氣笛他定的外用制剂所属技术领域本发明属于医药制剂技术。 His steam whistles given formulation belongs Technical Field The invention belongs to pharmaceutical topical formulation techniques. 背景技术近年来，由于气候和环境的变化，各种有害气体、粉尘及其他污染源的大量涌现，使其成为导致人们产生各种过敏反应的致敏原。 In recent years, due to changes in climate and the environment, harmful gases, dust and other sources of pollution in large numbers, making it the allergens cause people to produce a variety of allergic reactions. 季节的变迁，野外作业， 花粉过敏，吸入有害气体及尘粒等，造成越来越多的人群患有各种不同类型的过敏性疾病，如过敏性奥炎，荨麻疹，皮肤红肿、瘙痒、起红点及过敏原引起的哮喘等极为常见。 Change of season, field operations, pollen allergy, inhalation of harmful gases and dust particles, resulting in a growing number of people suffering from a variety of different types of allergic diseases, such as allergic Austria, urticaria, skin irritation, itching, from the red spots and allergen-induced asthma is very common. 因此，注意环境变化，加强自身护理，开发治疗过敏性药物都是非常重要的。 Therefore, pay attention to changes in the environment, strengthen self-care, the development of allergic drug treatment are very important. 氯雷他定由Schering Plough公司开发，1988年首先在比利时上市，它为一口服有效的第三代抗组胺药，具有选择性抑制外周H,受体的作用，氯雷他定作为一种强效抗过敏药，具有以下优点：1、 强效抗组胺作用有研究发现氯雷他定起效快、作用时间长，口服后30〜60分钟，过敏症状开始消退，临床抑制商峰在2〜4小时，且其体内的肝脏代谢物去羧乙氧基氣雷他定仍有很高的活性。 Loratadine developed by Schering Plow Corporation, 1988 First listed in Belgium, which is a third generation antihistamines orally active, selective inhibition of peripheral H, receptor action, loratadine as a potent antiallergic agent, has the following advantages: 1, a potent antihistamine action studies have found that desloratadine rapid onset, long duration of action after oral 30~60 minutes, allergy symptoms began to subside, the clinical peak suppressing supplier 2 ~ 4 hours, and its metabolites to the liver in vivo carboxyethoxy gas loratadine activity is still very high. 2、 服药次数少在临床使用中，本品每天只需服用一次，减少了病人的服药次数，提高了病人的依从性。 2, medication less often in clinical use, this product is taken once a day, reducing the number of patients with medication, improved patient compliance. 3、 剂量小成人每天一次，每次只霈服用本品10mg。 3, small adult dose once a time using this service Pei 10mg per day. 4、 不与心肌细胞的脂质分子结合，避免了对心肌细胞的电生理过程，因此没有心脏毒性。 4, does not bind lipid molecules cardiomyocytes avoided the physiological processes of myocardial cells, there is no cardiotoxicity. 虽然氯雷他定有着上述优良的特点，但现今临床上对一些比较顽固的皮肤过敏性疾病、皮炎尚没有很理想的治疗药物。 Although loratadine has the above excellent features, but now some of the more stubborn clinical skin allergies, dermatitis is still not ideal therapeutic agents. 越来越多的化学物质导致的环境污染, 使得现代工业社会中皮肤过敏和皮炎的发病率居高不下，多少年来，人们一直在努力开发疗效强大的抗过敏和抗炎药物，以便对现代工业社会中经常出现的皮肤过敏和皮肤炎症进行有效的治疗，氣雷他定经胃肠道吸收后，经血液循环到达皮肤，虽然能够达到一定的治疗效果，但它的中枢镇静等不良反应限制了它的大剂量应用，成年人服用本品40-180mg，可发生明显的嗜睡，心率失常和头痛等不良反应。 A growing number of environmental pollution caused by chemical substances, so that the incidence of skin allergies and dermatitis modern industrial society remains high, over the years, people have been trying to develop a strong efficacy of anti-allergy and anti-inflammatory drugs, in order to modern industry skin irritation and skin inflammation society that often appear effective treatment, after he was given mine gas absorbed through the gastrointestinal tract, via the blood circulation to the skin, even though it can achieve a therapeutic effect, but its central sedative and other adverse reactions limits its large dose of adult blindness 40-180mg, may occur significant drowsiness, headache, cardiac arrhythmias and other adverse reactions. 在每天服用10mg的剂量下，仍有头痛、嗜睡、乏力、口干、神经质、 喘息、过度运动、腹痛、结膜炎、口吃、抑郁、上呼吸道感染等众多不良反应的发生率大于2%。 Taking 10mg daily doses, the still headache, drowsiness, fatigue, dry mouth, nervousness, wheezing, excessive exercise, abdominal pain, the incidence of many adverse reactions conjunctivitis, stuttering, depression, upper respiratory tract infections than 2%. 氯雷他定可以长效、强力特异性地竞争外周H,受体，阻断组胺的作用。 Loratadine can be long-lasting, strong outer periphery specifically compete H, receptors, histamine blocking action. 但在皮肤表层组织中的浓度相对较低。 However, a relatively low concentration in the surface of the skin tissue. 组胺是变态反应的主要介质，组胺主要由肥大细胞和嗜碱细胞等释出组氨酸，后者经酶脱羧变为组胺。 Histamine is a major mediator of the allergic response, mainly histamine from mast cells and basophils release histidine and the like, which becomes enzymatically decarboxylated histamine. 在很多皮肤变态反应均涉及到的皮肤风团和红斑反应中，组胺起到很重要的作用，它具有对血管的直接效应，舒张血管和增强微血管的通透性以及导致广范围的神经原性的红斑反应。 In the skin wheal and erythema reaction a lot of skin allergies are involved, the histamine plays a very important role, it has a direct effect on blood vessels, relaxing blood vessels and enhanced microvascular permeability and lead to a wide range of neurons of erythema reaction. 组胺H,受体拮抗剂能与组胺竞争效应细胞上的组胺H,受体，使组胺不能同H,受体结合，从而抑制其引起的过敏反应。 