WO2017114379A1 - 一种治疗多发性硬化症的鼻用凝胶组合物 - Google Patents

一种治疗多发性硬化症的鼻用凝胶组合物 Download PDF

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WO2017114379A1
WO2017114379A1 PCT/CN2016/112274 CN2016112274W WO2017114379A1 WO 2017114379 A1 WO2017114379 A1 WO 2017114379A1 CN 2016112274 W CN2016112274 W CN 2016112274W WO 2017114379 A1 WO2017114379 A1 WO 2017114379A1
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glatiramer acetate
gel
add
water
gel composition
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PCT/CN2016/112274
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French (fr)
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戴荣欢
李国弢
颜携国
陶安进
袁建成
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深圳翰宇药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

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  • the present invention relates to a nasal mucosal administration composition for treating multiple sclerosis syndrome.
  • MS Multiple sclerosis
  • T human body physiologically reactive immune T.
  • the cells are caused by inflammation of the brain and spinal cord and demyelination of the nerves.
  • the incidence is not only high in the European and American countries, but also in the young and middle-aged population (especially in the 30-year-old population).
  • a common disease, the cause of which is generally associated with the body's own immune regulation disorder.
  • MS Currently recognized clinical classification of MS:
  • SPMS Secondary Progressive MS
  • a type of disease after RRMS is manifested as a process in which the disease is not completely relieved with recurrence and some sequelae are left after the relapsing and remission phase, and the disease gradually becomes heavier. About 50% of RRMS patients change to this type within 10 years/80% within 20 years.
  • Glatiramer acetate commercially available under the trade name It is a synthetic peptide compound composed of four amino acids: L-glutamic acid, L-alanine, L-lysine, L-stucine, for the treatment of multiple sclerosis. Both efficacy and tolerability have been well-recognized, and many studies and clinical experience have confirmed that it can significantly reduce the patient's recurrence rate, improve disability and reduce brain damage. In addition, related research also shows Compared with interferon, it can significantly reduce the recurrence rate, prevent further damage and deterioration of nerves, and also have better tolerance.
  • Glatiride acetate is clinically used as an injectable solution. In all clinical trials and user feedback, injection site atrophy was observed as the most common adverse reaction and most accepted Patients have this reaction, in addition Other most common side effects are irritation at the injection site, including: erythema, pain, swelling, itching, edema, inflammation, and allergic reactions.
  • ⁇ U.S. Patent No. 6,214,791> discloses the use of glatiramer acetate by ingestion or inhalation.
  • the disadvantage is that the degradation of the drug by the gastrointestinal fluid and the first-pass effect, enzymatic metabolism and enzymatic degradation of the liver cannot be avoided.
  • ⁇ CN201380067117> discloses a method of oral transmucosal administration, but the involuntary saliva secretion in the oral cavity and the effect of swallowing on the oral mucosal pathway; the taste stimulation of the drug affects the compliance of the pathway.
  • the alternative galamer acetate dosage regimen can be used to effectively treat glatiramer acetate in a form. Symptoms of multiple sclerosis.
  • Nasal administration system refers to a kind of preparation which exerts local or systemic treatment or prevention through nasal administration, and is especially suitable for drugs which are difficult to be administered in addition to injection and which need to exert systemic effects, such as oral polarity which is difficult to absorb.
  • Drugs drugs that are unstable in the gastrointestinal tract, drugs that are strong in the liver, and proteins and peptides.
  • the average molecular weight of glatiramer acetate is between 5,000 Daltons and 9,000 Daltons, which is not absorbed through the nasal mucosa.
  • some absorption enhancers were found to help the absorption of glatiramer acetate, but It has a certain toxic effect on the nasal mucosa, promotes the scavenging effect of cilia, and reduces the bioavailability of the drug.
  • the inventors unexpectedly discovered that a specific amount of specific bioadhesive material can avoid the scavenging effect of mucous membrane cilia in the nasal cavity and increase the drug in the mucosa. The residence time on the top, thereby increasing the bioavailability of the drug while reducing the toxicity to ciliary movement.
  • one aspect of the present invention provides a glatiramer acetate nasal gel composition prepared from glatiramer acetate, a gel matrix, and other pharmaceutically acceptable excipients, which are acceptable Other excipients include 1.15% to 1.75% (1.15%, 1.20%, 1.25%, 1.30%, 1.35%, 1.40%, 1.45%, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%) of bioadhesive materials. 1.75%), the bioadhesive material is selected from the group consisting of starch, chitin, dextran, and xanthan gum.
  • the acceptable other excipients include absorption enhancers, bioadhesive materials, osmotic pressure
  • the adjusting agent, the moisturizing agent, the preservative, the pH adjusting agent, the components thereof, the weight percentage of the gel composition is 2% to 5% of the absorption enhancer, the osmotic pressure adjusting agent is 4.5% to 9.0%, and the moisturizing agent is 1%. 5%, preservative 0.1% to 0.25, pH regulator 0.25% to 0.35.
