WO2023078366A1 - 一种盐酸鲁拉西酮口溶膜组合物、其制备方法及应用 - Google Patents
一种盐酸鲁拉西酮口溶膜组合物、其制备方法及应用 Download PDFInfo
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- WO2023078366A1 WO2023078366A1 PCT/CN2022/129623 CN2022129623W WO2023078366A1 WO 2023078366 A1 WO2023078366 A1 WO 2023078366A1 CN 2022129623 W CN2022129623 W CN 2022129623W WO 2023078366 A1 WO2023078366 A1 WO 2023078366A1
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- lurasidone hydrochloride
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Definitions
- the invention relates to the field of pharmaceutical preparations, in particular to a lurasidone hydrochloride mouth-dissolving film composition with simple process and good stability, its preparation method and application.
- Schizophrenia is a serious mental disorder. According to the World Health Organization, more than 21 million people worldwide are suffering from schizophrenia. This disease is also the eighth leading cause of disability in the 15-44 age group. As of the end of 2016, the number of registered schizophrenia patients in my country was about 4.05 million.
- the existing drugs for the treatment of schizophrenia can be roughly divided into two categories: one is typical antipsychotic drugs, also known as first-generation antipsychotic drugs; the other is atypical antipsychotic drugs, which generally have dopamine D2/5- HT2A receptor antagonism, also known as second-generation antipsychotics.
- dosage forms such as tablets and capsules are often ineffective for patients, and easy-to-use dosage forms should be considered for patients with schizophrenia.
- Lurasidone hydrochloride is a new atypical antipsychotic drug jointly developed by Takeda Pharmaceutical and Sumitomo Pharmaceutical for the treatment of schizophrenia. It is used for the treatment of schizophrenia and bipolar depression.
- the current clinical dosage form is ordinary tablet, and ordinary tablet is difficult to swallow, so it is not suitable for children and elderly patients to take this kind of dosage form medicine, and it is not convenient for patients to take it without water.
- the present invention provides a kind of lurasidone hydrochloride mouth-dissolving film composition, and it comprises active drug, film-forming material, plasticizer and corrective agent, and described active drug is the compound shown in formula I, namely ( 3aR, 4S, 7R, 7aS)-2-((1R,2R)-2-[4-(1.2-benzisothiazol3-yl)piperazine-1-methyl]cyclohexylmethyl)hexahydro- 4.7-Methylene-2H-isoindole-1,3-dione hydrochloride (lurasidone hydrochloride);
- the mass percentage of the active drug is preferably 1% to 60%, such as 10% to 55%, or 10% to 50%, such as 52.1%, 47.2%, 41.7%, 41.3% %, 38.5%, 35.7%, 33.3%, 30.0% or 25.0%, the mass percentage refers to the mass percentage of the active drug in the total mass of the lurasidone hydrochloride orally dissolving film composition.
- the film-forming material is a drug carrier, preferably xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, corn Prion, hypromellose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymer One or more of materials, polylactic acid and silicone rubber.
- the film-forming material is polyvinyl alcohol, hydroxypropyl cellulose, a mixture of polyvinyl alcohol and polyethylene glycol 6000, or a mixture of hydroxyethyl cellulose and pullulan.
- the mass percentage of the film-forming material is 20% to 60%, such as 30% to 50%, such as 57.0%, 50.0%, 47.0%, 45.8%, 41.7%, 41.3% , 38.5%, 37.7%, 35.7%, 33.0% or 31.2%, the mass percentage refers to the mass percentage of the film-forming material in the total mass of the lurasidone hydrochloride mouth-dissolving film composition.
- the plasticizer is used to reduce the glass transition temperature of the film, increase plasticity and toughness, and increase elongation, preferably polyethylene glycol, glycerin, propylene glycol, silicone oil, polypropylene glycol, hexylene glycol One or more of alcohols.
- the mass percentage of the plasticizer is 0 to 20%, such as 16.0%, 9.4%, 8.3%, 5.2%, 5.0%, 4.7%, 4.5%, 4.3% or 0% , said mass percentage refers to the mass percentage of plasticizer in the total mass of lurasidone hydrochloride orally dissolving film composition.
- the flavoring agent plays a flavoring role in the film, preferably aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, essence, spices, menthol, chlorine One or more of sodium chloride, citric acid, saccharin and sodium saccharin.
- the mass percentage of the flavoring agent is 0-25.0%, preferably 3.0%-25.0%, such as 17.7%, 17.1%, 16.4%, 12.5%, 10.4%, 10.0%, 9.5%, 9.4%, 8.3%, 5.0% or 3.0%, the mass percentage refers to the mass percentage of the flavoring agent in the total mass of the lurasidone hydrochloride orally dissolving film composition.
- the lurasidone hydrochloride orally dissolving film composition may further include a disintegrating agent, or a disintegrating agent may be mixed with a salivary stimulating agent, a filler, a coloring agent, an anti-adhesive agent and a bacteriostatic agent. one or a combination of more.