Histamine H, receptor antagonists and histamine on histamine H competition effector cells, receptors, not with histamine H, receptor binding, thereby inhibiting its cause allergic reactions. 氯雷他定为第三代抗组胺药，具有较强极性，不易通过血脑屏障，因而没有早期强亲脂性抗组胺药的明显嗜睡作用， 氣雷他定对周围器官细胞表面的H,受体比中枢H,受体的亲和力高，即对外周Hl受体具有高度选择性，优点为中枢镇静作用大大降低。 Loratadine is a third generation antihistamines, has a strong polarity, not through the blood-brain barrier, and therefore no early strong lipophilic antihistamines drowsiness significant effect on the gas surrounding organs Desloratadine cell surface H, central receptors than H, the high affinity receptor, i.e. peripheral Hl receptor is highly selective advantage central sedative effect is greatly reduced. 由于氯雷他定在血流相对较少的皮肤表层组织中的浓度分布相对较低，这对于变态反应性皮肤病的治疗是十分不利的。 Since loratadine in the bloodstream relatively small surface of the skin tissue is relatively low concentration distribution, which is very unfavorable for the treatment of allergic skin diseases. 氯雷他定和其代谢物脱乙氧羧基氯雷他定可抑制肥大细胞，嗜碱细胞释放组胺和其他介质。 Loratadine and its metabolites carboxy ethoxycarbonyl off desloratadine can inhibit mast cells, basophils release histamine and other media. 氯雷他定可减低ICAM-1在鼻粘膜上皮细胞的表达，从而阻断或减轻迟发相炎症反应。 Loratadine can reduce the expression of ICAM-1 in the nasal epithelial cells, thereby blocking or lessening the late phase inflammatory response. 体内研究也显示出氯雷他定对变态反应原诱导的炎性反应效果良好。 In vivo studies also showed good loratadine inflammatory effect on his given allergen induced. 口服和鼻内用药均减轻了鼻炎症状和炎性细胞的游走。 Oral and intranasal administration have reduced the symptoms of rhinitis and migration of inflammatory cells. 氯雷他定抑制变应原诱导的肥大细胞摄取Ca"和抑制肥大细胞内Ca2+，通过稳定肥大细胞， 抑制粘附分子表达，抑制嗜酸性粒细胞，降低白细胞介素的产生等药理作用，全面抑制过敏反应。氯雷他定自上市以来，临床上多用于治疗过敏性鼻炎。对于缓解与过敏性鼻炎有关的症状如喷嘍、流涕及鼻痒、輿塞以及眼部痒及烧灼感，临床效果好。口服给药后，鼻和眼部症状及体征得以迅速缓解，亦适用于缓解慢性荨麻疹，瘙痒性皮肤病及其他过敏性皮肤病的症状及体征。氯雷他定和西替利嗪对过敏性鼻炎的疗效和起效时间的研究中，对12例用浓度呈几何级数增加的组胺进行鼻腔喷雾刺瀲，在服用氯雷他定10mg,西替利嗪10mg或安慰剂后1.5小时，测量鼻腔气道阴力（NAR),服药后1.5小时，由组胺导致的NAR增加，被氯雷他定、氯马斯汀对各种观察指标明显优于氯马斯汀 Loratadine inhibiting allergen-induced mast cell uptake of Ca "and inhibition of mast cell Ca2 +, by stabilizing mast cells, inhibit the expression of adhesion molecules, inhibition of eosinophil, decreased pharmacological effects produced like interleukins, overall inhibition of allergic reactions. loratadine since listing, clinically used for the treatment of allergic rhinitis. for the relief of symptoms associated with allergic rhinitis such as spray myself, runny nose and nasal itching, Yu plugs and eye itching and burning sensation, good clinical effect after oral administration, nasal and eye symptoms and signs were quickly alleviated, but also for the relief of symptoms and signs of chronic urticaria, itching of the skin and other allergic skin diseases. loratadine and cetirizine efficacy of cetirizine to allergic rhinitis and the onset time, 12 patients with geometrically increasing concentrations of histamine nasal spray trough puncture, taking 10mg loratadine, cetirizine or comfort 10mg 1.5 hours after the agent, measuring the nasal airway negative force (the NAR), 1.5 hours after administration, the NAR by the increase due to histamine was loratadine, clemastine various parameters were significantly better than was observed clemastine 且不良反应小。DdCarpioetal对氯雷他定有效性和安全性进行评价，病人分别口服氣雷他定10mgOD,特非那定60mgBid或安慰剂14天，氣雷他定疗效优于特非那定，氯雷他定产生嗜睡、口干、头痛等症状明显低于特非那定组。 由于在鼻腔中，存在着丰富的毛细血管，氯雷他定等药物从彝腔吸收迅速，而从胃肠道吸收进入血液循环的氯雷他定在鼻腔内也有很好的组织分布，这就为氯雷他定治疗募炎奠定了很好的药动学基础。但在氯雷他定用于治疗变态反应性皮肤病时，效果却不尽人意，虽然在开放式多中心的临床研究中，对500例慢性荨麻疹的治疗在减轻临床症状方面优于特非那定。对许多顽固性皮肤过敏性疾病和皮肤炎症目前还没有理想的药物进行治疗。另外，氣雷他定临床应用表明，氯雷他定对过敏性哮喘具有很好的预防和治疗作用。12名不吸烟哮喘患者分 And side effects .DdCarpioetal of loratadine evaluate the efficacy and safety of patients were orally gas loratadine 10mgOD, terfenadine 60mgBid or placebo for 14 days gas loratadine effective than terfenadine , loratadine produce drowsiness, dry mouth, headache and other symptoms was significantly lower than group of terfenadine. Since in the nasal cavity, there is a rich capillary, loratadine is rapidly absorbed drugs such as Yi from the chamber, and from the stomach intestinal absorption into the blood circulation of loratadine in the nasal cavity also have a good tissue distribution, which for the treatment of loratadine raise inflammation has laid a good foundation pharmacokinetics. However, for the treatment of loratadine when allergic skin disease, the effect is unsatisfactory, although in clinical studies open multi-center, treating 500 cases of chronic urticaria is superior in reducing symptoms of terfenadine. for many intractable skin allergies disease and inflammation of the skin there is no ideal drug for treatment. in addition, gas loratadine clinical application showed that loratadine has a good prevention and treatment of allergic asthma .12 nonsmoking asthma patients were divided 口服氯雷他定10mg、 20mg，观察对呼吸道吸入组胺和过敏物质的影响，显著抑制呼吸道反应，对组胺诱导的支气管痉挛有较强的缓解作用。