  • the absorption enhancer is selected from the group consisting of sodium lauryl sulfate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, disodium edetate, 2-hydroxypropyl- One or more of ⁇ -cyclodextrin and lecithin;
  • the osmotic pressure adjusting agent is one or more selected from the group consisting of sodium chloride, mannitol, glucose, and sucrose;
  • the humectant is selected from the group consisting of propylene glycol, glycerin, sorbitol, and mannose One or more of the alcohols;
  • the preservative is selected from one or more of benzalkonium chloride, benzyl alcohol, phenylethyl alcohol, EDTA;
  • the pH adjusting agent is selected from one or more of acetic acid and sodium hydroxide.
  • the gel matrix accounts for 5.25% to 6.25% by weight of the gel composition, and is one or more selected from the group consisting of polyvinyl alcohol, hypromellose, carbomer, and methyl cellulose.
  • glatiramer acetate 1% by weight of the gel composition is 1% by weight.
  • the glatiramer acetate nasal gel composition comprises glatiramer acetate 1%, 2-hydroxypropyl- ⁇ -cyclodextrin 1%-5%, dextran 1.15%-1.75 %, carbomer 5.25% - 6.25% and osmotic pressure regulator, moisturizer, preservative and pH adjuster; preferably including glatiramer acetate 1%, 2-hydroxypropyl- ⁇ -cyclodextrin 5%, Portuguese
  • the glycan is 1.15%, the carbomer is 6.25%, and an osmotic pressure regulator, a humectant, a preservative, and a pH adjuster.
  • the glatiramer acetate nasal gel composition comprises glatiramer acetate 1%, lecithin 1%-5%, chitin 0.9%-1.75%, polyvinyl alcohol 5.25%-6.25% And osmotic pressure regulator, moisturizer, preservative and pH adjuster; preferably including glatiramer acetate 1%, lecithin 1%, chitin 1.75%, polyvinyl alcohol 5.25% and osmotic pressure regulator, moisturizer, antiseptic Agent and pH adjuster.
  • the glatiramer acetate nasal gel composition comprises glatiramer acetate 1%, sodium glycocholate 1%-5%, starch 0.9%-1.75%, hypromellose 5.25% - 6.25% and osmotic pressure regulator, moisturizer, preservative and pH adjuster; preferably including glatiramer acetate 1%, glycocholic acid 3.75%, starch 1.5%, hypromellose 5.5% and osmotic pressure regulator , moisturizers, preservatives and pH adjusters.
  • the glatiramer acetate nasal gel composition comprises glatiramer acetate 1%, sodium glycocholate 1%-5%, xanthan gum 0.9%-1.75%, methylcellulose 5.25 %-6.25% and osmotic pressure regulator, moisturizer, preservative and pH adjuster; preferably including glatiramer acetate 1%, glycocholic acid 3.75%, xanthan gum 0.9%, methyl cellulose 6% and osmotic pressure Conditioning agents, humectants, preservatives and pH adjusters.
  • the preparation method of the gel composition is:
  • Another aspect of the invention relates to a method for preparing a glatiramer acetate nasal gel composition as described above,
  • a glatiramer nasal gel composition for the manufacture of a medicament for the treatment of multiple sclerosis syndrome.
  • the present invention provides a pharmaceutical composition for treating multiple sclerosis syndrome, which comprises glatiramer acetate, a gel matrix, and other pharmaceutically acceptable excipient absorption enhancers, bioadhesive materials, osmotic pressure regulators , humectant, preservative, pH regulator composition, the weight percentage of glatiramer acetate 1%, gel matrix 5.25% ⁇ 6.25%, absorption enhancer 2% ⁇ 5%, bioadhesive material 1.15% ⁇ 1.75%
  • the osmotic pressure adjusting agent is 4.5% to 9.0%
  • the moisturizing agent is 1% to 5%
  • the preservative is 0.1% to 0.25
  • the pH adjusting agent is 0.25% to 0.35
  • the rest is solvent water.
  • Nasal administration can increase the distribution of drugs in brain tissue and can be used to treat central nervous system diseases.
  • the method of the present invention increases the skin mucosal permeability of the large molecular weight glatiramer acetate, increases the bioavailability of glatiramer acetate, and reduces the scavenging effect.
  • Figure 1 is a graph showing the results of the release of the results of Part 13 of Example 13.
  • Figure 2 is a graph showing the release results of the partial results of Example 13.
  • composition of glatiramer nasal gel Composition of glatiramer nasal gel:
  • mannitol, benzalkonium chloride, propylene glycol, and chitin are added with 1 to 2 times by weight of water to dissolve;
  • composition of glatiramer nasal gel Composition of glatiramer nasal gel:
  • step (3) adding the solution of the step (2) to the gel matrix solution of the step (1), adding the absorption-promoting agent 2-hydroxypropyl- ⁇ -cyclodextrin, stirring uniformly, then adding water to 200 g, stirring uniformly That is, the finished gel is obtained.
  • the in vitro release of glatiramer acetate gel was determined by a modified Franz diffusion cell.
  • the semipermeable membrane retention molecular weight 6500-9000
  • the inner diameter of the two cells in the diffusion cell was 1.3 cm.
  • the area is about 1.33cm 2 , and 2mL of glatiramer gelatin gel is accurately added to the drug pool.
  • the diffusion cell is placed in 16ml of artificial nasal fluid at 37°C, and the artificial nose preheated to 37°C is added to the receiving pool. 10mL of liquid is used as the receiving liquid.
