WO2020155507A1 - 一种不含防腐剂的固体剂型氨己烯酸药物组合物 - Google Patents
一种不含防腐剂的固体剂型氨己烯酸药物组合物 Download PDFInfo
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Classifications
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- the invention relates to a novel preservative-free pharmaceutical composition, which can be reconstituted into a solution and used multiple times.
- Vignacin is a product marketed in the United States under the trade name Developed by Lingbei Pharmaceutical Company for the treatment of intractable and complicated partial seizures and infantile spasms.
- Vigabatrin is an amino acid, which is unstable in acidic or alkaline environments.
- preservatives are added to inhibit microbial growth, contamination and biodegradation, and to ensure that the drug product is safe and effective.
- preservatives can keep the container or packaging sterile during multiple uses of oral liquids, they may induce or increase adverse reactions in some individuals, especially in pediatrics and infants.
- the multi-dose, ready-to-use vigabatrin product of the present invention reduces the risk of administering dose errors and improves patient compliance.
- this invention is an excellent choice for a preservative-free drug delivery system for epilepsy patients who need long-term treatment.
- the invention relates to a solid dosage form of vigabatrin without preservatives and which can be reconstituted into an oral solution.
- the dosage form and its solution basically do not contain, for example, parabens, potassium sorbate, sodium benzoate, organic solvents or other commonly used to stabilize drugs, which can be tolerated while maintaining the efficacy of the drugs.
- the vigabatrin solution without any preservatives can be used multiple times without excessive degradation and or microbial growth or contamination for a long time.
- the present invention includes a preservative-free powder for vigabatrin oral solution, and the reconstituted solution is colorless and transparent with good taste.
- the resulting solution can be used multiple times in a suitable pH range and a desired concentration range.
- This solid dosage form or composition is contained in a suitable container, and the tools for preparing the solid dosage form or composition into a solution are also included in the scope of the present invention. At the same time, the tool can also be used for drug delivery and drug treatment and treatment.
- Another object of the present invention is to provide a stable dry-mixed powder or granule that can prepare a solution, the prepared solution contains vigabatrin or a pharmaceutically equivalent derivative thereof, and the solution has good chemical stability.
- the present invention also provides a method for treating CNS diseases, which comprises administering a solution reconstituted with the solid dosage form composition described herein to a subject in need.
- the present invention relates to a solid composition containing active ingredients, which comprises vigabatrin or its pharmaceutically acceptable salts, isomers, complexes, polymorphs, hydrates or esters and other derivatives.
- the composition is essentially preservative-free or preservative-free.
- composition of the present invention can be reconstituted into an oral solution for the treatment of CNS diseases including children and infants, such as resistant epilepsy, complex partial epileptic seizures, secondary generalized epileptic seizures, refractory and complex Patients with partial seizures and infantile spasms.
- CNS diseases including children and infants
- resistant epilepsy complex partial epileptic seizures
- secondary generalized epileptic seizures refractory and complex Patients with partial seizures and infantile spasms.
- the composition and the solution that can be used multiple times after reconstitution provide convenience for medical staff, improve patient compliance, and reduce human errors during dispensing. This also improves the safety of medication for children and infants.
- the articles “a” and “an” used herein mean “one or more” or “at least one.” That is to say, referring to any element or component of the embodiment by the indefinite article “a” or “an” does not exclude the possibility that there is more than one element or component.
- sweetener refers to commonly used taste masking agents for the preparation of pharmaceutical products, such as sucrose, glucose, sorbitol, sucralose, aspartame, sodium saccharin and any other pharmaceutically acceptable Sweeteners or combinations thereof.
- flavoring agent refers to the common flavoring agents used in the preparation of pharmaceutical products, such as peppermint, menthol, cherry flavor, orange flavor, lemon flavor, pomegranate flavor, berry flavor, strawberry flavor, banana flavor, and orange flavor. Flavor and mint flavor, other acceptable fruit flavors or mixtures thereof.
- multiple use refers to the divided administration of a portion of the solution to a subject in need. There may be an interval such as about 1 hour to about 2 months between two consecutive dosing intervals.
- preservative refers to common preservatives used in the preparation of pharmaceutical products, such as bacteriostatic agents and chelating agents.
- preservatives include, but are not limited to, benzalkonium chloride, sitacium chloride, benzoates (such as sodium benzoate), benzyl alcohol, methyl paraben, propyl paraben, alkyl esters, Parabens and salts thereof (for example, methyl or propyl p-hydroxybenzoate or salts thereof).
