WO2017206096A1 - Préparation de capsule molle d'agomélatine - Google Patents

Préparation de capsule molle d'agomélatine Download PDF

Info

Publication number
WO2017206096A1
WO2017206096A1 PCT/CN2016/084251 CN2016084251W WO2017206096A1 WO 2017206096 A1 WO2017206096 A1 WO 2017206096A1 CN 2016084251 W CN2016084251 W CN 2016084251W WO 2017206096 A1 WO2017206096 A1 WO 2017206096A1
Authority
WO
WIPO (PCT)
Prior art keywords
agomelatine
soft capsule
capsule preparation
polyethylene glycol
surfactant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/084251
Other languages
English (en)
Chinese (zh)
Inventor
彭俊清
顾颂恩
王志云
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Huahai Pharmaceutical Co Ltd
Original Assignee
Zhejiang Huahai Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Huahai Pharmaceutical Co Ltd filed Critical Zhejiang Huahai Pharmaceutical Co Ltd
Priority to PCT/CN2016/084251 priority Critical patent/WO2017206096A1/fr
Priority to CN201680085528.0A priority patent/CN109069437A/zh
Publication of WO2017206096A1 publication Critical patent/WO2017206096A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a gelatin preparation of agomelatine.
  • Agomelatine tablets are developed by Servier, France. The specification is 25mg. The Chinese product name is Dimension New and the English name is English. Agomelatine tablets are mainly used for the treatment of adult depression. They were approved by the European Union in February 2009 and are the world's first melatonin receptor agonist antidepressants.
  • the active ingredient of agomelatine tablets is agomelatine, and its molecular structure is as follows:
  • Agomelatine is poorly soluble in a pH 2.0 hydrochloric acid solution similar to the human body environment, a pH 4.5 acetate buffer solution, a pH 6.8 phosphate buffer solution, and water, resulting in dissolution of the formulation. Low, it brings great technical difficulties to the development of the preparation, and low dissolution leads to difficulty in absorption or decreased bioavailability; in addition, agomelatine is currently only available in oral tablets, and its oral absolute bioavailability is less than 5 %, and for elderly patients or those with dysphagia, there is also a problem of poor compliance.
  • the object of the present invention is to provide a gelatin preparation of agomelatine, which can improve the dissolution rate of the drug, solve the problem of poor bioavailability, and improve the compliance of elderly patients or those with difficulty in swallowing.
  • the agomelatine soft capsule preparation is composed of a liquid composition and a soft capsule shell, the liquid The body composition is sealed in a soft capsule shell containing agomelatine, polyethylene glycol, a surfactant and a humectant, and agomelatine is completely dissolved in the polyethylene glycol .
  • Polyethylene Glycol is a polymer obtained by addition polymerization of ethylene oxide with water.
  • polyethylene glycol of grade 200-600 is a transparent, colorless or light yellow viscous liquid.
  • Polyethylene glycol grades above 600 are gradually becoming semi-solid, and polyethylene glycol of grade 1000 or higher is usually It is solid.
  • PEG Polyethylene glycol
  • the liquid PEG can be filled in a soft capsule as a solvent.
  • polyethylene glycol can better dissolve agomelatine, thereby contributing to an increase in drug dissolution rate and bioavailability.
  • Polyethylene glycol having an average molecular weight of from 200 to 650, such as one or more of the types PEG200, PEG300, PEG400, and PEG600, may be selected in the present invention.
  • the inventors have also discovered that the addition of a surfactant to a liquid composition can effectively improve the solubility of agomelatine in polyethylene glycol, and is advantageous for reducing the volume of agomelatine soft capsules, thereby improving the patient's Compliance.
  • the above surfactant is generally a nonionic surfactant, and may be, for example, one or more of caprylic acid diglyceride, polyoxyethylene 40 hydrogenated castor oil, and polyoxyethylene 35 castor oil.
  • a preferred surfactant is glyceryl caprylate.
  • the surfactant accounts for 1-3% by weight of the polyethylene glycol, preferably 2-3%.
  • the use of the above surfactant can significantly increase the solubility of agomelatine in polyethylene glycol, effectively reducing the amount of PEG used, thereby reducing the loading of agomelatine soft capsules, and ultimately reducing
  • the volume of agomelatine soft capsules plays a positive role in improving patient compliance.
  • a surfactant is typically added in an amount of from 2 to 3% by weight based on the weight of the polyethylene glycol, and only 25 mg of the drug can be dissolved by simply containing a liquid composition of 100-110 mg of polyethylene glycol.
  • the weight ratio of polyethylene glycol to agomelatine can generally be 100 to 150:25, preferably 100 to 110:25.
  • the soft capsule shell of the present invention may be a conventional material in the art, for example, the soft capsule shell may contain gelatin, glycerin, water, etc., and may be added with an appropriate amount of a preservative, an opacifier or a pigment.
  • the liquid composition of the present invention also contains a moisturizing agent.
  • the moisturizing agent can use one of glycerin, propylene glycol and the like. Or a variety.
  • the humectant accounts for 5-15% by weight of PEG to achieve a better moisturizing effect.
  • the agomelatine soft capsule preparation of the present invention can be prepared by a conventional method in the art, for example, agmelatin, PEG, a surfactant, a moisturizer, etc., and the agmelatin is completely dissolved by stirring.
  • PEG a clear liquid composition is obtained in which the content of each substance can be adjusted as described above.
