CN102475681A - Separation-type water suspension medicament for treating dermatopathy - Google Patents

Separation-type water suspension medicament for treating dermatopathy Download PDF

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CN102475681A
CN102475681A CN 201010556781 CN201010556781A CN102475681A CN 102475681 A CN102475681 A CN 102475681A CN 201010556781 CN201010556781 CN 201010556781 CN 201010556781 A CN201010556781 A CN 201010556781A CN 102475681 A CN102475681 A CN 102475681A
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skin
water
example
pharmaceutical composition
composition according
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孙亮
赵琳
陈松
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天津金耀集团有限公司
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Abstract

A separation-type water suspension medicament for treating dermatopathy comprises an individually-packaged water-insoluble skin medicament with a D90 particle size of 0.1-10 microns, and individually-packaged water containing one or more than one skin pharmaceutic adjuvants; the individually-packaged water-insoluble skin medicament has a D90 particle size of 1-10 microns preferably; and the particle form is spherical or spheroidic.

Description

治疗皮肤病的分离式水混悬剂药物 Separate aqueous suspensions of drug treatment of skin diseases

技术领域: FIELD:

[0001] 本发明涉及一种皮肤用药物,由作为单独包装的不溶于水的粒径为0. 1-10μπι的皮肤用药物、单独包装的含有一种或几种皮肤药用辅料的水共同组成。 [0001] The present invention relates to a pharmaceutical skin, as the water-insoluble particle is individually packaged pharmaceutical 0. 1-10μπι skin, individually packaged skin comprising one or more pharmaceutically acceptable excipients common water composition.

背景技术: Background technique:

[0002] 皮肤炎症如湿疹(eczema)、变应性皮炎(allergic dermatitis)、特应性皮炎(atopic dermatitis)荨麻疹Urticaria)等都是由某种变应原引起变态反应而造成皮肤炎症。 [0002] inflammatory skin conditions such as eczema (eczema), allergic dermatitis (allergic dermatitis), atopic dermatitis (atopic dermatitis) Urticaria urticaria) and the like are made to an allergen causing allergic reactions caused by inflammation of the skin.

[0003] 皮肤给药系统中,皮肤是药物进入体内的主要屏障,研究发现只有极少数药物具有优良的皮肤透过性,多数药物不易穿过人体皮肤这一有效的,选择性的屏障,相对而言脂溶性较高的药物更容易穿过表皮。 [0003] The transdermal administration system, the skin is the major barrier to the drug into the body, the study found that only a very few drugs having an excellent skin permeability, most drugs do not readily cross the skin an effective, selective barrier, the relative For high lipophilic drug more easily through the epidermis. 治疗皮肤病,最常见的制剂类型是透皮吸收给药,透皮给药系统或经皮吸收制齐Ll (transdermal thrapeutic systems, transdermal drug delivery systems,简称TTS,TDDS):是指在皮肤表面给药,使药物以恒定速率(或接近恒定速率)通过皮肤,进入体循环产生全身或局部治疗作用的新剂型。 Treatment of skin diseases, the most common types of transdermal absorption preparations, transdermal system or transdermal absorption system Qi Ll (transdermal thrapeutic systems, transdermal drug delivery systems, referred to as TTS, TDDS): refers to the skin surface drug, the drug at a constant rate (or nearly constant rate) through the skin into the systemic circulation for systemic or local therapeutic effect of new formulations. 其优点体现在:药物吸收不受消化道内PH、食物、转运时间等因素影响;避免肝脏首过效应;克服因吸收过快产生血药浓度过高而引起的不良反应;可持续控制给药速度,灵活给药等,常见的透皮给药系统包括巴布齐U、软膏剂、搽剂、凝胶剂等。 The advantage is reflected in: drug absorption in the digestive tract is not affected by PH, food, transit time and other factors; avoid hepatic first-pass effect; overcome the adverse effects due to absorption by excessive high blood concentration caused; sustainable controlled rate of administration flexible administration, etc., common transdermal drug delivery system comprising a homogeneous Babu U, ointments, liniments, gels and the like.

[0004] 但是由于上述制剂需要添加大量的辅料,这些辅料同时会对皮肤产生各种不良反应,例如某些患者会对辅料产生过敏症状,尤其是2岁以下的婴幼儿皮肤较成人更加薄,膏齐U、凝胶剂中的长链脂、酒精等辅料对皮肤存在刺激作用,所以针对部分易过敏人群及2岁以下的婴幼儿,应该尽量减少药物辅料的使用,水混悬剂就具有类似的效果。 [0004] However, the above formulations require a large amount of materials, these materials while generating a variety of adverse reactions on the skin, materials such as certain patient will have symptoms, especially infants under 2 years of age than in adults more thinner skin, homogeneous paste U, gels long chain aliphatic alcohol and the like materials present a stimulating effect on the skin, it is easy for some people with allergies and infants below two years, should minimize the use of pharmaceutical excipients, to aqueous suspensions having a similar effect. 但是作为治疗皮肤的制剂,水混悬剂的药效作用较弱,关键在于水混悬剂没有脂溶性辅料如羊毛脂等,所以该种制剂通过皮肤的能力较差,所以该种水混悬剂剂型在实际上并不通过透皮吸收治疗皮肤病。 However, as the skin treatment formulations, aqueous suspensions pharmacodynamics weak, aqueous suspensions is not critical that the fat-soluble materials such as lanolin and the like, so that the poor capacity of the formulations through the skin, so that this kind of water suspension in fact dosage form is not absorbed by the transdermal treatment of skin diseases.

[0005] 同时,水混悬剂通过透皮吸收还存在一种制剂的困难,如果混悬粒子较大,则无法通过表皮组织,如果混悬粒子过小如纳米级,但是与大粒子相比,小粒子比表面积大, 具有较高的表面能,因此该系统为尽量降低其表面能而使小粒子表面的分子脱离小粒子,通过溶液扩散吸附到大粒子表面。 [0005] Meanwhile, the percutaneous absorption of aqueous suspensions by a formulation difficulties still exist, and if larger suspended particles, can not pass through the epidermal tissue, suspended if the particles are too small nanoscale, but compared with large particles , large specific surface area small particles, having a high surface energy, so that the system is to minimize its surface energy of the small particles from the surface of the molecule small particles, large particles adsorbed to the surface by solution diffusion. 最终,小粒子逐渐变小而大粒子逐渐长大,即奥斯特瓦尔德熟化现象。 Eventually, the small particles gradually become smaller and large particles gradually grown or Ostwald ripening phenomenon. 奥斯特瓦尔德熟化的速度主要由分子扩散和表面作用决定。 Ostwald ripening is mainly determined by the rate of molecular diffusion and surface effect. 混悬微粒由于其粒径分布不均勻,因此奥斯特瓦尔德熟化现象尤其明显((Welin-Berger K, Bergenstahl B.Inhibition of Ostwald ripening in local anesthetic emulsions by using hydrophobic excipients in the disperse phase[J]. Int J Pharm,2000,200(2): 249-260.)。 Because of its fine suspension particle size distribution is uneven, so Ostwald ripening phenomenon is particularly evident ((Welin-Berger K, Bergenstahl B.Inhibition of Ostwald ripening in local anesthetic emulsions by using hydrophobic excipients in the disperse phase [J] . Int J Pharm, 2000,200 (2): 249-260)..

