provide a skin condition, or the appearance of positive symptoms impact. 该组合物优选给药,这样组合物覆盖被治疗的整个区域。 The compositions are preferably administered so that the composition covers the entire area to be treated. “直接给药”意指以可靠的医学或化妆实验释放组合物至患者而无需使用别的组合物、释放剂或装置的方法。 "Direct administration" is meant to sound medical or cosmetic experiments release composition to a patient without the use of other compositions, releasing agents or devices. “间接给药”意指借助于至少一种其它组合物、释放剂或装置将可靠的医学或化妆实验释放组合物至患者的任意方法。 "Indirect administration" means by means of at least one other composition, the release agent, or means of sound medical or cosmetic composition to the experimental release a patient by any method.

[0035] 如这里使用的术语“商业目的”意指根据FDA规则或条例需要的时间长度或储藏条件的任意目的,包括运送时间、存储、分配和冷冻。 [0035] As used herein the term "commercial purpose" means any purpose in accordance with FDA rules or regulations or the length of time required storage conditions, including delivery time, storage, distribution and freezing.

[0036] 如这里使用的短语有效剂或成分或药学上有效剂或成分的“有效量”或“治疗有效量”在这里是同义的,意指足以有效作用涂敷区域的药学上活化剂的量。 [0036] The "effective amount" or the phrase ingredient or a pharmaceutically effective agent used herein active agent or ingredient or "therapeutically effective amount" as used herein are synonymous and mean a pharmaceutically effective enough to effect an activating agent coated region amount. 因此,这些量足以改善需要治疗的皮肤病症、症状或外观,但又低至足以避免在合理医学或皮肤学报道之内的严重副作用。 Therefore, these amounts sufficient to improve skin condition in need of treatment, symptoms or appearance, but low enough to avoid serious side effects within a reasonable medical or school reports of the skin. 当重复地涂敷药学上有效剂的治疗有效量随着时间将导致症状的实际上的缓解。 When repeatedly applying a therapeutically effective amount of a pharmaceutically effective agent over time will lead to substantially alleviate the symptoms. 药学上有效剂的有效量将随着具体的症状或治疗的症状、症状的严重度、治疗的持续时间、使用组合物的具体组分和类似因素而改变。 An effective amount of a pharmaceutically effective dose will vary with the symptoms specific symptoms or treatment, the severity of symptoms, duration of the treatment, the use of the specific components of the composition and the like factors.

[0037] 如这里使用的短语“时间的延长期”意指目前优选组合物的贮存期限,包括在该组合物保持指出用途有效性期间在药房架子所用去的时间以及组合物销售后的整个周期。 [0037] As used herein, the phrase "extended period of time" is meant a presently preferred composition shelf life, the composition comprising the entire holding period stated in the pharmacy shelf elapsed time and the validity period of use of the composition after sales .

[0038] 如这里使用的短语“标签声明(label claim)”意指包括商标、包装和/或存在于产品中任意活性成分的药剂数量文献上的指示。 [0038] As used herein, the phrase "label declaration (label claim)" is intended to include trademarks, packaging, and / or present in the product literature indicates the number of agents on any of the active ingredient.

[0039] 如这里使用的术语“儿科的”意指包括治疗儿童的医药分支,以及特别对儿童或非成年患者的各种特殊治疗。 [0039] As used herein the term "pediatrics" is meant to include the treatment of children in the pharmaceutical branch, as well as a variety of special treatment especially for children and non-adult patients. 在这点上,儿科治疗主要针对年龄最多为和包括18岁的患者。 In this regard, pediatric therapy aimed at ages up to and including 18 year-old patient.

[0040] 如这里使用的术语“药学上可接受的盐”意指活性化合物的盐,其具有如活性化合物相同的药理活性,既非生物学上又不是其它不合需要的。 [0040] As used herein, the term "pharmaceutically acceptable salts" refers to salts of the active compound, which has the same pharmacological activity of the active compound, but not the other neither biologically undesirable. 盐可以是如有机或无机酸生成的。 Salt can be organic or inorganic acids generated. 非限定合适酸的例子包括乙酸、乙酰水杨酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯甲酸、苯磺酸、二磺酸、硼酸、丁酸、樟脑酸、樟脑磺酸、碳酸、柠檬酸、环己烷甲酸、葡萄糖二酸、十二烷基磺酸、乙磺酸、甲酸、富马酸、甘油酸、甘油磷酸、甘氨酸、葡庚糖酸(glucoheptanoic acid)、葡糖酸、谷氨酸、戊二酸、羟基乙酸、半硫酸(hemisulficacid)、庚酸、己酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘磺酸、萘酸、烟酸、亚硝酸、草酸、壬酸、磷酸、丙酸、糖精、水杨酸、山梨酸、琥珀酸、硫酸、酒石酸、硫氰酸、巯基乙酸、硫代硫酸、甲苯磺酸(tosylic acid)、十一烯酸,天然和合成的衍生氨基酸。 Non-limiting examples of suitable acids include acetic acid, acetylsalicylic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, di-sulfonic acid, boric acid, butyric acid, camphor acid, camphor sulfonic acid , carbonic acid, citric acid, cyclohexane carboxylic acid, glucose acid, dodecyl sulfonic acid, acetic acid, formic acid, fumaric acid, glycerol acid, glycerol phosphate, glycine, gluceptate (glucoheptanoic acid), Portugal sugar acid, glutamic acid, glutaric acid, glycolic acid, sulfuric acid half (hemisulficacid), heptanoic acid, adipic acid, maleic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxy acid, lactic acid, maleic acid, malic acid, propionic acid, mandelic, methanesulfonic, mucic acid, naphthalene sulfonic acid, naphthalene acid, nicotinic acid, nitrous acid, oxalic acid, azelaic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, sorbic acid, amber acid, sulfuric acid, tartaric acid, thiocyanate, thioglycolic acid, thiosulfate, toluene sulfonic acid (tosylic acid), undecylenic acid, derived from natural and synthetic amino acids.

[0041] 非限定碱盐的例子包括铵盐;碱金属盐,例如钠和钾盐;碱土金属盐,例如钙和镁盐;有机碱盐,例如二环己基胺盐;甲基-D-葡糖胺;以及氨基酸盐,例如精氨酸、赖氨酸等。 [0041] Non-limiting examples of base salts include ammonium salts; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, e.g., dicyclohexylamine salts; methyl -D- glucosamine glucosamine; and amino acid salts, such as arginine, lysine and the like. 包含碱性氮的基团也可以季铵化药剂如低级卤烃类,例如甲基、乙基、丙基和丁的氯化物、溴化物和碘化物;二烃基硫酸盐例如二甲基、二乙基、二丁基和二戊基硫酸盐;长链卤化物例如癸基、月桂基、十四烷基和硬脂酰的氯化物、溴化物和碘化物;asthma卤化物,例如苯甲基和苯乙基溴化物;以及其它。 Basic nitrogen-containing groups may be quaternized with agents such as lower halogenated hydrocarbons, such as methyl, ethyl, propyl, and butyl chloride, bromide and iodide; dihydrocarbyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; asthma halides, such as benzyl and phenethyl bromides; and others. 由此获得水油溶或可分散的产物。 Thereby obtaining an oil-soluble or water-dispersible product.

[0042] 如这里使用的短语“冷藏”或“冷藏温度”意指不超过15℃的温度。 [0042] As used herein, the phrase "frozen" or "refrigerating temperature" means a temperature not exceeding 15 ℃.

[0043] 如这里使用的短语“室温”意指温度为约20℃到约25℃。 [0043] As used herein, the phrase "room temperature" means a temperature of about 20 ℃ to about 25 ℃.

[0044] 如这里使用的术语“敏感度”意指皮肤刺激性或皮肤炎症的程度,例如在合适测定作测量灵敏度、炎症、刺激等的参数。 [0044] As used herein, the term "sensitivity" refers to skin irritation or skin inflammation degree, e.g., for measuring sensitivity, inflammation, irritation in the appropriate measurement parameters. 一种这样的测定是Jordan-King试验。 One such assay is Jordan-King trial.

[0045] 如这里使用的短语“存储稳定”或“存储-稳定”可以交替使用,意指本发明组合物具有长贮存期限的能力,包括包括在该组合物保持指出用途有效性期间在药房架子所用去的时间以及组合物销售后的整个周期,其间该组合物保持其有效性和药学上可接受的外观。 [0045] As used herein, the phrase "storage stable" or "storage - stability" can be used interchangeably, meaning the composition of the present invention has the ability to long shelf life, including including the use of the composition maintains the validity period stated in the pharmacy shelves the entire cycle time elapsed after the sale and composition, the composition therebetween maintaining the effectiveness and pharmaceutically acceptable appearance. 因此,由于在贮存持续时间中显示最低量降解,所以本发明的组合物是稳定的。 Therefore, since the display at the lowest amount of storage duration degradation, so the composition of the present invention are stable.

[0046] 如这里使用的皮肤疾病、病症或症状“治疗”和“治疗”包括减轻其至少一种症状、降低严重性或延迟、防止或抑制其发展。 [0046] As used herein, a skin disease, disorder or condition, "treating" and "treatment" include alleviating at least one symptom thereof, reduce the severity or delay, prevent or inhibit its development. 治疗不必意指完全治愈处理了的疾病、病症或症状。 Treatment need not mean a complete cure of the treated disease, disorder or condition. 这里有用的组合物仅需要降低皮肤疾病、病症或症状的严重性,降低与此相关联症状的严重性,提供改善病人的生活质量,或延迟、防止或抑制皮肤疾病、病症或症状的发病。 The composition useful herein is only necessary to reduce skin disease, disorder, or severity of symptoms, reduce the severity of symptoms associated with this, provide improved patients' quality of life, or delay, prevent or inhibit the onset of skin disease, disorder or condition.

[0047] 其它如这里使用的术语意指由本领域它们公知含义所定义。 [0047] Other terms as used herein means the well known in the art are defined meanings.

[0048] 局部用组合物 [0048] The topical composition

[0049] 这里表达的主要内容通常涉及用于治疗皮肤病症、疾病或症状的各种局部用组合物,以及使用相同的局部用组合物治疗这些皮肤病症、疾病或症状的方法。 [0049] The main content expressed herein relates generally used to treat skin disorders, these skin disorders, various diseases or symptoms thereof topical composition or symptoms of disease, and the use of the same therapeutic topical composition.

[0050] 关于这一点,在一个优选方面,本发明涉及通常用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物。 [0050] In this regard, in a preferred aspect, the present invention relates generally used to treat various skin diseases or symptoms topical composition, comprising: a composition comprising benzoyl peroxide, the antibiotic or a pharmaceutically acceptable salt or ester thereof, depending on the type of pigment, or a pharmaceutically acceptable salt storage and a pharmaceutically acceptable carrier stable mixture. 在一个优选的实施方案中,配制组合物以致组合物具有最终pH为约3至约8。 In a preferred embodiment, the composition is formulated such that the composition has a final pH of from about 3 to about 8.

[0051] 在本发明的一个特别优选的实施方案中,本发明配制的组合物具有比以前得到所述稳定贮存混合物更低的含过氧化苯甲酰组合物的粘度。 [0051] In a particularly preferred embodiment of the present invention, the present invention is formulated composition having storage stability than previously obtained the lower the viscosity of the mixture containing benzoyl peroxide compositions. 在另一个特别优选的实施方案中,本发明配制的组合物以致一种或多种所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐包封或圈闭在固体或半固体的成分内。 In another particularly preferred embodiment, the compositions of the present invention is formulated so that one or more of the benzoyl peroxide, the antibiotic or a pharmaceutically acceptable salt thereof and a retinoid or a pharmaceutically A acceptable salt or traps encapsulated in solid or semi-solid ingredients.

[0052] 在本发明另一个选择的优选的实施方案中,本发明配制的组合物使存在的活性成分降解生成的量最小化。 [0052] In a preferred embodiment of the present invention is an alternative, the present invention is formulated composition so that degradation of the active ingredient present in the amount of generation is minimized. 在这方面,这里优选组合物优选有效维持在所述过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐成分的各个浓度内,即要求所述各个成分标注要求为至少90%。 In this regard, preferred compositions herein preferably effective to maintain the benzoyl peroxide, the concentration of each of the antibiotic or a pharmaceutically acceptable salt thereof and a retinoid or a pharmaceutically acceptable salt thereof A component , which requires the labeling requirements for the respective components of at least 90%.