- the disintegrant refers to an adjuvant that promotes rapid disintegration of the drug into small particles in the gastrointestinal tract, preferably low-substituted hydroxypropyl cellulose, cross-linked povidone, cross-linked carboxymethyl One or more of sodium cellulose, sodium carboxymethyl starch, starch, microcrystalline cellulose and pregelatinized starch.
- the mass percentage of the disintegrant is preferably 0-10.0%, such as 3.6%, 6.9%, 7.0% or 7.1%, and the mass percentage refers to the disintegrant
- the mass accounts for the percentage of total mass of lurasidone hydrochloride orally dissolving film composition.
- the saliva stimulating agent refers to a substance that stimulates saliva production, preferably one or more of tartaric acid, malic acid and mannitol.
- the mass percentage of the saliva stimulating agent is 0-10.0%, such as 0.6%, 0.9%, 6.9%, 7.0%, 7.1% or 7.7%, and the mass percentage refers to the percentage of the quality of the saliva stimulating agent in the total mass of the lurasidone hydrochloride orally dissolving film composition.
- the filler refers to a solid substance that can be added to the material to improve the performance of the material, or to increase the volume, increase the weight, and reduce the cost of the material, preferably mannitol, sucrose, glucose, maltose, lactose, One or more of sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose.
- the mass percentage of the filler is 0 to 10.0%, such as 6.0% or 3.0%, and the mass percentage means that the mass of the filler accounts for The percentage of the total mass of the film-dissolving composition.
- the coloring agent refers to a substance that can improve the appearance color of the preparation, can be used to identify the concentration of the preparation, distinguish the application method and reduce the patient's aversion to taking the medicine, preferably titanium dioxide, pigments and color lakes one or more.
- the mass percentage of the colorant is 0 to 5.0%, such as 1.1%, 1.0% or 0.8%, and the mass percentage means that the mass of the colorant accounts for The percentage of the total mass of the ketone orally dissolving film composition.
- the anti-adhesive agent refers to the ability to improve the performance of the preparation and avoid the adhesion between the preparations, preferably one or more of talcum powder, magnesium stearate, and calcium stearate.
- the mass percentage of the anti-adhesive agent is 0 to 5.0%, such as 0.7% or 0.8%, and the mass percentage refers to that the mass percentage of the anti-adhesive agent accounts for The percentage of the total mass of the ketone orally dissolving film composition.
- the bacteriostatic agent refers to a substance capable of inhibiting bacterial production, preferably one or more of methylparaben, ethylparaben, and sodium thiosulfate.
- the mass percent content of the bacteriostatic agent is 0 to 1.0%, such as 0.6%, and the mass percent content refers to that the mass percent content of the bacteriostatic agent occupies The percentage of the total mass of the film composition.
- the lurasidone hydrochloride orally dissolving film composition can be any of the following prescriptions:
- Prescription 1 47.2% lurasidone hydrochloride, 33.0% hydroxypropyl cellulose, 9.4% glycerin, 9.4% sucralose and 1.0% titanium dioxide;
- Prescription 2 30.0% lurasidone hydrochloride, 45.0% polyvinyl alcohol, 12.0% polyethylene glycol 6000, 5.0% sucralose, 3.5% menthol, 0.9% mannitol, 3.0% lactose, and 0.6% paraben ester;
- Prescription 3 33.3% lurasidone hydrochloride, 45.8% polyvinyl alcohol, 8.3% glycerin, 3.3% sodium chloride, 4.2% citric acid, 4.3% sucralose, 0.4% essence and 0.4% menthol;
- Prescription 4 25.0% lurasidone hydrochloride, 50.0% polyvinyl alcohol, 16.0% glycerin, 2.5% steviol glycoside, 0.5% essence and 6.0% lactose;
- Prescription 5 41.3% lurasidone hydrochloride, 24.8% hydroxyethyl cellulose, 16.5% pullulan, 8.3% glycerin, 8.3% sucralose and 0.8% titanium dioxide;
- Prescription 7 52.1% lurasidone hydrochloride, 20.8% hydroxyethylcellulose, 10.4% pullulan, 5.2% glycerin, 10.4% sucralose and 1.1% titanium dioxide;
- Prescription 8 41.7% lurasidone hydrochloride, 25.0% hydroxyethylcellulose, 16.7% pullulan, 5.0% glycerin, 8.3% sucralose, 1.7% menthol, 0.8% talc and 0.8% titanium dioxide;
- Prescription 9 38.5% lurasidone hydrochloride, 23.1% hydroxyethyl cellulose, 15.4% pullulan, 4.5% glycerin, 7.7% sucralose, 1.5% menthol, 0.8% essence, 7.7% citric acid and 0.8% talc;
- Prescription 10 35.7% lurasidone hydrochloride, 21.4% hydroxyethyl cellulose, 14.3% pullulan, 4.3% glycerin, 7.1% sodium carboxymethyl starch, 7.1% sucralose, 1.4% menthol, 0.8 % fragrance, 7.1% citric acid and 0.8% talc.