[0006] 微粒混悬剂属热动力学不稳定体系,粒子有聚集的趋势,以最小化其表面自由能。 [0006] The metal fine particle suspensions thermodynamically unstable system, the particles tend to move together to minimize surface free energy. 由于微粒的比表面积大,因此粒子相互接触碰撞的机会增加,同时粒子间存在较强的相互吸引力,分子间作用力强,粒子很容易发生不可逆聚集以降低其表面能(Wong J,Brugger A,Khare A,et al. Suspensions for intravenous (IV) injection :a review of development,preclinical and clinical aspects[J]. Adv Drug Deliv Rev,2008,60(8): 939-954 ;Kesisoglou F,Panmai S,Wu Y. Nanosizing—oral formulation development and biopharmaceutical evaluation[J]. Adv Drug Deliv Rev,2007,59(7) :631-644.)。 Due to the large particles have a specific surface area, the particles collide with each other to increase the chance of contact, while there is a strong mutual attraction between the particles, and strong intermolecular interaction, the particles are prone to irreversible aggregation to reduce its surface energy (Wong J, Brugger A , Khare A, et al Suspensions for intravenous (IV) injection: a review of development, preclinical and clinical aspects [J] Adv Drug Deliv Rev, 2008,60 (8):.. 939-954; Kesisoglou F, Panmai S, wu Y. Nanosizing-oral formulation development and biopharmaceutical evaluation [J] Adv Drug Deliv Rev, 2007,59 (7):.. 631-644).

[0007] 如何解决微粒混悬剂中粒子不稳定的问题,一直是制剂学中需要解决的问题之一,但是无论通过添加辅料,还是改善粒子结构,都无法保证微粒混悬剂长期保存,尤其是皮肤类混悬剂属于多次使用,更有可能出现上述问题。 [0007] how to solve the problem of particulate suspensions of particles in the unstable, it has been one of pharmaceutics need to solve the problem, but whether by adding accessories, or improve the particle structure, particle suspension can not guarantee long-term preservation, especially skin class suspensions belong to multiple use, the above problem is more likely to occur.

发明内容: SUMMARY:

[0008] 通过试验,我们惊奇的发现,将由作为单独包装的难溶于水的粒径为0. I-IOym 皮肤用药物、单独包装的含有一种或几种皮肤药用辅料的水共同组成,两者在使用时通过简单震荡可以形成皮肤用水混悬剂。 [0008] By testing we have surprisingly found that, as a sparingly soluble in water by a particle size individually packaged as 0. I-IOym dermopharmaceutical, composed individually packaged skin comprising one or more pharmaceutically acceptable excipients Water , both of which use the skin may be formed by simple shaking water suspensions. 这种全新的透皮吸收治疗皮肤疾病的剂型,既可以在使用时保证水混悬剂可以以微粒形式透过皮肤治疗皮肤病,又可以储存较长时间,避免出现奥斯特瓦尔德熟化现象致使颗粒变大,从而影响药物的疗效。 This new transdermal therapeutic systems for treating skin diseases, both to ensure that water suspension in particulate form may treat skin diseases through the skin, and can be stored for a long time, avoid Ostwald ripening phenomenon occurs when you use resulting in larger particles, thus affecting the efficacy of the drug.

[0009] 技术的关键在于单独包装的难溶于水的D90粒径为0. 1-10 μ m皮肤用药物经过一定时间的储存,并不出现结块、颗粒聚集、分散能力下降等问题,仍然能经过简单震荡与单独包装的含有一种或几种皮肤药用辅料的水形成均勻混悬状态而易被皮肤吸收。 Key [0009] The art is individually packaged sparingly water-soluble particle diameter D90 skin elapsed 0. 1-10 μ m certain storage time, agglomeration does not occur with drugs, particle aggregation, decrease dispersing ability and so on, still form a homogeneous aqueous suspended state through the skin comprising one or more pharmaceutically acceptable excipients and individually packaged simply and shock absorption through the skin.

[0010] 本发明所指的粒径是D90粒径,即一个样品的累计粒度分布数达到90%时所对应的粒径。 The invention is referred to a particle size [0010] D90 particle size is present, i.e., a cumulative number particle size distribution of the sample reaches 90% of the corresponding particle diameter. 它的物理意义是粒径小于它的的颗粒占90%。 It is the physical meaning of a particle size of less than its 90%.

[0011] 本发明提供一种透皮吸收治疗皮肤病的药物组合物,由作为单独包装的难溶于水的D90粒径为0. 1-10 μ m皮肤用药物、单独包装的含有一种或几种皮肤药用辅料的水共同组成。 [0011] The present invention provides a percutaneous absorption pharmaceutical composition for the treatment of dermatoses, the individually packaged as a water-insoluble particle diameter D90 0. 1-10 μ m dermopharmaceutical, containing one individually packaged several pharmaceutical excipients or skin composed of water. 所述的单独包装的难溶于水皮肤用药物的D90粒径优选为1-10 μ m,微粒形态是球形或类球形。 The individually packaged skin poorly water-soluble drug particle size D90 is preferably 1-10 μ m, fine particles are spherical or spheroidal morphology. 所述的药物组合物,还可以增加一种混合药物与水的器具。 The pharmaceutical compositions may also be added a mixture of water with a pharmaceutical appliance.

[0012] 所述的药物组合物,其特征是难溶于水的皮肤用药物为糖皮质激素。 [0012] The pharmaceutical composition, characterized in that a water-insoluble dermopharmaceutical glucocorticoid. 所述糖皮质激素可选自可的松、氟米龙、地塞米松、倍他米松、泼尼松龙、泼尼松、氢化可的松、瑞美松龙(Rimexolone)、氯替泼诺、布地奈德、环索奈德、阿氯米松、倍氯米松、倍他米松、氯泼尼松、氯倍他索、氯倍他松、氯可托龙、氯波尼醇、地夫可特、地奈德、去羟米松、二氟拉松、二氟可龙、二氟泼尼酯、氟氯奈德、氟米松、氟尼缩松、氟轻松、氟可龙、氟培龙、氟泼尼定、氟泼尼松龙、氟氢缩松、哈西奈德、卤倍他索、卤米松、卤泼尼松、氢可他酯、甲羟松、甲泼尼松、甲泼尼松龙、莫米松、帕拉米松、泼尼卡酯、波尼立定、曲安西龙、曲安奈德、安西奈德、氟替卡松、 地奈德、马泼尼酮、替可的松中的一种化合物或其可药用的酯。 Selected from the glucocorticoid hydrocortisone, fluorometholone, dexamethasone, betamethasone, prednisolone, prednisone, hydrocortisone, Ruimei Song Long (Rimexolone), loteprednol , budesonide, ciclesonide, alclometasone, beclomethasone, betamethasone, prednisone, clobetasol, clobetasone, clocortolone, chloro Boni alcohol, may Cardiff Patent, desonide, desoximetasone, diflorasone, di fluocortolone, two difluprednate, fluclorolone acetonide, flumethasone, flunisolide, fluocinolone, fluocortolone, fluperolone, fluprednidene, fluoro-prednisolone, flurandrenolide, halcinonide, halobetasol, halometasone, halopredone, he hydrogen carbonate, medrysone, methylprednisolone, prednisone A prednisolone, mometasone, Parra paramethasone, prednicarbate, Boni standing, triamcinolone, triamcinolone acetonide, amcinonide, fluticasone, budesonide, prednisone one horse, one compound of tixocortol or a pharmaceutically acceptable ester. 优选自低效糖皮质激素泼尼松龙、泼尼松、氢化可的松、甲泼尼龙或其可药用的盐或酯。 Preferably from inefficient glucocorticoid prednisolone, prednisone, hydrocortisone, methylprednisolone, or a pharmaceutically acceptable salt or ester thereof. 所述糖皮质激素的用量为0.01% 〜1%。 The glucocorticoid used in an amount of 0.01% ~ 1%. 优选0.1% 〜1%。 Preferably from 0.1% ~ 1%.