- Methylmercury such as borate or nitrate
- sodium hypochlorite sodium hypochlorite
- paraben potassium sorbate
- sodium benzoate sodium benzoate
- acetic acid organic solvents such as ethanol, benzyl alcohol, bronopol, chlorobutanol, propylene glycol or Other preservative systems.
- solid formulation refers to a solid dosage form.
- Non-limiting examples include powders, granules, flakes, spheroids and other dosage forms, which when added to ingestible liquids, are easily prepared into desired solutions.
- the solid formulation is dry and flowable.
- the term "essentially free of (something)” means that something does not have a meaningful influence and effect. Or, even if a very small amount of the substance is present, its effect on the composition or solution of the present invention is at best negligible.
- therapeutically effective amount refers to the amount of a compound or active pharmaceutical ingredient (API) that is effective in preventing, alleviating or improving disease symptoms or prolonging the survival period of the subject to be treated.
- API active pharmaceutical ingredient
- subject refers to an animal or a human.
- the subject in need of treatment for CNS disease may be a pediatric patient.
- the term “treatment” or “therapy” of a disease or disorder refers to a method of ameliorating the disease or disorder (ie, inhibiting or slowing the development of the disease or the development of at least one clinical symptom therein).
- “treatment” or “therapy” refers to improving at least one physical parameter, which may be indistinguishable or conscious of the subject.
- “treatment” or “therapy” refers to the regulation of diseases or diseases by the human body (for example, stabilization of recognizable symptoms), or physiologically (for example, stabilization of human physiological parameters) or both. disease.
- “treatment” or “therapy” refers to delaying the onset of a disease or condition, or even preventing the onset of a disease or condition.
- “Prophylactic treatment” should be interpreted as any treatment modality used to prevent the progression of a disease, or to prevent the development of a disease in persons at risk.
- the solid dosage form composition may contain any pharmaceutically acceptable excipients suitable for the present invention.
- the composition includes at least one of sugar and sugar alcohol, and optional other components such as buffers, sweeteners and flavors.
- the solid dosage form composition is in powder form.
- Sugar and sugar alcohol refer to but not limited to one or more of sucrose, lactose, fructose, glucose, mannitol, sorbitol and xylitol.
- the composition can be any combination containing sugar and/or sugar alcohol.
- the sugar and/or sugar alcohol according to the present invention can also be used as a sweetener in a solid dosage composition that can be reconstituted into an oral solution. Based on the total weight of the solid dosage form composition, the amount of sugar and/or sugar alcohol used in the solid dosage form composition of the present invention ranges from about 10% to 99% w/w.
- the amount of sugar and/or sugar alcohol used in the solid dosage form composition ranges from about 20% to about 99%, or from about 30% to about 99%, or from about 40% to about 99%, or from about 50% to about 99%, or from about 60% to about 99%, or from about 70% to about 99%, or from about 80% to about 99%, or from about 60% to about 90%, or from about 60% to about 80%.
- a buffer can be added to the composition.
- suitable buffers include, but are not limited to: sodium citrate, citric acid, fumaric acid, tartaric acid, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide and Potassium dihydrogen phosphate.
- the buffer should have sufficient buffering capacity to ensure that the reconstituted solution is still within the expected pH range.
- the concentration of the buffer after reconstitution is about 10 mM to 200 mM, preferably 10 mM to 50 mM.
- the sweetener may include, for example, sucrose, glucose, sorbitol, sucralose, aspartame, sodium saccharin and any other pharmaceutically acceptable sweetener or any other combination.
- the amount of sweetener in the powder used in the oral solution composition is generally about 0.1% to about 99%, preferably 0.1%-10% w/w of the total weight of the oral solution powder.
- the sweetener is sucrose, glucose, sorbitol, sucralose, aspartame, sodium saccharin, any other pharmaceutically acceptable sweetener, or any combination thereof.
- the flavoring agent can be selected from, for example, pomegranate flavor, berry flavor, strawberry flavor, banana flavor, orange flavor and mint flavor.
- the amount of flavor in the powder for oral solution accounts for about 0.1% to about 5% w/w of the total weight of the powder for oral solution.
- composition powder described herein that can be reconstituted into an oral solution.
- the composition may include more than one kind of sugar, sweetener, and the like.
- a single excipient may also have multiple functions.