- the present invention also provides the preparation method of described lurasidone hydrochloride orally dissolving film composition, it comprises the following steps:
- step 2) Add each component except the active drug and the film-forming material to the solution obtained in step 1), and stir to obtain a blank glue solution;
- step 3 placing the active drug in the blank glue solution obtained in step 2), stirring until uniformly dispersed, stirring and defoaming under vacuum conditions, to obtain the drug-containing glue;
- the thickness of the lurasidone hydrochloride orally dissolving film composition is 10 ⁇ m to 300 ⁇ m, for example, 10 ⁇ m to 300 ⁇ m.
- the lurasidone hydrochloride orally dissolving film composition can be completely disintegrated within 2 minutes in 1000 mL of simulated saliva at 37°C ⁇ 1°C.
- the present invention also provides the use of the lurasidone hydrochloride orally dissolving film composition in the preparation of medicaments for treating and/or preventing depression.
- the present invention also provides a method for treating and/or preventing depression, which comprises administering a therapeutically effective amount of the lurasidone hydrochloride orally dissolving film composition to patients in need.
- the lurasidone hydrochloride orally dissolving film composition is a pharmaceutical preparation.
- the lurasidone hydrochloride mouth-dissolving film composition of the present invention has thin thickness, good taste, stable properties, good dissolution rate, and can be melted immediately in the oral cavity without drinking water. It has the advantages of no gritty feeling after dissolution, fast oral absorption speed, uniform appearance, good flexibility, simple process, no sedimentation during the preparation of membrane solution, content uniformity meets requirements, and high drug loading capacity.
- the invention solves the defects of the existing preparations such as inconvenient taking and poor patient compliance, and is especially suitable for patients with dysphagia.
- therapeutically effective amount refers to an amount of a pharmaceutically active ingredient of the invention sufficient to achieve the intended use, including but not limited to the treatment of diseases as defined below.
- a therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and the disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, etc., which can be readily determined by one of ordinary skill in the art.
- the specific dosage will vary depending upon the particular active ingredient chosen, the dosing regimen upon which it is administered, whether it is administered in combination with other compounds, the timing of administration, the tissue administered and the physical delivery system employed .
- Fig. 1 is the stripping curve of embodiment 3 lurasidone hydrochloride orally dissolving film preparation in pH 1.2 hydrochloric acid solution;
- Fig. 2 is the dissolution curve of embodiment 3 lurasidone hydrochloride orally dissolving film preparation in pH 3.8 acetate buffer solution.
- step 2) Add each component except the active drug and the film-forming material to the solution obtained in step 1), and stir to obtain a blank glue solution;
- step 3 placing the active drug in the blank glue solution obtained in step 2), stirring until uniformly dispersed, stirring and defoaming under vacuum conditions, to obtain the drug-containing glue;
- step 4) Apply the drug-containing glue solution obtained in step 3) after defoaming evenly on the release film with a coating machine, heat, dry, and cut to obtain a lurasidone hydrochloride orally dissolving film composition.
- lurasidone orally dissolving film preparations were prepared by the preparation method provided by the present invention and the disintegration time limit was determined.
- the specific determination methods are as follows:
- Example Disintegration time limit (s) 1 47 ⁇ 9 2 51 ⁇ 12 3 63 ⁇ 6 4 53 ⁇ 4 5 67 ⁇ 15 6 49 ⁇ 9 7 44 ⁇ 6 8 52 ⁇ 5 9 54 ⁇ 8 10 27 ⁇ 9
- the dissolution curve of lurasidone hydrochloride orally dissolving film preparation prepared by the prescription of embodiment 3 is measured, and the specific assay method is as follows:
- Test medium 900ml pH 1.2 hydrochloric acid solution (37°C ⁇ 0.5°C), 900ml pH 3.8 acetate buffer solution (37°C ⁇ 0.5°C).
- Dissolution method "Chinese Pharmacopoeia” 2020 Edition 0931 Dissolution and Release Determination Method 2 (paddle method), the rotation speed is 50rpm.
- the related substance detecting method of lurasidone hydrochloride orally dissolving film prepared according to the prescription of embodiment 3 is as follows:
- Impurities IM-2 and IM-4 were calculated by the principal component external standard method with correction factor; unknown impurities were calculated by the principal component external standard method without correction factor, and the total impurity was the sum of each known impurity and unknown impurity.
- the lurasidone hydrochloride mouth-dissolving film composition provided by the present invention has thin thickness, good taste, stable properties, low impurity content, and can be instantly dissolved in the oral cavity without drinking water, and the oral absorption rate is fast.