[0053] 在一个特别优选的实施方案中,本发明组合物在过氧化苯甲酰、所述抗生素或其药学上可接受的盐和所述类维生素A或其药学上可接受的盐成分的各个浓度内,即要求各个成分标注要求为至少90%,这些成分在冷藏或室温下能够维持至少30天。 [0053] In a particularly preferred embodiment, the compositions of the present invention is benzoyl peroxide, said antibiotic or a pharmaceutically acceptable salt thereof and a retinoid or a pharmaceutically acceptable salt thereof A component within each concentration, i.e., labeling requirements for the respective components requires at least 90%, these ingredients under refrigeration or at room temperature can be maintained at least 30 days. 在进一步优选的实施方案中,本发明组合物在冷藏或室温下能够维这些活性成分浓度持至少60天。 In a further preferred embodiment, the compositions of the invention at room temperature or refrigerated active ingredient concentration of these dimensions can be held at least 60 days. 在另一个优选的实施方案中,本发明组合物在冷藏或室温下能够维这些活性成分浓度持至少90天。 In another preferred embodiment, the compositions of the invention at room temperature or refrigerated active ingredient concentration of these dimensions can be held at least 90 days. 在另一个优选的实施方案中,本发明组合物在冷藏下能够维这些活性成分浓度持至少6个月。 In another preferred embodiment, the compositions of the present invention in a refrigerated dimension of these active ingredient concentration can hold at least six months.

[0054] 本发明进一步另一个特别优选的实施方案涉及一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物具有最终pH为约3至约8。 [0054] The present invention further another particularly preferred embodiment relates to a composition comprising benzoyl peroxide, the antibiotic or a pharmaceutically acceptable salt or ester thereof, a retinoid or a pharmaceutically acceptable salt thereof and Acceptable storage stable mixture of a pharmaceutically carrier, wherein the composition has a final pH of from about 3 to about 8. 另一个可选择的实施方案涉及组合成分,即不超过15℃的冷藏温度下稳定贮存至少60天。 Another alternative embodiment relates to a combination of ingredients, i.e., no more than 15 ℃ under refrigerated temperature storage stability of at least 60 days.

[0055] 本发明组合物的过氧化苯甲酰成分优选引入生成的初始含过氧化苯甲酰组合物作为溶液、分散液或悬浮液。 [0055] The compositions of the present invention is preferably introduced into the benzoyl peroxide component to generate an initial benzoyl peroxide-containing composition as a solution, dispersion or suspension. 过氧化苯甲酰为制药级。 Pharmaceutical-grade benzoyl peroxide. 过氧化苯甲酰可以磨碎粉剂的泥浆形式或以含水的颗粒物质的形式,其根据本发明在处理中减小颗粒大小。 Benzoyl peroxide can be pulverized mud powder form or in the form of an aqueous particulate matter, which reduces the particle size in the process according to the invention. 在医学和专利文献中已很好描述了合适过氧化苯甲酰组分的制备。 In the medical and patent literature it has been well described in the preparation of suitable benzoyl peroxide constituents.

[0056] 本发明组合物的过氧化苯甲酰成分通常以在过氧化苯甲酰的总组合物重量约0.1%到约10%之间的量存在。 Benzoyl peroxide component [0056] The present composition of the present invention generally in an amount of from about 0.1% to about 10% benzoyl peroxide between the total composition by weight. 在一个优选的实施方案中,组合物包含过氧化苯甲酰的总组合物重量从约0.5%到约5%之间的量。 In a preferred embodiment, the composition comprises an excess of from about 0.5% to about 5% benzoyl peroxide between the total composition weight. 另外,本发明组合物是独特的,由于能够优选有效保持过氧化苯甲酰的浓度,即要求过氧化苯甲酰标注为至少90%。 In addition, the compositions of the present invention is unique, since it is possible to maintain over the effective concentration preferably benzoyl peroxide, benzoyl peroxide dimension which requires at least 90%.

[0057] 根据该实施方案,在混合之前的初始含过氧化苯甲酰组合物具有优选的粘性为约25,000到约1,250,000厘泊。 [0057] According to this embodiment, in the initial mixing prior benzoyl peroxide-containing composition preferably has a viscosity of from about 25,000 to about 1,250,000 centipoise.

[0058] 在另一个优选的实施方案中,在本发明组合物内含之前可以减小过氧化苯甲酰的颗粒大小。 [0058] In another preferred embodiment, the compositions of the present invention containing benzoyl peroxide can be reduced prior to particle size. 通过处理可以进行减少颗粒大小,例如处理包括一个粉碎步骤或微粉化步骤使用溶剂。 By reducing the particle size of the treatment can be carried out, for example, the processing step comprises a pulverizing step using a solvent or micronized.

[0059] 本发明组合物的抗菌素成分通常以总组合物重量约0.5%到约3%之间的量存在。 [0059] the amount of the antibiotic component of the composition of the present invention is generally based on the total weight of the composition is between about 0.5% to about 3% exists. 另外,本发明组合物是独特的,由于优选能够有效保持抗菌素的浓度,即要求氯洁霉素标注要求为至少90%。 In addition, the composition of the present invention is unique, since it is preferable to keep the concentration of effective antibiotics, which called clindamycin labeling requirements for at least 90%.

[0060] 任意公知在治疗皮肤疾病、病症或症状预期有用的各种不同的抗生素被归入本发明组合物。 [0060] any known in the treatment of skin disease, disorder or condition is expected to be useful in a variety of different antibiotics are included in the compositions of the present invention. 关于这一点,优选本发明组合物有用抗生素非限定的例子包括氯洁霉素、四环素、红霉素、林肯霉素、阿奇霉素、卡包霉素、氯四环素、克拉霉素、脱甲四环素、强力霉素、庆大霉素、交沙霉素、卡那霉素、北里霉素、新霉素、甲烯土霉素、麦迪霉素、美欧卡霉素、竹桃霉素、土霉素、伯霉素、核糖霉素、罗他霉素、吡咯甲基四环素、蔷薇霉素、罗红霉素、大观霉素、螺旋霉素、链霉素、磺胺醋酰、苯酰磺胺、磺胺嘧啶、6-二甲氧嘧啶、磺胺甲基嘧啶、磺胺二甲嘧啶、磺胺甲噻二唑、磺胺甲基异恶唑、托普霉素、三乙酰夹竹桃霉素、其盐、其酯、其衍生物和其混合物。 In this regard, the compositions of the present invention are preferably non-limiting examples of useful antibiotics include clindamycin, tetracycline, erythromycin, clindamycin, azithromycin, card pack neomycin, chlortetracycline, clarithromycin, tetracycline off armor, power neomycin, gentamicin, josamycin, kanamycin, North, neomycin, methacycline, Midecamycin, US Oka adriamycin, oleandomycin, oxytetracycline , primycine, ribostamycin, rokitamycin, pyrrolylmethyl tetracycline, neomycin rose, Luo erythromycin, spectinomycin, spiramycin, streptomycin, sulfonamides sulfacetamide, benzoyl sulfonamides, sulfadiazine , 6-methoxy-pyrimidine, sulfamethyldiazine, sulfamethazine, sulfamethoxazole thiadiazole, sulfamethoxazole, tobramycin, triacetyl oleandomycin, its salt, ester, derivatives and mixtures thereof. 关于这一点特别优选氯洁霉素、红霉素和四环素以及其盐或衍生物。 In this regard particularly preferred clindamycin, erythromycin and tetracycline and the salt or derivative thereof. 在最优选的实施方案中,抗菌素是氯洁霉素或其盐或衍生物。 In a most preferred embodiment, the antibiotic is clindamycin or a salt or derivative thereof.

[0061] 关于这一点,本发明组合物的抗菌素成分优选氯洁霉素的药物级盐或酯。 [0061] In this regard, the compositions of the present invention is preferably antibiotic clindamycin component pharmaceutical grade salt or ester thereof. 氯洁霉素药学上可接受的盐或酯意指那些具有想得到药理学活性和既不是生物学上也不是其它不需要的。 Clindamycin pharmaceutically acceptable salts or esters means those having wanted pharmacological activity and is neither biologically nor other undesirable. 氯洁霉素磷酸盐(酯)和氯洁霉素盐酸盐(盐)优选药学上可接受的盐和氯洁霉素的酯,由于它们与胶凝剂的配伍性和局部使用的广泛历史,其可被用于本发明组合物。 Clindamycin phosphate (ester) and clindamycin hydrochloride (salt), preferably a pharmaceutically acceptable salt and clindamycin esters, due to the extensive history of their compatibility with gelling agents and topical , which it may be used in the compositions of the present invention.

[0062] 本发明组合物的类维生素A成分优选类维生素A的药物级盐。 A component of the composition of the present invention preferably retinoid retinoid A pharmaceutical grade salt [0062] The present. 类维生素A药学上可接受的盐或酯意指那些具有想得到药理学活性和既不是生物学上也不是其它不需要的。 Class vitamin A pharmaceutically acceptable salt or ester means those having wanted pharmacological activity and is neither nor other undesirable biological. 本发明组合物的类维生素A成分通常以总组合物重量约0.01%到约1.5%之间的量存在。 A quantity of the retinoid component of the composition of the present invention is generally based on the total weight of the composition between about 0.01% to about 1.5% exists. 在一个特别的优选的实施方案中,类维生素A以总组合物重量约0.01%到约0.5%之间的量存在。 In a particularly preferred embodiment, the amount of vitamin A class weight of the total composition between about 0.01% to about 0.5% of the present.

[0063] 另外,本发明组合物是独特的,由于能够优选有效保持类维生素A的浓度,即要求类维生素A标注为至少90%。 [0063] In addition, the compositions of the present invention is unique, since it is possible to maintain an effective concentration of the preferred class of vitamin A, vitamin A class which requires at least 90% labeled.

[0064] 在另一个优选的实施方案中,在本发明组合物内含之前可以减小类维生素A的颗粒大小。 [0064] In another preferred embodiment, the compositions of the invention can reduce the particle size prior to inclusion of vitamin A in the class. 通过处理可以进行减少颗粒大小,例如处理包括一个粉碎步骤或微粉化步骤使用溶剂。 By reducing the particle size of the treatment can be carried out, for example, the processing step comprises a pulverizing step using a solvent or micronized.

[0065] 任意公知在治疗皮肤疾病、病症或症状预期有用的各种不同的抗生素被归入本发明组合物。 [0065] any known in the treatment of skin disease, disorder or condition is expected to be useful in a variety of different antibiotics are included in the compositions of the present invention. 关于这一点,优选本发明组合物有用类维生素A非限定的例子包括他佐罗汀、视黄酸、维甲酸、异维甲酸、阿达帕林、贝卡瑞特、9-顺式视黄酸、维生素A、视黄醇、视黄素、棕榈酸视黄酯、乙酸视黄酯、5-(2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基)噻吩-2-羧酸乙酯、6-(2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基)-3-吡啶甲醇、2-(2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基)-5-吡啶甲醛,其盐、其酯、其衍生物和其混合物。 In this regard, the compositions of the present invention are preferably useful classes vitamin A non-limiting examples include tazarotene, retinoic acid, tretinoin, isotretinoin, adapalene, Bekaa Reiter, 9-cis retinoic acid , vitamin A, retinol, retinoids, retinyl palmitate, retinyl acetate, 5- (2- (4,4-dimethyl-thiochroman-6-yl) ethynyl) thiophene-2-carboxylate, 6- (2- (4,4-dimethyl-thiochroman-6-yl) ethynyl) -3-pyridine methanol, 2- (2- (4, 4-dimethyl-thiochroman-6-yl) ethynyl) -5-pyridinecarboxaldehyde, salts thereof, esters thereof, derivatives thereof, and mixtures thereof. 关于这一点特别优选他佐罗汀、视黄酸、维甲酸和异维甲酸,以及其盐或衍生物,特别是视黄酸、维甲酸或异维甲酸的盐或衍生物。 In this regard particularly preferred tazarotene, retinoic acid, tretinoin and isotretinoin, and their salts or derivatives, particularly retinoic acid, retinoic acid or a salt or derivative isotretinoin. 在最优选的实施方案中,类维生素A是他佐罗汀。 In a most preferred embodiment, the retinoid is tazarotene A.