- the device or tool contains the reconstituted composition and instructions on how to administer it.
- the solid dosage form that can be reconstituted into an oral solution can be prepared by a general method known in the art. Examples include dry powder mixing, wet granulation, dry granulation, spray drying, hot melt extrusion, extrusion spheronization and fluidized bed granulation.
- an oral solution reconstituted from the solid dosage form composition described herein provides an oral solution reconstituted from the solid dosage form composition described herein.
- the solid dosage form composition that can be reconstituted into an oral solution is stored in a suitable container before being reconstituted in a solute (eg, water).
- the solution can be prepared by a pharmacist according to the instructions of the solid dosage form composition.
- the solution is prepared by adding the exact amount of water to the bottle containing the powder, and then shaking the bottle to mix the water with the powder until all solids have dissolved. Therefore, the oral solution without preservatives is the actual dosage form that patients can use multiple times. Oral administration syringes can draw an appropriate amount of liquid medicine according to the prescription to give the patient.
- the solution can provide convenient and accurate dose titration for subjects undergoing treatment, including, for example, infant patients and patients who cannot swallow tablets due to difficulty in swallowing.
- the composition in the solid dosage form after reconstitution with water for oral solution is a solution containing about 500 mg of the drug per about 10 ml of liquid.
- the composition in solid dosage form is stable during storage, and when administered after reconstitution with water, the corresponding liquid solution is also stable during use during treatment.
- the concentration of the drug in the solution is higher than about 10 mg/ml.
- the drug concentration in the solution is about 10 to about 100 mg/ml, about 20 to about 100 mg/ml, about 30 to about 100 mg/ml, about 40 to about 100 mg/ml, about 40 to about 90 mg/ml ml, about 40 to about 80 mg/ml, about 40 to about 70 mg/ml, or about 40 to about 60 mg/ml.
- the pH of the solution ranges from about 5.0 to about 8.0. In some embodiments, the pH of the solution ranges from about 5.5 to about 7.5, from about 6.0 to about 7.5, or from about 6.0 to about 7.0.
- the content of sugar and/or sugar alcohol in the solution is 40-80% (weight ratio). In some embodiments, the weight ratio of sugars and/or sugar alcohols in the solution is about 50% to about 70%, about 55% to about 65%, or about 60% to about 70% by weight.
- the solution can be used multiple times. During the entire period of multiple uses, the quality of the solution is still within the quality standard range.
- the solution prepared from the solid composition described herein is in its second, third, fifth, tenth, eleventh, fourteenth, twentieth, thirtieth, and fortieth , 50th, 60th, 80th or 90th day can pass the antibacterial test (AET) under USP ⁇ 51>.
- the drug in the solution can maintain its efficacy throughout the entire period of multiple uses, of which at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the drug Remain stable or undecomposed.
- the drug is vigabatrin.
- Another aspect of the present invention provides a method of treating central nervous system (CNS) diseases, comprising administering the oral solution described herein to a subject in need.
- the solution administration interval is at least about 30 minutes, at least about 1 hour, at least about 5 hours, at least about 10 hours, at least 24 hours, at least 2 days, at least 5 days, at least 7 days, at least 15 days, at least 20 days, at least 30 days, at least 50 days, at least 60 days, or any combination of the above intervals.
- the second administration part of the solution can be administered within 8 hours
- the third administration part of the solution can be administered within 24 hours after the second administration.
- the subsequent part of the oral solution can be administered at appropriate intervals.
- the interval is at least 1 week.
- the interval is about 1 week to about 3 months, about 1 week to about 2 months, or about 2 weeks to about 2 months.
- the dosage of each individual part can be determined by a person of ordinary skill in the art according to the specific disease condition of the subject in need. Of course, the instructions on the container or device of the composition will also provide guidance for the patient to administer the appropriate amount of solution.
- the CNS disease may be infantile spasms, complex refractory seizures, Tourette syndrome, refractory autoimmune encephalitis, cocaine dependence, infantile spasms caused by tuberous sclerosis .
- API solution With a single API as a control, the reconstituted API solution and API+sucrose solution were tested for bacteriostasis (AET) in accordance with the requirements of USP ⁇ 51>. Each solution was tested on two different bottles.
- AET bacteriostasis
- Antibacterial efficacy standard 3 types of products (non-antacid oral products, solutions prepared with water as a matrix or carrier)
- Bacteria (Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Burkholderia cepacia): Decrease not less than 1.0 log from the initial count on the 14th day, and count from the 14th day to the 28th day The count did not increase.