[0013] 所述单独包装的含有一种或几种皮肤药用辅料的水中的辅料包括pH调节剂、渗透压调节剂、粘度调节剂、促渗剂、表面活性剂或稳定剂中的一种或几种。 [0013] The water containing one or more pharmaceutically acceptable excipients skin excipients include one individually packaged pH adjusting agents, tonicity adjusting agents, viscosity adjusting agents, penetration agents, surfactants or stabilizers or more. 所述辅料中的PH 调节剂为磷酸及其盐、硼酸及其盐、枸橼酸及其盐、醋酸及其盐、酒石酸及其盐、盐酸、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氨基丁三醇中的一种或几种。 The materials in the PH adjusting agent is phosphoric acid and salts thereof, boric acid and salts thereof, citric acid and its salts, acetic acid and salts thereof, tartaric acid and its salts, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, one or more of potassium, sodium bicarbonate, potassium bicarbonate, tromethamine in. 优选醋酸、盐酸、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾中的一种或几种。 Preferably acetic acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, one or several.

[0014] 所述辅料中的渗透压调节剂为甘油、丙二醇、氯化钠、氯化钾、山梨糖醇、甘露醇中的一种或几种。 [0014] The materials of the tonicity modifier is glycerol, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, one or several. 优选采用0. 4% -0. 9%的氯化钠。 Preferably using 0.4% -0. 9% sodium chloride.

[0015] 所述辅料中的粘度调节剂为羧甲基纤维素钠、羟乙基纤维素、羟丙基甲基纤维素、 羟丙基纤维素、聚乙烯基醇、羧乙烯聚合物、聚乙烯基吡咯烷酮中的一种或几种,用量为0. 〜2%。 [0015] The viscosity modifier materials of sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxyvinyl polymers, polyethylene vinylpyrrolidone one or more, in an amount of 0.5 ~ 2%.

[0016] 所述辅料中的表面活性剂可选非离子表面活性剂。 The [0016] materials in the surfactant optionally non-ionic surfactant. 为吐温-80,聚氧乙烯氢化蓖麻油60,聚乙二醇-硬脂酸酯,聚乙二醇4000,卵磷脂,蔗糖酯,聚氧乙烯烷基醚,聚氧乙烯-聚氧丙烯二醇及其类似物、泊洛沙姆、泰洛沙泊中的一种或几种,用量优选为0. 〜 Tween 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol - monostearate, polyethylene glycol 4000, lecithin, sucrose esters, polyoxyethylene alkyl ethers, polyoxyethylene - polyoxypropylene glycols and the like, poloxamers, tyloxapol of one or more, preferably 0. to an amount

2 % ο 2% ο

[0017] 所述辅料中的稳定剂为乙二胺四乙酸二钠。 [0017] The excipients stabilizer is disodium edetate. 优选的稳定剂为0. 〜0.01%的乙 Preferred stabilizers 0. ~0.01% acetic

二胺四乙酸二钠。 Diamine disodium.

[0018] 所述辅料中的促渗剂为氮酮、亚砜及其类似物、乙醇、脂肪醇、吡咯酮类、脂肪酸类、薄荷醇、精油、冰片中的一种或几种,选自氮酮、月桂氮卓酮、二氯亚砜、癸基甲基亚砜、 丙二醇、N-甲基-2-吡咯酮、2-吡咯酮、月桂酸、油酸、亚油酸、亚麻酸、薄荷醇、杜香萜烯、桉叶油中的一种或几种。 [0018] The materials of the permeation enhancer is azone, sulfoxides and the like, ethanol, fatty alcohols, pyrrole ketones, fatty acids, menthol, oil, borneol in one or more selected from azone, azone, thionyl chloride, decyl methyl sulfoxide, propylene glycol, N- methyl-2-pyrrolidone, 2-pyrrolidone, lauric acid, oleic acid, linoleic acid, linolenic acid, menthol, terpene Ledum, one or more of eucalyptus oil.

[0019] 所述皮肤药物组合物,其特征在于所述的单独包装的含有一种或几种皮肤药用辅料的水的PH选自5-7。 [0019] The pharmaceutical composition of the skin, characterized in that the water contains one or more pharmaceutically acceptable excipients skin of the PH 5-7 selected individually packaged.

[0020] 所述的药物组合物,其特征在于所述单独包装的难溶于水的D90粒径为0. 1-10 μ m皮肤用药物的微粉化方法可以采用喷雾干燥法,流化床超音速气流粉碎法,高速研磨法、球磨法、流能磨法、溶剂法、CO2超临界法制备。 [0020] The pharmaceutical composition, characterized in that said individually packaged sparingly water-soluble particle diameter D90 skin 0. 1-10 μ m may be micronized pharmaceutical spray drying, fluidized-bed supersonic jet milling method, a high speed grinding, ball milling, fluid energy milling method, the solvent method, supercritical CO2 preparation method. 所述微粉化方法采用喷雾干燥法、 CO2超临界辅助雾化法制备。 The micronization process of spray drying, supercritical assisted atomization Preparation Method CO2.

[0021] 所述的药物组合物,其特征在于所述皮肤用药物可以采用单次或多次剂量的形式包装,所述单次或多次剂量的形式包装为密封防水包装。 [0021] The pharmaceutical composition, characterized in that the skin can be employed with the drug or multiple doses of a single package form, a single or multiple dose form is a sealed package waterproof packing. 所述多次剂量的形式包装为铝箔泡罩。 The multiple dose form is a foil blister package.

[0022] 所述的药物组合物,在制备治疗人或动物皮肤炎症药物中的应用。 [0022] The pharmaceutical composition for use in the preparation of the treatment of human or animal skin inflammatory drugs.

[0023] 所述的药物组合物,在制备治疗人或动物皮肤湿疹、日光疹药物中的应用。 [0023] The pharmaceutical compositions, prepared in the treatment of human or animal skin eczema, sunburn, rash use in medicine.

[0024] 所述的药物组合物,在制备治疗2岁以下中婴幼儿皮肤炎症药物中的应用。 [0024] The pharmaceutical compositions, in the preparation of applications infants under 2 years of skin inflammation in a pharmaceutical treatment.

[0025] 所述的药物组合物,在制备治疗2岁以下中婴幼儿的尿布疹、脂溢性皮炎、异位性皮炎应用。 [0025] The pharmaceutical compositions, prepared in the treatment of diaper rash in infants under 2 years, seborrheic dermatitis, atopic dermatitis use.