  • a stirrer is placed in the receiving tank to rotate at 100r/min.
  • Samples are taken at 15, 30, 45, 60, 90, 120, 180min, and all the medium is taken out and quickly added with the same amount of preheating.
  • the artificial nasal fluid, the sample solution was appropriately diluted, filtered through a 0.45 ⁇ m microporous membrane, and the filtrate was continuously filtered according to the chromatographic conditions to determine the peak area of glatiramer acetate, and the cumulative release was calculated.
  • bioadhesive materials can greatly improve the release of glatiramer acetate, the initial release time is accelerated, the release rate is stable, and the release amount is compared to the sample without bioadhesive material. Increased by 2 times, significantly improve the bioavailability of the drug, and not all bioadhesive materials can achieve good results. This may be due to the interaction between different bioadhesive materials and glatiramer acetate, which also makes a big difference. When povidone is selected as the bioadhesive material, the release rate of the composition cannot meet the therapeutic effect requirement within a prescribed time. From the data in the table and the results of FIG. 2, it can be seen that the amount of release is closely related to the type of the bioadhesive material, and the non-adhesive material of the present invention is inferior, and is similar only to the result of not adding the bioadhesive material.
  • Example 14 Effect of the drug on the ciliary movement of the nasal mucosa of the nasal cavity:
  • the cilia was continuously divided by the time of the test sample to obtain the cilia.
  • the relative percentage of sustained exercise the higher the percentage, indicates that the test sample has less toxic effects on the cilia.
  • the duration of exercise after recovery can indicate whether the sample is reversible for cilia toxicity.
  • Example 5 has a greater influence on cilia toxicity, and can be produced by post-recovery exercise time. The continuous exercise time after the recovery of the sample of Example 5 was drastically decreased to less than 1 min, which proved that the use of povidone as a bioadhesive material in the sample of Example 5 had great damage to ciliary motion, and its toxic effect was irreversible, and the other four examples The toxic effects are reversible.