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Abstract
提供一种盐酸鲁拉西酮口溶膜组合物、制备方法及应用。盐酸鲁拉西酮口溶膜组合物，其包含活性药物、成膜材料、增塑剂和矫味剂，所述的活性药物为如式I所示的(3aR,4S,7R,7aS)-2-((1R,2R)-2-[4-(1.2-苯并异噻唑3-基)哌嗪-1-甲基]环已基甲基)六氢-4.7-亚甲基-2H-异吲哚-1,3-二酮盐酸盐。得到的盐酸鲁拉西酮口溶膜组合物具有良好的溶出速率，在口腔中溶解后不会有沙砾感、且外观均一、柔韧性好、同时在膜液配制过程中不会发生沉降，含量均一性符合要求。
Description
本申请要求享有2021年11月4日向中国国家知识产权局提交的，专利申请号为202111301406.X，发明名称为“一种盐酸鲁拉西酮口溶膜组合物、其制备方法及应用”的在先申请的优先权权益。所述在先申请的全文通过引用的方式结合于本申请中。
本发明涉及药物制剂领域，具体涉及一种工艺简单、稳定性良好的盐酸鲁拉西酮口溶膜组合物、其制备方法及应用。
精神分裂症是一种严重的精神障碍，据世界卫生组织统计，全球有超过2100万人正在遭受精神分裂症的困扰，这种疾病还是15至44岁年龄组人群的第八大致残原因。截至2016年底，我国登记在册的精神分裂症患者人数约为405万。现有精神分裂症治疗药物大致可分为两大类：一类为典型抗精神病药，又称为第一代抗精神病药；另一类为非典型抗精神病药，普遍具有多巴胺D2/5-HT2A受体拮抗作用，又称为第二代抗精神病药。2010年以来，国内样本医院的精神类药物市场规模从12.5亿元增长到2015年的24.7亿元，5年的复合年均增长率达14.6％。鉴于精神分裂症发病机理尚未完全阐明、现有治疗药物疗效的局限及不良反应，临床需要疗效更好、不良反应更小的治疗药物。国内精神科医疗资源缺乏，精神药物市场潜力巨大。然而，精神分裂患者急性期时，常常出现患者拒绝服药，口腔中藏药及吐药情况，患者用药依从性问题普遍存在。因此，片剂和胶囊剂这种剂型常常无法对患者发挥作用，对于精神分裂患者应考虑使用易于使用的剂型。有鉴于此，有必要提供一种使用方便、顺应性较好 且质量稳定的新制剂，以解决上述问题。
盐酸鲁拉西酮(lurasidone hydrochloride)是一款由武田制药及住友制药联合开发的用于治疗精神分裂症的新型非典型抗精神病药，用于精神分裂症和双相抑郁症的治疗。目前临床用剂型为普通片剂，而普通片剂由于难以下咽，少儿人群和老年患者在服用这类剂型药品时不太适用，在没有水的情况下也不能方便患者服用。
因此，目前需要开发一种盐酸鲁拉西酮的剂型，以解决患者服药顺应性差的问题，特别适宜有吞咽困难的患者，以其提高患者的依从性。
发明内容
本发明提供了一种盐酸鲁拉西酮口溶膜组合物，其包含活性药物、成膜材料、增塑剂和矫味剂，所述的活性药物为如式I所示的化合物，即(3aR，4S，7R，7aS)-2-((1R，2R)-2-[4-(1.2-苯并异噻唑3-基)哌嗪-1-甲基]环己基甲基)六氢-4.7-亚甲基-2H-异吲哚-1，3-二酮盐酸盐(盐酸鲁拉西酮)；
根据本发明的实施方案，所述的活性药物的质量百分含量优选1％～60％，比如10％～55％，又如10％～50％，例如52.1％、47.2％、41.7％、41.3％、38.5％、35.7％、33.3％、30.0％或25.0％，所述的质量百分含量是指活性药物的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的成膜材料为药物的载体，优选黄原胶、瓜尔胶、果胶、明胶、虫胶、阿拉伯胶、淀粉、糊精、琼脂、海藻酸钠、玉米朊、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、聚乙烯醇、聚 乙烯吡咯烷酮、聚乙二醇、聚氧乙烯、普鲁兰多糖、丙烯酸共聚物、聚乳酸和硅橡胶中的一种或多种。在一些实施方案中，所述成膜材料为聚乙烯醇、羟丙基纤维素、聚乙烯醇与聚乙二醇6000的混合物、或者羟乙基纤维素与普鲁兰多糖的混合物。
根据本发明的实施方案，所述的成膜材料的质量百分含量为20％～60％，比如30％～50％，例如57.0％、50.0％、47.0％、45.8％、41.7％、41.3％、38.5％、37.7％、35.7％、33.0％或31.2％，所述的质量百分含量是指成膜材料的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的增塑剂用于降低膜的玻璃化转化温度，增加塑性和韧性，提高拉伸率，优选聚乙二醇、甘油、丙二醇、硅油、聚丙二醇、己二醇中的一种或多种。
根据本发明的实施方案，所述的增塑剂的质量百分含量为0～20％，例如16.0％、9.4％、8.3％、5.2％、5.0％、4.7％、4.5％、4.3％或0，所述的质量百分含量是指增塑剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述矫味剂在膜剂中起矫味作用，优选阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊糖苷、甘草甜素、香精、香料、薄荷脑、氯化钠、枸橼酸、糖精和糖精钠中的一种或多种。