[0026] 本发明提供的药物组合物,由单独包装的药物微粒和含有药物辅料的水构成,两者在使用时通过简单震荡可以形成皮肤用水混悬剂并可以保持一定时间的稳定性。 [0026] The present invention provides a pharmaceutical composition, composed of a separately packaged drug particles and pharmaceutical excipients containing water, both in the use of the skin may be formed simply by shaking a suspension of water and can maintain the stability of a certain time. 同时由于药物与水分开包装,当病症程度不同时,可以调整加入到含有药物辅料的水中药物剂量, 使单一药物可以在实际使用中拥有多种剂量,便于患者使用,同时本发明提供的药物,在与混悬用水混合后也能在一定时间内保持药物的粒径从而保证混悬稳定性,因此也减少了药物的浪费,符合低碳减排的要求。 Water and because drugs are packaged separately and, when the degree of disorder is not the same, may be added to adjust the dose of water containing pharmaceutical auxiliaries, so that a single dose of the drug can have a variety of practical use, ease of patient use, while the present invention provides a medicament, after mixing with water and suspended particle diameter of the drug can be maintained for a certain time in order to ensure stability of the suspension, therefore reducing the waste of the drug, to meet the requirements of carbon emissions.

具体实施方式 detailed description

[0027] 下述实施例所指的粒径为D90粒径。 Within the meaning of the particle size [0027] The following examples of particle diameter D90.

[0028] 一、透皮吸收药物微粒的制备 [0028] First, the transdermal absorption of the drug microparticles prepared

[0029] 实施例1至10所得到的药物微粒分装的胶囊为植物胶囊,分装后胶囊用铝箔泡罩包装。 [0029] Examples 1 to dispensing the drug particles of the obtained capsules Capsule 10 plants, after dispensing capsules aluminum foil blister packs.

[0030] 实施例1 [0030] Example 1

[0031] 将Ig氢化可的松溶于乙醇,过滤后,滤液喷雾干燥,微粉化使粒径达到3 μ m,过200目筛3次混勻后灭菌,分装在3号胶囊中,每粒胶囊有氢化可的松10mg。 [0031] The Ig Hydrocortisone was dissolved in ethanol, after filtration, the filtrate was spray-dried, so that micronization particle diameter of 3 μ m, the 200-mesh sieve 3 times to mix sterilized packed in No. 3 capsules, Each capsule has hydrocortisone 10mg. 电镜观察微粒为类球形。 Spherical particles as electron microscopy.

[0032] 工艺条件为:进口温度为105°C,出口温度为68°C,气流量90%,喷嘴出口内径为0. Icm,喷嘴空气流速800ml/min,进样速度50mL/h [0032] Process conditions were: inlet temperature of 105 ° C, outlet temperature 68 ° C, air flow rate of 90%, an inner diameter of the nozzle outlet 0. Icm, an air nozzle flow rate of 800ml / min, feed rate 50mL / h

[0033] 实施例2 [0033] Example 2

[0034] 将醋酸曲安奈德Ig溶于乙醇,过滤后,滤液喷雾干燥,微粉化使之粒径达到3 μ m, 用200目筛3次混勻后灭菌,分装到3号胶囊内,每粒胶囊有醋酸曲安奈德lmg。 [0034] The Ig triamcinolone acetonide was dissolved in ethanol, after filtration, the filtrate was spray-dried, so as micronization particle diameter of 3 μ m, with a 200 mesh screen 3 times to mix after sterilization, dispensed into a No. 3 capsule each capsule has triamcinolone acetonide lmg. 电镜观察微粒为类球形。 Spherical particles as electron microscopy.

[0035] 工艺条件为:进口温度为105°C,出口温度为70°C,气流量90%,喷嘴出口内径为0. Icm,喷嘴空气流速800ml/min,进样速度50mL/h。 [0035] Process conditions were: inlet temperature of 105 ° C, outlet temperature 70 ° C, air flow rate of 90%, an inner diameter of the nozzle outlet 0. Icm, an air nozzle flow rate of 800ml / min, feed rate 50mL / h.

[0036] 实施例3 [0036] Example 3

[0037] 将丙酸倍氯米松Ig溶于乙醇,过滤后,滤液喷雾干燥,使之粒径达到3 μ m,过200 目筛3次混勻后灭菌,分装到3号胶囊内,每粒胶囊有丙酸倍氯米松lmg。 [0037] The Ig beclomethasone was dissolved in ethanol, after filtration, the filtrate was spray-dried, so as to achieve a particle size 3 μ m, the 200-mesh sieve 3 times to mix sterilization, dispensed into a No. 3 capsule, Each capsule has beclomethasone dipropionate lmg. 电镜观察微粒为类球形。 Spherical particles as electron microscopy.

[0038] 工艺条件为:进口温度为105°C,出口温度为68°C,气流量90%,喷嘴出口内径为0. Icm,喷嘴空气流速800ml/min,进样速度50mL/h。 [0038] Process conditions were: inlet temperature of 105 ° C, outlet temperature 68 ° C, air flow rate of 90%, an inner diameter of the nozzle outlet 0. Icm, an air nozzle flow rate of 800ml / min, feed rate 50mL / h.

[0039] 实施例4 [0039] Example 4

[0040] 将醋酸地塞米松Ig溶于乙醇,过滤后,滤液喷雾干燥,使之粒径达到2. 5 μ m,过200目筛3次混勻后灭菌,分装到3号胶囊内,每粒胶囊有醋酸地塞米松lmg。 [0040] The Ig dexamethasone acetate dissolved in ethanol. After filtration, the filtrate was spray-dried, so as to particle diameter 2. 5 μ m, the 200-mesh sieve 3 times to mix sterilization, dispensed into a No. 3 capsule each capsule has dexamethasone acetate lmg. 电镜观察微粒为类球形。 Spherical particles as electron microscopy.

[0041] 工艺条件为:进口温度为105°C,出口温度为68°C,气流量90%,喷嘴出口内径为0. Icm,喷嘴空气流速800ml/min,进样速度50mL/h。 [0041] Process conditions were: inlet temperature of 105 ° C, outlet temperature 68 ° C, air flow rate of 90%, an inner diameter of the nozzle outlet 0. Icm, an air nozzle flow rate of 800ml / min, feed rate 50mL / h.

[0042] 实施例5 [0042] Example 5

[0043] 将他扎罗汀Ig溶于乙醇,过滤后,滤液喷雾干燥,使之粒径达到3 μ m,过200目筛3次混勻后灭菌,分装到3号胶囊内,每粒胶囊有他扎罗汀lmg。 [0043] Ig tazarotene was dissolved in ethanol, after filtration, the filtrate was spray-dried, so as to achieve a particle size 3 μ m, the 200-mesh sieve 3 times to mix sterilization, dispensed into No. 3 capsules, each capsules have tazarotene lmg. 电镜观察微粒为类球形。 Spherical particles as electron microscopy.

[0044] 工艺条件为:进口温度为105°C,出口温度为68°C,气流量90%,喷嘴出口内径为0. Icm,喷嘴空气流速800ml/min,进样速度50mL/h。 [0044] Process conditions were: inlet temperature of 105 ° C, outlet temperature 68 ° C, air flow rate of 90%, an inner diameter of the nozzle outlet 0. Icm, an air nozzle flow rate of 800ml / min, feed rate 50mL / h.