  • Fifty SD rats were randomly divided into 5 groups, 10 in each group.
  • a glatiramer acetate gel administration group a blank control group (administered with physiological saline), and an excipient group (blank gel matrix) were set.
  • the drug was administered once a day for 7 consecutive days.
  • the rats were sacrificed 24 hours after the last administration, and the local nasal mucosa was taken out to observe whether there was congestion or redness. The results are shown in the following table:
  • the nasal gels of Examples 1 to 4 did not cause significant irritation to the local tissues of the drug users under conventional doses.

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Abstract

一种醋酸格拉替雷鼻用凝胶组合物，其由醋酸格拉替雷、凝胶基质和药学上可接受的其他辅料制成，所述可接受的其他辅料包括生物粘附材料0.9％～1.75％，所述生物粘附材料选自淀粉、甲壳素、葡聚糖、黄原胶其中一种或多种的组合。

Description

[根据细则37.2由ISA制定的发明名称]　一种治疗多发性硬化症的鼻用凝胶组合物 技术领域
本发明涉及一种治疗多发性硬化综合症的鼻腔粘膜给药组合物。
背景技术
多发性硬化综合症(Multiple sclerosis，MS)在临床上是能够发生在人体的中枢神经系统中的一种的自身型的免疫性疾病，该类疾病的发生主要以人体生理自身反应性的免疫T细胞引起的，导致大脑及脊髓炎症及神经脱髓鞘变化为特征，其发病率不仅在欧美等国家属于高发性疾病，而且在我们果青壮年人群(尤其是三十岁人群中)中也是比较常见的一种疾病，该类疾病发病的原因一般与人体自身的免疫调节紊乱相关。
目前公认MS临床分型：
1.复发缓解型MS(RRMS)
MS的最常见病程类型，80％MS患者发病初期为本类型，表现为明显的复发和缓解过程，每次发作均基本恢复，不留或仅留下轻微后遗症。随着病程的进展多数在5～15年内最终转变为SPMS。
2.继发进展型MS(SPMS)
RRMS后的一个病程类型，表现为在复发缓解阶段以后，疾病随着复发不能完全缓解并留下部分后遗症，疾病逐渐缓慢加重的过程。RRMS患者中约50％在10年内/80％在20年内转变为本型。
3.原发进展型MS(PPMS)
MS的少见病程类型，10％～15％MS患者最初即表现为本类型，临床没有缓解复发过程，疾病呈缓慢进行性加重，并且病程大于一年。
4.进展复发型MS(PRMS)
MS的少见病程类型，约5％～10％MS患者表现为本类型，疾病始终呈缓慢进行性加重，病程中有少数缓解复发过程。
醋酸格拉替雷，市售商品名为
Figure PCTCN2016112274-appb-000001
是一种合成的多肽类化合物，由四种氨基酸组成：L-谷氨酸，L-丙氨酸，L-赖氨酸，L-络氨酸，用于治疗多发性硬化症。
Figure PCTCN2016112274-appb-000002
的疗效与耐受性皆获得十足的肯定，许多研究与临床经验证实其能大幅度地减低患者的复发率，改善失能的病况，减少脑部损伤之外。另外，相关研究亦显示
Figure PCTCN2016112274-appb-000003
较之干扰素更能显著地降低复发率，防止神经进一步的损伤与恶化，而且也具有更好的耐受性。在其它长期使用的疗效研究里(6年至最长 12年不等)，
Figure PCTCN2016112274-appb-000004
亦证实能持续地延缓患者其神经学上病程的恶化或者让患者维持稳定的病况，减少脑内损伤并防止神经元大量遭受破坏终至丧失功能的恶化情形。
醋酸格拉替雷临床上以注射溶液使用，在所有的临床试验和用户使用反馈中，注射部位萎缩据观察为最常见的不良反应且大多数接受
Figure PCTCN2016112274-appb-000005