根据本发明的实施方案，所述的矫味剂的质量百分含量为0～25.0％，优选3.0％～25.0％，例如17.7％、17.1％、16.4％、12.5％、10.4％、10.0％、9.5％、9.4％、8.3％、5.0％或3.0％，所述的质量百分含量是指矫味剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的盐酸鲁拉西酮口溶膜组合物可以进一步包括崩解剂，或者崩解剂与唾液刺激剂、填充剂、着色剂、抗粘剂和抑菌剂中的一种或多种的组合。
根据本发明的实施方案，所述的崩解剂是指促使药物在胃肠道中迅速崩解成小粒子的辅料，优选低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素 钠、羧甲基淀粉钠、淀粉、微晶纤维素和预胶化淀粉中的一种或多种。
根据本发明的实施方案，所述的崩解剂的质量百分含量优选为0～10.0％，例如3.6％、6.9％、7.0％或7.1％，所述的质量百分含量是指崩解剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的唾液刺激剂是指刺激唾液产生的物质，优选酒石酸、苹果酸和甘露醇一种或多种。
根据本发明的实施方案，所述的唾液刺激剂的质量百分含量为0～10.0％，例如0.6％、0.9％、6.9％、7.0％、7.1％或7.7％，所述的质量百分含量是指唾液刺激剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的填充剂是指加入物料中可以改善物料性能，或能增容、增重，降低物料的成本的固体物质，优选甘露醇、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种。
根据本发明的实施方案，所述的填充剂的质量百分含量为0～10.0％，例如6.0％或3.0％，所述的质量百分含量是指填充剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的着色剂是指能改善制剂的外观颜色，可用来识别制剂的浓度、区分应用方法和减少病人对服药的厌恶感的物质，优选二氧化钛、色素和色淀中一种或多种。
根据本发明的实施方案，所述的着色剂的质量百分含量为0～5.0％，例如1.1％、1.0％或0.8％，所述的质量百分含量是指着色剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的抗粘剂是指能改善制剂的性能，避免制剂间的黏连，优选滑石粉、硬脂酸镁、硬脂酸钙中一种或多种。
根据本发明的实施方案，所述的抗粘剂的质量百分含量为0～5.0％，例如 0.7％或0.8％，所述的质量百分含量是指抗粘剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的抑菌剂是指能够抑制细菌产生的物质，优选羟苯甲酯、羟苯乙酯、硫代硫酸钠中的一种或多种。
根据本发明的实施方案，所述的抑菌剂的质量百分含量为0～1.0％，例如0.6％，所述的质量百分含量是指抑菌剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
根据本发明的实施方案，所述的盐酸鲁拉西酮口溶膜组合物可以为以下任一处方：
处方1：47.2％盐酸鲁拉西酮、33.0％羟丙基纤维素、9.4％甘油、9.4％三氯蔗糖和1.0％二氧化钛；
处方2：30.0％盐酸鲁拉西酮、45.0％聚乙烯醇、12.0％聚乙二醇6000、5.0％三氯蔗糖、3.5％薄荷脑、0.9％甘露醇、3.0％乳糖和0.6％羟苯甲酯；
处方3：33.3％盐酸鲁拉西酮、45.8％聚乙烯醇、8.3％甘油、3.3％氯化钠、4.2％枸橼酸、4.3％三氯蔗糖、0.4％香精和0.4％薄荷脑；
处方4：25.0％盐酸鲁拉西酮、50.0％聚乙烯醇、16.0％甘油、2.5％甜菊糖苷、0.5％香精和6.0％乳糖；
处方5：41.3％盐酸鲁拉西酮、24.8％羟乙基纤维素、16.5％普鲁兰多糖、8.3％甘油、8.3％三氯蔗糖和0.8％二氧化钛；
处方6：47.2％盐酸鲁拉西酮、28.3％羟乙基纤维素、9.4％普鲁兰多糖、4.7％甘油、9.4％三氯蔗糖和1.0％二氧化钛；
处方7：52.1％盐酸鲁拉西酮、20.8％羟乙基纤维素、10.4％普鲁兰多糖、5.2％甘油、10.4％三氯蔗糖和1.1％二氧化钛；
处方8：41.7％盐酸鲁拉西酮、25.0％羟乙基纤维素、16.7％普鲁兰多糖、5.0％甘油、8.3％三氯蔗糖、1.7％薄荷脑、0.8％滑石粉和0.8％二氧化钛；
处方9：38.5％盐酸鲁拉西酮、23.1％羟乙基纤维素、15.4％普鲁兰多糖、4.5％甘油、7.7％三氯蔗糖、1.5％薄荷脑、0.8％香精、7.7％枸橼酸和0.8％滑石粉；
处方10：35.7％盐酸鲁拉西酮、21.4％羟乙基纤维素、14.3％普鲁兰多糖、4.3％甘油、7.1％羧甲基淀粉钠、7.1％三氯蔗糖、1.4％薄荷脑、0.8％香精、7.1％枸橼酸和0.8％滑石粉。