[0045] 实施例6 [0045] Example 6

[0046] 将氧氟沙星Ig溶于乙醇,过滤后,滤液喷雾干燥,使之粒径达到3 μ m,过200目筛3次混勻后灭菌,分装到3号胶囊内,每粒胶囊有氧氟沙星lmg。 [0046] The Ig Ofloxacin was dissolved in ethanol, after filtration, the filtrate was spray-dried, so as to achieve a particle size 3 μ m, the 200-mesh sieve 3 times to mix sterilization, dispensed into No. 3 capsules, each there ofloxacin capsules lmg. 电镜观察微粒为类球形。 Spherical particles as electron microscopy.

[0047] 工艺条件为:进口温度为105°C,出口温度为68°C,气流量90%,喷嘴出口内径为0. Icm,喷嘴空气流速800ml/min,进样速度50mL/h。 [0047] Process conditions were: inlet temperature of 105 ° C, outlet temperature 68 ° C, air flow rate of 90%, an inner diameter of the nozzle outlet 0. Icm, an air nozzle flow rate of 800ml / min, feed rate 50mL / h.

[0048] 实施例7 [0048] Example 7

[0049] 将阿达帕林Ig溶于乙醇,过滤后,滤液喷雾干燥,使之粒径达到3 μ m,过200目筛3次混勻后灭菌,分装到3号胶囊内,每粒胶囊有阿达帕林lmg。 [0049] The adapalene Ig was dissolved in ethanol, after filtration, the filtrate was spray-dried, so as to achieve a particle size 3 μ m, the 200-mesh sieve 3 times to mix sterilization, dispensed into No. 3 capsules, each capsule adapalene lmg. 电镜观察微粒为类球形。 Spherical particles as electron microscopy.

[0050] 工艺条件为:进口温度为105°C,出口温度为68°C,气流量90%,喷嘴出口内径为0. 1cm,喷嘴空气流速800ml/min,进样速度50mL/h。 [0050] Process conditions were: inlet temperature of 105 ° C, outlet temperature 68 ° C, air flow rate of 90%, an inner diameter of the nozzle outlet 0. 1cm, an air nozzle flow rate of 800ml / min, feed rate 50mL / h.

[0051] 实施例8 [0051] Example 8

[0052] 将硝酸咪康唑Ig溶于乙醇,过滤后,滤液喷雾干燥,使之粒径达到3 μ m,过200目筛3次混勻后灭菌,分装到3号胶囊内,每粒胶囊有硝酸咪康唑lmg。 [0052] The Ig miconazole nitrate dissolved in ethanol, after filtration, the filtrate was spray-dried, so as to achieve a particle size 3 μ m, the 200-mesh sieve 3 times to mix sterilization, dispensed into No. 3 capsules, each miconazole nitrate capsules have lmg. 电镜观察微粒为类球形。 Spherical particles as electron microscopy.

[0053] 工艺条件为:进口温度为105°C,出口温度为68°C,气流量90%,喷嘴出口内径为0. Icm,喷嘴空气流速800ml/min,进样速度50mL/h。 [0053] Process conditions were: inlet temperature of 105 ° C, outlet temperature 68 ° C, air flow rate of 90%, an inner diameter of the nozzle outlet 0. Icm, an air nozzle flow rate of 800ml / min, feed rate 50mL / h.

[0054] 实施例9 [0054] Example 9

[0055] 将Ig氢化可的松利用流能磨(使用南京大学仪器厂QM-3A)粉碎微粉化使之粒径达到3 μ m,过200目筛3次混勻后灭菌,分装在3号胶囊中,每粒胶囊有氢化可的松10mg。 [0055] The Ig hydrocortisone using a fluid energy mill (Nanjing University Instrument using QM-3A) pulverized so as micronization particle diameter of 3 μ m, the 200-mesh sieve 3 times to mix sterilization, dispensed into No. 3 capsules, each capsule has hydrocortisone 10mg. 电镜观察微粒为无确定形。 Electron microscopy no particles as determined shape.

[0056] 实施例10 [0056] Example 10

[0057] 将Ig醋酸曲安奈德利用流能磨(使用南京大学仪器厂QM-3A)粉碎微粉化使之粒径达到3 μ m,过200目筛3次混勻后灭菌,分装在3号胶囊中,每粒胶囊有醋酸曲安奈德Img0电镜观察微粒为无确定形。 [0057] The Ig triamcinolone acetonide using a fluid energy mill (Nanjing University Instrument using QM-3A) pulverized so as micronization particle diameter of 3 μ m, the 200-mesh sieve 3 times to mix sterilization, dispensed into No. 3 capsules, each capsule has triamcinolone acetonide Img0 electron microscopy no particles as determined shape.

[0058] 实施例11 [0058] Example 11

[0059] EDTA-2Na(乙二胺四乙酸二钠)0. 2g,氯化钠适量,羧甲基纤维素钠2. 5g,泊洛沙姆0. 5g,氢氧化钠适量,加蒸馏水至IOOOg [0059] EDTA-2Na (disodium edetate) 0. 2g, an appropriate amount of sodium chloride, sodium carboxymethyl cellulose 2. 5g, poloxamers 0. 5g, Sodium hydroxide q.s. Distilled water to IOOOg

[0060] 配制方法:将处方量的EDTA_2Na、羧甲基纤维素钠、泊洛沙姆溶于500ml注射用水中,搅拌溶清,用氢氧化钠调PH至5. 5,用氯化钠调至等渗后加入余量的注射用水,灭菌后分装Iml/安瓿密闭保存。 [0060] Preparation method: The formulation amounts of EDTA_2Na, sodium carboxymethylcellulose, poloxamer was dissolved in 500ml water for injection, a clear solution was stirred, adjusted with sodium hydroxide to PH 5.5, adjusted with sodium chloride was added to the balance of the water for injection, isotonic, after sterilization packaging Iml / ampoule sealed.

[0061] 实施例12 [0061] Example 12

[0062] EDTA-2Na 0. lg,氯化钠适量,羟丙基甲基纤维素4g,N-甲基_2_吡咯酮5g,氢氧化钠适量,加蒸馏水至IOOOg [0062] EDTA-2Na 0. lg, an appropriate amount of sodium chloride, hydroxypropyl methylcellulose 4g, N- methyl pyrrolidone _2_ 5g, Sodium hydroxide qs Distilled water to IOOOg

[0063] 配制方法:将处方量的EDTA_2Na、羟丙基甲基纤维素、N-甲基_2_吡咯酮溶于500ml注射用水中,搅拌溶清,用氢氧化钠调pH至5. 5,用氯化钠调至等渗后加入余量的注射用水,灭菌后分装Iml/安瓿密闭保存。 [0063] Preparation method: The formulation amounts of EDTA_2Na, hydroxypropyl methylcellulose, N- methyl pyrrolidone _2_ dissolved in 500ml water for injection, a clear solution was stirred, adjusted with sodium hydroxide to pH 5.5 , rendered isotonic with sodium chloride is added the balance of water for injection, sterilized and dispensed Iml / ampoule sealed.