发明内容对于氣雷他定的普通口服制剂，主要是通过胃肠道吸收后，再通过血液循环分布于皮肤的真皮组织中，从而拮抗炎症介质组胺的作用。达到对全身皮肤过敏性炎症的治疗作用。皮肤组织的血流分布相对较少，这使得氣雷他定的组织分布很不利于它对皮肤过敏性疾病和皮炎的治疗，口服途径大剂量应用对皮肤疾病而言可能存在严重的全身不良反应的危险，是一种十分不理想的给药方式。而对于临床上常见的皮肤过敏和皮肤炎症，其发病机理也很复杂，并不单单是由组胺介导的，因而现有的l哮床治疗药物中，对皮肤过敏和皮肤炎症的治疗效果都不是十分理想。 Oral loratadine 10mg, 20mg, was observed on histamine inhalation of allergens and, significantly inhibited the airway responses, with strong relief effect on histamine-induced bronchospasm. SUMMARY airway loratadine ordinary oral formulations, mainly through the gastrointestinal absorption, distribution of blood circulation through the skin in the dermal tissue, thereby antagonizing inflammatory mediators histamine. systemic therapeutic effect on allergic skin inflammation. skin tissue relative blood flow distribution less, which makes gas loratadine its tissue distribution is not conducive to skin allergies and dermatitis treatment, a large dose of the oral route for skin diseases there may be danger of serious systemic adverse reactions, is a very undesirable mode of administration. for common clinical skin irritation and inflammation of the skin, its pathogenesis is very complex, not solely mediated by histamine, and thus the conventional bed l asthma drugs in the skin treatment of allergies and skin inflammation are not very good. 对皮肤过敏性疾病寻找一种理想的治疗药物或者药物剂型，是广大皮肤病患者所急需的。 Skin allergies find an ideal therapeutic drug or pharmaceutical dosage forms, the majority of patients with skin disease is urgently needed. 本发明提供了几种氯雷他定外用制剂，动物实验发现，和氣雷他定口服途径给药相比较，氣雷他定的外用制剂对几种皮肤过敏模型有着意想不到的效果。 The present invention provides several loratadine external preparation, animal experiments found that loratadine and gas compared to the oral route, the gas Desloratadine external preparation for skin irritation model has several unexpected results. 将氯雷他定制备成局部外用制剂，通过透皮吸收，增加机体过敏炎症部位皮肤的局部组织游离药物浓度，可有效拮抗组胺的致敏作用，更好发挥其局部抗过敏和抗炎疗效，降低不良反应。 The desloratadine prepared as topical preparations, transdermal absorption, increasing the local tissue concentration of the free drug allergic inflammation of the body part of the skin, which can effectively antagonize histamine sensitization, better exert its local anti-allergic and anti-inflammatory effect and reduce adverse reactions. 但氯雷他定很难通过皮肤的角质层，只能够停留在皮肤的表面，现有技术认为它外用不可能透过皮肤角质层，不能在皮肤组织中达到有效的组织浓度，因而无法发挥其抗过敏和抗炎的疗效。 But loratadine difficult through the stratum corneum of the skin, can only stay on the surface of the skin, the prior art considered it impossible for external use through the stratum corneum, can not achieve an effective concentration of tissue in the skin tissue, and therefore can not play it anti-allergic and anti-inflammatory effect. 因此氯雷他定1988年在比利时上市后的近二十年来，却一直未见外用制剂上市。 So loratadine 1988 after nearly two decades on the market in Belgium, has been no topical formulations on the market. 我们通过脂质体等技术，将氯雷他定制备成为可以外用的搽剂、软裔剂等剂型，并进一步通过大量的药理学实验证实了氣雷他定皮肤表面的局部应用，能够更为有效的发挥氯雷他定的抗组胺活性，尤其值得关注的是我们在药效学实验中意外的发现，氯5仅对组胺诱导的皮肤过敏有着强大的拮抗作用，而且对以二硝基氟苯为代表的化学物质导致的皮肤迟发性超敏反应也有相当理想的效果，对二甲苯所致的小鼠耳急性炎症效果也相当理想，而这在全身给药途径中，没有任何的迹象能够提示氣雷他定具有此种药理学活性。 We liposome technology, the loratadine external liniment can be prepared, soft descent agent formulations, and further confirmed by a large number of mine gas pharmacological test he will topical application of a skin surface, can be more effective play loratadine antihistamine activity, especially noteworthy is our accidental discovery in pharmacodynamic experiments, chlorine only 5 histamine-induced skin allergy has a strong antagonism, but also to Dinitromethylene delayed hypersensitivity skin-fluorophenyl group represented by the chemical substance also results in a significant desirable effect on the xylene-induced ear inflammation in mice with acute effect is quite satisfactory, and that the systemic routes of administration, there is no the signs can prompt gas loratadine having such pharmacological activity. 氯雷他定的外用途径给药方式能够对皮肤的迟发性超敏反应有着良好的治疗作用，这意味着氣雷他定外用制剂对临床常见的各种化学物质导致的慢性皮肤炎症有着很好的应用前景，解决了多年来临床对皮肤炎症没有理想治疗药物的问题，符合广大患者的利益。 Loratadine topical route of administration can have a good therapeutic effect on delayed hypersensitivity of the skin, which means that gas loratadine topical formulations for a variety of clinical common chemicals cause chronic inflammation of the skin has a very good prospects to solve the many years of clinical inflammation of the skin is not ideal for the treatment of drug problems, in the interests of the majority of patients. 而这种氯雷他定新的药理活性的发现，对于氯雷他定的药理作用机制研究也具有重要的启示意义。 