的患者均有此反应，另外
Figure PCTCN2016112274-appb-000006
其他最常见的副作用为注射部位的刺激反应，包括：红斑、疼痛、肿胀、搔痒、水肿、发炎与过敏反应。
<美国专利6,214,791>公开的通过摄入或吸入来服用醋酸格拉替雷，缺点是无法避免胃肠液对药物的降解作用及肝脏的首过效应、酶代谢及酶降解。
<美国专利申请公开第2001/0055568A1号>中的口服缺点同<美国专利6,214,791>，吸入方式虽可以避免高首过效应，但长时间吸入给药需要定期检查肺部生理情况。且醋酸格拉替雷属于长期服用药物，若连续给药易对肺部造成一定程度的损伤，药物剂量也不好控制，用法麻烦。
<CN201380067117>公开一种口腔透黏膜给药的方式，但口腔内不自主的唾液分泌以及吞咽影响口腔黏膜途径的效能；药物的味觉刺激影响该途径的依从性。
为了克服现有注射给药可能导致患者各种不良反应、依从性差或治疗暂停等负担，开发备选醋酸格拉默给药方案，使用所述的方案使醋酸格拉替雷能有效治疗一种形式的多发性硬化症症状。
鼻腔给药系统指经由鼻腔给药，发挥局部或全身治疗或预防作用的一类制剂，尤其适用于除注射外其他途径给药困难而又需发挥全身作用的药物，如口服难以吸收的极性药物、在胃肠道中不稳定的药物、肝脏首过作用强的药物和蛋白及多肽类药物等。
发明内容
醋酸格拉替雷的平均分子量在5000道尔顿～9000道尔顿之间，不宜透过鼻腔黏膜被吸收，实验者在实验过程中发现有些吸收促进剂有助于醋酸格拉替雷的吸收，但对鼻黏膜有一定的毒性作用，促进纤毛的清除作用，降低药物的生物利用度，发明人通过实验意外发现特定含量的特定生物粘附材料可以避免鼻腔中黏膜纤毛的清除作用，增加药物在黏膜上的停留时间，从而提高药物的生物利用度，同时能够减少对纤毛运动的毒性。
为了克服上述技术缺陷，本发明一个方面提供了一种醋酸格拉替雷鼻用凝胶组合物，其由醋酸格拉替雷、凝胶基质和药学上可接受的其他辅料制成，所述可接受的其他辅料包括生物粘附材料1.15％～1.75％(1.15％、1.20％、1.25％、1.30％、1.35％、1.40％、1.45％、1.50％、1.55％、1.60％、1.65％、1.70％、1.75％)，所述生物黏附材料选自淀粉、甲壳素、葡聚糖、黄原胶其中一种或多种的组合。
进一步地，所述可接受的其他辅料包括吸收促进剂、生物粘附材料、渗透压 调节剂、保湿剂、防腐剂、pH调节剂，其组分的占凝胶组合物的重量百分比为吸收促进剂2％～5％、渗透压调节剂4.5％～9.0％、保湿剂1％～5％、防腐剂0.1％～0.25、pH调节剂0.25％～0.35。
进一步地，吸收促进剂选自十二烷基硫酸钠、去氧胆酸钠、胆酸钠、甘胆酸钠、牛磺胆酸钠、乙二胺四乙酸二钠、2-羟丙基-β-环糊精、卵磷脂其中一种或多种；渗透压调节剂选自氯化钠、甘露醇、葡萄糖、蔗糖其中一种或多种；保湿剂选自丙二醇、甘油、山梨醇、甘露醇其中一种或多种；防腐剂选自苯扎氯胺、苯甲醇、苯乙醇、EDTA其中一种或多种；pH调节剂选自醋酸、氢氧化钠其中一种或多种。
进一步地，凝胶基质占凝胶组合物的重量百分比为5.25％～6.25％，选自聚乙烯醇、羟丙甲纤维素、卡波姆、甲基纤维素中的一种或多种。
进一步地，醋酸格拉替雷1％占凝胶组合物的重量百分比为1％。
本发明一个具体实施方案中，醋酸格拉替雷鼻用凝胶组合物包括醋酸格拉替雷1％，2-羟丙基-β-环糊精1％-5％，葡聚糖1.15％-1.75％，卡波姆5.25％-6.25％以及渗透压调节剂、保湿剂、防腐剂和pH调节剂；优选包括醋酸格拉替雷1％，2-羟丙基-β-环糊精5％，葡聚糖1.15％，卡波姆6.25％以及渗透压调节剂、保湿剂、防腐剂和pH调节剂。
本发明一个具体实施方案中，醋酸格拉替雷鼻用凝胶组合物包括醋酸格拉替雷1％，卵磷脂1％-5％，甲壳素0.9％-1.75％，聚乙烯醇5.25％-6.25％以及渗透压调节剂、保湿剂、防腐剂和pH调节剂；优选包括醋酸格拉替雷1％，卵磷脂1％，甲壳素1.75％，聚乙烯醇5.25％以及渗透压调节剂、保湿剂、防腐剂和pH调节剂。
本发明一个具体实施方案中，醋酸格拉替雷鼻用凝胶组合物包括醋酸格拉替雷1％，甘胆酸钠1％-5％，淀粉0.9％-1.75％，羟丙甲纤维素5.25％-6.25％以及渗透压调节剂、保湿剂、防腐剂和pH调节剂；优选包括醋酸格拉替雷1％，甘胆酸3.75％，淀粉1.5％，羟丙甲纤维素5.5％以及渗透压调节剂、保湿剂、防腐剂和pH调节剂。
本发明一个具体实施方案中，醋酸格拉替雷鼻用凝胶组合物包括醋酸格拉替雷1％，甘胆酸钠1％-5％，黄原胶0.9％-1.75％，甲基纤维素5.25％-6.25％以及渗透压调节剂、保湿剂、防腐剂和pH调节剂；优选包括醋酸格拉替雷1％，甘胆酸3.75％，黄原胶0.9％，甲基纤维素6％以及渗透压调节剂、保湿剂、防腐剂和pH调节剂。
进一步地，所述凝胶组合物的制备方法为：
将卡波姆加入水中，充分溶胀，用碱性的pH调节剂调节pH值得凝胶，然后将醋酸格拉替雷溶于水，加入其他组分混合，搅匀，得醋酸格拉替雷溶液，将此溶液加入到卡波姆溶胀物中，得醋酸格拉替雷鼻用凝胶剂；或