[0064] 对照实施例1-1 [0064] Comparative Example 1-1

[0065] 将实施例1得到的微粒与实施例11得到的水按照10mg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0065] The fine particles obtained in Example 1 Embodiment Example 11 was obtained according to the proportion of water 10mg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0066] 对照实施例1-2 [0066] Comparative Example 1-2

[0067] 将实施例1得到的微粒与实施例12得到的水按照10mg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0067] The fine particles obtained in Example 1 was carried out to the water obtained in Example 12 in proportion to 10mg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0068] 对照实施例2-1 [0068] Comparative Example 2-1

[0069] 将实施例2得到的微粒与实施例11得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0069] The fine particles obtained in Example 2 of Example Embodiment 11 according to the proportion of water obtained lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0070] 对照实施例2-2 [0070] Comparative Example 2-2

[0071] 将实施例2得到的微粒与实施例12得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0071] The fine particles obtained in Example 2 described embodiment obtained in Example 12 according to the proportion of water lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed. [0072] 对照实施例3-1 [0072] Comparative Example 3-1

[0073] 将实施例3得到的微粒与实施例11得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0073] The fine particles obtained in Example 3 of Example 11 was obtained according to the proportion of water lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0074] 对照实施例3-2 [0074] Comparative Example 3-2

[0075] 将实施例3得到的微粒与实施例12得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0075] The fine particles obtained in Example 3 was carried out to the water obtained in Example 12 in proportion to lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0076] 对照实施例4-1 [0076] Comparative Example 4-1

[0077] 将实施例4得到的微粒与实施例11得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0077] The fine particles obtained in Example 4 with the embodiments obtained in Example 11 according to the proportion of water lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0078] 对照实施例4-2 [0078] Comparative Example 4-2

[0079] 将实施例4得到的微粒与实施例12得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0079] The fine particles obtained in Example 4 was carried out to the water obtained in Example 12 in proportion to lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0080] 对照实施例5-1 [0080] Comparative Example 5-1

[0081] 将实施例5得到的微粒与实施例11得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0081] The fine particles obtained in Example 5 with the embodiments obtained in Example 11 according to the proportion of water lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0082] 对照实施例5-2 [0082] Comparative Example 5-2

[0083] 将实施例5得到的微粒与实施例12得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0083] The fine particles obtained in Example 5 was carried out to the water obtained in Example 12 in proportion to lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0084] 对照实施例6-1 [0084] Comparative Example 6-1

[0085] 将实施例6得到的微粒与实施例11得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0085] The fine particles obtained in Example 6 with the embodiments obtained in Example 11 according to the proportion of water lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0086] 对照实施例6-2 [0086] Comparative Example 6-2

[0087] 将实施例6得到的微粒与实施例12得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0087] The fine particles obtained in Example 6 was carried out to the water obtained in Example 12 in proportion to lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0088] 对照实施例7-1 [0088] Comparative Example 7-1

[0089] 将实施例7得到的微粒与实施例11得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0089] The microparticles obtained in Example 7 Example 11 was obtained according to the proportion of water lmg / ml, and were mixed, sterilized, dispensed after 30 seconds with ultrasonic agitation Iml / ampoule sealed.

[0090] 对照实施例7-2 [0090] Comparative Example 7-2

[0091] 将实施例7得到的微粒与实施例12得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0091] The fine particles obtained in Example 7 with the embodiment of Example 12 to give the water in proportion to lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0092] 对照实施例8-1 [0092] Comparative Example 8-1

[0093] 将实施例8得到的微粒与实施例11得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0093] The fine particles obtained in Example 8 with the embodiment obtained in Example 11 according to the proportion of water lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0094] 对照实施例8-2 [0094] Comparative Example 8-2

[0095] 将实施例8得到的微粒与实施例12得到的水按照lmg/ml的比例,进行混合,灭菌,用超声波震荡30秒后分装Iml/安瓿密闭保存。 [0095] The microparticles obtained in Example 8 with the embodiment obtained in Example 12 of water in proportion to lmg / ml, and were mixed, sterilized, dispensed with ultrasonic vibration for 30 seconds Iml / ampoule sealed.

[0096] 二、相关药效学试验 [0096] Second, the relevant pharmacodynamics

[0097] 实施例15稳定性实验 [0097] Example 15 Stability test

[0098] 将实施例1-12、对照实施例1-1至8-2分成实施例1_10组、对照实施例1_1至8_2组,实施例11-12组每组500支,其余每组40个单位,在40°C 士2°C,相对湿度75% 士5% 的情况下进行稳定性试验,分别于存储0个月、1个月、3个月时取样测药物的D90粒径,每次取10个单位,其中实施例1-10组每次所取的10个胶囊在进行粒径试验前,取5个胶囊的药物分别与实施例11得到的5个单位含有辅料的水在安瓿内混合、取5个胶囊的药物分别与实施例12得到的5个单位含有辅料的水在安瓿内混合,并用手上下震荡10秒后立即进行测定粒径;对照实施例1-1至8-2组在进行粒径试验前,用手上下震荡10秒后立即进行测定粒径。 [0098] Examples 1-12, Comparative Examples 1-1 to 8-2 into groups embodiment 1_10, 8_2 set to Comparative Example 1 1, Example 11-12 each group 500, the remaining 40 in each group units, at 40 ° C with disabilities 2 ° C, relative humidity of 75% ± 5% of the stability testing were stored at 0 months, 1 month, samples D90 particle size of the drug measured at 3 months, every front views taken 10 units, of which Examples 1-10 set of particle size 10 capsules each test taken embodiments, take 5 capsules pharmaceutical water were obtained Example 11 5 units in ampoules containing excipient and implementation mixing, to take 5 capsules of medicament embodiment respectively obtained in Example 125 units of mixed materials containing water in an ampoule, and the particle size measured by hand fluctuated immediately after 10 seconds; Comparative Examples 1-1 to 8 2 before the test group of particle size, particle size was measured immediately after the hand shaking up and down for 10 seconds. 3个月时测定粒径后,将实施例1-10分别与实施例11、12混合形成的混悬剂、 对照实施例1-1至8-2的混悬剂加盖在40°C 士2°C,相对湿度45% 士5%的情况下保存M 小时后,用手上下震荡10秒后进行粒径试验。 After 3 months, measuring the particle size, the suspensions of Examples 1-10 and Examples 11 and 12 are respectively formed in the mixing embodiment embodiment, the control suspensions of Examples 1-1 to 8-2 [deg.] C capping disabilities in embodiment 40 2 ° C, 45% relative humidity case of ± 5% of the M hours after storage, the particle size after the test by hand shaking up and down for 10 seconds.

[0099] 实验结果如下: [0099] The results are as follows:

[0100] [0100]

Figure CN102475681AD00091

[0101] [0101]

Figure CN102475681AD00101

[0102] 通过上述实验表明,按照本发明中的技术对药品与含有辅料的水进行分离,经过 [0102] By the above-described experiments show that the separation of water containing pharmaceutical excipients according to the present invention in the art, after

长时间储存,使用时再进行混合,对粒径影响较小,经过高温的条件下储存M小时后,D90 Long-term storage, and then mixed when used, little effect on the particle size, high temperature conditions after M hour after storage, the D90

粒径基本保持在10 μ m以下,同时药物微粒外形为球形或类球形比无确定形态的保持粒径的能力更好。 Particle size remains substantially at 10 μ m or less, while the outer shape of the drug particles and better particle size capacity retention ratio of spherical or spheroidal morphology inconclusive. 而如果将药物与通过与含有辅料的水形成混悬剂经过长时间储存,保持粒径的能力较差,粒径明显提高。 If the drug with poor ability after prolonged storage, the particle size is maintained by forming a water suspension containing materials, particle size improved significantly.