  • the agomelatine soft capsule preparation is prepared by dissolving the liquid composition in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit.
  • the invention provides a new gelatin preparation of agomelatine, which not only has good stability, but also improves on the one hand compared with the conventional ordinary tablet.
  • the drug dissolution rate solves the problem of poor bioavailability.
  • due to the addition of the surfactant only a small amount of PEG is needed to dissolve the unit dose of agomelatine, thereby making the Ago of the present invention
  • the loading of Melatin soft capsules is significantly reduced, improving the compliance of elderly patients or those with dysphagia.
  • agomelatine weigh 25g of agomelatine, 110g of PEG400, 3.3g of polyoxyethylene 40 hydrogenated nettle The oil and 10 g of glycerol were then mixed and stirred until a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • agomelatine 25 g of agomelatine, 100 g of PEG 400, 2 g of polyoxyethylene 35 castor oil and 15 g of propylene glycol were weighed, and then stirred and mixed to a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • agomelatine 25 g of agomelatine, 100 g of PEG400, 2.5 g of caprylic acid diglyceride and 5 g of glycerin were weighed and then mixed and stirred until a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • agomelatine 25 g of agomelatine, 100 g of PEG400, 2 g of caprylic acid diglyceride, 0.5 g of polyoxyethylene 35 castor oil and 5 g of glycerin were weighed, and then stirred and mixed to a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • agomelatine 25 g
  • 110 g of PEG400, 1 g of caprylic acid diglyceride, 0.5 g of polyoxyethylene 35 castor oil and 7 g of glycerin were weighed and then mixed and stirred until a clear solution.
  • the solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • agomelatine 25 g of agomelatine, 110 g of PEG 200, 2 g of caprylic acid diglyceride, 0.5 g of polyoxyethylene 35 castor oil and 10 g of glycerin were weighed, and then stirred and mixed to a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • agomelatine 25 g of agomelatine, 100 g of PEG300, 1 g of caprylic acid diglyceride, 1 g of polyoxyethylene 35 castor oil and 10 g of propylene glycol were weighed, and then stirred and mixed to a clear solution. Will dissolve The solution was filled in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • agomelatine 25 g of agomelatine, 100 g of PEG 600, 1 g of caprylic acid diglyceride, 2 g of polyoxyethylene 35 castor oil and 10 g of propylene glycol were weighed, and then stirred and mixed to a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • agomelatine soft capsule preparation was prepared by dissolving the solution in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit.
  • agomelatine soft capsule preparation was prepared by dissolving the solution in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit.
  • agomelatine soft capsule preparation was prepared by dissolving the solution in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit.
  • agomelatine 25 g of agomelatine, 180 g of PEG 300 and 10 g of glycerin were weighed and then mixed and stirred until a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.
  • the results in Table 1 show that the agomelatine soft capsule preparation of the present invention has a significantly faster dissolution rate than the original tablet.
  • the lowest use of 100 mg of PEG can dissolve 25 mg of agomelatine, while the dissolution of the same weight of agomelatine in Comparative Examples 1-4 requires 180 mg of PEG.
  • the quality of the PEG required for the unit dose drug (25 mg) of the present invention was significantly smaller, indicating that the surfactant can significantly increase the solubility of agomelatine in polyethylene glycol. Effectively reduce the amount of PEG used, thereby reducing the loading of agomelatine soft capsules, and ultimately reducing the volume of agomelatine soft capsules, which plays a positive role in improving patient compliance.
  • the agomelatine soft capsules prepared in Examples 1-8 were placed at a temperature of 60 ° C, relatively wet A forced acceleration test was conducted under a high temperature and high humidity environment of 75% to examine the stability.
  • the total impurity change of the fresh sample and the sample after 10 days in a high temperature and high humidity environment was compared as shown in Table 2 below. The results showed that the fresh impurities and the total impurities of the samples after being placed in a high temperature and high humidity environment for 10 days were less than 0.05%, which was less than the instrument detectable range, indicating that the agomelatine soft capsule preparation prepared by the invention has good stability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation de capsules molles d'agomélatine composées d'un liquide et de l'enveloppe de la capsule molle. Le composé liquide, scellée à l'intérieur de la capsule, contient de l'agomélatine dissoute dans du polyéthylène glycol, un tensioactif et un humectant. La préparation de la capsule présente une bonne stabilité et améliore le taux de dissolution du médicament ce qui résout le problème de faible biodisponibilité. Grace à l'addition d'un tensioactif, seule une faible quantité de PEG par unité est nécessaire pour dissoudre l'agomélatine. Ainsi, la capacité de chargement d'une capsule de cette invention est plus faible, ce qui permet d'améliorer la compliance des patients âgés ou souffrant de dysphagie.
PCT/CN2016/084251 2016-06-01 2016-06-01 Préparation de capsule molle d'agomélatine Ceased WO2017206096A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2016/084251 WO2017206096A1 (fr) 2016-06-01 2016-06-01 Préparation de capsule molle d'agomélatine
CN201680085528.0A CN109069437A (zh) 2016-06-01 2016-06-01 一种阿戈美拉汀软胶囊制剂