将甲基纤维素或羟丙甲纤维素加入水中，充分溶胀，然后加入醋酸格拉替雷以及其他辅料混合，搅匀，得醋酸格拉替雷鼻用凝胶剂；或
将聚乙烯醇加入水中，充分溶胀，用酸性pH调节剂调节pH值得凝胶，然后 将醋酸格拉替雷溶于水，加入其他辅料混合，搅匀，得醋酸格拉替雷溶液，将此溶液加入到聚乙烯醇溶胀物中，得醋酸格拉替雷鼻用凝胶剂。
本发明的另一方面涉及如前所述的醋酸格拉替雷鼻用凝胶组合物的制备方法，
其包括如下步骤：
将卡波姆加入水中，充分溶胀，用碱性的pH(7.0-8.0)调节剂调节pH值得凝胶，然后将醋酸格拉替雷溶于水，加入其他组分混合，搅匀，得醋酸格拉替雷溶液，将此溶液加入到卡波姆溶胀物中，得醋酸格拉替雷鼻用凝胶剂；或
将甲基纤维素或羟丙甲纤维素加入水中，充分溶胀，然后加入醋酸格拉替雷以及其他辅料混合，搅匀，得醋酸格拉替雷鼻用凝胶剂；或
将聚乙烯醇加入水中，充分溶胀，用酸性pH(5.0-6.0)调节剂调节pH值得凝胶，然后将醋酸格拉替雷溶于水，加入其他辅料混合，搅匀，得醋酸格拉替雷溶液，将此溶液加入到聚乙烯醇溶胀物中，得醋酸格拉替雷鼻用凝胶剂。
本发明的再一个方面提供了醋酸格拉替雷鼻用凝胶组合物在制备治疗多发性硬化综合症的药物中的用途。
本发明提供是一种治疗多发性硬化综合征的药物组合物，该组合物由醋酸格拉替雷、凝胶基质和药学上可接受的其他辅料吸收促进剂、生物粘附材料、渗透压调节剂、保湿剂、防腐剂、pH调节剂组成，其重量百分比为醋酸格拉替雷1％、凝胶基质5.25％～6.25％、吸收促进剂2％～5％、生物粘附材料1.15％～1.75％、渗透压调节剂4.5％～9.0％、保湿剂1％～5％、防腐剂0.1％～0.25、pH调节剂0.25％～0.35，其余为溶剂水。
有益效果
1、生物利用度高。与口服给药相比，鼻腔给药可避免药物在胃肠液中降解和肝脏首过效应，生物利用度高。小分子药物生物利用度接近静脉注射，大分子多肽类药物高于口服。
2、速效，鼻黏膜面积大，黏膜下血管非常丰富，动脉、静脉和毛细血管交织成网状，药液可迅速吸收，从血管进人体循环。通过鼻腔给药可增加药物在脑组织中的分布，可用于治疗中枢神经系统疾病。
3、胃肠道中容易破坏的药物，极性大而胃肠道难于吸收的药物，鼻黏膜都能很好的吸收，分子量大的多肽类、蛋白类药物，也能在吸收促进剂的存在下较好地吸收。
4、使用方便，患者依从性好。与注射给药相比，鼻腔给药使用方便，易于被患者接受，便于自己用药。
5、本发明的方法提高了大分子量的醋酸格拉替雷的皮肤粘膜透过率，能够增加醋酸格拉替雷的生物利用度，并降低清除作用。
附图说明
附图1为实施例13部分结果的释放结果曲线图。
附图2为实施例13部分结果的释放结果曲线图。
具体实施方式
实施例1：
醋酸格拉替雷鼻用凝胶剂组成：
Figure PCTCN2016112274-appb-000007
每200克的凝胶制剂的制备步骤为:
(1)取处方量的凝胶基质卡波姆，加3～5重量倍的水，搅拌使其充分溶胀，滴加氢氧化钠调节pH值至7.0～8.0，搅拌得凝胶；
(2)另取处方量醋酸格拉替雷加2～5重量倍的水溶解；
(3)将葡聚糖、葡萄糖、甘油、EDTA加2～3重量倍水搅拌，使其溶解；
(4)将步骤(2)和步骤(3)的溶液加入到步骤(1)的凝胶基质溶液中，再加入促吸收剂2-羟丙基-β-环糊精，搅拌均匀，然后加水至200g，搅拌均匀，即制得成品凝胶。
实施例2
Figure PCTCN2016112274-appb-000008
每200克的凝胶制剂的制备步骤为:
(1)取处方量的凝胶基质聚乙烯醇，加4～7重量倍的水，滴加醋酸调节pH值 至5.0～6.0，搅拌使其充分溶胀；
(2)另取处方量醋酸格拉替雷加2～5重量倍的水溶解；
(3)将甘露醇、苯扎氯胺、丙二醇、甲壳素加1～2重量倍水搅拌，使其溶解；
(4)将步骤(2)和步骤(3)的溶液加入到步骤(1)的凝胶基质溶液中，再加入促吸收剂卵磷脂，搅拌均匀，然后加水至200g，搅拌均匀，即制得成品凝胶。实施例3：
醋酸格拉替雷鼻用凝胶剂组成：
Figure PCTCN2016112274-appb-000009
每200克的凝胶制剂的制备步骤为:
(1)称取处方量的羟丙甲纤维素，加入4～7重量倍的水，边加边搅拌，使其充分溶胀；
(2)另取处方量醋酸格拉替雷加2～5重量倍的水溶解；
(3)将氯化钠、EDTA、甘油、淀粉加3～4重量倍水搅拌，使其溶解；
(4)将步骤(2)和步骤(3)的溶液加入到步骤(1)的凝胶基质溶液中，再加入促吸收剂甘胆酸钠，搅拌均匀，然后加水至200g，搅拌均匀，即制得成品凝胶。
实施例4：
Figure PCTCN2016112274-appb-000010
每200克的凝胶制剂的制备步骤为:
(1)称取处方量的甲基纤维素，加入4～7重量倍的水，边加边搅拌，使其充分溶胀；
(2)另取处方量醋酸格拉替雷加2～5重量倍的水溶解；
(3)将氯化钠、EDTA、甘油、黄原胶加3～4重量倍水搅拌，使其溶解；
(4)将步骤(2)和步骤(3)的溶液加入到步骤(1)的凝胶基质溶液中，再加入促吸收剂甘胆酸钠，搅拌均匀，然后加水至200g，搅拌均匀，即制得成品凝胶。
实施例5
Figure PCTCN2016112274-appb-000011