[0103] 实施例16体外经皮渗透实验 [0103] Example 16 Transdermal permeation experiments embodiment

[0104] 取3月龄健康大鼠和10天龄大鼠麻醉处死后,用剪刀除尽腹部毛,取下无损伤的皮肤,除去皮下组织,洗净后分别固定于Franz扩散池的释放口,接受室中加入pH7. 4磷酸缓冲液作释放介质,保持内皮层与溶液密切接触。 [0104] 3-month-old rats to take and 10-day old rats were sacrificed after anesthesia, the abdomen divisible hair with scissors, remove intact skin, the subcutaneous tissue, are fixed to washing to remove discharge port of Franz diffusion cell receiving chamber added pH7. 4 phosphate buffer as release medium, holding the solution in close contact with skin. 取0. Iml药液涂布在皮肤上,调节水浴使外层套层温度恒定于(37士1) °C,搅拌速度为lOOrpm,分别于0、0· 15,0. 5,0. 75、1、1· 5、2小时吸取释放介质細1,同时补加等量PBS液。 Take 0. Iml liquid was coated on the skin, so that adjusting the water bath temperature was constant at the outer jacket layer (37 persons 1) ° C, stirring speed of lOOrpm, respectively, 0,0-15,0. 5,0. 75 , 1,1 · 5,2 hours thin suction release medium 1, while an equal amount of PBS supplemented. 释放液用中国药典2010年版的方法确定浓度Ci,根据下式求得单位面积药物累积透过量Q :Q = CiV/A,式中,Q为单位面积药物累积透过量,Ci为t时间内释放介质中的药物浓度,V为接收室体积,A为皮肤扩散面积。 Release was determined using Chinese Pharmacopoeia, 2010 edition of the method of the concentration Ci, the cumulative permeation amount Q in accordance with the following formula unit area drugs: Q = CiV / A, formula, Q is the basis drug accumulation, Ci to release t time permeation amount Drug concentration in the medium, V is the volume of the receiving chamber, a is the diffusion area of ​​skin. 分别以Q和C对时间进行线性回归,求得渗透率(J/ μ g. IT1) Q and C respectively of the linear regression of time, determined permeability (J / μ g. IT1)

[0105] 实验药物的制备:将实施例1-12、对照实施例1-1至8-2分成实施例1_10组、对照实施例1-1至8-2组,实施例11-12组每组500支,其余每组40个单位,在40°C 士2°C, 相对湿度75% 士5%的情况下进行稳定性试验,存储3个月后,其中实施例1-10组每次所取的20个胶囊进行渗透性试验。 Preparation of [0105] Experimental drugs: Examples 1-12, Comparative Examples 1-1 to 8-2 into embodiments 1_10 group, the control group Examples 1-1 to 8-2, Examples 11-12 for each group the rear group 500, the remaining 40 units each, at 40 ° C with disabilities 2 ° C, relative humidity of 75% ± 5% of the stability testing, 3 months of storage, wherein each group embodiment Examples 1-10 20 capsules taken permeabilities.

[0106] 在进行渗透试验前,取10个胶囊的药物分别与实施例11得到的10个单位含有辅料的水在安瓿内混合、取10个胶囊的药物分别与实施例12得到的10个单位含有辅料的水在安瓿内混合,并用手上下震荡10秒后立即涂布在3月龄健康大鼠皮肤上;对照实施例1-1至8-2组在进行渗透试验前,用手上下震荡10秒后立即涂布在3月龄健康大鼠皮肤上。 Prodrugs [0106] during the penetration test, taken the drug capsules 10 are obtained in Example 11 of water containing 10 units of excipients were mixed in ampoules, respectively, taking 10 capsules obtained in Example 10 units of embodiment 12 excipients containing water mixed in the ampoule and applying the hand fluctuated immediately after 10 seconds 3-month-old rats onto the skin; front Comparative Examples 1-1 to 8-2 set during the penetration test, the hand fluctuated immediately after 10 seconds was applied on 3-month-old rat skin.

[0107] 同样地,在10天龄大鼠皮肤进行同样的试验。 [0107] Similarly, 10-day-old rat skin the same test was carried out.

[0108] 实验结果如下: [0108] The results are as follows:

Figure CN102475681AD00111

实施例1 实施例12 ΓΪ 222.1 士7.6 282.1±6.9 Example 1 Example 12 ΓΪ 222.1 7.6 282.1 ± 6.9 Disabled

实施例2 实施例12 (O 39.4±4.3 43.6±4.2 Example Example 12 2 (O 39.4 ± 4.3 43.6 ± 4.2

实施例3 实施例12 Ol 38.8±4.1 45.9±3.4 Example 3 Example 12 Ol 38.8 ± 4.1 45.9 ± 3.4

实施例4 实施例12 Ol 39.9土4.3 46_4士4.1 Example 4 Example 12 Ol 39.9 4.3 46_4 earth disabilities 4.1

实施例5 实施例12 0Λ 28.4±4.0 34.2±3.4 Example 5 Example 12 0Λ 28.4 ± 4.0 34.2 ± 3.4

实施例6 实施例12 Ol 34.3±4.4 39.3±4.0 Example Example 6 12 Ol 34.3 ± 4.4 39.3 ± 4.0

实施例7 实施例12 Ol 35.8±3.9 40.7±3.2 Example 7 Example 12 Ol 35.8 ± 3.9 40.7 ± 3.2

实施例8 实施例12 OJ 40.5±4.3 44.3士3.7 Example 8 Example 12 OJ 40.5 ± 4.3 44.3 3.7 disabilities

实施例9 实施例12 1 233.1±14.4256.4±13.1 —_〜.』 Example 9 Example 12 1 233.1 ± 14.4256.4 ± 13.1 -_~. "

实施例10 实施例12 Ol 32.4±4.1 36.7±3.5 —..… Example 10 Example 12 Ol 32.4 ± 4.1 36.7 ± 3.5 Embodiment - .. ...

对照实施例1-1 1 81.2 士6.1 105.4±5.4 Disabled Control Example 1-11 81.2 6.1 105.4 ± 5.4 Embodiment

对照实施例1-2 Ϊ 104.5 士5.3 114.3±6.1 Comparative Example 1-2 Ϊ 104.5 5.3 114.3 ± 6.1 Disabled

对照实施例2-1 Ol 10.1 士2.7 11.5±1.9 Comparative Example 2-1 Ol 10.1 2.7 11.5 ± 1.9 Disabled embodiment

对照实施例2-2 0.1 12.4±3.1 13.7±2.1 Comparative Example 2-2 0.1 12.4 ± 3.1 13.7 ± 2.1

对照实施例3-1 (λϊ 10.3±2.4 11.1±2.6 Comparative Example 3-1 (λϊ 10.3 ± 2.4 11.1 ± 2.6

对照实施例3-2 Ol 12.0±2.9 13.7±3.0 Comparative Example 3-2 Ol 12.0 ± 2.9 13.7 ± 3.0

对照实施例4-1 Ol 11.2士3.2 12.8±2.6 Comparative Example 4-1 Ol 11.2 3.2 12.8 ± 2.6 Disabled

对照实施例4-2 Ol 14.3±3.5 16.1 士2.7 Comparative Example 4-2 Ol 14.3 ± 3.5 16.1 2.7 disabilities