And this loratadine pharmacological activity of new discoveries for the study of the pharmacological mechanism of action Loratadine also has important implications. 我们根据盐酸氣雷他定的理化性质，在实验过程中筛选到合适的辅料，发明制备了盐酸氯雷他定的脂质体搽剂、普通搽剂和软音剂三种氣雷他定的外用制剂。 We desloratadine hydrochloride The gas physical and chemical properties, the screening experiment suitable auxiliaries, chlorine hydrochloride loratadine invention liniments liposome preparation, liniment and ordinary soft tone agent gas three kinds of loratadine topical preparations. 在脂质体搽剂的制剂处方中选择了卵磷脂和胆固酵作为脂质体的基本膜材， 十八胺、维生素E和神经酰胺、薄荷脑等对脂质体进行修饰，在普通搽剂的处方中选择了乙醇、丙二醇和蒸馏水、磷酸盐缓冲液作为搽剂的基本成分，我们在实验中选择了羧甲基纤维素、甘油、尼泊金乙酯、尿素、卡波普940、吐温80、三乙醇胺和蒸馆水用来制备软裔剂。 Cholesterol and lecithin is selected as the basic fermentation liposome membrane, octadecylamine, vitamin E and ceramides, menthol liposome is modified in pharmaceutical formulations in liposome liniment, ordinary paint formulation agent selected ethanol, propylene glycol and distilled water, phosphate buffer liniment as an essential component, we selected carboxymethylcellulose, glycerol, ethyl paraben, urea, carbopol 940 in the experiments, Tween 80, triethanolamine and distilled water used for preparing the soft descent Kan agent. 具体实施方式1.氣雷他定外用制剂抗过敏炎症作用研究实验目的为了验证氣雷他定脂质体搽剂、普通搽剂和软裔剂对大鼠同种被动皮肤过敏反应（RatPCA)模型的抗过敏作用、对小鼠耳二甲苯致炎模型的抗炎作用以及对二硝基氟苯诱导的迟发性超敏反应的影响。 1. DETAILED DESCRIPTION gas loratadine external preparation Allergy Experimental Study Objective To verify the role of inflammation gas loratadine liposomes liniment, liniments and ordinary soft descent agent isotype rat passive cutaneous anaphylaxis (RatPCA) Model anti-allergic effects, anti-inflammatory effects on the mouse ear inflammatory model of xylene and the influence on delayed hypersensitivity induced to dinitrofluorobenzene. 受试药物采用上述处方制备的氯雷他定质脂体搽剂、普通搽剂和软裔剂。 Test drug prepared using the above recipe loratadine his qualitative Liposome liniment, liniments and soft common origin agent. 组别设置设立正常对照组、模型对照组和灌胃给药对照组，对氣雷他定的三种外用制剂，即脂质体搽剂、普通搽剂和软裔剂分别设高、低剂量组。 Group disposed normal control group, model control group and the control group intragastric administration of loratadine gas three external preparation, i.e. liposomes liniment, liniments and ordinary soft American agents are located high and low dose group. 外用制剂髙、低剂量组的浓度分别为10mg/ml和3mg/ml,灌胃对照组的给药剂量为,大鼠1.2mg/kg， 小鼠1.5mg/kg。 Gao external preparation, the concentration of the low dose group were 10mg / ml and 3mg / ml, dose control group was fed rats 1.2mg / kg, Mice 1.5mg / kg. 6操作步職1.氣雷他定外用制剂对大鼠同种被动皮肤过敏反应（PCA)的影响将致敏大鼠的血清（内含丰富的IgE抗体）皮内注射于正常大鼠腹壁或背部， 每点形成一皮丘。 Operation Step 1. 6 functional gas loratadine external preparation on homologous passive cutaneous anaphylaxis (PCA) in the rat sensitized serum (containing a wealth of IgE antibodies) in rats injected intradermally in the abdominal wall or normal rats back, each point of a ridge is formed. IgE与局部皮肤肥大细胞的Fc受体结合，使之被动致敏。 IgE binding to the local skin mast cell Fc receptors make it passive sensitization. 当抗原攻击时，引起局部肥大细胞释放过敏介质，从而使局部血管的通透性增加，注入伊文思蓝，可渗出于皮丘内，形成一个篮斑。 When the antigen challenge, causing local release of allergy mediators of mast cells, thereby increasing the permeability of local blood vessels, Evans blue injection, the ridge may be in the exudate to form a basket spots. 根据篮斑范围或深浅程度，判定血管通透性变化，以反映皮肤过敏反应的程度。 According to basket spots scope or depth extent, determine vascular permeability changes to reflect the degree of skin allergic reactions. 抗血淸的制备取体重90-100g的健康大鼠8只，后大腿两側肌肉注射经Na2S04重结晶3-5次的卵白蛋白（10mg/kg)，同时腹腔注射百日咳三联疫苗2Xl(T/只。致敏后10-14天，处死动物采血，经低速离心，分离血清，置-40 'C冰箱备用。被动皮肤致敏及抗原攻击另取体重150"200g健康大鼠90只，按体重随机分为正常对照组、模型组、质脂体搽剂高剂»组、脂质脂体搽剂低剂量组、普通搽剂高级Jt组、普通搽剂低剂量组、软裔剂高剂量组、软膏剂低剂量组和灌胃对照组。将大鼠在麻醉状态下剪去背部的毛，将稀释的抗血清（稀释度为1: 6) 皮内注射于鼠背部致敏，共注射四点，每点0.1ml。 48小时后进行抗原攻击，静脉注射lml0.5n/i伊文思蓝溶液，内含卵白蛋白lmg。外用制剂各剂量组于攻击前30分钟在致敏皮肤部位涂抹氣雷他定外用制剂适量。灌胃对照组在攻击前30分钟灌胃1.2mg/kg。 Preparation of ascorbic Qing taken in healthy rats 90-100g body weight 8, on both sides of the thigh by intramuscular Na2S04 recrystallized 3-5 times ovalbumin (10mg / kg), intraperitoneal injection of pertussis DPT 2Xl (T / only 10-14 days after sensitization, the animals were sacrificed blood by low speed centrifugation, serum was separated, set to -40 'C refrigerator spare passive skin sensitization and antigen challenge another weighing 150 "200g 90 healthy rats, body weight randomly divided into normal control group, model group, high quality fat, liniment agents »groups, lipid liposome liniments low dose group, Common advanced Jt group liniments, liniments ordinary low dose group, high dose group of soft descent agent , ointments and the low dose group of rats fed control group will cut back the hair under anesthesia, the diluted antiserum (dilution 1: 6). intradermal injection of sensitized murine back, a total of four injections and spot after antigen challenge 0.1ml. 48 hours a point, intravenous lml0.5n / i Evans blue solution containing ovalbumin lmg. external preparation in each dose group 30 minutes mine gas applied to the skin site in sensitized prior to challenge he external preparation predetermined amount. intragastric gavage 30 minutes group 1.2mg / kg before challenge. 