[0066] 在优选的实施方案中,一种或多种过氧化苯甲酰、抗菌素或其药学上可接受的盐和类维生素A或其药学上可接受的盐包封或圈闭在固体或半固体的成分内,以内含最终的组合物。 [0066] In a preferred embodiment, the one or more benzoyl peroxide, on the antibiotic or a pharmaceutically acceptable salt thereof, and retinoids A or a pharmaceutically acceptable salt thereof encapsulated or trapped in a solid or the semi-solid composition, containing in the final composition. 活性成分的包封或圈闭可以帮忙阻止类维生素A、抗菌素和过氧化苯甲酰组分之间的反应,因此提高各自这些成分和作为总体组合物的贮存稳定性。 Encapsulated active ingredient or traps can help prevent the kind of vitamin A, antibiotics and benzoyl peroxide through the reaction between the components, so as to enhance each of these components and the overall composition of the storage stability.

[0067] 因此本发明的一个优选的实施方案涉及本发明主题还涉及通常用于治疗患者痤疮的方法,包含对所述患者进行过氧化苯甲酰、抗菌素和类维生素A组合局部给药,其中所述组合包含低浓度的林肯霉素亚砜磷酸盐、林肯霉素亚砜、氯洁霉素亚砜磷酸盐、氯洁霉素亚砜、他佐罗汀亚砜、他佐罗汀砜、苯甲酸和其混合物。 [0067] Thus a preferred embodiment of the present invention relates generally relating to the present invention also relates to a method for the treatment of acne patients, the patient contains benzoyl peroxide, antibiotics and retinoids A composition for topical administration, wherein The composition comprises a low concentration of lincomycin phosphate sulfoxide, lincomycin sulfoxide, clindamycin phosphate sulfoxide, clindamycin sulfoxide, sulfone he Zuoluotingya, tazarotene sulfone, benzoic acid and mixtures thereof.

[0068] 在进一步优选的实施方案中,该固体或半固体成分具有约哺乳动物体温如人体温的熔点。 [0068] In a further preferred embodiment, the solid or semi-solid temperature component having a mammal such as a human body temperature of about the melting point. 在这点上,有用的具体的固体和半固体的成分为本领域普通技术人员所熟知,例如Budavari等人编写的《默克索引》第十三版,默克公司,Rahway,NJ(2001);CTFA(化妆、化妆品和香料联合会)《国际化妆成分词典和手册》第十版(2004);以及《惰性成分指南》,管理美国食品与药物管理局(FDA)药品评估和研究中心中(CDER)办公室,http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm中描述的那些,其全部内容在此一并作为参考。 In this regard, useful and specific solid component semisolid those of ordinary skill in the art, for example Budavari et al., "The Merck Index" Thirteenth Edition, Merck & Co., Rahway, NJ (2001) ; CTFA (Cosmetic, cosmetics and perfume Federation) "International Cosmetic Ingredient Dictionary and Handbook" Tenth Edition (2004); and "inert ingredients Guide" management by the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research ( CDER) Office, http: //www.accessdata.fda.gov/scripts/cder/iig/index.cfm those described, the entire contents of which are incorporated herein by reference.

[0069] 类似地,在一个优选的实施方案中,一种或多种过氧化苯甲酰、抗菌素或其药学上可接受的盐和类维生素A或其药学上可接受盐可存在于溶液、悬浮液或分散液中的最终组合物。 [0069] Similarly, in a preferred embodiment, one or more of benzoyl peroxide, the antibiotic or a pharmaceutically acceptable salt thereof and a retinoid A or a pharmaceutically acceptable salt thereof may be present in solution, suspension or dispersion of the final composition. 关于这一点,在一个特别优选的实施方案中,过氧化苯甲酰、抗菌素或其药学上可接受的盐在悬浮液中,类维生素A或其药学上可接受盐在溶液中。 In this regard, in a particularly preferred embodiment, the benzoyl peroxide, antibiotic or a pharmaceutically acceptable salt thereof in the suspension, A retinoid acceptable salt or a pharmaceutically acceptable solution.

[0070] 一旦所有成分组合,这里优选最终组合物具有最终粘度为约20,000到约1,000,000厘泊。 [0070] Once all combinations of ingredients, preferably where the final composition has a final viscosity of about 20,000 to about 1,000,000 centipoise. 在一个特别优选的实施方案中,最终组合物具有最终粘度为约40,000到约500,000厘泊。 In a particularly preferred embodiment, the final composition has a final viscosity of from about 40,000 to about 500,000 cps. 该最终粘度具有比初始含过氧化苯甲酰更低的含过氧化苯甲酰组合物显示的粘度,本发明组合物更容易一起混合,包含更少的降解和比本领域以前已知的那些组合物具有更大的均匀度。 The final viscosity has a viscosity of the benzoyl peroxide-containing composition shows too lower than the initial benzoyl peroxide-containing composition of the present invention is more readily mixed together, and containing more than previously known in the art that less degradation compositions having a greater degree of homogeneity.

[0071] 在一个优选的实施方案中,最终组合物显示最终pH为约3到约8。 [0071] In a preferred embodiment, the final composition exhibits a final pH of from about 3 to about 8. 在一个特别优选的实施方案中,本发明组合物显示最终pH为约3.5到约5.5。 In a particularly preferred embodiment, the compositions of the present invention exhibit a final pH of from about 3.5 to about 5.5. 该精细处理的pH是本发明组合物比本领域以前已知的那些组合物具有更先进储藏稳定性的部分原因。 The pH of the fine processing is a composition of the present invention than those previously known in the art having compositions in part because more advanced storage stability. 关于这一点,本发明优选组合物可以在约25℃的温度下稳定贮存至少30天或更长。 In this regard, preferred compositions of the present invention can be stably stored at a temperature of about 25 ℃ at least 30 days or longer. 在一个特别优选的实施方案中,本发明组合物可以在约25℃的温度下稳定贮存至少60天。 In a particularly preferred embodiment, the compositions of the present invention can be stably stored for at least 60 days at a temperature of about 25 ℃.

[0072] 在另一个优选的实施方案中,本发明组合物可以在约15℃的冷藏温度下稳定贮存至少60天。 [0072] In another preferred embodiment, the compositions of the present invention can be stably stored for at least 60 days at refrigerated temperatures of about 15 ℃. 在一个特别优选的实施方案中,本发明组合物用于治疗各种皮肤病或症状的局部用组合物,其包含:一种包含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或其酯,类视色素或其药学上可接受的盐和一种药学上可接受载体的储存稳定的混合物,其中组合物在不超过15℃下的冷冻温度下稳定贮存至少60天。 In a particularly preferred embodiment, the compositions of the present invention is used to treat various skin diseases or symptoms topical composition, comprising: a composition comprising benzoyl peroxide, antibiotic or a pharmaceutically acceptable salt or ester thereof, retinoids mixture was storage stable pigment or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is frozen at a temperature not exceeding 15 ℃ stable under storage for at least 60 days.

[0073] 一个特别优选的实施方案中,本发明组合物在约2℃到约8℃的冷藏温度下稳定贮存至少6个月。 [0073] A particularly preferred embodiment, the compositions of the present invention at refrigeration temperatures of about 2 ℃ to about 8 ℃ stable storage for at least six months. 在另一个特别优选的实施方案中,本发明组合物在约2℃到约8℃的冷藏温度下稳定贮存至少12个月。 In another particularly preferred embodiment, the compositions of the present invention at refrigeration temperatures of about 2 ℃ to about 8 ℃ stable storage for at least 12 months.

[0074] 在另一个实施方案中,本发明组合物可以在选自包含低于约0℃、约2℃到约8℃,约8℃到约15℃,约23℃到约27℃,直到约25℃,约15℃到约30℃的冷藏条件下保持稳定贮存。 [0074] In another embodiment, the compositions of the present invention may be selected from the group comprising less than about 0 ℃, about 2 ℃ to about 8 ℃, about 8 ℃ to about 15 ℃, about 23 ℃ to about 27 ℃, until about 25 ℃, about 15 ℃ to 30 ℃ under refrigerated conditions remained stable about storage.

[0075] 尽管过氧化苯甲酰、抗菌素和类维生素A的相对不相容性,本发明优选组合物不需要在配制时混合和保持稳定性用于依赖于贮存温度的延长周期。 [0075] Although benzoyl peroxide, antibiotics and retinoids relative incompatibility of A, preferred compositions of the present invention does not require mixing and to maintain the stability depends on the storage temperature for extended periods in the preparation. 这表现出大于目前本领域已知制剂的明显优点。 This represents a greater than currently known in the art formulation of clear advantages.

[0076] 本发明组合物可以为每日一次或每日两次给药配制。 [0076] The compositions of the invention may be formulated as a once daily or twice daily dosing. 在一个优选的实施方案中,在傍晚或夜晚每日一次给药增加适应性以减轻炎症,并报告对皮肤症状最有利。 In a preferred embodiment, in the evening or at night once daily administration increases the adaptability to reduce inflammation and skin conditions most favorable report.

[0077] 药学上可接受的载体 [0077] a pharmaceutically acceptable carrier

[0078] 起始的含过氧化苯甲酰组合物以及最终组分,可以采取溶液、凝胶、油膏、洗液、悬浮液、乳状液、软膏、喷雾剂、泡沫、糊剂或其任意结合的形式。 [0078] The initial benzoyl peroxide-containing composition and the final composition, may take the solutions, gels, ointments, lotions, suspensions, emulsions, ointments, sprays, foams, pastes, or any bound form. 其它本领域技术人员所知的化妆品治疗组合物包括液体和香膏,另外预期落入本发明的范围内。 Other known to those skilled in the cosmetic treatment composition comprising a liquid and ointment, while intended to fall within the scope of the invention. 因此,本发明组合物进一步包括适合提供具体所要剂型的任意药学上可接受的载体。 Thus, the compositions of the present invention further comprises any pharmaceutically specifically adapted to provide the desired dosage form acceptable carrier.

[0079] 可选择用于局部制剂的乳状液如油包水或水包油体系以获得活性成分的有效性和/或避免由于碱或活性成分引起的过敏性和刺激性反应(如接触性皮炎)。 [0079] Alternatively for topical formulations such as oil-in-water emulsion or a water-in-oil system in order to obtain the effectiveness of the active ingredient and / or avoid allergic and irritating reactions caused due to the base or the active ingredient (e.g., contact dermatitis ).

[0080] 因此,本发明组合物可以任意进一步包含一种乳化剂。 [0080] Thus, the compositions of the present invention may optionally further comprise an emulsifier. 使用的乳化剂非限定实施例包括乙二醇酯、脂肪酸、脂肪醇、脂肪酸乙二醇酯、脂肪酸酯、脂肪醚、甘油酯、丙二酯、聚乙二醇脂肪酸酯、聚丙二醇脂肪酸酯、山梨糖酯、山梨聚糖酸酐酯、羧酸共聚物、葡萄糖酯和醚、乙氧基醚、乙氧基醇、磷酸烷基酯、聚氧化乙烯脂肪醚磷酸酯、脂肪酸酰胺、酰乳酸、皂、其衍生物和其混合物。 Emulsifier used in non-limiting embodiment include ethylene glycol esters, fatty acids, fatty alcohols, fatty acid glycol esters, fatty acid esters, fatty ethers, esters, malonic esters, polyethylene glycol fatty acid esters, polyethylene glycol fatty esters, sorbitan esters, sorbitan esters of anhydrides, carboxylic acid copolymers, esters and ethers of glucose, ethoxylated ethers, ethoxylated alcohols, alkyl phosphates, polyoxyethylene fatty ether phosphates, fatty acid amides, acyl lactic acid, soaps, derivatives thereof, and mixtures thereof.