对照实施例5-1 OJ 8.4±2.1 10.1±1.7 :~ Comparative Example 5-1 OJ 8.4 ± 2.1 10.1 ± 1.7: ~

对照实施例5-2 Ol 9.5士2.8 11.6士2.3 Comparative Example 5-2 Ol 9.5 Disabled Disabled 2.3 2.8 11.6

对照实施例6-1 07l 8.7±2.2 10.9±1.8 Example 6-1 07l 8.7 ± 2.2 10.9 ± 1.8 Control Embodiment

对照实施例6-2 Ol 10.1±2.4 12.0±1.9 Comparative Example 6-2 Ol 10.1 ± 2.4 12.0 ± 1.9

对照实施例7-1 0Λ 11.4±2.5 13.4±2.1 Comparative Example 7-1 0Λ 11.4 ± 2.5 13.4 ± 2.1

对照实施例7-2 0.1 14.1±2.6 16.3±1.7 Comparative Example 7-2 0.1 14.1 ± 2.6 16.3 ± 1.7

对照实施例8-1 CU 15.2±2.7 17.5±2.3 Comparative Example 8-1 CU 15.2 ± 2.7 17.5 ± 2.3

对照实施例8-2 Ol “ 18.5±3.1 20.0士2.8 Comparative Example 8-2 Ol "embodiment disabilities 2.8 18.5 ± 3.1 20.0

[0111] 通过上述实验,可以看出粒径较大的对照实施例渗透速率明显较低,而粒径较小的实施例渗透速率较高,尤其是对于皮肤较薄的10天龄大鼠渗透速率明显提高,可以说明本发中的混悬剂更适应给予皮肤较薄的幼儿。 [0111] Through the above experiment, it can be seen a large particle size Comparative Example permeation rate was significantly lower, while a smaller particle size Example embodiments higher permeation rate, especially for thin skin 10 days old rats permeation rate significantly increased, the present invention can be described more suitable to give suspensions thin skin children.

Claims (10)

  1. 1. 一种透皮吸收治疗皮肤病的药物组合物,由作为单独包装的难溶于水的D90粒径为0. 1-10 μ m皮肤用药物、单独包装的含有一种或几种皮肤药用辅料的水共同组成。 A percutaneous absorption pharmaceutical composition the treatment of dermatoses, the individually packaged as a water-insoluble particle diameter D90 0. 1-10 μ m dermopharmaceutical, individually packaged contain one or more skin pharmaceutical excipients composed of water.
  2. 2.如权利要求1所述的药物组合物,其特征是单独包装的难溶于水皮肤用药物的D90 粒径为1-10 μ m。 2. The pharmaceutical composition according to claim 1, characterized in that the separately packaged skin poorly water-soluble drug particle diameter D90 of 1-10 μ m.
  3. 3.如权利要求1所述的药物组合物,其特征是难溶于水的皮肤用药物为糖皮质激素。 The pharmaceutical composition according to claim 1, wherein the sparingly water-soluble dermopharmaceutical glucocorticoid.
  4. 4.如权利要求3所述的药物组合物,其特征是糖皮质激素可选自可的松、氟米龙、地塞米松、倍他米松、泼尼松龙、泼尼松、氢化可的松、瑞美松龙(Rimexolone)、氯替泼诺、布地奈德、环索奈德、阿氯米松、倍氯米松、倍他米松、氯泼尼松、氯倍他索、氯倍他松、氯可托龙、氯波尼醇、地夫可特、地奈德、去羟米松、二氟拉松、二氟可龙、二氟泼尼酯、氟氯奈德、氟米松、 氟尼缩松、氟轻松、氟可龙、氟培龙、氟泼尼定、氟泼尼松龙、氟氢缩松、哈西奈德、商倍他索、 卤米松、卤泼尼松、氢可他酯、甲羟松、甲泼尼松、甲泼尼松龙、莫米松、帕拉米松、泼尼卡酯、 波尼立定、曲安西龙、曲安奈德、安西奈德、氟替卡松、地奈德、马泼尼酮、替可的松中的一种化合物或其可药用的酯。 4. The pharmaceutical composition according to claim 3, characterized in that the glucocorticosteroid selected from hydrocortisone, fluorometholone, dexamethasone, betamethasone, prednisolone, prednisone, hydrocortisone Song, Ruimei Song Long (Rimexolone), loteprednol, budesonide, ciclesonide, alclometasone, beclomethasone, betamethasone, prednisone, clobetasol, clobetasone , clocortolone, chloro Boni alcohol, deflazacort, desonide, desoximetasone, diflorasone, di fluocortolone, two difluprednate, fluclorolone acetonide, flumethasone, niflumic shrinkage, fluocinolone, fluocortolone, fluperolone, fluprednidene, fluoro-prednisolone, flurandrenolide, halcinonide, clobetasol supplier, halometasone, halopredone, hydrocodone him esters, medrysone, meprednisone, methylprednisolone, mometasone, paramethasone Parra, prednicarbate, Boni standing, triamcinolone, triamcinolone acetonide, amcinonide, fluticasone, budesonide , -one horse prednisone, hydrocortisone for one compound or a pharmaceutically acceptable ester.
  5. 5.如权利要求4所述的药物组合物,其特征是所述糖皮质激素的用量为0.01%〜1%。 5. A pharmaceutical composition according to claim 4, wherein said glucocorticoid in an amount of 0.01% ~ 1%.
  6. 6.如权利要求1中所述的药物组合物,其特征是所述单独包装的含有一种或几种皮肤药用辅料的水中的辅料包括PH调节剂、渗透压调节剂、粘度调节剂、促渗剂、表面活性剂或稳定剂中的一种或几种。 6. A pharmaceutical composition according to claim 1, characterized in that the water contains one or more pharmaceutically acceptable excipients skin excipients include the individually packaged PH adjusting agents, tonicity adjusting agents, viscosity modifiers, one or more penetration enhancer, a surfactant or stabilizer.
  7. 7.如权利要求1中所述的药物组合物,其特征在于所述单独包装的难溶于水的D90粒径为0. l-ΙΟμπι皮肤用药物的微粉化方法可以采用喷雾干燥法,流化床超音速气流粉碎法,高速研磨法、球磨法、流能磨法、溶剂法、CO2超临界法制备。 7. A pharmaceutical composition according to claim 1, characterized in that said individually packaged poorly water-soluble particle diameter D90 of 0. l-ΙΟμπι skin micronized pharmaceutical spray drying method may be employed, flow bed supersonic jet grinding method, high speed grinding, ball milling, fluid energy milling method, the solvent method, supercritical CO2 preparation method.
  8. 8.如权利要求1中所述的药物组合物,其特征在于所述皮肤用药物可以采用单次或多次剂量的形式包装。 8. A pharmaceutical composition according to claim 1, wherein said dermopharmaceutical single or multiple doses may take the form of packaging.
  9. 9.如权利要求1-8中任一所述的药物组合物,在制备治疗人或动物皮肤炎症药物中的应用。 1-8 a pharmaceutical composition according to any of the treatment in the manufacture of human or animal skin inflammatory medicament as claimed in claim.
  10. 10.如权利要求1-8中任一所述的药物组合物,在制备治疗2岁以下中婴幼儿皮肤炎症药物中的应用。 1-8 10. The pharmaceutical composition according to any one of claims, inflammation of the skin applications infants under 2 years of drug in the preparation of the treatment.
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