攻击30分钟后断头处死动物，收集血样l.Oml,精密加入内标溶液（盐酸萘喹啉，0.5Jig'ml'1〉 混合后加入lmol • U1氢氧化钠溶液O.lml,加入甲基叔丁基醚-正己烷（1:1) 3ml，漩涡混合5min ，离心4000r'min"10min，取上清液（有机层），水层用甲基叔丁基醚-正己烷（1:1) 2ml 同上再提取一次，合并有机层，置离心管中加入1.0mo卜L"盐酸溶液3ml，漩涡混合、离心取水层，加入10mol'L"氢氧化钠溶液0.5ml，摇匀，加入甲基叔丁基醸-正己烷（1:1) 3ml，振摇3min，离心10min,取上淸液，60'C水浴中氮气吹干。残渣加流动相50yl，漩涡振摇lmin,髙速离心12000; • min"10min， 取上淸夜20nl用高效液相色谱仪进样分析，测定氯雷他定的血药浓度。色谱条件为：色谱柱（4.6inmX300mm);固定相：n Bondapak C18(10 u 1);流动相：甲醇-乙腈-0.01 mol'L"磷酸氢二钾（35:35:30)，以磷酸调pH至7.5;流速： 2m卜min";检测波长275nm; Attack After 30 minutes the animals were decapitated, blood samples were collected l.Oml, sodium hydroxide solution was added lmol • U1 Precision O.lml mixed standard solution was added (quinoline Hydrochloride, 0.5Jig'ml'1>, methyl t-butyl ether - hexane (1: 1) in 3 ml of, vortexed for 5min, centrifuged 4000r'min "10min, the supernatant (organic layer), the aqueous layer with methyl tert-butyl ether - hexane (1: 1 ) 2ml once re-extracted as above, the organic layers were combined, placed in a centrifuge tube was added 1.0mo Bu L "hydrochloric acid 3ml, vortexed, centrifuged aqueous layer, was added 10mol'L" sodium hydroxide solution 0.5ml, shake, methyl tert-butyl Niang - hexane (1: 1) 3ml, shaken 3min, centrifuged 10min, the solution on the Qing, 60'C water bath and the residue dried by nitrogen flow phase 50yl, swirl shaking lmin, Gao centrifugation 12,000. ; • min "10min, take the night 20nl Qing sample by high performance liquid chromatography analysis, determination of loratadine plasma concentration chromatographic conditions: column (4.6inmX300mm); stationary phase: n Bondapak C18 (10 u 1); mobile phase: methanol - acetonitrile -0.01 mol'L "dipotassium hydrogen phosphate (35:35:30), adjusted to pH 7.5 phosphoric acid; flow rate: 2m Bu min"; detection wavelength 275nm; 柱温：50'C。将皮肤篮斑剪下置于试管内，加lmol/LKOHlml， 37'C消化15小时，然后加磷酸丙酮混合液3.75ml,经震荡提取后，2500r/min离心10分钟，取上清液用分光光度计在640nm处测定吸收度。用下式计算PCA抑制百分率：抑制百分率- (模型组吸收度值一各用药组吸收度值）/模型组吸收度值比较各组血药浓度的差异。 Column temperature:. 50'C skin patches cut basket placed in a test tube, add lmol / LKOHlml, 37'C digested for 15 hours and then was added 3.75 ml of phosphate acetone mixture, by extracting the shock, 2500r / min centrifuged for 10 minutes , the supernatant absorbance was measured at 640nm with a spectrophotometer at a percentage of inhibition calculated using the formula PCA:. percent inhibition - (a model group absorbance values for each treatment group absorbance value) / absorbance values of the model group compared among groups differences in blood concentration. 2.氯雷他定外用制剂对二甲苯致小鼠耳炎症的影响取体重26-30g雄性小鼠80只，随机分为模型组、脂质体搽剂高剂量组、脂质体搽剂低剂量组、普通搽剂高剂量组、普通搽剂低剂量组、软裔剂高剂量组、 软膏剂低剂量组和灌胃对照组，每组10只。 2. The external preparation loratadine xylene INDUCED ear inflammation in mice were 80 male mice weighing 26-30g, were randomly divided into model group of low, high dose group liniments liposomes, liposomes liniments dose group and high dose group ordinary liniments, liniments ordinary low dose, high dose group of soft-born agents, ointments and the group fed the control low dose group, 10 rats. 将二甲苯0.03-0.05ml滴于鼠右耳致炎，左耳作为对照。 Xylene 0.03-0.05ml dropwise murine ear inflammation, ear as a control. 外用制剂各组分别在致炎后30分钟涂抹相应的氯雷他定外用制剂适豕，灌胃对照组在致炎30分钟后经灌胃给与氯雷他定1.5mg/kg。 The external preparation in each group were inflammation after 30 minutes applicator respective loratadine hog appropriate external preparation, the control group orally 30 minutes after gavage administered after inflammation desloratadine 1.5mg / kg. 2小时后将小鼠脱臼处死，沿耳廓基线剪下两耳，用直径8mm的打孔器分别在左、 右耳同一部位打下圆耳片，称重，求左、右耳片重量之差，作为肿胀度，比较组间差异显著性。 After 2 hours the mice were sacrificed dislocation, cut along the baseline ear ears respectively laid round the left ear, with the right ear parts of the same diameter of 8mm hole punch, weighed, seeking left, the difference between the weight of right ear piece as the degree of swelling, the difference between the comparison groups was significant. 3.氣雷他定外用制剂对二硝基氟苯诱导的小鼠迟发性超敏反应（PTH)的影响取体重18-22g小鼠60只，按体重随枫分为正常对照组、模型对照组、普通搽剂高剂量组、普通搽剂低剂量组、脂质体搽剂高剂量组、脂质体搽剂低剂量组、 软裔剂高剂量组、软裔剂低剂量组和灌胃对照组，每组10只。 3. Gas loratadine external preparation on dinitrofluorobenzene-induced delayed type hypersensitivity in mice (PTH) is taken 60 mice 18-22g body weight, according to body weight into maple with normal control group, model control group, high dose group of ordinary liniments, liniments ordinary low dose, high dose group liniments liposomes, liposomes liniments low dose, high dose group of soft-born agents, soft low-dose group and descent irrigation stomach control group, n = 10. 