[0081] 在这点上,在本发明组合物中使用乳化剂的具体非限定实施例包括聚乙二醇20去水山梨糖醇月桂酸酯(吐温20)、聚乙二醇5大豆甾醇、硬脂醇聚醚-2、硬脂醇聚醚-20、硬脂醇聚醚-21、鲸蜡硬脂醇聚醚-20、PPG-2甲基葡萄糖醚二硬脂酸酯、ceteth-10、吐温85、十六烷基磷酸盐、十六烷基磷酸钾、十六烷基磷酸二乙醇胺、吐温60、硬脂酸甘油酯、PEG-100硬脂酸酯、黄蓍胶、聚(丙烯酰胺-b-丙烯酸)、10-30烷基丙烯酸酯交联聚合物、其衍生物和其混合物。 [0081] In this regard, the use of emulsifiers in the compositions of the present invention in particular non-limiting examples include polyethylene glycol 20 sorbitan sugar alcohols monolaurate (Tween 20), polyethylene glycol 5 soya sterol , steareth -2, steareth-20, steareth -21, cetearyl alcohol polyether -20, PPG-2 methyl glucose ether distearate, ceteth- 10, Tween 85, cetyl phosphate, potassium cetyl phosphate, diethanolamine cetyl phosphate, Polysorbate 60, glyceryl stearate, PEG-100 stearate, tragacanth, poly (acrylamide -b- acrylic acid), 10-30 alkyl acrylate crosspolymer, derivatives thereof and mixtures thereof.

[0082] 在本发明组合物中使用的油膏也可以是油包水的半固体乳状液;容易涂敷和在与皮肤摩擦时消失。 [0082] In the compositions of the present invention, the ointment used may be a semi-solid oil-in-water emulsion; easily applied and disappears when the friction with the skin.

[0083] 在本发明组合物中使用的洗液包括老定义如粉末材料(如炉甘石)在水或乙醇碱中的悬浮液,以及现代的洗液(如一些类固醇)如水基的乳状液。 [0083] lotion in the compositions of the present invention comprises an emulsion old definition of powdery material (such as calamine) in water or alcohol base of the suspension, and a modern wash (as some steroids) water group . 为了便于涂敷,同时冷却洗液有助于干燥急性炎症和渗出性的损伤。 For ease of coating, while cooling lotion helps acute inflammatory and exudative drying damage.

[0084] 使用的软膏是油脂性,如果有水则包含微量水;感觉油腻但通常具有很好的耐受性;特别是如果涂敷在水性皮肤时最好使用润滑;它们优选用于因厚硬壳、苔癣样硬化或堆积状鳞片的损害,用于一些受腐蚀或开放的损害(如郁血性溃疡)的刺激比油膏更少。 [0084] oleaginous ointment is used, if the water contains trace amounts of water; feel greasy but usually have well tolerated; especially if applied when the skin is preferable to use an aqueous lubrication; they are preferably used because thick hard shell, like lichen sclerosis or scales of damage accumulation, for some excitement damage by corrosion or open (such as stasis ulcers) less than the ointment. 软膏中的药物常常比油膏的药物更有效。 Ointment drug is often more effective than ointment drugs.

[0085] 在一个优选实施方案中,本发明组合物可以采取凝胶的形式。 [0085] In one preferred embodiment, the compositions of the present invention may take the form of a gel. 在这点上,本发明组合物可以包括胶凝剂和/或增稠剂。 In this regard, the compositions of the present invention may include a gelling agent and / or thickening agents. 在本发明组合物中使用的合适胶凝剂和/或增稠剂包括含水增稠剂如中性、阴离子和阳离子的聚合物,及其混合物。 Suitable gelling agents in the compositions of the present invention and / or thickening agents include aqueous thickening agents such as neutral, anionic and cationic polymers, and mixtures thereof. 在起始组合物中使用的聚合物例子包括羧基乙烯基聚合物如卡波姆。 Examples of polymers used in the starting composition include carboxyvinyl polymers such as carbomers. 优选的增稠剂是卡波姆如Carbopol,brand聚羧乙烯聚合物,其可以从Noveon公司,Cleveland,OH买到。 Preferred thickeners are carbomers such as Carbopol, brand Carbopol polymer, which is available from Noveon Company, Cleveland, OH buy. 在这一点使用的其它例子包括亲水性/疏水性的graft共聚物如作为聚苯乙烯/微海绵/Carbopol混合物生成的聚合物。 In other examples of this use include hydrophilic / hydrophobic graft copolymers such as polystyrene / microsponge / Carbopol mixture resulting polymer. 在这点上一种这样的聚合物是二甲基丙烯酰胺/丙烯酸/聚苯乙烯甲基丙烯酸乙酯共聚物,例如Pharmadur商标共聚物,其可以从Polytherapeutics公司,Bridgewater,NJ买到。 In this regard, such a polymer is a dimethylacrylamide / acrylic acid / polystyrene ethyl methacrylate copolymer, e.g. Pharmadur trademarks copolymer available from Polytherapeutics Corporation, Bridgewater, NJ buy.

[0086] 其它,这里使用的合适增稠剂非限定实施例包括纤维素聚合物如阿拉伯胶、阿拉伯树胶、黄蓍树胶、刺槐豆胶、瓜耳豆胶、羟丙基瓜尔胶、黄原胶、纤维素胶、菌类植物胶、鹿角菜胶、刺梧桐树胶、纤维素胶、松香、甲纤维素、羟乙基纤维素、羟丙纤维素、羟甲基纤维素、羟丙基甲基纤维素、甲基羟乙基甲基纤维素、十六烷基羟乙基纤维素、羧甲基纤维素、玉米淀粉、羟丙基淀粉磷酸酯、磷酸双淀粉、distarch二亚甲基尿素、辛烯基琥珀酸铝淀粉、麦芽糖糊精、右旋糖酐、聚(丙烯酰胺)、PEG-150二硬脂酸酯、PEG-150/癸醇/SMDI共聚物、PEG-150/硬脂酰乙醇/SMDI共聚物、PEG-180/Laureth-50/TMMG共聚物、聚醚1、丙烯酸/丙烯酰胺基丙烷磺酸共聚物、丙烯酸酯/C10-30烷基丙烯酸酯交联聚合物、丙烯酸酯/山萮醇聚醚-25异丁烯酸共聚物、丙烯酸酯/硬脂醇聚醚-20异丁烯酸共聚物、丙烯酰二甲基牛磺酸铵/山萮醇聚醚-25异丁烯酸共聚物、丙烯酰二甲基牛磺酸铵/VP共聚物、辛/癸甘油三酯(和)丙烯酸酯橡胶钠、PVM/MA癸二烯交联聚合物、藻酸、丙二醇藻朊酸酯、二甲基硅油、甲基烷基化硅石、二甲基丙烯酰胺/丙烯酸/聚苯乙烯甲基丙烯酸乙酯共聚物,其衍生物和其混合物。 [0086] Other suitable thickening agents used herein non-limiting examples include cellulosic polymers such as gum arabic, gum arabic, tragacanth gum, locust bean gum, guar gum, hydroxypropyl guar gum, xanthan gum, cellulose gum, fungi gum, carrageenan, karaya gum, cellulose gum, rosin, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, methyl hydroxyethyl cellulose, cetyl hydroxyethyl cellulose, carboxymethyl cellulose, corn starch, hydroxypropyl starch phosphate, starch double, distarch dimethylene urea , aluminum starch octenyl succinate, maltodextrin, dextran, poly (acrylamide), PEG-150 distearate, PEG-150 / decyl alcohol / SMDI copolymer, PEG-150 / stearyl alcohol / SMDI copolymer, PEG-180 / Laureth-50 / TMMG copolymer, Polyether 1, acrylic acid / acrylamido propane sulfonic acid copolymers, acrylates / C10-30 alkyl acrylate crosspolymer, acrylates / Mountain stearic alcohol polyether -25 methacrylic acid copolymers, acrylate / steareth-20 methacrylate copolymer, Acryloyldimethyl taurine ammonium / behenyl alcohol polyether -25 methacrylic acid copolymers, acrylic acid Ammonium taurate / VP copolymer, octyl / capric triglyceride (and) sodium acrylate rubber, PVM / MA decadiene cross-linked polymer, alginic acid, propylene glycol alginates, dimethicone methyl alkylated silica, dimethyl acrylamide / acrylic acid / polystyrene ethyl methacrylate copolymer, derivatives thereof, and mixtures thereof. 其它常见的增稠剂和/或胶凝剂如聚丙烯聚合物,这里可以进一步有用。 Other common thickening and / or gelling agents such as polypropylene polymer, may further be useful here. 这些增稠剂和/或胶凝剂可以存在于起始组合物,不考虑最终组分生成什么。 These thickening and / or gelling agents may be present in the starting composition, does not consider what the final component production.

[0087] 任意其它无毒、惰性和有效的载体可用来配制本发明优选的组合物。 [0087] any other non-toxic, inert, and effective carrier may be used to formulate the preferred compositions of the present invention. 用于配制对人给药的其它治疗化合物的公知的载体在本发明组合物中特别有用。 People on other carriers used in formulating the administration's treatment of the known compounds are particularly useful in the compositions of the present invention. 对本领域技术人员所公知的药学上可接受的载体、赋形剂和稀释剂例如Budavari等人编写的《默克索引》第十三版,默克公司,Rahway,NJ(2001),其全部内容在此一并作为参考。 To the person skilled in the known pharmaceutically acceptable carriers, excipients and diluents such Budavari et al., "The Merck Index" Thirteenth Edition, Merck & Co., Rahway, NJ (2001), the entire contents herein incorporated by reference. 有用的药学上可接受的载体、赋形剂和稀释剂的例子包括蒸馏水、生理盐水、林格氏溶液、葡萄糖溶液、Hank溶液和DMSO,它们之一优选在本发明中使用。 Useful pharmaceutically acceptable carriers, excipients, and diluents examples include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank solution and DMSO, one of them is preferably used in the present invention.

[0088] 这些另外的组分以及本领域公知的有效制剂和给药工序在标准教科书中描述,如Goodman和Gillman的《药理学基础和治疗学》,第8版,Gilman等人编写,Pergamon印刷(1990)和Remington的《药物科学》,第17版,Mack出版公司,Easton,Pa.(1990),其两者全部内容在此一并作为参考。 [0088] These additional components as well known in the art of effective preparation and administration processes are described in standard texts, such as Goodman and Gillman's "The Pharmacological Basis and Therapeutics", edition 8, Gilman et al write, Pergamon printing (1990) and Remington's "Pharmaceutical Sciences", 17th Edition, Mack Publishing Company, Easton, Pa. (1990), both of which the entire contents of which are incorporated herein by reference.

[0089] 根据本发明优选实施例可以使用的优选赋形剂例子包括但不局限于卡波姆、聚丙烯聚合物、甘油、氢氧化钠、硫代硫酸钠、培酸丙酯、烷基对羟苯甲酸、纯化水及其混合物。 [0089] According to a preferred embodiment of the present invention may be used to implement the preferred excipients include, but are not limited to, carbomer, polypropylene polymers, glycerine, sodium hydroxide, sodium thiosulfate, training gallate, an alkyl group of paraben, purified water and mixtures thereof.

[0090] 用于起始局部用组合物的其它任意成分包括湿润剂如丙二醇;溶剂如乙醇(deminimis);防晒霜如二氧化钛、氧化锌和碳酸钙;以及抗细菌的防腐剂如对羟基苯甲酸甲酯和对羟苯甲酸丙酯。 Other optional components [0090] The starting topical compositions include humectants such as propylene glycol; solvents such as ethanol (deminimis); sunscreens such as titanium dioxide, zinc oxide and calcium carbonate; and antibacterial preservatives such as p-hydroxybenzoic acid methyl and propyl paraben. 局部用组合物同时可包括一种有机或无机碱如氢氧化钠,其用于调节最初成分和最终产品的pH。 While topical composition may comprise an organic or inorganic base such as sodium hydroxide, which is used to adjust the pH of the initial components and the final product.