- Yeasts and molds (Candida albicans and Aspergillus niger): The counts that were not present at 14 days and 28 days from the initial calculation did not increase. No increase is defined as no more than 0.5 log10 units higher than the previously measured value.
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Abstract
一种不含防腐剂的固体剂型氨己烯酸药物组合物，包含治疗有效量的氨己烯酸或药学上可接受的盐、异构体、复合物、多晶型、水合物或酯类，还包含至少一种糖和糖醇及可选的缓冲剂、甜味剂和矫味剂的一种或多种，可用于制备治疗中枢神经系统CNS疾病的药物。
Description
该发明涉及一个新型不含防腐剂的药物组合物，可复溶成溶液并多次使用。
氨己烯酸是在美国的上市产品，商品名为
由灵北制药公司研发用于治疗顽固性复杂性部分发作癫痫和婴儿痉挛症。
目前在市场上只有两种剂型，口服片剂和散剂。由于儿童和婴幼儿的患者人群的特点，需要调节给药剂量，因此仅散剂可用于这部分人群患者。然而
散剂在服用前，需要用水配制成溶液，并且该药液是一次性使用。这可能导致给药错误，剂量浪费，或由于非医疗专业人员(例如患者和监护人)配制错误药液浓度而给予不正确的剂量。给予错误剂量的氨己烯酸可能是致命的，因其可能导致视力损害，该上市药品需要采取REMS风控计划。考虑到经济和安全的原因，剂量浪费也需要引起重点关注，一些患者可能将未使用的粉末或溶液储存以备将来使用，这是目前批准的标签所不支持的。
Vigabatrin是一种氨基酸，在酸性或碱性环境下不稳定。在大多数可多次使用的口服溶液中，会添加防腐剂以抑制微生物生长和污染以及生物降解，并确保药物产品安全有效。虽然防腐剂在口服液多次使用过程中可保持容器或包装无菌，然而，它们可能诱导或增加某些个体的不良反应，尤其是在儿科和婴儿中使用。
发明内容
本发明涉及的多剂量，即用型的氨己烯酸产品降低了给药剂量错误的风险并改善了患者的依从性。此外，该发明对于需要长期治疗的癫痫患者，无防腐剂的可多次使用的药物递送系统是绝佳的选择。
本发明涉及一种无防腐剂，可复溶成口服溶液的氨己烯酸固体剂型。该剂型和其溶液基本不含例如对羟基苯甲酸酯，山梨酸钾，苯甲酸钠，有机溶剂或其它的常用于稳定药物，可耐受，同时保持药物功效防腐剂体系。意想不到的是，不含任何防腐剂的该氨己烯酸溶液，在较长时间内无超限的降解和或者微生物生长或污染，可多次使用。
本发明包括不含防腐剂的氨己烯酸口服溶液用粉末，其复溶的溶液为无色透明，口感良好。所得溶液在合适的pH范围和所需的浓度范围内，可以多次使用。
这个固体剂型或者组合物盛装在合适的容器内，其用于将所述固体剂型或组合物制备溶液的工具也包含在本发明的范围内。同时，该工具也可用于给药和药物处理及治疗。
本发明的另一个目的是提供了可制备溶液的稳定干混粉末或颗粒，所制得的溶液包含氨己烯酸或其药学上等同的衍生物，该溶液具有良好化学稳定性的。
本发明还提供了治疗CNS疾病的方法，其包括向有需要的受试者服用由本文所述的固体剂型组合物复溶的溶液。
详细的发明
本发明涉及一种含有活性成分的固体组合物，其包括氨己烯酸或其药学上可接受的盐，异构体，复合物，多晶型，水合物或酯及其他衍生物。该组合物基本上不含防腐剂或不含防腐剂。