本发明还提供了所述的盐酸鲁拉西酮口溶膜组合物的制备方法，其包括以下步骤：
1)将成膜材料在60℃～70℃条件下加热溶于水中，形成溶液；
2)向步骤1)得到的溶液中加入除活性药物、成膜材料外的各组分，搅拌均匀后得空白胶液；
3)将活性药物置于步骤2)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；
4)将所述含药胶用涂布机均匀涂布于离型膜上，加热、干燥、切割，得盐酸鲁拉西酮口溶膜组合物。
根据本发明的实施方案，所述的盐酸鲁拉西酮口溶膜组合物厚度为10μm～300μm，例如10μm～300μm。
根据本发明的实施方案，所述的盐酸鲁拉西酮口溶膜组合物，在1000mL、37℃±1℃的模拟唾液中2min内能够完全崩解。
本发明还提供了所述的盐酸鲁拉西酮口溶膜组合物在制备治疗和/或预防抑郁症的药物中的用途。
本发明还提供了一种治疗和/或预防抑郁症的方法，其为需要的患者施用治疗有效量的所述的盐酸鲁拉西酮口溶膜组合物。
根据本发明的实施方案，所述的盐酸鲁拉西酮口溶膜组合物为药物制剂。
本发明的有益效果：本发明的盐酸鲁拉西酮口溶膜组合物，具有厚度薄、口感良好、性质稳定、具有良好的溶出速率，且无需饮水即可在口腔内即刻溶 化、在口腔中溶解后不会有沙砾感、口服吸收速度快的优点，，且外观均一、柔韧性好，同时工艺简单，在膜液配制过程中不会发生沉降，含量均一性符合要求，载药量高。解决了现有制剂服用不方便、患者顺应性差等缺陷，特别适宜有吞咽困难的患者。
术语定义与说明
除非另有说明，本申请说明书和权利要求书中记载的术语定义，包括其作为实例的定义、示例性的定义、优选的定义、实施例中具体的定义等，可以彼此之间任意组合和结合。这样的组合和结合应当属于本申请说明书记载的范围内。
术语“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明药物活性成分的量。治疗有效量可以取决于以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定活性成分、所依据的给药方案、是否与其它化合物组合给药、给药的时间安排、所给药的组织和所承载的物理递送系统。
图1为实施例3盐酸鲁拉西酮口溶膜制剂在pH 1.2盐酸溶液中的溶出曲线；
图2为实施例3盐酸鲁拉西酮口溶膜制剂在pH 3.8醋酸盐缓冲溶液中的溶出曲线。
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保
制备方法：
1)将成膜材料在60℃～70℃条件下加热溶于水中，形成溶液；
2)向步骤1)得到的溶液中加入除活性药物、成膜材料外的各组分，搅拌均匀后得空白胶液；
3)将活性药物置于步骤2)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；
4)将脱泡后的步骤3)得到的含药胶液用涂布机均匀涂布于离型膜上，加热、干燥、切割，得盐酸鲁拉西酮口溶膜组合物。
1.崩解时限测试
按照实施例1至实施例10的处方，采用本发明提供的制备方法制备鲁拉西酮口溶膜制剂并测定其崩解时限，具体测定方法如下：
任取每个实施例所得药膜6片，每次取1片，轻轻置于1000ml，37℃±1℃人工唾液中，静置状态下，观察本品完全崩解的时间，结果如表2所示。
表2
| 实施例 | 崩解时限(s) |
| 1 | 47±9 |
| 2 | 51±12 |
| 3 | 63±6 |
| 4 | 53±4 |
| 5 | 67±15 |
| 6 | 49±9 |
| 7 | 44±6 |
| 8 | 52±5 |
| 9 | 54±8 |
| 10 | 27±9 |
2.溶出结果测定
对实施例3处方制备的盐酸鲁拉西酮口溶膜制剂测定其溶出曲线，具体测定方法如下：
试验介质：900ml pH 1.2盐酸溶液(37℃±0.5℃)、900ml pH 3.8醋酸盐缓冲溶液(37℃±0.5℃)。
溶出方法：《中国药典》2020版0931溶出度与释放度测定法第二法(桨法)，转速为50rpm。
取样时间：5min、10min、15min、20min、30min。
取盐酸鲁拉西酮口溶膜制剂6片，按以上方法测定溶出曲线，结果如表3和图1～2所示。
表3
3.有关物质结果
按照实施例3的处方制备的盐酸鲁拉西酮口溶膜的有关物质检测方法如下：
3.1有关物质分析方法描述
1)色谱条件
2)计算
杂质IM-2和IM-4按加校正因子的主成分外标法计算；未知杂质按不加校正因子的主成分外标法计算，总杂为各已知杂质与未知杂质的总和。
3)杂质限度
| 名称 | IM-4 | IM-2 | 未知单杂 | 总杂 |
| 限度(％) | 0.25 | 0.25 | 0.2 | 0.4 |
实施例3的样品有关物质检出结果如表4所示。
表4
| 样品信息 | 最大未知单杂 | 总杂 |
| 盐酸鲁拉西酮口溶膜 | 0.05％ | 0.06％ |
综合上述实验数据可知，本发明提供的盐酸鲁拉西酮口溶膜组合物，具有厚度薄、口感良好、性质稳定、杂质含量低、且无需饮水即可在口腔内即刻溶化、口服吸收速度快的优点。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