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2016/084251 WO2017206096A1 (fr) 2016-06-01 2016-06-01 Préparation de capsule molle d'agomélatine

Publications (1)

Publication Number Publication Date
WO2017206096A1 true WO2017206096A1 (fr) 2017-12-07

Family

ID=60478326

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/084251 Ceased WO2017206096A1 (fr) 2016-06-01 2016-06-01 Préparation de capsule molle d'agomélatine

Country Status (2)

Country Link
CN (1) CN109069437A (fr)
WO (1) WO2017206096A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114306233A (zh) * 2020-09-27 2022-04-12 常州恒邦药业有限公司 一种阿戈美拉汀自微乳制剂
CN114452255A (zh) * 2020-10-30 2022-05-10 常州恒邦药业有限公司 一种阿戈美拉汀微乳、微乳凝胶及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103623423A (zh) * 2013-11-29 2014-03-12 蒋爱芳 阿戈美拉汀包合物、其制备方法及其应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101991577A (zh) * 2009-08-19 2011-03-30 北京利乐生制药科技有限公司 新型精神类药物组合物
CN101966167A (zh) * 2010-09-16 2011-02-09 杭州海王生物工程有限公司 一种褪黑素软胶囊及其制备方法
WO2015189778A1 (fr) * 2014-06-10 2015-12-17 Laboratorio Chimico Internazionale S.P.A. Adsorbats et compositions d'agomélatine en solution

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103623423A (zh) * 2013-11-29 2014-03-12 蒋爱芳 阿戈美拉汀包合物、其制备方法及其应用

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114306233A (zh) * 2020-09-27 2022-04-12 常州恒邦药业有限公司 一种阿戈美拉汀自微乳制剂
CN114306233B (zh) * 2020-09-27 2025-11-21 常州恒邦药业有限公司 一种阿戈美拉汀自微乳制剂
CN114452255A (zh) * 2020-10-30 2022-05-10 常州恒邦药业有限公司 一种阿戈美拉汀微乳、微乳凝胶及其制备方法

Also Published As

Publication number Publication date
CN109069437A (zh) 2018-12-21

Similar Documents

Publication Publication Date Title
Tuğcu-Demiröz et al. Development of long-acting bioadhesive vaginal gels of oxybutynin: Formulation, in vitro and in vivo evaluations
JP7440591B2 (ja) ロキソプロフェン配合皮膚用外用剤
EP2704703B1 (fr) Compositions transdermiques d'ibuprofène et leurs méthodes d'utilisation
AU754490B2 (en) Topical hormonal composition with systemic effect
EP2191828B1 (fr) Composition pharmaceutique antifongique
NO169155B (no) Fremgangsmaate for fremstilling av ibuprofenholdige kapsler av myk gelatin
HUP0204349A2 (en) Novel topical oestroprogestational compositions with systemic effect
EP3909567B1 (fr) Formulations pharmaceutiques de naproxène pour une encapsulation dans du gel mou et leurs combinaisons
US20130116271A1 (en) Tacrolimus-containing oil-in-water type creamy composition
IL115891A (en) Hemorrhoidal compositions and their use
JP2009197015A (ja) ハードシェルカプセル剤のためのイブプロフェン溶液
CN105147595B (zh) 吡嘧司特钾温度敏感性水凝胶及其制备方法
Raja Manali et al. Oral medicated jelly: a recent advancement in formulation
Meenakshi et al. Preparation and evaluation of thermoreversible formulations of flunarizine hydrochloride for nasal delivery
ES2962154T3 (es) Composición tópica
WO2017206096A1 (fr) Préparation de capsule molle d'agomélatine
US20150164913A1 (en) Testosterone gel compositions and related methods
WO2016084099A1 (fr) Composition de capsule en gélatine souple d'agents antitussifs
Yadav et al. A review recent advancement in formulation of oral medicated jelly
CN111096947A (zh) 氨磺必利口服溶液
CN102552140B (zh) 罗格列酮的液体组合物
CN108210929A (zh) 一种含有依托考昔的药物组合物及其制备方法
CN106265486A (zh) 一种硝酸咪康唑缓释凝胶及其制备方法
JP2932086B2 (ja) 新規なピコスルファートナトリウム液充填硬カプセル剤
MAHAPATRA et al. Formulation and evaluation of thermal induced intranasal in-situ gel of sumatriptan succinate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16903481

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16903481

Country of ref document: EP

Kind code of ref document: A1