本发明中的组合物可以复溶成口服溶液，用于治疗包括儿童和婴儿在内患有CNS疾病，例如抗性癫痫，复杂部分性癫痫发作，继发性全身性癫痫发作，难治性复杂部分性发作和婴儿痉挛的患者。该组合物和复溶后可多次使用的溶液为医护人员提供了便利，改善患者依从性并减少配药时的人为错误。这也提高了儿童和婴儿的用药安全性。
下列文字提及或举例说明的组合物，口服溶液或治疗疾病的方法的具体实施方案，但并不意图将组合物，溶液或治疗方法的范围限定于这些特定说明或实施例。出于实际和经济方面的考虑，本领域技术人员可进行各种修改，例如组合物的辅料和用于治疗或预防疾病或病症溶液的给药间隔。
除非另有说明，否则本文所用的冠词“一”和“一个”是指“一个或多个”或“至少一个”。也就是说，通过不定冠词“一”或“一个”来引用实施例的任何元素或组分并不排除存在多于一个元素或组分的可能性。
本文所用的术语“甜味剂”是指用于制备药物产品的常用掩味剂，例如蔗糖，葡萄糖，山梨糖醇，三氯蔗糖，阿斯巴甜，糖精钠和任何其它药学上可接受的甜味剂或其组合。
本文所用的术语“矫味剂”是指用于制备药物产品的常用矫味剂，例如薄荷，薄荷醇，樱桃香精，桔子香精，柠檬香精，石榴香精，浆果香精，草莓香精，香蕉香精，橙味香精和薄荷香精，其他可接受的水果味香精或其混合物。
如本文所用的术语“多次使用”是指向有需要的受试者分次给予该溶液的一部分。在两个连续给药间隔可存在诸如约1小时至约2个月的间隔。
如本文所用的术语“防腐剂”是指用于制备药物产品的常用防腐剂，例如抑菌剂和螯合剂。防腐剂的实例包括但不限于苯扎氯铵，西他氯铵，苯甲酸盐(例如苯甲酸钠)，苯甲醇，对羟基苯甲酸甲酯，对羟基苯甲酸丙酯，烷基酸酯，羟苯酸酯及其盐(例如对羟基苯甲酸甲酯或丙酯或其盐)。甲基汞盐(例如硼酸盐或硝酸盐)，次氯酸钠，对羟基苯甲酸酯，山梨酸钾，苯甲酸钠和乙酸，有机溶剂如乙醇，苯甲醇，溴硝醇，氯丁醇，丙二醇或其它防腐剂体系。
如本文所用的术语“固体制剂”是指固态的剂型。非限制性实例包括粉末，颗粒，薄片，球状体和其他剂型，当加入可摄取的液体中时，易制备成所需的溶液。在一些实施方案中，固体制剂是干燥的且可流动的。
本文所用的术语“基本上不含(某物)”是指某物不具有有意义的影响和作用。或者，即使存在非常少量的物质，它对本发明的组合物或溶液的影响最多也是可忽略不计的。
本文所用的术语“治疗有效量”是指有效预防，缓解或改善疾病症状或延长所治疗对象生存期的化合物或活性药物成分(API)的量。治疗有效量的确定完全在本领域技术人员的能力范围内，特别是根据本文提供和披露的详细内容。
如本文所用的术语“受试者”是指动物或人。例如，需要治疗CNS疾病的受试者可以是儿科患者。
在一些实施方案中，术语中疾病或病症的“治疗”或“疗法”是指改善疾病或病症(即，抑制或减缓疾病的发展或其中的至少一种临床症状的发展)的方法。在一些实施方案中，“治疗”或“疗法”是指改善至少一种身体的参数，其可能是受试者无法辨别的或意识到的。在一些实施方案中，“治疗”或“疗法”是指通过人体上(例如，可识别症状的稳定)地，或生理学上(例如，人体生理学参数的稳定)地或两者共同来调节疾病或病症。在一些实施方案中，“治疗”或“疗法”是指延迟疾病或病症的发作，或甚至预防疾病或病症的发作。“预防性治疗”应解释为用于预防疾病进展，或用于有病症发展风险的人的预防目的的任何治疗方式。
该固体剂型组合物可含有适用于本发明的任何药学上可接受的辅料。在一些实施方案中，组合物包含糖和糖醇中的至少一种，和可选的其他组分如缓冲剂，甜味剂和香精。在一些实施方案中，固体剂型组合物为粉末形式。
糖和糖醇是指但不限于蔗糖，乳糖，果糖，葡萄糖，甘露醇，山梨醇和木糖醇中的一种或多种。该组合物可为含有糖和/或糖醇的任何组合。根据本发明的糖和/或糖醇还可以在用作可复溶成口服溶液的固体剂型组合物的甜味剂。基于固体剂型组合物的总重量， 本发明中固体剂型组合物中使用的糖和/或糖醇的量范围从约占10％至99％w/w。在一些实施方案中，固体剂型组合物中使用的糖和/或糖醇量占组合物的总重量的范围从约20％至约99％，或从约30％至约99％，或从约40％至约99％，或从约50％至约99％，或从约60％至约99％，或从约70％至约99％，或从约80％至约99％，或从约60％至约90％，或从约60％至约80％。