剪去小鼠腹毛， 腹部涂抹1%二硝基氟苯（DNFB) 50nl致敏，致敏后第5天每只小鼠左耳廓涂抹1。 Mouse abdominal hair cut, abdominal applicator 1% dinitrofluorobenzene (DNFB) 50nl sensitized on day 5 after sensitization left auricle of each mouse applicator 1. /。 /. DNFB5iil发敏，正常对照组同样涂耳，但未致敏。 Min DNFB5iil hair, ears coating similar normal control group, but not sensitized. 外用制剂各剂量组分别在发敏后30分钟涂抹相应的氣雷他定外用制剂适量，灌胃对照组在发敏30分钟后经灌胃给与氯雷他定1.5mg/kg。 The external preparation in each dose group were applied 30 minutes after the mine respective gas sensitive hair he external preparation given amount, fed in the control group 30 minutes after gavage administered sensitized hair desloratadine 1.5mg / kg. 24h后将小鼠脱臼处死，沿耳廓基线剪下两耳，用直径8mm的打孔器分别在左、右耳同一部位打下圆耳片，称重，求左、 右耳片重量之差，作为肿胀度'，比较组间差异显著性。 Mice were sacrificed after 24h dislocation, cut along the baseline ear ears respectively laid round the left ear right ear of the same area with a diameter of 8mm hole punch, weighed to find the left, the difference between the weight of right ear piece, as swelling ', comparison between groups were statistically significant. 实验结果l.氣雷他定外用制剂对大鼠同种被动皮肤过敏反应（PCA)的影响实验结果表明，氣雷他定的质脂体搽剂、普通搽剂和软裔剂对大鼠同种被动皮肤过敏反应有着显著的抑制作用，其效果显著优于灌胃对照组，而其血药浓度却显著低于灌胃对照组。 The results l. Gas loratadine topical formulations affect the results of the same kind of passive cutaneous anaphylaxis (PCA) in rats showed that gas loratadine quality fat liniment, liniment and soft-American general agent with rats passive cutaneous anaphylaxis has a significant inhibitory effect was significantly better than the control group orally, and plasma concentration was lower than that in the control group orally. 结果见表l。 The results in Table l. 表1，氯雷他定的外用制剂与灌胃给药对大鼠同种被动皮肤过敏反应抑制作用和血药浓度比较。 Table 1, Comparative loratadine topical formulation for oral administration in rat passive cutaneous anaphylaxis isoform inhibition and plasma concentration. <table>table see original document page 9</column></row> <table>*与氯雷他定的外用制剂各组相比较，P<0.05。 <Table> table see original document page 9 </ column> </ row> <table> * Loratadine with topical formulations compared to each group, P <0.05. 注.各外用制剂的高剂量浓度为10mg/ml,低剂量浓度为3mg/ral。 Note the high dose topical formulation is the concentration of each 10mg / ml, a low concentration dosage of 3mg / ral. 2.氯雷他定外用制剂对二甲苯致小鼠耳炎症的影响实验结果表明，氯雷他定的脂质体搽剂、普通搽剂和软裔剂对二甲苯所致的小鼠耳炎症有着很好的抑制作用，而灌胃给药未见此抑制作用。 2. The external preparation loratadine xylene-induced ear inflammation in mice affect the results show, mouse ear inflammation loratadine liposomes liniment, liniments and soft common origin induced by xylene agents It has a good inhibitory effect, and this inhibition seen gavage. 结果见表2。 The results are shown in Table 2. 表2，氣雷他定外用制剂和灌胃给药对二甲苯所致的小鼠耳炎症抑制作用的比较。 Table 2, an external gas loratadine and comparative formulation intragastric administration xylene-induced ear inflammation in mice inhibition. <table>table see original document page 9</column></row> <table>灌胃对照组0.0133±0.004 0.0250±0.009 0.0107±0.006"与模型对照组比较，PO.01 *与模型对照组比较，PO.05注.各外用制剂的高剂量浓度为10mg/ml,低剂量浓度为3mg/ml。3.氣雷他定外用制剂对二硝基氟苯诱导的小鼠迟发性超敏反应（PTH)影响实验结果表明，氣雷他定的脂质体搽剂、普通搽剂和软膏剂对二硝基氟苯诱导的小鼠耳迟发性超敏反应有着很好的抑制作用，而灌胃给药未见此抑制作用。结果见表3。表3,氯雷他定外用制剂和灌胃给药对二硝基氣苯诱导的小鼠耳迟发性超敏反应抑制作用的比较。 左耳重（克） 右耳重（克） 耳重差（克）模型对照组 0.0120 ±0.005 0.0260 ±0.009 0.0140±0.006脂质体搽剂高剂量组 0.0119 ±0.005 0.0183±0.011 0.0064 ±0.005**脂质体搽剂低剂量组 0.0117 ±0.004 0.0195 ±0.009 0.0078 ±0細**普通搽剂高剂量组 0.0120±0.005 <Table> table see original document page 9 </ column> </ row> <table> ig control group 0.0133 ± 0.004 0.0250 ± 0.009 0.0107 ± 0.006 "with the model group compared with the model group PO.01 *, PO.05 Note the high dose topical formulation is the concentration of each 10mg / ml, a low concentration dosage of 3mg / ml.3. loratadine gas external preparation for dinitrofluorobenzene-induced delayed type hypersensitivity in mice ( PTH) would affect the results show that the gas desloratadine liposomes liniments, ointments and liniments ordinary dinitrofluorobenzene to the ears of mice induced good delayed type hypersensitivity with inhibition, the irrigation this no inhibition of gastric administration. the results are shown in table 3. table 3, and Comparative loratadine external preparation for oral administration dinitro benzene gas-induced mouse ear inhibition of delayed type hypersensitivity. left ear weight (g) right ear weight (g) weight difference of the ear (g) model control group 0.0120 ± 0.005 0.0260 ± 0.009 0.0140 ± 0.006 liposomes liniments high dose group 0.0119 ± 0.005 0.0183 ± 0.011 0.0064 ± 0.005 ** lipid plastid liniments low dose group 0.0117 ± 0.004 0.0195 ± 0.009 0.0078 ± 0 ** normal fine liniments high dose group 0.0120 ± 0.005 0.0187±0.010 0.0067 ± 0.006**普通搽剂低剂i组 0.0121 ±0扁 0.0202 ±0.011 0.0081 ±0.007软裔剂髙剂量组 0.0119 ±0.003 0.0188±0.015 0.0069 ± 0.006*软裔剂低剂量组 0.0120 ±0.005 0.0196±0.012 0.0076 ± 0.009*灌胃对照组 0.0119 ±0.004 0.0230 ±0.008 0.0111 ±0.005"与模型对照组比较，P<0.01 *与模型对照组比较，P<0.05注.