[0091] 在这点上,这里论述的优选组合物可以另外包含一种或多种经皮肤专家认可可接受赋形剂的剩余数量。 [0091] In this regard, preferred compositions discussed herein may further comprise one or more of the remaining number of recognized experts through the skin acceptable excipient. 在这些组合物中使用的优选经皮肤专家认可可接受赋形剂的非限定例子是选自包括表面活性剂、防腐剂、软化剂、湿润剂、液体烷基醇、增稠剂、乳化剂、悬浮剂、pH调节剂/缓冲剂、螯合剂、防晒霜、其衍生物和其混合物。 Preferably through the skin experts employed in these compositions acceptable excipients recognized by non-limiting examples are selected from the group comprising a surfactant, preservatives, emollients, humectants, fluid alkyl alcohol, thickening agents, emulsifiers, suspending agents, pH modifiers / buffering agents, chelating agents, sunscreens, their derivatives and mixtures thereof. 尽管本发明组合物可以任意进一步包含抗氧化剂作为一种经皮肤专家认可可接受赋形剂,在这点上抗氧化剂的使用不是特别优选。 While the compositions of the present invention may optionally further contain an antioxidant as a transdermal recognized experts acceptable excipients, antioxidants are not particularly preferred to use at this point.

[0092] 因此,在局部用组合物中有用的任意表面活性剂、防腐剂、润肤剂、湿润剂、液体烷基醇、增稠剂、乳化剂、悬浮剂、pH调节剂/缓冲剂、螯合剂、防晒霜或其它经皮肤专家认可可接受的赋形剂通常为本领域普通技术人员所知,可以预期在这里描述的组合物中是有用的。 [0092] Thus, useful in the topical composition of any of surfactants, preservatives, emollients, humectants, fluid alkyl alcohol, thickening agents, emulsifying agents, suspending agents, pH modifiers / buffering agents, chelating agents, sunscreen or other skin experts recognized by generally acceptable excipients are known to those of ordinary skill can be expected compositions described herein are useful. 进一步,任意无毒、惰性和有效的载体可用来配制这里描述的组合物。 Further, any non-toxic, inert, and effective carrier may be used to formulate the compositions described herein. 这些组分的例子如Budavari等人编写的《默克索引》第十三版,默克公司,Rahway,NJ(2001);CTFA(化妆、化妆品和香料联合会)《国际化妆成分词典和手册》第十版(2004);以及《惰性成分指南》,管理美国食品与药物管理局(FDA)药品评估和研究中心中(CDER)办公室,http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm中描述的那些,其全部内容在此一并作为参考。 Examples of these components as Budavari et al., "The Merck Index" Thirteenth Edition, Merck & Co., Rahway, NJ (2001); CTFA (Cosmetic, cosmetics and perfume Federation) "International Cosmetic Ingredient Dictionary and Handbook" Tenth Edition (2004); and "inert ingredients Guide" management by the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office, http: //www.accessdata.fda.gov/scripts/cder /iig/index.cfm those described, the entire contents of which are incorporated herein by reference.

[0093] 在严重的情况下,闭塞治疗在出现痤疮的地方伴随有有其它迹象或症状如牛皮癣、特应性皮炎、红斑狼疮和慢性手皮炎上可以是有效的。 [0093] In severe cases, acne treatment occlusion accompanied where there are other signs or symptoms such as psoriasis, atopic dermatitis, on lupus and chronic hand dermatitis can be effective. 使用无孔的封闭敷裹覆盖在治疗表面可以提高本发明组合物的吸收和效果。 Use non-porous closed dressing covering the surface treatment can improve the absorption and effect of the composition of the present invention. 通常,聚乙烯薄膜(塑料家庭包)用油膏或软膏涂敷过夜,其比用于闭塞治疗的洗液具有更少的刺激。 Typically, polyethylene film (plastic household package) coated with ointment or ointment overnight, it has less exciting than lotions for occlusion therapy. 塑料带可以注入药物,特别便于治疗隔离或顽抗的损害;在大面积上进行延长闭塞的治疗可使儿童和(常常较少)成人受到脑垂体和肾抑制。 Plastic can be injected with drugs, especially to facilitate the treatment of isolated or recalcitrant damage; be prolonged occlusive therapy over a large area can protect a child and (often less) Adult inhibition by the pituitary gland and kidney.

[0094] 在一个选择性的实施方案中,本发明进一步涉及用于治疗皮肤病症或症状的局部用组合物,其包含:1)类维生素A或其药学上可接受的盐,2)或含过氧化苯甲酰组合物或抗菌素或其药学上可接受的盐或其酯,和3)一种药学上可接受载体的储存稳定的混合物。 [0094] In an alternative embodiment, the present invention further relates to methods for the treatment of skin disorders or symptoms topical composition, comprising: 1) the class of vitamin A or a pharmaceutically acceptable salt thereof, 2) or an The mixture was storage stable over the benzoyl peroxide composition or the antibiotic or a pharmaceutically acceptable salt or ester thereof, and 3) a pharmaceutically acceptable carrier. 在一个优选实施方案中,配制组合物的最终pH为约3至约8。 In a preferred embodiment, the composition is formulated in a final pH of from about 3 to about 8.

[0095] 添加的活性成分 [0095] added the active ingredient

[0096] 除过氧化苯甲酰、抗菌素和类维生素A之外,本发明组合物可以进一步包含容易为本领域技术人员所知的其它活性成分,其在皮肤疾病或症状局部治疗有用。 [0096] In addition to over than benzoyl peroxide, antibiotics and retinoids A, compositions of the present invention may further comprise readily known to those skilled other active ingredients, useful for its topical treatment of skin diseases or symptoms. 另外活性成分的例子包括但不局限于其它大环内酯类抗生素、杀菌性药物、抑菌的药物、净化剂、吸附剂、抗感染药、消炎药、收敛药(沉淀蛋白和缩小和收缩和收紧皮肤的干燥剂)、软化剂(皮肤软化剂)、增湿剂、角质松解症(软化、松弛剂,促进表皮鳞状上皮细胞的脱落)及其混合物。 Additional examples of active ingredients include, but are not limited to other macrolide antibiotics, bactericidal drugs, antibacterial drugs, cleaning agents, adsorbents, anti-infectives, anti-inflammatories, astringents (precipitated protein and shrink and shrink and skin tightening desiccant), softeners (skin softeners), moisturizers, keratolysis (softening, relaxants, promote skin squamous cell shedding) and mixtures thereof.

[0097] 预期在本发明范围内另外大环内酯类抗生素的例子包括但不局限于阿奇霉素、克拉霉素、红霉素、林肯霉素及其混合物。 [0097] contemplated within the scope of the present invention additionally macrolide antibiotics include, but are not limited to, azithromycin, clarithromycin, erythromycin, clindamycin, and mixtures thereof. 大环内酯在结构和活性上都类似。 Macrolides are similar in structure and activity. 所有的大环内酯容易被吸收,所有的主要用来抑菌并结合核糖体的50S亚单元,因此抑制细菌蛋白合成。 All macrolide easily absorbed, all mainly used antibacterial combination with 50S ribosomal subunits, thereby inhibiting bacterial protein synthesis. 这些药物通常在除肠道球菌之外的对抗好氧和厌氧的革兰氏阳性球菌和对抗革兰氏阴性厌氧菌具有活性并且在本发明组合物中有用。 These drugs are usually in addition to enterococci against aerobic and anaerobic gram-positive bacteria and against gram-negative anaerobic active and useful compositions of the present invention.

[0098] 预期在本发明范围内杀菌药物(如它们杀死细菌)的例子包括但不局限于青霉素、头孢霉素、万古霉素、氨基糖苷类、喹诺酮和多粘菌素。 [0098] Examples of contemplated within the scope of the present invention bactericidal drugs (as they kill bacteria) include, but are not limited to, penicillins, cephalosporins, vancomycin, aminoglycosides, quinolone and polymyxin.

[0099] 预期在本发明范围内抑菌的药物(如它们延缓细菌生长)的例子包括但不局限于红霉素、四环素、氯霉素、林可霉素、克拉霉素、阿奇霉素和磺胺类药。 [0099] contemplated within the scope of the present invention antibacterial drugs (such as they retard bacterial growth) include, but are not limited to erythromycin, tetracycline, chloramphenicol, clindamycin, clarithromycin, azithromycin and sulfa drugs. 然而,公知一些杀菌药物可以对某些微生物抑制,反之亦然。 However, a number of well-known bactericidal drugs can suppress certain microorganisms and vice versa. 这些药物为本领域公知,并可以在如《默克诊断和治疗手册》,第13版,第13部分第153章抗细菌药物,2001,全部内容在此一并作为参考。 These drugs known in the art, and can be as "Merck Manual of diagnosis and treatment," 13th Edition, Section 13, Chapter 153 of anti-bacterial drugs, 2001, the entire contents of which are incorporated herein by reference.

[0100] 在另一个优选实施方案中,本发明组合物可以与一种另外的药物剂型结合使用以它们在治疗皮肤疾病、病症或症状的效果。 [0100] In another preferred embodiment, the compositions of the present invention may be used in which the effect of the treatment of skin disease, disorder or condition in combination with an additional pharmaceutical dosage form. 在这点上,本发明组合物可以作为给药的部分方式,另外包括本领域已知的作为治疗皮肤病症有效的任意其它药物和/或药物剂型。 In this regard, the compositions of the present invention may be administered as part of the other as known in the art including the treatment of any other skin conditions effective drug and / or pharmaceutical dosage form. 因此,可以直接或间接、伴随或连续地将另外活性成分或另外的药物剂型和这里描述的优选组合物涂敷在患者上。 Preferably the composition is applied and therefore, either directly or indirectly, with or continuously additional active ingredient or additional pharmaceutical dosage form and the patient described here.

[0101] 在这点上,在一个实施方案中,本发明组合物和另外的药物剂型可以同时对患者给药。 [0101] In this regard, in one embodiment, the compositions of the present invention and the additional pharmaceutical dosage form can be administered to the patient. 在一种选择性的实施方案中,本发明组合物和另外的药物剂型中之一可以在早上给药,另一个可以在晚上给药。 In an alternative embodiment, the compositions of the present invention and the additional pharmaceutical dosage form can be administered in the morning, the other may be administered in the evening.

[0102] 在另一个优选实施方案中,另外的药物剂型可以是口服药物剂型。 [0102] In another preferred embodiment, the additional pharmaceutical dosage form can be an oral dosage form. 在这点上,本发明的局部剂型可以在患者目标区域施用可以在口服给药之前,同时或之后。 In this regard, topical dosage forms of the present invention may be administered in the patient target area, before or after oral administration.

[0103] 此外,可以使用其它附属的治疗和处理如用普通肥皂预先洗涤而后用温和的洗涤剂洗涤来配方。 [0103] In addition, other ancillary treatment and pre-treatment such as with ordinary soap to wash formula and then washed with a mild detergent. 然而,因为抗菌皂和擦洗皂可能增加刺激和滤泡性药物,当治疗皮肤病如痤疮时选择是重要的。 However, since the anti-bacterial soap and scrubbing soaps may increase irritation and follicular drugs, treatment of skin diseases such as acne when selection is important. 这样滤泡性药物可以包括局部抗菌素和消毒剂以及瘤内类固醇。 Such follicular drugs may include topical antibiotics and disinfectants and intratumoral steroid.

[0104] 在浅表的脓疱性痤疮中,可以结合一种滤泡性药物预局部过氧化苯甲酰/抗菌素/类维生素A组合物一起使用。 [0104] In the superficial pustular acne, it can be combined with a pre-follicle drug use with topical benzoyl peroxide / antibiotic / retinoid A composition.

[0105] 另一种联合治疗包括壬二酸油膏20%,其具有抗增殖和抗菌的作用,已知在痤疮或炎症痤疮中有效。 [0105] Another combination therapy include azelaic acid ointment 20%, which has antiproliferative and antibacterial effect, known acne or inflammatory acne effectively.

[0106] 当治疗浅表的脓疱性痤疮时,其它局部药物包括OTC药物,各种硫-间苯二酚组合、口服抗生素也可以在与本发明组合物结合使用时有益。 [0106] When treating superficial pustular acne, other topical drugs, including OTC drugs, the various sulfur - resorcinol combinations, oral antibiotics may be helpful when used in combination with the compositions of the present invention.

[0107] 使用的方法 Methods used [0107]

[0108] 本发明同时涉及一种在患者治疗皮肤病症或症状的方法,其通过将一种上述治疗皮肤病症有效量的局部用组合物对所需患者进行局部给药。 [0108] The present invention relates to a method of treating skin disorders in a patient or symptoms at the same time, which is obtained by treating a skin condition effective amount of said topical composition to the desired patient administered topically.