可在该组合物中加入缓冲剂。合适的缓冲剂的实例包括但不限于：柠檬酸钠，柠檬酸，富马酸，酒石酸，柠檬酸钾，碳酸氢钠，碳酸氢钾，磷酸二氢钠，磷酸氢二钠，氢氧化钠和磷酸二氢钾。当使用来自具有不同pH范围的不同来源的水复溶粉末成口服溶液时，缓冲剂应具有足够的缓冲能力以确保复溶的溶液仍在预期的pH范围内。复溶后的缓冲液浓度范围约为10mM至200mM，优选10mM至50mM。
甜味剂可包括例如蔗糖，葡萄糖，山梨醇，三氯蔗糖，阿斯巴甜，糖精钠和任何其他药学上可接受的甜味剂或任意其他组合。用于口服溶液组合物的粉末中的甜味剂的量通常为口服溶液粉末总重量的约0.1％至约99％，优选0.1％-10％w/w。在一些示例性实施方案中，甜味剂是蔗糖，葡萄糖，山梨醇，三氯蔗糖，阿斯巴甜，糖精钠，任何其他药学上可接受的甜味剂或其任意组合。
矫味剂可选自，例如，石榴香精，浆果香精，草莓香精，香蕉香精，橙味和薄荷香精。口服溶液用粉末中的香精量占口服溶液用粉末的总重量为约0.1％至约5％w/w。
前述列表中具体提及的合适的糖，糖醇，缓冲剂，甜味剂和矫味剂旨在阐述可用于实施本发明的具体辅料的示例，而非穷举性的。还应进一步理解，任何特定类型的辅料中，其可能不止一种用于本文所述的可复溶成口服溶液的组合物粉末中。例如，组合物可包含一种以上的糖，甜味剂等。此外，单一辅料也可能具有多种功能。
本文还提供了含有本发明所述固体剂型组合物的装置或工具包。该装置或工具包含有复溶组合物和如何给药的说明。
可复溶成口服溶液的固体剂型可通过本领域已知的一般方法制备。实例包括干粉混合，湿法制粒，干法制粒，喷雾干燥，热熔挤出，挤出滚圆和流化床造粒。
本发明的另一方面提供了由本文所述的固体剂型组合物复溶的口服溶液。通常，可复溶成口服溶液的固体剂型组合物在复溶于溶质(例如水)之前储存在合适的容器中。该溶液可以由药剂师根据固体剂型组合物的说明书制备。在一个示例性实施方案中，通过向装有粉末的瓶子中加入准确量的水，然后摇动瓶子以使水与粉末混合直至所有固体已经溶解来制备溶液。因此，不含防腐剂的该口服溶液就是患者可多次使用的实际剂型。 口服给药注射器可根据处方吸取合适的药液量来给予病人。
在将固体剂型的组合物复溶成口服溶液后，该溶液可为接受治疗的受试者提供便利和准确的剂量滴定，包括例如婴幼儿患者和由于吞咽困难而不能吞咽片剂的患者。
在一些实施方案中，固体剂型的组合物用水复溶后用于口服溶液为每约10ml液体含有约500mg药物的溶液。固体剂型的组合物在储存时是稳定的，并且当用水复溶后给药时，相应的液体溶液在治疗期间使用时也是稳定的。在一些实施方案中，溶液中的药物浓度高于约10mg/ml。在一些实施方案中，溶液中的药物浓度为约10至约100mg/ml，约20至约100mg/ml，约30至约100mg/ml，约40至约100mg/ml，约40至约90mg/ml，约40至约80mg/ml，约40至约70mg/ml，或约40至约60mg/ml。
溶液的pH范围为约5.0至约8.0。在一些实施方案中，溶液的pH范围为约5.5至约7.5，约6.0至约7.5或约6.0至约7.0。
溶液中糖和/或糖醇的含量为40-80％(重量比)。在一些实施方案中，溶液中糖和/或糖醇的重量比为约50％至约70％，约55％至约65％，或约60％至约70％重量。