- 一种盐酸鲁拉西酮口溶膜组合物，其特征在于，所述组合物包含：活性药物、成膜材料、增塑剂和矫味剂，所述的活性药物为如式I所示的化合物，即(3aR,4S,7R,7aS)-2-((1R,2R)-2-[4-(1.2-苯并异噻唑3-基)哌嗪-1-甲基]环已基甲基)六氢-4.7-亚甲基-2H-异吲哚-1,3-二酮盐酸盐；
- 如权利要求1所述的盐酸鲁拉西酮口溶膜组合物，其特征在于：所述的活性药物的质量百分含量为1％～60％，所述的质量百分含量是指活性药物的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
- 如权利要求1或2所述的盐酸鲁拉西酮口溶膜组合物，其特征在于：所述的成膜材料为黄原胶、瓜尔胶、果胶、明胶、虫胶、阿拉伯胶、淀粉、糊精、琼脂、海藻酸钠、玉米朊、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、聚氧乙烯、普鲁兰多糖、丙烯酸共聚物、聚乳酸和硅橡胶中的一种或多种；和/或，所述的增塑剂为聚乙二醇、甘油、丙二醇、硅油、聚丙二醇、己二醇中的一种或多种；和/或，所述矫味剂为阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊糖苷、甘草甜素、香精、香料、薄荷脑、氯化钠、枸橼酸、糖精和糖精钠中的一种或多种。
- 如权利要求1～3任一项所述的盐酸鲁拉西酮口溶膜组合物，其特征在于：所述的成膜材料的质量百分含量为20％～60％，所述的质量百分含量是指成膜材料的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比；和/或，所述的增塑剂的质量百分含量为0～20％，所述的质量百分含量是指增塑剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比；所述的矫味剂的质量百分含量为0～25.0％，所述的质量百分含量是指矫味剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。
- 如权利要求1～4任一项所述的盐酸鲁拉西酮口溶膜组合物，其特征在于：所述的盐酸鲁拉西酮口溶膜组合物，进一步包括崩解剂，或者包括崩解剂与唾液刺激剂、填充剂、着色剂、抗粘剂和抑菌剂中的一种或多种的组合。
- 如权利要求5所述的盐酸鲁拉西酮口溶膜组合物，其特征在于：所述的崩解剂为低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、淀粉、微晶纤维素和预胶化淀粉中的一种或多种；和/或，所述的唾液刺激剂为酒石酸、苹果酸和甘露醇一种或多种；和/或，所述的填充剂为甘露醇、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种；和/或，所述的着色剂为二氧化钛、色素和色淀中一种或多种；和/或，所述的抗粘剂为滑石粉、硬脂酸镁、硬脂酸钙中一种或多种；和/或，所述的抑菌剂为羟苯甲酯、羟苯乙酯、硫代硫酸钠中的一种或多种。
- 如权利要求5或6所述的盐酸鲁拉西酮口溶膜组合物，其特征在于：所述的崩解剂的百分含量为0～10.0％，所述的质量百分含量是指崩解剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比；和/或，所述的唾液刺激剂百分含量为0～10.0％，所述的质量百分含量是指唾液刺激剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比；和/或，所述的填充剂百分含量为0～10.0％，所述的质量百分含量是指填充剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比；和/或，所述的着色剂百分含量为0～5.0％，所述的质量百分含量是指着色剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比。和/或，所述的抗粘剂百分含量为0～5.0％，所述的质量百分含量是指抗粘剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比；和/或，所述的抑菌剂百分含量为0～1.0％，所述的质量百分含量是指抑菌剂的质量占盐酸鲁拉西酮口溶膜组合物总质量的百分比；