[0109] 根据本发明方法可治疗的皮肤疾病或症状包括但不局限于细菌引起的感染和组织炎症。 [0109] including, but not limited to infection and inflammation caused by bacteria according to the invention to treat skin diseases or symptoms. 细菌引起的感染可以由革兰氏阳性细菌、革兰氏阴性细菌及其结合所引起。 Bacterial infections can be caused by gram-positive bacteria, Gram-negative bacteria and combinations caused. 通过本发明组合物可治疗特定细菌的例子包括但不局限于痤疮、链球菌、pyogenes、大肠杆菌、绿脓杆菌、金黄色葡萄球菌及其结合。 Treatable by the compositions of the present invention is the specific bacterium acne include but are not limited, Streptococcus, pyogenes, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and combinations thereof.

[0110] 通过本发明组合物可治疗非限定特定皮肤病症、疾病或症状的例子包括但不局限于痤疮、脓疱病、红斑痤疮、牛皮癣、皮炎、继发性的皮肤感染、响应性皮肤病及其结合。 [0110] The compositions of the present invention to treat non-limiting specific skin disorders, examples of diseases or conditions include, but are not limited to acne, impetigo, rosacea, psoriasis, dermatitis, secondary skin infections, responsive dermatoses and combinations thereof. 其它通过本发明组合物可治疗特定皮肤病症包括皮脂溢、皮肤损害、特应性皮炎和细菌皮肤感染。 Other compositions of the present invention through the skin to treat specific disorders include seborrhea, skin lesions, atopic dermatitis and bacterial skin infections. 在一个优选实施方案中,使用本发明组合物进行治疗后改善了皮肤病症或症状。 In one preferred embodiment, the use of the compositions of the present invention to improve the treatment of skin disorders or symptoms.

[0111] 在另一个优选实施方案中,本发明进一步涉及一种治疗所需患者痤疮的方法,包含已经为所述患者冷藏过氧化苯甲酰、抗菌素和类维生素A的联合给药。 [0111] In another preferred embodiment, the present invention further relates to a method of treating a patient in need of acne, containing benzoyl peroxide has been chilled to the patient, co-administration of antibiotics and retinoids A. 根据以下提交的数据该联合给药具有一个特定的降解图。 According to the data submitted by the following co-administered with a specific degradation of FIG.

[0112] 在一个优选实施方案中,本发明组合物意图治疗儿科和成年病人。 [0112] In a preferred embodiment, the compositions of the present invention is intended to treat pediatric and adult patients. 在这点上,儿科患者一般一直到18岁。 At this point, the general pediatric patients until 18 years old. 在另一个优选实施方案中,需要治疗的成年患者的年龄在19-85岁之间。 In another preferred embodiment, the need for treatment of adult patients between the ages of 19-85 years old. 在一个特别优选实施方案中,需要治疗的成年患者的年龄在19-45岁之间。 In a particularly preferred embodiment, the need for treatment of adult patients between the ages of 19-45 years old. 在又一个优选实施方案中,需要治疗的患者的年龄在19-25岁之间。 In a further preferred embodiment, the patient in need of treatment between the ages of 19-25 years old.

[0113] 制备方法 [0113] Preparation

[0114] 本发明进一步涉及一种制备含过氧化苯甲酰悬浮液、抗菌素或其药学上可接受盐、类维生素A或其药学上盐和药学上可接受载体贮存稳定混合物的局部用组合物的方法。 [0114] The present invention further relates to a process for preparing a suspension containing benzoyl peroxide, the antibiotic or a pharmaceutically acceptable salt thereof, a retinoid or a pharmaceutically acceptable carrier A storage-stable mixture of a salt thereof and a pharmaceutically topical composition approach.

[0115] 本发明优选的方法可以在不同步骤中进行。 [0115] A preferred method of the invention can be carried out in different steps. 一个优选的步骤需要分别制备过氧化苯甲酰中间体组合物、类维生素A中间体组合物和抗菌素溶液,它们中的每一项在温度为约15至约30℃下制备。 One preferred step requires separately preparing a benzoyl peroxide intermediate composition, a retinoid intermediate composition and antibiotic A solution, which was prepared in each case from about 15 to about 30 ℃ of temperature.

[0116] 在一个优选的工序中,在与类维生素A中间体组合物和抗菌素溶液混和之前可以调整过氧化苯甲酰中间体组合物的pH,在此条件下足以生产具有最终pH为约3至约8的局部用组合物。 [0116] In a preferred process, before the retinoid intermediate composition and antibiotic A mixed solution can be adjusted with the pH of the benzoyl peroxide intermediate composition, under conditions sufficient to produce a final pH of about 3 with to the topical composition of about 8. 因此生成的组合物优选包含足够的惰性成分以提供一个治疗周期的贮存稳定性和有效性。 Therefore, the resulting composition preferably contains sufficient inert ingredients to provide storage stability and effectiveness of a treatment cycle.

[0117] 在一个选择性的实施方案中,可以包封或圈闭存在于组合物的类维生素A。 [0117] In an alternative embodiment, may be encapsulated or trap retinoids present in the composition A. 优选在固体或半固体中包封或圈闭,其具有约为哺乳动物体温的熔点。 Preferably encapsulated or trapped in a solid or semi-solid, having a melting point of about mammalian body. 在进一步选择性的实施方案中,存在于过氧化苯甲酰中间体组合物的过氧化苯甲酰或存在于抗菌素溶液的抗菌素,或这些三种或任意混合物的任意组合,在混和之前可以包封或圈闭在固体或半固体材料中。 In a further alternative embodiment, the benzoyl peroxide is present in over benzoyl peroxide intermediate composition, or any combination of these three or any mixture or antibiotic present in the antibiotic solution, may be coated before mixing seal or trapped in solid or semi-solid material. 包封或圈闭步骤可以提高局部用组合物的贮存稳定性。 Encapsulating step or traps can be improved storage stability of the topical composition.

[0118] 在一个进一步选择性的实施方案中,在与抗菌素溶液混和之前可以分别研磨过氧化苯甲酰中间体组合物和类维生素A中间体组合物。 [0118] In a further alternative embodiment, the antibiotic solution prior to mixing with the milled benzoyl peroxide can be separately intermediate composition A and retinoid intermediate composition.

[0119] 在一个优选实施方案中,根据本发明方法制备的最终组分比过氧化苯甲酰中间体组合物具有更低的粘度。 [0119] In one preferred embodiment, the final composition prepared according to the method of the present invention than benzoyl peroxide intermediate composition having a lower viscosity.

[0120] 本发明方法可以优选产生过氧化苯甲酰杂质或降解不超过约0.15重量%、抗菌素杂质或降解不超过约0.01重量%和类维生素A杂质或降解不超过约0.001重量%的组合物,此时组合物在制备或产生。 [0120] The method of the present invention may preferably be produced benzoyl peroxide impurities or degradation of no more than about 0.15% by weight, antibiotic impurities or degradation of no more than about 0.01% by weight of A and retinoid impurities or degradation of no more than about 0.001% by weight of the composition In this case the composition in the manufacture or production.

[0121] 根据这些方法产生的组合在室温(如22℃)和相对湿度或环境下可以维持稳定性至少一个月。 [0121] The combination of these methods produced at room temperature (e.g. 22 ℃) and relative humidity stability can be maintained at ambient or at least one month. 给药途径/剂量 Route of administration / dosage

[0122] 为了有效,在本发明方法和药物组合物中使用的组合物给药途径必须易于作用于目标区域。 [0122] To be effective, the composition in the methods of the present invention, the route of administration and pharmaceutical compositions for use in the target area must be easily applied. 特别地,已知在脸、颈、背部、耳朵和头皮感染痤疮。 In particular, it is known in the face, neck, back, ears and scalp infections acne.

[0123] 抗菌素、过氧化苯甲酰和类维生素A的剂量水平为本领域所熟知,选择用于最佳化上述症状的治疗。 [0123] antibiotics, benzoyl peroxide and vitamin A dose level classes known in the art, the best choice for the treatment of the above symptoms. 用于任意特定患者的具体剂量水平不同,其取决于各种因数包括使用具体化合物的活性;年龄、体重、常规健康、性别和患者的饮食;给药的时间;排泄率;药物结合;治疗特别疾病的严重性;以及给药的形式。 Different specific dose level for any particular patient, depending on a variety of factors including the activity of the specific compound used; the time of administration;; the rate of excretion; the drug combination; the age, body weight, regular health, sex and diet therapy especially in patients with as well as the form of administration; the severity of the disease. 一般地,体外剂量作用结果可以在患者给药适当剂量上提供有用的指导。 Typically, in vitro dosage effect results provide useful guidance on the proper doses administered in the patient. 动物模型研究也是有帮助的。 Animal model studies also helpful. 用于确定适当剂量水平的考虑在本领域是公知的,这里一并在本发明中考虑。 Considered for determining the appropriate dosage levels are well known in the art, and here be considered in the present invention.

[0124] 药代动力学参数比如生物利用度、吸收速率常数、分配表观容积、非结合型分数、总清除率、原型排泄分数、首过代谢、消除速度常数、半衰期和平均滞留期为本领域所熟知。 [0124] The pharmacokinetic parameters such as bioavailability, absorption rate constant, the apparent distribution volume, non-binding fraction, total clearance, fractional excretion prototype, first-pass metabolism, elimination rate constant, half-life and mean residence time of the present It is known in the art.

[0125] 通过每日一次给药减少暴露影响数倍药代动力学参数,提供初始机制以避免皮肤刺激性和炎症以及这里论述的其它毒性问题。 [0125] reducing multiple pharmacokinetic parameters Exposure administered once a day by providing the initial mechanism in order to avoid skin irritation and inflammation and the other toxicity issues discussed herein. 可以制备另外制剂的因数以抗菌素、过氧化苯甲酰和类维生素A组合物的利益/风险比值计算。 Additional factor formulations can be prepared with the interests of antibiotics, benzoyl peroxide and retinoids A composition / risk ratio calculations. 这些化合物的毒性水平已知,包装说明书作了Cleocin T和BenzaClin和它们临床试验的有害的事件报告,因此包装说明书全部特定地并入作为参考。 Toxic levels of these compounds are known, and package inserts made Cleocin T BenzaClin clinical trials and their adverse event reports, and therefore the entire package insert specifically incorporated herein by reference. 特别地,BenzaClin报道具有以下事件:使皮肤干燥(12%)、搔痒(2%)、搔痒(<1%)、脱皮(-)、红疹(<1%)和晒斑(-),或作为赋形剂粗略两倍副作用量。 In particular, BenzaClin reported to have the following events: dry skin (12%), pruritus (2%), pruritus (<1%), peeling (-), rash (<1%) and sunburn (-), or roughly twice as excipients amount of side effects.

[0126] 因为过氧化苯甲酰是一种溶角蛋白剂,即导致皮肤表面细胞的软化和膨胀,以至于皮肤的外层脱掉或可以容易除去,降低暴露于它以减少刺激。 [0126] Since benzoyl peroxide is a keratolytic agent, i.e., the surface of cells cause skin softening and swelling, so that the outer layer off the skin or can be easily removed, reducing exposure to it reduces irritation. 在外敷法上,过氧化苯甲酰转变成苯甲酸并具有抗细菌和抗真菌特性。 On the external application, benzoyl peroxide into benzoic acid and has anti-bacterial and anti-fungal properties. 另外,本发明制剂的低pH也许对皮肤附加的角质层分离作用上和在抗细菌特性上有作用。 In addition, the low pH formulation of the invention may attached on the skin keratolytic action and role in the anti-bacterial properties. 过氧化苯甲酰可同时作为制剂内的防腐剂。 Benzoyl peroxide can simultaneously within the formulation as a preservative. 这里描述的抗菌素如氯洁霉素,可以在pH更高于约6.5时降解,因此需要维持pH低于该水平。 As described herein antibiotic clindamycin, it may be higher than about 6.5 pH degradation, and therefore below the level needed to maintain pH. 本发明制剂会考虑这些和其它因数,用于制备减少灵敏度、刺激和/或炎症。 Formulations of the present invention will consider these and other factors, for the preparation of reducing sensitivity, irritation and / or inflammation.