各外用制剂的高剂豕浓度为10mg/ml，低剂量浓度为3mg/ml。 0.0187 ± 0.010 0.0067 ± 0.006 ** Normal liniments low dose group i 0.0121 ± 0 flat 0.0202 ± 0.011 0.0081 ± 0.007 Gao soft descent agent dose 0.0119 ± 0.003 0.0188 ± 0.015 0.0069 ± 0.006 * American soft low-dose group 0.0120 ± 0.005 0.0196 ± 0.012 0.0076 ± 0.009 * control group orally 0.0119 ± 0.004 0.0230 ± 0.008 0.0111 ± 0.005 "compared with the model control group, P <0.01 * and the model control group, P <0.05 Note swine high concentrations of external preparation agent of 10mg / ml, a low concentration dosage of 3mg / ml. 讨论我们通过采用大鼠同种被动皮肤过敏反应（PCA)， 二甲苯致小鼠耳炎症和二硝基氟苯，导的小鼠迟发性超敏反应（PTH)三种模型对氯雷他定外用制剂的药效学进行了实验研究，发现氯雷他定的外用制剂不仅对组胺诱导的皮肤过敏有着强大的拮抗作用，而且对以二硝基氟苯为代表的化学物质导致的皮肤迟发性超敏反应也有相当理想的效果，对二甲苯所致的小鼠耳急性炎症效果也相当理想， 而这在全身给药途径中，没有任何的迹象能够提示氣雷他定具有此种药理学活性。 We discuss the use of homologous passive cutaneous anaphylaxis (PCA) in rats, and the xylene-induced ear inflammation in mice DNFB Mice mediated delayed hypersensitivity (PTH) for three models Loratadine given external preparation pharmacodynamics were studied experimentally found that loratadine external preparation not only histamine-induced skin irritation with a strong antagonistic action, but also to dinitrofluorobenzene represented by the skin caused by chemical substances delayed type hypersensitivity is also quite satisfactory results, xylene-induced ear inflammation in mice with acute effect is quite satisfactory, and that the systemic route of administration, no signs of gas can be presented with such desloratadine pharmacological activity. 氯雷他定的外用途径给药方式能够对皮肤的迟发性超敏反应有着良好的治疗作用，这意味着氯雷他定外用制剂对临床常见的各种化学物质导致的慢性皮肤炎症有着很好的应用前景，解决了多年来临床对皮肤炎症没有理想治疗药物的问题，符合广大患者的利益。 Loratadine topical route of administration can have a good therapeutic effect on delayed hypersensitivity of the skin, which means that loratadine chronic inflammatory skin external preparations for clinical common cause of various chemical substances have a very good prospects to solve the many years of clinical inflammation of the skin is not ideal for the treatment of drug problems, in the interests of the majority of patients. 而这种氣雷他定新的药理活性的发现，对于氯雷他定的药理作用机制研究也具有重要的启示意义。 And this gas loratadine pharmacological activity of new discoveries for the study of the pharmacological mechanism of action Loratadine also has important implications. 最近的基础研究表明，皮肤角质细胞在皮肤过敏性反应和皮肤炎症过程中扮演者重要的角色，但经口服途径给药的氯雷他定却无法接触到皮肤的角质细胞，我们的研究结果提示，高剂量的氯雷他定对角质细胞活化可能具有抑制作用；二硝基氟苯诱导的小鼠迟发性超敏反应(PTH)主要是由Thl细胞介导的，此次研究结果提示我们，局部高剂量的氯雷他定对皮肤中Thl细胞介导的免疫反应可能具有重要的调节作用。 Recent studies have shown that the basis of skin keratinocytes in the allergic skin reactions and skin inflammation during the actor an important role, but via the oral route of administration of loratadine could not come into contact with the skin keratinocytes, our results suggest , high doses of loratadine might have inhibitory effect on keratinocyte cell activation; dinitrofluorobenzene-induced delayed type hypersensitivity in mice (PTH) is mainly mediated Thl cells, this result suggested that , local high-dose loratadine may play an important role in regulating skin Thl cell-mediated immune response. 这值得进行进一步的研究，对深入研究氯雷他定等组胺受体拮抗剂的药理活性和药物作用机制具有重要的启发意义。 This deserves further study has important instructive for in-depth study of loratadine and other pharmacological activities and mechanisms of action of histamine receptor antagonists. 我们的实验研究结果预示着瓶雷他定外用对以迟发性超敏反应为主的慢性皮肤炎症具有很好的治疗效果，具有良好的临床应用前景。 Our experimental results indicate bottles loratadine topical treatment has a good effect on delayed hypersensitivity to a chronic inflammation of the skin, has good prospects for clinical application. 2.氣霣他定外用制剂的制备实施例l氣雷他定脂质体搽剂氣雷他定卵磷脂胆固醇十八胺维生素E Tris缓冲液10g75g35g2g5g1000ml制备工艺：将处方中的脂溶性膜材卵磷脂、胆固醇、十八胺、维生素E和药物氯雷他定按处方量的溶于适量的氯仿乙醇混合有机溶剂中（氯仿：乙醇体积比为3:1)，置旋转蒸发仪上进行有机溶剂的蒸发，卵磷脂胆固醇脂质在圆底烧瓶壁形成一薄膜，用氣气流将残余的痕量有机溶剂除去。 Example l mine gas 2. Gas rainstorm external preparation prepared he will he given embodiment liposomes liniments gas loratadine lecithin cholesterol-octadecylamine vitamin E Tris buffer 10g75g35g2g5g1000ml Preparation process: The formulation of a lipophilic membrane eggs phospholipids, cholesterol, stearylamine, vitamin E and drug loratadine by prescription dissolved in a suitable amount of chloroform and ethanol in a mixed organic solvent (chloroform: ethanol ratio of 3: 1), carried out in a rotary evaporator and the organic solvent evaporation, lecithin cholesterol lipid film in a round bottom flask to form a wall, the gas stream to remove residual traces of organic solvent. 