- 如权利要求1～7任一项所述的盐酸鲁拉西酮口溶膜组合物，其特征在于：所述的盐酸鲁拉西酮口溶膜组合物，选自以下任一处方：处方1：47.2％盐酸鲁拉西酮、33.0％羟丙基纤维素、9.4％甘油、9.4％三氯蔗糖和1.0％二氧化钛；处方2：30.0％盐酸鲁拉西酮、45.0％聚乙烯醇、12.0％聚乙二醇6000、5.0％三氯蔗糖、3.5％薄荷脑、0.9％甘露醇、3.0％乳糖和0.6％羟苯甲酯；处方3：33.3％盐酸鲁拉西酮、45.8％聚乙烯醇、8.3％甘油、3.3％氯化钠、4.2％枸橼酸、4.3％三氯蔗糖、0.4％香精和0.4％薄荷脑；处方4：25.0％盐酸鲁拉西酮、50.0％聚乙烯醇、16.0％甘油、2.5％甜菊糖苷、 0.5％香精和6.0％乳糖；处方5：41.3％盐酸鲁拉西酮、24.8％羟乙基纤维素、16.5％普鲁兰多糖、8.3％甘油、8.3％三氯蔗糖和0.8％二氧化钛；处方6：47.2％盐酸鲁拉西酮、28.3％羟乙基纤维素、9.4％普鲁兰多糖、4.7％甘油、9.4％三氯蔗糖和1.0％二氧化钛；处方7：52.1％盐酸鲁拉西酮、20.8％羟乙基纤维素、10.4％普鲁兰多糖、5.2％甘油、10.4％三氯蔗糖和1.1％二氧化钛；处方8：41.7％盐酸鲁拉西酮、25.0％羟乙基纤维素、16.7％普鲁兰多糖、5.0％甘油、8.3％三氯蔗糖、1.7％薄荷脑、0.8％滑石粉和0.8％二氧化钛；处方9：38.5％盐酸鲁拉西酮、23.1％羟乙基纤维素、15.4％普鲁兰多糖、4.5％甘油、7.7％三氯蔗糖、1.5％薄荷脑、0.8％香精、7.7％枸橼酸和0.8％滑石粉；处方10：35.7％盐酸鲁拉西酮、21.4％羟乙基纤维素、14.3％普鲁兰多糖、4.3％甘油、7.1％羧甲基淀粉钠、7.1％三氯蔗糖、1.4％薄荷脑、0.8％香精、7.1％枸橼酸和0.8％滑石粉；
- 如权利要求1～8任一项所述的盐酸鲁拉西酮口溶膜组合物的制备方法，其特征在于包括以下步骤：1)将成膜材料在60℃～70℃条件下加热溶于水中，形成溶液；2)向步骤1)得到的溶液中加入除活性药物外的其他各组分，搅拌均匀后得空白胶液；3)将活性药物置于步骤2)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；4)将脱泡后的步骤3)得到的含药胶液用涂布机均匀涂布于离型膜上，加热、干燥、切割，得盐酸鲁拉西酮口溶膜组合物。优选地，所述的盐酸鲁拉西酮口溶膜组合物厚度为10μm～300μm；和/或，所述的盐酸鲁拉西酮口溶膜组合物，在1000ml，37℃±1℃的模拟唾液中 2min内能够完全崩解。
- 如权利要求1～8任一项所述的盐酸鲁拉西酮口溶膜组合物在制备治疗和/或预防抑郁症的药物中的用途。
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| US20040028741A1 (en) * | 2000-09-22 | 2004-02-12 | Kazuyuki Fujihara | Oral preparations with favorable disintegration characteristics |
| CN103054824A (zh) * | 2012-12-21 | 2013-04-24 | 北京万全德众医药生物技术有限公司 | 盐酸鲁拉西酮口崩片制剂及其制备方法 |
| WO2016139683A2 (en) * | 2015-03-05 | 2016-09-09 | Jubilant Generics Limited | Pharmaceutical compositions of lurasidone and process for preparing the same |
| CN108567758A (zh) * | 2017-03-08 | 2018-09-25 | 湖南洞庭药业股份有限公司 | 盐酸鲁拉西酮片剂及其制备方法 |
| CN112618518A (zh) * | 2021-01-18 | 2021-04-09 | 江苏谛奇医药科技有限公司 | 盐酸鲁拉西酮口腔速溶膜制剂及其制备方法 |
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|---|---|---|---|---|
| US20040028741A1 (en) * | 2000-09-22 | 2004-02-12 | Kazuyuki Fujihara | Oral preparations with favorable disintegration characteristics |
| CN103054824A (zh) * | 2012-12-21 | 2013-04-24 | 北京万全德众医药生物技术有限公司 | 盐酸鲁拉西酮口崩片制剂及其制备方法 |
| WO2016139683A2 (en) * | 2015-03-05 | 2016-09-09 | Jubilant Generics Limited | Pharmaceutical compositions of lurasidone and process for preparing the same |
| CN108567758A (zh) * | 2017-03-08 | 2018-09-25 | 湖南洞庭药业股份有限公司 | 盐酸鲁拉西酮片剂及其制备方法 |
| CN112618518A (zh) * | 2021-01-18 | 2021-04-09 | 江苏谛奇医药科技有限公司 | 盐酸鲁拉西酮口腔速溶膜制剂及其制备方法 |
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