每200克的凝胶制剂的制备步骤为:
(1)称取处方量的甲基纤维素，加入4～7重量倍的水，边加边搅拌，使其充分溶胀；
(2)另取处方量醋酸格拉替雷加2～5重量倍的水溶解；
(3)将氯化钠、EDTA、甘油、聚维酮加3～4重量倍水搅拌，使其溶解；
(4)将步骤(2)和步骤(3)的溶液加入到步骤(1)的凝胶基质溶液中，再加入促吸收剂2-羟丙基-β-环糊精，搅拌均匀，然后加水至200g，搅拌均匀，即制得成品凝胶
实施例6
Figure PCTCN2016112274-appb-000012
制备步骤同实施例1。
实施例7
Figure PCTCN2016112274-appb-000013
Figure PCTCN2016112274-appb-000014
制备步骤同实施例1。
实施例8
Figure PCTCN2016112274-appb-000015
制备步骤同实施例1。
实施例9
Figure PCTCN2016112274-appb-000016
制备步骤同实施例1。
实施例10
Figure PCTCN2016112274-appb-000017
Figure PCTCN2016112274-appb-000018
制备步骤同实施例1。
实施例11空白凝胶基质对照组
Figure PCTCN2016112274-appb-000019
每200克的凝胶制剂的制备步骤为:
(1)取处方量的凝胶基质卡波姆，加3～5重量倍的水，搅拌使其充分溶胀，滴加氢氧化钠调节pH值至7.0～8.0，搅拌得凝胶；
(2)将葡聚糖、葡萄糖、甘油、EDTA加2～3重量倍水搅拌，使其溶解；
(3)将步骤(2)的溶液加入到步骤(1)的凝胶基质溶液中，再加入促吸收剂2-羟丙基-β-环糊精，搅拌均匀，然后加水至200g，搅拌均匀，即制得成品凝胶。
实施例12无生物粘附材料对照组
Figure PCTCN2016112274-appb-000020
每200克的凝胶制剂的制备步骤为:
(1)取处方量的凝胶基质卡波姆，加3～5重量倍的水，搅拌使其充分溶胀，滴加氢氧化钠调节pH值至7.0～8.0，搅拌得凝胶；
(2)另取处方量醋酸格拉替雷加2～5重量倍的水溶解；
(3)将葡萄糖、甘油、EDTA加2～3重量倍水搅拌，使其溶解；
(4)将步骤(2)和步骤(3)的溶液加入到步骤(1)的凝胶基质溶液中，再加入促吸收剂2-羟丙基-β-环糊精，搅拌均匀，然后加水至200g，搅拌均匀，即制得成品凝胶。
实施例13药物的鼻腔吸收模型：
采用改良的Franz扩散池测定醋酸格拉替雷凝胶的体外释放度，将半透膜(截留相对分子质量6500～9000)固定在扩散池两池问，扩散池两池内径为1.3cm，释药面积约为1.33cm2，向给药池中准确加入2mL醋酸格拉替雷凝胶，将扩散池放入16ml的37℃人工鼻液中，向接收池中加入已预热至37℃的人工鼻液10mL作为接收液，接收池中置一搅拌子以100r/min的转速转动，于15，30，45，60，90，120，180min分别取样，将介质全部取出并迅速补加等量预热的人工鼻液，样品液经适当稀释，0.45μm微孔滤膜过滤，并续滤液按色谱条件，测定醋酸格拉替雷的峰面积，计算累积释放度。
色谱方法：照高效液相色谱法，采用Kromasil NH2色谱柱,4.6×250mm，5μm，流动相为0.08mol/L磷酸盐缓冲液(磷酸调pH至4.0±0.1)-乙腈(35：65)为流动相，进行等度洗脱，检测波长275nm，柱温为30℃，流速1.0ml/min。醋酸格拉替雷拖尾因子应小于3.0。
结果见下表(单位:％)：
Figure PCTCN2016112274-appb-000021
从表中数据以及附图1的结果可知，一些生物粘附材料能极大的提高醋酸格拉替雷的释放，初始释放时间加快，释放速度稳定，释放量相比于不添加生物黏附材料的样品提高2倍，显著提高药物的生物利用度，而并非所有生物黏附材料均能达到良好的效果。这可能是由于不同的生物黏附材料与醋酸格拉替雷之间存在相互作用导致其效果也有很大差异。当选择聚维酮作为生物粘附材料时，其组合物的释放度在规定时间内无法达到治疗效果的要求。从表中数据以及附图2的结果可知，能够看出释放量与生物黏附材料的种类密切相关，非本发明的生物黏附材料效果较差，仅与不添加生物黏附材料的结果类似。
实施例14药物对鼻腔上颚黏膜纤毛运动影响模型试验：
选取中华大蟾蜍30只，随机分成6组，每组5只，即醋酸格拉替雷凝胶给药组；空白对照组，即0.9％氯化钠注射液；将蟾蜍仰卧固定，使口腔张开，分离并 洗净上颚黏膜，于上颚黏膜处滴加试验样品溶液0.3ml，使浸没上颚黏膜，持续接触4h后用生理盐水洗净，将黏膜面向上平铺于载玻片上，滴加生理盐水，盖上盖玻片，于44×10倍光学显微镜下观察纤毛的运动情况，随后搁置于加有少量蒸馏水的层析缸中，密闭，使水蒸气近饱和状态，环境温度为20～25℃、以后每隔一段时间取出标本观察，记录从洗净试验样品至纤毛运动停止的时间，用生理盐水洗净黏膜上药液，继续观察纤毛运动是否恢复，记录恢复后持续运动的时间。以上实验中，取自蟾蜍上腭的黏膜先分成两小块，其中一块滴加受试液，另一块滴加生理盐水作为对照，用试验样品的纤毛持续运动时间除以对照组的时间得纤毛持续运动相对百分率，百分率越高，表示试验样品对纤毛的毒性影响越小。恢复后持续运动时间可以表明样品对纤毛毒性是否可逆。