该溶液可多次使用。在多次使用的整个期间，溶液的质量仍在质量标准范围内。在一些实施方案中，由本文所述的固体组合物制备的溶液在其第二，第三，第五，第十，第十一，第十四，第二十，第三十，第四十，第五十，六十，八十或第九十天的可通过在USP<51>项下抑菌试验测试(AET)。溶液中的药物在多次使用的整个期间仍能保持其功效，其中至少约70％，至少约80％，至少约85％，至少约90％，至少约95％或，至少约98％的药物保持稳定或未分解。在一些实施方案中，该药物是氨己烯酸。
本发明的另一方面提供治疗中枢神经系统(CNS)疾病的方法，包括向有需要的受试者施用本文所述的口服溶液。该溶液给药间隔至少约30分钟，至少约1小时，至少约5小时，至少约10小时，至少24小时，至少2天，至少5天，至少7天，至少15天，至少20天，至少30天，至少50天，至少60天，或上述间隔的任何组合。例如，在初次给药后，第二次给予部分该溶液可以在8小时内给药，第三次给予部分该溶液可以在第二次给药后24小时内给药。随后的部分该口服溶液可以以合适的间隔进行给药。在一些实施方案中，间隔至少为1周。在一些实施方案中，间隔为约1周至约3个月，约1周至约2个月或约2周至约2个月。每个单独部分的剂量可以由本领域普通技术人员根据有此需要的受试者的具体疾病状况来确定。当然，组合物的容器或装置上的说明也会为患者提供指导以给予适当量的溶液。在一些实施方案中，CNS疾病可为婴儿痉挛症，复杂难治性癫痫发作，妥瑞氏综合征，难治性自身免疫性脑炎，可卡因依赖性，结 节性硬化症引起的婴儿痉挛症。
提供以下实施例是为了使本领域技术人员能够实施本发明，并且仅是对本发明的说明。这些实施例不应理解为限制本发明中权利要求所定义的范围。
如下表1中所述制备不含防腐剂的粉末组合物，用于制备口服溶液
表1 250ml瓶装用于制备口服溶液的粉末组合物处方
| 成分 | g/250ml | ％(w/w) | 功能 |
| 氨己烯酸 | 12.5 | 5.6％ | 活性成分 |
| 蔗糖 | 212.5 | 94.4％ | 填充剂/甜味剂 |
将112.5g水加入到瓶中的粉末，制成250ml溶液。剧烈摇动瓶子直至所有固体溶解并形成浓度为50mg/ml的无色透明溶液。
以单一的API作为对照，按照USP<51>要求对复溶的API溶液和API+蔗糖溶液进行了抑菌试验测试(AET)。在两个不同的瓶子上对每种溶液都进行测试。
在不同的瓶子复溶的API+蔗糖溶液全部通过AET测试，而单一的API溶液在14天时未通过测试，因为B.cepacian不符合要求。结果显示在表2和表3中
表2在HDPE瓶中API溶液和API+蔗糖溶液之间的AET结果的对比
抑菌效力标准：3类产品(非抗酸药类口服产品，以水为基质或载体配成的溶液)
细菌(金黄色葡萄球菌，大肠杆菌，绿脓杆菌和洋葱伯克霍尔德菌)：从初始计在第14天的计数减少不少于1.0对数，并且从第14天计算，至28天计数没有增加。
酵母和霉菌(白色念珠菌和黑曲霉)：从初始计算在14天和28天时没有的计数没有增加。没有增加定义为不超过0.5log10单位高于之前测量的值。
表3在AET瓶中API溶液和API+蔗糖溶液之间的AET结果的对比
Claims (21)
- 一种不含防腐剂的固体剂型氨己烯酸药物组合物，包含治疗有效量的氨己烯酸或药学上可接受的盐、异构体、复合物、多晶型、水合物或酯类，其中所述不含防腐剂的固体剂型氨基烯酸药物组合物基本上不含防腐剂，进一步地，其中所述不含防腐剂的固体剂型氨基烯酸药物组合物可复溶成能够多次使用的口服溶液。
- 根据权利要求1所述的不含防腐剂的固体剂型氨基烯酸药物组合物，还包含至少一种糖和糖醇及可选的缓冲剂、甜味剂和矫味剂的一种或多种。
- 根据权利要求2的不含防腐剂的固体剂型氨基烯酸药物组合物，其中所述至少一种糖和糖醇选自蔗糖、乳糖、果糖、葡萄糖、甘露醇、山梨醇、麦芽糖醇和木糖醇及其组合。