[0127] 单一剂量盒和包装包含可以制备的本发明组合物的每天一次的量。 [0127] boxes and packaging containing a single dose once-daily amount can be prepared in compositions of the present invention. 单剂量、单元剂量和在本发明范围内预期的混合物和组合物每日一次的日常可任意使用的容器。 Single-dose, unit dose and within the scope of the present invention contemplates the mixtures and compositions once-daily routine can be any container used.

[0128] 本发明组合物可配制用于贮存在大体上非电抗的包装中以提高产品的稳定性。 [0128] The compositions of the invention may be formulated for storage in a substantially non-reactive package to improve the stability of the product. 这种贮存的新方法与先前纸基的包装相比提供了更高的产品稳定性。 This new method of storage of the previous paper-based packaging products provide greater stability compared. 关于这一点,优选非电抗的包装的非限定例子包括玻璃包装、模塑或软质塑料包装、单个剂量小瓶、铝包装、锡包装、复合纸板包装、层压包装、分层小包、泵及其组合。 About this non-limiting examples, preferred non-reactive packages include glass package, a molded or flexible plastic package, a single-dose vial, an aluminum package, a tin package, a composite cardboard package, laminated packaging, layered packet, and the pump combination. 关于这一点,有用的复合纸板包装包括蜡涂渍的纸板包装。 In this regard, useful composite paperboard packaging including wax coated paperboard packaging.

[0129] 在优选的实施方案中,惰性气体的覆盖下该组合物可以贮存在非电抗的包装中。 [0129] In a preferred embodiment, the cover under an inert gas, the composition can be stored in a non-reactive packaging. 关于这一点,有用的惰性气体的非限定例子优选包括氮气、氩气及其混合物。 Non-limiting examples of this, useful for the inert gas preferably comprises nitrogen, argon, and mixtures thereof.

[0130] 另外,这些包装系统的其中一种使用允许本发明组合物储存,因此任意两种初始含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或酯和类维生素A或其药学上可接受的盐的组合在室温下是稳定的。 [0130] In addition, the use of a packaging system which allows storage of the compositions of the present invention, and therefore any two initial benzoyl peroxide-containing composition, the antibiotic or a pharmaceutically acceptable salt or ester thereof, and vitamin A or class a pharmaceutically acceptable salt thereof in combination at room temperature is stable. 在另一个优选的实施方案中,至少两种初始含过氧化苯甲酰组合物、抗菌素或其药学上可接受的盐或酯和类维生素A或其药学上可接受的盐需要冷藏。 In another preferred embodiment, at least two of the initial benzoyl peroxide-containing composition, the antibiotic or a pharmaceutically acceptable salt or ester thereof, and retinoids A or a pharmaceutically acceptable salt thereof require refrigeration.

[0131] 每个单一包装组合物量的范围可以在约0.1mL到约20.0mL之间,优选在约0.5mL到约5.0mL之间,更优选在约1mL到约3mL之间。 [0131] The composition range of each single package, the amount may be between about 0.1mL to about 20.0mL, preferably between about 0.5mL to about 5.0mL, more preferably between about 1mL to about 3mL.

[0132] 在另一个可选择的实施方案中,本发明组合物可以使用涂药器给药。 [0132] In a further alternative embodiment, the compositions of the present invention may be administered using an applicator. 关于这一点,有用的涂药器的非限定例子包括脱脂棉、药签、垫片及其组合。 In this regard, non-limiting examples of useful applicators include cotton, swabs, pads, and combinations thereof. 关于这一点,可以从本领域普通的技术人员熟知的任意材料制备这些有用的涂药器,包括但不限于聚氨酯泡沫体、人造丝、聚乙烯、聚丙烯、棉花、聚酯及其组合。 In this regard, it can be prepared from any of those of ordinary skill in these useful materials known applicator, including, but not limited to polyurethane foam, rayon, polyethylene, polypropylene, cotton, polyester, and combinations thereof. 另外,本发明进一步打算用小于5克局部用组合物作为一种有用单位的包装来提供任何局部用组合物。 Further, the present invention is further intended to use less than 5 g topical composition as a useful unit of packaging to provide any topical compositions.

[0133] 这里同时打算配制能长期储存的组合物而不用要求在施用之前预混合或化合。 [0133] Here are also going to formulate a composition rather than long-term storage requirements prior to administration of pre-mixed or combined. 具体地,本发明组合物在存储中仍然出乎意料地稳定,周期包括在约2周和约18月,优选在约3周和约15月,更优选在约30天和约12月。 In particular, the compositions of the present invention remains surprisingly stable in storage, including the period of about two weeks and about 18 months, preferably between about 3 weeks and about 15 months, and more preferably from about 30 days at about 12 months.

[0134] 每天一次的包装同时可以改善病人特别是少年的适应性。 [0134] once a day package at the same time can improve the adaptability of patients, especially teenagers.

[0135] 在环境或室温下局部制剂的稳定性和有效性可以持续至少1至18个月。 [0135] at ambient or room temperature stability and effectiveness of topical preparations may last for at least 1-18 months. 因为通过贮存温度延缓降解,在冷藏下保持稳定性持续延长一段时间。 Because by delaying storage temperature degradation, maintaining stability under refrigeration for an extended period of time. 改善的稳定性提供了使用产品药物处理的药剂师和其它配药员在配制的时候不再需要混合。 Improved stability provides for the use of products treated with the drug pharmacists and other dispensers when no longer needed in the formulation mixed. 因为不再需要混合,在制造的时候控制均匀性,其改善了剂量给药和最终的适应性。 No longer needed because the mixing, at the time of manufacture of uniformity control, which improves the adaptability and final dose.

[0136] 方便地,最终产品不需药剂师混合。 [0136] Conveniently, the final product does not require a pharmacist mixing. 此外,使用精确数量的适应性成为可能,同时减小了杂质进入产品和污染产品的概率。 In addition, the use of precise amounts of adaptability possible, while reducing the probability of contamination of impurities into the product and the product.

[0137] 通过保持组合物在本发明具体的pH,基本上克服了过氧化苯甲酰氧化的趋势和抗菌素和类维生素A的降解,因此在室温下贮存的产品保持了稳定以延长周期。 [0137] The compositions of the present invention to maintain a specific pH, substantially overcomes the tendency of benzoyl peroxide oxidation and degradation of antibiotics and retinoids A, so the product stored at room temperature remained stable for extended periods.

[0138] 这里下述实施例是优选的实施方案说明性的,不理解为限定本发明的主题。 [0138] The following examples herein are illustrative of the preferred embodiment, the present invention is not construed as limiting the subject matter. 所有聚合物分子量意指平均摩尔重量。 All polymer molecular weight means weight average mol. 除非另有说明,最终输送系统或准备的制剂的所有百分比都基于重量百分数,全部总和等于100重量%。 Unless otherwise indicated, all percentages of the final delivery system or formulation prepared are based on weight percent, is equal to the sum of all 100 wt%.

[0139] 实施例1 [0139] Example 1

[0140] 一起混合含过氧化苯甲酰组合物、含他佐罗汀组合物和氯洁霉素溶液制备一种具有下述组分的最终组合物。 [0140] mixing together compositions containing benzoyl peroxide containing compositions 佐罗汀 he and clindamycin solution having the following components of the final composition.

[0141] [0141]

[0142] 实施例2 [0142] Example 2

[0143] 一起混合含过氧化苯甲酰组合物、含他佐罗汀组合物和氯洁霉素溶液制备一种具有下述组分的最终组合物。 [0143] mixing together compositions containing benzoyl peroxide containing compositions 佐罗汀 he and clindamycin solution having the following components of the final composition.

[0144] [0144]

[0145] 实施例3 [0145] Example 3

[0146] 化合含过氧化苯甲酰组合物、含维甲酸组合物和氯洁霉素溶液制备一种具有下述组分的最终组合物。 [0146] Compound compositions containing benzoyl peroxide, retinoic acid compositions and clindamycin solution containing a final composition having the following composition.

[0147] [0147]

[0148] [0148]

[0149] 实施例4 [0149] Example 4

[0150] 化合含过氧化苯甲酰组合物、含维甲酸组合物和氯洁霉素溶液制备一种具有下述组分的最终组合物。 [0150] Compound compositions containing benzoyl peroxide, retinoic acid compositions and clindamycin solution containing a final composition having the following composition.

[0151] [0151]

[0152] 实施例5 [0152] Example 5

[0153] 化合含过氧化苯甲酰组合物、含阿达帕林组合物和氯洁霉素溶液制备一种具有下述组分的最终组合物。 [0153] Compound compositions containing benzoyl peroxide, adapalene compositions and clindamycin solution containing a final composition having the following composition.

[0154] [0154]

[0155] 实施例6 [0155] Example 6

[0156] 表1、2和3显示了活性成分的稳定性。 [0156] Tables 1, 2 and 3 show the stability of the active ingredient. 对含5.54%过氧化苯甲酰、0.101%他佐罗汀和1.06%氯洁霉素的组合物进行的一个分析。 Containing 5.54% benzoyl peroxide, an analysis of 0.101% and 1.06% tazarotene clindamycin compositions performed. 在2周和90天末进行的测定。 Two weeks and were measured at the end of 90 days. 组合物储存在4种不同温度,即6℃、25℃、30℃和40℃下储存组合物。 The composition is stored at four different temperatures, namely 6 ℃, 25 ℃, 30 ℃ and 40 ℃ under storage composition. 在各个温度下测定过氧化苯甲酰、他佐罗汀和氯洁霉素的水平。 Determination of benzoyl peroxide at each temperature, the level of tazarotene and clindamycin are. 结果如下: The results are as follows:

[0157] 表1 [0157] Table 1

[0158] 过氧化苯甲酰(BPO)(如%重量/重量):初始5.54% [0158] Benzoyl Peroxide (BPO) (as% w / w): Initial 5.54%

[0159] [0159]

[0160] 表2 [0160] Table 2

[0161] 他佐罗汀(如%重量/重量):初始0.101% [0161] tazarotene (such as% w / w): The initial 0.101%

[0162] [0162]

[0163] 表3 [0163] Table 3

[0164] 氯洁霉素(如%重量/重量):初始1.06% [0164] Clindamycin (such as% w / w): Initial 1.06%

[0165] [0165]

[0166] 实施例7 [0166] Example 7

[0167] 表4、5和6显示了在含5.22%过氧化苯甲酰、0.103%他佐罗汀和1.06%氯洁霉素的组合物中活性成分的稳定性。 [0167] Tables 4, 5 and 6 show the benzoyl peroxide, stability 0.103% and 1.06% tazarotene clindamycin compositions containing the active ingredient 5.22%.

[0168] 按照实施例4的程序对组合物进行2周和6个月的分析。 [0168] The procedure of Example 4 was analyzed for composition of two weeks and six months.

[0169] 表4 [0169] Table 4

[0170] 氯洁霉素(如%重量/重量):初始1.06% [0170] Clindamycin (such as% w / w): Initial 1.06%

[0171] [0171]

[0172] 表5 [0172] Table 5

[0173] 过氧化苯甲酰(BPO)(如%重量/重量):初始5.22% [0173] benzoyl peroxide (BPO) (as% w / w): Initial 5.22%

[0174] [0174]

[0175] 表6 [0175] Table 6

[0176] 他佐罗汀(如%重量/重量):初始0.103% [0176] tazarotene (such as% w / w): The initial 0.103%

[0177] [0177]

[0178] 实施例8 [0178] Example 8

[0179] 表16、17和18显示了在含2.15%过氧化苯甲酰、0.103%他佐罗汀和1.07%氯洁霉素的组合物中活性成分的稳定性。 [0179] Table 16, 17 and 18 show containing 2.15% benzoyl peroxide, stability 0.103% and 1.07% tazarotene clindamycin composition of the active ingredient.

[0180] 按照实施例4的程序对组合物进行6个月的分析。 [0180] The procedure of Example 4 was subjected to composition analysis six months.