将烧瓶连接真空泵，放置过夜。 The flask was connected to a vacuum pump overnight. 加入1000ml,在漩涡振荡器上水化脂质薄膜，超声10min,在45'C条件下放置1小时，实施例2氯雷他定脂质体搽剂氯雷他定卵磷脂胆固醇神经酰胺维生素ETris缓冲液制备工艺同实施例l。 Add 1000ml, vortex oscillator Sheung lipid film, ultrasonic 10min, allowed to stand at 45'C for 1 hour, Example 2 loratadine he will liposomes liniments loratadine vitamin lecithin cholesterol ceramides ETris preparation Example l with buffer embodiment. 4g50g40g20g15glOOOml实施利3氯雷他定脂质体搽剂氯雷他定12g卵磷脂65g胆固醇20g十八胺5g维生素E 10g薄荷脑3gTris缓冲液1000ml 制备工艺同实施例l。 Embodiment 3 4g50g40g20g15glOOOml Lee loratadine liposomes liniments loratadine 12g 65g lecithin cholesterol octadecylamine Example l 20g 5g of vitamin E 10g menthol 3gTris buffer 1000ml Preparation same embodiment. 用上述处方和方法制备的脂质体稳定性好，用葡聚糖凝胶（G-50)过滤法测定的包封率均在30%以上。 Liposomes prepared by the above method and formulation stability, as measured with dextran gel filtration (G-50) Method encapsulation efficiency above 30%. 实施例4氯雷他定普通搽剂氯雷他定乙醇20g 35ml丙二醇】80ml 磷酸盐缓冲液（PBS) 加至1000ml制备工艺：先将氣雷他定溶于处方量的乙醇和丙二醇中，加入处方量的磷酸盐缓冲液(PBS)即可。 Example 4 loratadine given his ordinary liniments desloratadine] ethanol propylene glycol 20g 35ml 80ml phosphate buffered saline (PBS) was added to a preparation process 1000ml: first dissolved gas loratadine formulation amounts of ethanol and propylene glycol was added formulation amounts of phosphate buffered saline (PBS) to. 实施例5氯雷他定普通搽剂氣雷他定10g 乙醇200ml 丙二酵500ml 蒸馏水加至1000ml制备工艺：先将氣雷他定溶于处方量的乙醇和丙二醇中，再用蒸馏水加至1000ml即可。 Example 5 loratadine embodiment given his ordinary liniments gas loratadine malonate 10g 200ml ethanol fermentation 500ml distilled water to 1000ml Preparation: loratadine first gas is dissolved in ethanol and the prescribed amount of propylene glycol was added to 1000ml with distilled water It can be. 实施例4和实施例5所制备的搽剂装入特定的容器（喷雾器或雾化器）内，可以作为喷雾剂使用。 Examples 4 and 5 prepared in Example liniment specific embodiment of a container charged with (a nebulizer or atomizer) inside, it can be used as a spray. 实施例6氣雷他定的软裔剂氯雷他定8g 羧甲基纤维素40g 甘油400g 尼泊金乙酯2g 蒸馏水加至1000g制备工艺：将羧甲基纤维素与甘油混匀，然后加入溶解有处方量氯雷他定的热蒸馏水， 放置待溶胀'成凝胶后，再加入含有尼泊金乙酯的水溶液，加水圭足量即可。 His given soft American agent gas loratadine Example 6 Ray embodiment carboxymethylcellulose he will 8g 40g glycerol 2g 400g ethyl paraben were added to 1000g of distilled water Preparation: carboxymethylcellulose mixed with glycerol, followed by addition of dissolved prescriptions loratadine hot distilled water, until swelling is placed 'into the gel, and then an aqueous solution containing ethyl paraben, and sufficient water was added to Kyu. 实施例7氣雷他定的软裔剂氣雷他定卡波普940甘油吐温80尼泊金乙酯三乙醉胺蒸馏水加至5glg 65g2g 0.5g4glOOOg制备共艺：将处方量的卡波普加入到含有氯雷他定的水溶液中，形成低粘度的酸性溶液，搅拌使氯雷他定完全溶解，加入处方量的甘油、吐温80和尼泊金乙酯后，用三乙酵胺调节PH值至7.0即可。 His given soft American agent gas mine gas Example 7 Carbopol 940 he will Ray embodiment glycerol Tween 80 ethylparaben triethylamine was added to distilled water drunk amine were prepared 5glg 65g2g Art 0.5g4glOOOg: the formulation amounts of Carbopol he was added to an aqueous solution containing loratadine given in low viscosity form an acidic solution, and stirred to complete dissolution of loratadine, were added prescribed amount of glycerol, Tween 80 and ethyl paraben, adjusted with triethyl amine yeast PH value to 7.0 can be. 实施例8氯雷他定的软裔剂氣雷他定3g 羧甲基纤维素50g 甘油200g 尼泊金乙酯5g 尿素12g 蒸馏水加至1000g制备共艺：将羧甲基纤维素与甘油混匀，然后加入含有处方量氯雷他定的热蒸馏水，放置待溶胀成凝胶后，再加入含有尿素和尼泊金乙酯的水溶液，加水至足量即可。 He will mine gas soft American agent Example 8 loratadine he will carboxymethylcellulose 3g 200g 50g Glycerol 5g Ethylparaben 12g of urea was added to 1000g of distilled water were prepared Arts: carboxymethylcellulose mixed with glycerol , followed by addition of formulations containing loratadine amount of hot distilled water, until swollen to a gel on standing, was added an aqueous solution containing urea and ethyl paraben, and sufficient water was added to the can. 实施例9氯雷他定的气雾剂氣雷他定10 g乙醇30ml二氣二氟甲烷150 g维生素C 7.5 g无菌蒸馏水加至1000ml制备工艺：将处方量的氯雷他定、维生素C溶于无菌蒸馏水和乙醇的混合液中， 砂芯漏斗过滤，用无菌蒸馏水加至1000ml,分剂量灌装，封接剂量阀门系统， 分别再加压注入二氯二氟甲烷，即得。 His given mine gas aerosol loratadine Example 9 10 g of ethanol 30ml given his two gas difluoromethane 150 g Vitamin C 7.5 g of sterile distilled water to 1000ml Preparation process: the formulation amounts of loratadine, vitamin C dissolved in sterile distilled water and a mixture of ethanol, filtered fritted funnel, added with sterile distilled water to 1000ml, filling in divided doses, dose sealing valve system, respectively, and then injected under pressure into dichlorodifluoromethane, ie.