- 根据权利要求2的不含防腐剂的固体剂型氨基烯酸药物组合物，其中所述不含防腐剂的固体剂型氨基烯酸药物组合物为粉状制剂，所述至少一种糖和糖醇的质量分数为约10％至约99％w/w，优选60％至99％。
- 根据权利要求1所述的不含防腐剂的固体剂型氨基烯酸药物组合物，其中所述不含防腐剂的固体剂型氨基烯酸药物组合物储存在合适的容器中，所述容器的质地是指但不限于具有防儿童开启盖的HDPE、聚乙烯瓶或聚丙烯聚合物瓶。
- 根据权利要求2的不含防腐剂的固体剂型氨基烯酸药物组合物，其中缓冲剂选自柠檬酸钠、柠檬酸、富马酸、酒石酸、柠檬酸钾、碳酸氢钠、碳酸氢钾、磷酸二氢钠、磷酸氢二钠、氢氧化钠、磷酸二氢钾及其任意组合，进一步地，其中，在将所述不含防腐剂的固体剂型氨基烯酸药物组合物复溶成溶液后，缓冲液具有足够的缓冲能力维持溶液pH范围在约5.0——约8.0之间，进一步地，其中所述溶液中缓冲剂的浓度范围为约10mM——约200mM。
- 根据权利要求2所述的不含防腐剂的固体剂型氨基烯酸药物组合物，其中所述甜味剂选自蔗糖、葡萄糖、山梨糖醇、三氯蔗糖、阿斯巴甜、糖精钠及其任意组合。
- 根据权利要求2所述的不含防腐剂的固体剂型氨基烯酸药物组合物，其中所述矫味剂选自石榴香精、浆果香精、草莓香精、香蕉香精、橙子香精、薄荷香料及其任意组合，其中所述香精占所述组合物总质量的约0.1％w/w——约5％w/w。
- 根据权利要求1的不含防腐剂的固体剂型氨基烯酸药物组合物，其中所述不含防腐剂的固体剂型氨基烯酸药物组合物的固体状态为片剂、颗粒剂、粉剂、小球、迷你片 剂和丸剂。
- 一种口服给药的溶液，包含一种含有氨己烯酸的活性药物成分或其药学上可接受的盐、异构体、复合物、多晶型、水合物、酯等衍生物，其中所述溶液基本上不含防腐剂。
- 根据权利要求10所述的溶液，还包含至少一种糖或糖醇、及任选的缓冲剂、甜味剂和矫味剂的一种或多种成分。
- 根据权利要求11所述的溶液，其中所述至少一种糖和糖醇选自蔗糖、乳糖、果糖，葡萄糖、甘露醇、山梨醇、麦芽糖醇和木糖醇，及其任意组合。
- 根据权利要求11所述的的溶液，其中所述至少一种糖和糖醇在溶液中质量分数为40％-80％，优选50％-70％。
- 根据权利要求10所述的溶液，所述溶液由权利要求1所述不含防腐剂的固体剂型氨基烯酸药物组合物制备而成，溶液在制备后第14天时，可通过USP<51>项下的抗微生物效力试验的测试要求。
- 根据权利要求10所述的溶液，所述溶液由权利要求1所述不含防腐剂的固体剂型氨基烯酸药物组合物制备而成，溶液在制备后第14天时，可通过USP<51>项下的抗微生物效力试验测试，其中测试菌含B.cepacia.
- 根据权利要求10所述的溶液，所述溶液适合多次使用，给药间隔为至少约1小时、至少约5小时、至少约10小时、至少24小时、至少2天、至少5天、至少7天、至少15天、至少20天、至少30天、至少50天或至少60天。
- 根据权利要求10的溶液，所述API浓度为约10mg/ml以上，优选40-60mg/ml。
- 根据权利要求10的溶液，其pH范围为约5.0——约8.0，优选约6.0——约7.0。
- 一种治疗中枢神经系统CNS疾病的方法，包括给与有需求的患者权利要求10所述的口服溶液的步骤。
- 根据权利要求19所述的方法，其中所述溶液的给药间隔为至少约1小时、至少约5小时、至少约10小时、至少24小时、至少2天、至少5天、至少7天、至少15天、至少20天、至少30天、至少50天或至少60天。
- 根据权利要求19所述的方法，其中CNS疾病包括婴儿痉挛症、复杂难治性癫痫发作、妥瑞氏综合征、难治性自身免疫性脑炎、可卡因依赖性，以及防治结节性硬化症引起的婴儿癫痫。
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