Figure PCTCN2016112274-appb-000022
从表中数据可知，实施例1、2对纤毛的毒性影响最小，实施例3、4对纤毛有一定的毒性影响，实施例5对纤毛毒性影响较大，且通过恢复后运动时间可以产出，实施例5样品恢复后的持续运动时间急剧下降至1min以内，这证明实施例5样品中采用了聚维酮作为生物粘附材料对纤毛运动损伤大，其毒性作用不可逆，其余四个实施例的毒性作用均可逆。
实施例15局部刺激性试验：
取SD大鼠50只，随机分层5组，每组10只。设置醋酸格拉替雷凝胶给药组、空白对照组(给予生理盐水)、赋形剂组(空白凝胶基质)。每天给药1次，连续7天，在最后一次给药后24h处死大鼠，取出局部鼻腔黏膜，观察有无充血、红肿等现象，结果见下表：
  全身状况 局部刺激症状 局部黏膜组织状况
空白对照组 未见明显状况 未见哮喘、咳嗽、呕吐、窒息 无充血、红肿、溃破
实施例11 未见明显状况 未见哮喘、咳嗽、呕吐、窒息 无充血、红肿、溃破
实施例1 未见明显状况 未见哮喘、咳嗽、呕吐、窒息 无充血、红肿、溃破
实施例2 未见明显状况 未见哮喘、咳嗽、呕吐、窒息 无充血、红肿、溃破
实施例3 未见明显状况 未见哮喘、咳嗽、呕吐、窒息 无充血、红肿、溃破
实施例4 未见明显状况 未见哮喘、咳嗽、呕吐、窒息 无充血、红肿、溃破
从表中数据可知，常规用药剂量下，实施例1～4鼻腔凝胶剂不会对用药者的局部组织产生明显的刺激作用。

Claims (8)

  1. 一种醋酸格拉替雷鼻用凝胶组合物，其由醋酸格拉替雷、凝胶基质和药学上可接受的其他辅料制成，所述可接受的其他辅料包括生物粘附材料0.9％～1.75％，所述生物黏附材料选自淀粉、甲壳素、葡聚糖、黄原胶其中一种或多种的组合。
  2. 根据权利要求1所述的醋酸格拉替雷鼻用凝胶组合物，其中，所述可接受的其他辅料包括吸收促进剂、生物粘附材料、渗透压调节剂、保湿剂、防腐剂、pH调节剂，各组分占凝胶组合物的重量百分比为吸收促进剂1％～5％、渗透压调节剂4.5％～9.0％、保湿剂1％～5％、防腐剂0.1％～0.25％、pH调节剂0.25％～0.35％。
  3. 根据权利要求1-2任一项所述的醋酸格拉替雷鼻用凝胶组合物，其中，吸收促进剂选自十二烷基硫酸钠、去氧胆酸钠、胆酸钠、甘胆酸钠、牛磺胆酸钠、乙二胺四乙酸二钠、2-羟丙基-β-环糊精、卵磷脂其中一种或多种；渗透压调节剂选自氯化钠、甘露醇、葡萄糖、蔗糖其中一种或多种；保湿剂选自丙二醇、甘油、山梨醇、甘露醇其中一种或多种；防腐剂选自苯扎氯胺、苯甲醇、苯乙醇、EDTA其中一种或多种；pH调节剂选自醋酸、氢氧化钠其中一种或多种。
  4. 根据权利要求1-3任一项所述的醋酸格拉替雷鼻用凝胶组合物，其中，凝胶基质占凝胶组合物的重量百分比为5.25％～6.25％，选自聚乙烯醇、羟丙甲纤维素、卡波姆、甲基纤维素中的一种或多种。
  5. 根据权利要求1-4任一项所述的醋酸格拉替雷鼻用凝胶组合物，其中，醋酸格拉替雷占凝胶组合物的重量百分比为1％。
  6. 根据权利要求1-5任一项所述的醋酸格拉替雷鼻用凝胶组合物，所述凝胶组合物的制备方法为：
    将卡波姆加入水中，充分溶胀，用碱性的pH调节剂调节pH值得凝胶，然后将醋酸格拉替雷溶于水，加入其他组分混合，搅匀，得醋酸格拉替雷溶液，将此溶液加入到卡波姆溶胀物中，得醋酸格拉替雷鼻用凝胶剂；或
    将甲基纤维素或羟丙甲纤维素加入水中，充分溶胀，然后加入醋酸格拉替雷以及其他辅料混合，搅匀，得醋酸格拉替雷鼻用凝胶剂；或
    将聚乙烯醇加入水中，充分溶胀，用酸性pH调节剂调节pH值得凝胶，然后将醋酸格拉替雷溶于水，加入其他辅料混合，搅匀，得醋酸格拉替雷溶液，将此溶液加入到聚乙烯醇溶胀物中，得醋酸格拉替雷鼻用凝胶剂。
  7. 根据权利要求1-6任一项所述的醋酸格拉替雷鼻用凝胶组合物的制备方法，其包括如下步骤：
    将卡波姆加入水中，充分溶胀，用碱性的pH(7.0-8.0)调节剂调节pH值得凝胶，然后将醋酸格拉替雷溶于水，加入其他组分混合，搅匀，得醋酸格拉替雷溶液，将此溶液加入到卡波姆溶胀物中，得醋酸格拉替雷鼻用凝胶剂；或
    将甲基纤维素或羟丙甲纤维素加入水中，充分溶胀，然后加入醋酸格拉替雷以及其他辅料混合，搅匀，得醋酸格拉替雷鼻用凝胶剂；或
    将聚乙烯醇加入水中，充分溶胀，用酸性pH(5.0-6.0)调节剂调节pH值得凝胶，然后将醋酸格拉替雷溶于水，加入其他辅料混合，搅匀，得醋酸格拉替雷溶液，将此溶液加入到聚乙烯醇溶胀物中，得醋酸格拉替雷鼻用凝胶剂。
  8. 根据权利要求1-6任一项所述的醋酸格拉替雷鼻用凝胶组合物在制备治疗多发性硬化综合症的药物中的用途。
PCT/CN2016/112274 2015-12-29 2016-12-27 一种治疗多发性硬化症的鼻用凝胶组合物 WO2017114379A1 (zh)

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