[0181] 表16 [0181] Table 16

[0182] 氯洁霉素(如%重量/重量):初始1.07% [0182] Clindamycin (such as% w / w): Initial 1.07%

[0183] [0183]

[0184] 表17 [0184] Table 17

[0185] 过氧化苯甲酰(BPO)(如%重量/重量):初始2.15% [0185] benzoyl peroxide (BPO) (as% w / w): Initial 2.15%

[0186] [0186]

[0187] 表18 [0187] Table 18

[0188] 他佐罗汀(如%重量/重量):初始0.103% [0188] tazarotene (such as% w / w): The initial 0.103%

[0189] [0189]

[0190] 实施例9 [0190] Example 9

[0191] 表19、20和21显示了在含2.02%过氧化苯甲酰、0.106%他佐罗汀和1.06%氯洁霉素的组合物中活性成分的稳定性。 [0191] Table 19, 20 and 21 show the benzoyl peroxide, stability 0.106% and 1.06% tazarotene clindamycin compositions containing the active ingredient 2.02%.

[0192] 按照实施例4的程序对组合物进行90天和6个月的分析。 [0192] The procedure of Example 4 was subjected to composition analysis of 90 days and 6 months.

[0193] 表19 [0193] Table 19

[0194] 氯洁霉素(如%重量/重量):初始1.06% [0194] Clindamycin (such as% w / w): Initial 1.06%

[0195] [0195]

[0196] 表20 [0196] Table 20

[0197] 过氧化苯甲酰(BPO)(如%重量/重量):初始2.02% [0197] Benzoyl Peroxide (BPO) (as% w / w): Initial 2.02%

[0198] [0198]

[0199] 表21 [0199] Table 21

[0200] 他佐罗汀(如%重量/重量):初始0.106% [0200] tazarotene (such as% w / w): The initial 0.106%

[0201] [0201]

[0202] 实施例10 [0202] Example 10

[0203] 表19、20和21显示了在含1.54%过氧化苯甲酰、0.105%他佐罗汀和1.04%氯洁霉素的组合物中活性成分的稳定性。 [0203] Table 19, 20 and 21 show the benzoyl peroxide, stability 0.105% and 1.04% tazarotene clindamycin compositions containing the active ingredient 1.54%.

[0204] 按照实施例4的程序对组合物进行90天和6个月的分析。 [0204] The procedure of Example 4 was subjected to composition analysis of 90 days and 6 months.

[0205] 表22 [0205] Table 22

[0206] 氯洁霉素(如%重量/重量):初始1.04% [0206] Clindamycin (such as% w / w): Initial 1.04%

[0207] [0207]

[0208] 表23 [0208] Table 23

[0209] 过氧化苯甲酰(BPO)(如%重量/重量):初始1.54% [0209] Benzoyl Peroxide (BPO) (as% w / w): Initial 1.54%

[0210] [0210]

[0211] 表24 [0211] Table 24

[0212] 他佐罗汀(如%重量/重量):初始0.105% [0212] tazarotene (such as% w / w): The initial 0.105%

[0213] [0213]

[0214] 实施例11 [0214] Example 11

[0215] 表7、8和9显示了在含1.01%过氧化苯甲酰、0.104%他佐罗汀和1.1%氯洁霉素的组合物中活性成分的稳定性。 [0215] Table 7, 8 and 9 show containing 1.01% benzoyl peroxide, stability 0.104% and 1.1% tazarotene clindamycin composition of the active ingredient.

[0216] 按照实施例4的程序对组合物进行2周、30天、90天和6个月的分析。 [0216] The procedure of Example 4 was subjected to two weeks of the combination, 30 days, 90 days and 6 months of analysis.

[0217] 表7 [0217] Table 7

[0218] 氯洁霉素(如%重量/重量):初始1.10% [0218] Clindamycin (such as% w / w): Initial 1.10%

[0219] [0219]

[0220] 表8 [0220] Table 8

[0221] 过氧化苯甲酰(BPO)(如%重量/重量):初始1.01% [0221] Benzoyl Peroxide (BPO) (as% w / w): Initial 1.01%

[0222] [0222]

[0223] [0223]

[0224] 表9 [0224] Table 9

[0225] 他佐罗汀(如%重量/重量):初始0.104% [0225] tazarotene (such as% w / w): The initial 0.104%

[0226] [0226]

[0227] 实施例12 [0227] Example 12

[0228] 表10、11和12显示了在含1.02%过氧化苯甲酰、0.099%他佐罗汀和1.05%氯洁霉素的组合物中活性成分的稳定性。 [0228] Table 10, 11 and 12 show the benzoyl peroxide, stability 0.099% and 1.05% tazarotene clindamycin compositions containing the active ingredient 1.02%.

[0229] 按照实施例4的程序对组合物进行2周、90天和6个月的分析。 [0229] The procedure of Example 4 was subjected to two weeks of the combination, 90 days and 6 months of analysis.

[0230] 表10 [0230] Table 10

[0231] 氯洁霉素(如%重量/重量):初始1.05% [0231] Clindamycin (such as% w / w): Initial 1.05%

[0232] [0232]

[0233] 表11 [0233] Table 11

[0234] 过氧化苯甲酰(BPO)(如%重量/重量):初始1.02% [0234] Benzoyl Peroxide (BPO) (as% w / w): Initial 1.02%

[0235] [0235]

[0236] 表12 [0236] Table 12

[0237] 他佐罗汀(如%重量/重量):初始0.099% [0237] tazarotene (such as% w / w): The initial 0.099%

[0238] [0238]

[0239] 实施例13 [0239] Example 13

[0240] 表13、14和15显示了在含1.04%过氧化苯甲酰、0.098%他佐罗汀和1.06%氯洁霉素的组合物中活性成分的稳定性。 [0240] Tables 13, 14 and 15 show the benzoyl peroxide, stability 0.098% and 1.06% tazarotene clindamycin compositions containing the active ingredient 1.04%.

[0241] 按照实施例4的程序对组合物进行行2周、90天和6个月的分析。 [0241] The procedure of Example 4 was subjected to a combination of row two weeks, 90 days and 6 months of analysis.

[0242] 表13 [0242] Table 13

[0243] 氯洁霉素(如%重量/重量):初始1.06% [0243] Clindamycin (such as% w / w): Initial 1.06%

[0244] [0244]

[0245] 表14 [0245] Table 14

[0246] 过氧化苯甲酰(BPO)(如%重量/重量):初始1.04% [0246] Benzoyl Peroxide (BPO) (as% w / w): Initial 1.04%

[0247] [0247]

[0248] 表15 [0248] Table 15

[0249] 他佐罗汀(如%重量/重量):初始0.098% [0249] tazarotene (such as% w / w): The initial 0.098%

[0250] [0250]

[0251] 实施例14 [0251] Example 14

[0252] 表25和26显示了在含0.209%他佐罗汀和2.13%氯洁霉素的组合物中活性成分的稳定性。 [0252] Table 25 and 26 show the stability of the composition containing 0.209% and 2.13% tazarotene Clindamycin of the active ingredient.

[0253] 按照实施例4的程序对组合物进行4周、90天和6个月的分析。 [0253] The procedure of Example 4 composition 4 weeks, 90 days and 6 months of analysis.

[0254] 表25 [0254] Table 25

[0255] 氯洁霉素(如%重量/重量):初始2.13% [0255] Clindamycin (such as% w / w): Initial 2.13%

[0256] [0256]

[0257] 表26 [0257] Table 26

[0258] 他佐罗汀(如%重量/重量):初始0.209% [0258] tazarotene (such as% w / w): The initial 0.209%

[0259] [0259]

[0260] 实施例15 [0260] Example 15

[0261] 表27和28显示了在含0.109%他佐罗汀和1.07%氯洁霉素的组合物中活性成分的稳定性。 [0261] Tables 27 and 28 show the stability containing 0.109% and 1.07% tazarotene clindamycin composition of the active ingredient.

[0262] 按照实施例4的程序对组合物进行60天和90天的分析。 [0262] The procedure of Example 4 of compositions for 60 days and 90 days of analysis.

[0263] 表27 [0263] Table 27

[0264] 氯洁霉素(如%重量/重量):初始1.07% [0264] Clindamycin (such as% w / w): Initial 1.07%

[0265] [0265]

[0266] 表28 [0266] Table 28

[0267] 他佐罗汀(如%重量/重量):初始0.109% [0267] tazarotene (such as% w / w): The initial 0.109%

[0268] [0268]

[0269] 实施例16 [0269] Example 16

[0270] 表29和30显示了在含0.105%他佐罗汀和1.07%氯洁霉素的组合物中活性成分的稳定性。 [0270] Tables 29 and 30 show the stability containing 0.105% and 1.07% tazarotene clindamycin composition of the active ingredient.

[0271] 按照实施例4的程序对组合物进行6个月的分析。 [0271] The procedure of Example 4 was subjected to composition analysis six months.

[0272] 表29 [0272] Table 29

[0273] 氯洁霉素(如%重量/重量):初始1.07% [0273] Clindamycin (such as% w / w): Initial 1.07%

[0274] [0274]

[0275] 表30 [0275] Table 30

[0276] 他佐罗汀(如%重量/重量):初始0.105% [0276] tazarotene (such as% w / w): The initial 0.105%

[0277] [0277]

[0278] 实施例17 [0278] Example 17

[0279] 表31和32显示了在含2.02%过氧化苯甲酰和0.099%他佐罗汀的组合物中活性成分的稳定性。 [0279] Table 31 and 32 shows the stability of benzoyl peroxide containing 2.02% and 0.099% tazarotene composition of the active ingredient.

[0280] 按照实施例4的程序对组合物进行90天和6个月的分析。 [0280] The procedure of Example 4 was subjected to composition analysis of 90 days and 6 months.

[0281] 表31 [0281] Table 31

[0282] 过氧化苯甲酰(如%重量/重量):初始2.02% [0282] Benzoyl Peroxide (e.g.% w / w): Initial 2.02%

[0283] [0283]

[0284] 表30 [0284] Table 30

[0285] 他佐罗汀(如%重量/重量):初始0.099% [0285] tazarotene (such as% w / w): The initial 0.099%

[0286] [0286]

[0287] [0287]

[0288] 实施例18 [0288] Example 18

[0289] 表33和34显示了在含5.18%过氧化苯甲酰和0.099%他佐罗汀的组合物中活性成分的稳定性。 [0289] Table 33 and 34 show the stability of benzoyl peroxide containing 5.18% and 0.099% tazarotene composition of the active ingredient.

[0290] 按照实施例4的程序对组合物进行90天和6个月的分析。 [0290] The procedure of Example 4 was subjected to composition analysis of 90 days and 6 months.

[0291] 表33 [0291] Table 33

[0292] 过氧化苯甲酰(如%重量/重量):初始5.18% [0292] Benzoyl Peroxide (e.g.% w / w): Initial 5.18%

[0293] [0293]

[0294] 表34 [0294] Table 34

[0295] 他佐罗汀(如%重量/重量):初始0.099% [0295] tazarotene (such as% w / w): The initial 0.099%

[0296] [0296]

[0297] 实施例19 [0297] Example 19

[0298] 患有痤疮的病人。 [0298] patients with acne. 将这里优选的组合物对病人给药。 The preferred composition herein is administered to the patient. 可以预期病人将改善他/她的症状或痊愈。 Patients can be expected to improve his / her symptoms or cure.

[0299] 因此,描述的本发明主题明显相同的地方可能在多个方面存在差异。 [0299] Accordingly, the present invention relating to the same place as described may obviously differ in many aspects. 这些差异不认为偏离本发明的精神和范围,所有这些改变将包括在下述权利要求的范围内。 These differences were not considered departing from the spirit and scope of the invention, and all such changes be included within the scope of the following claims.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
CN102740846A *24 Mar 201117 Oct 2012索尔-格尔科技有限公司Compositions for topical administration
Classifications
International ClassificationA61K31/00
Cooperative ClassificationA61K31/192, A61K8/38, A61K8/671, A61Q17/005, A61Q19/00, A61K45/06, A61K9/0014, A61K31/203, A61K31/36
European ClassificationA61K31/192, A61K31/203, A61K31/36, A61K45/06, A61Q19/00, A61K9/00M3, A61Q17/00F, A61K8/38, A61K8/67C
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