WO2015096186A1 - 一种稳定的晶x型阿戈美拉汀片剂及其制备方法 - Google Patents

一种稳定的晶x型阿戈美拉汀片剂及其制备方法 Download PDF

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WO2015096186A1
WO2015096186A1 PCT/CN2014/000526 CN2014000526W WO2015096186A1 WO 2015096186 A1 WO2015096186 A1 WO 2015096186A1 CN 2014000526 W CN2014000526 W CN 2014000526W WO 2015096186 A1 WO2015096186 A1 WO 2015096186A1
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agomelatine
crystalline
type
protective agent
polyvinylpyrrolidone
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PCT/CN2014/000526
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English (en)
French (fr)
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周世旺
代奕
安适之
赵健
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天津泰普药品科技发展有限公司
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Priority to CA2912733A priority Critical patent/CA2912733A1/en
Priority to JP2016546131A priority patent/JP2016536351A/ja
Priority to EP14873358.7A priority patent/EP3087976A4/en
Priority to US14/896,087 priority patent/US20160120825A1/en
Publication of WO2015096186A1 publication Critical patent/WO2015096186A1/zh

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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
    • A61K31/16—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and relates to a crystalline X-type agomelatine tablet and a preparation method thereof.
  • Agomelatine - a melatonin-type psychotropic drug.
  • Melatonin analogue agomelatine agomelatine
  • 5-HT2C serotonin 2C
  • the first melatonin receptor agonist is a melatonin analogue, which is also a serotonin 2C (5-HT2C) receptor antagonist.
  • the affinity of melatonin to its receptors MT1 and MT2 is 8.85x10 -11 and 2.63x10 -11 , respectively, and agomelatine is similar, and has high affinity for cloned human melatonin receptors MT1 and MT2 (Ki They are 6.15x10 -11 and 2.68x10 -11 respectively.
  • Clinical studies have shown that agomelatine has a good effect on patients with depression, and the adverse reactions are very few.
  • agomelatine may increase the plasticity and nerves of neurons in the hippocampus.
  • Immunostaining method was used to measure the proliferation, regeneration and death of nerve cells in adult rat brain. It has been found that long-term (3 weeks) administration of agomelatine increases ventral dentate cell proliferation and neuronal regeneration in the hippocampus. This part is related to emotional reflection. However, no similar conditions were observed during acute or subacute administration (4 hours or 9 weeks). Following After prolonged administration, cell proliferation and neuronal regeneration occurred in the entire dentate gyrus, indicating that agomelatine can be different. The nerve regeneration of the hippocampus is increased to a certain extent, thereby producing new granulosa cells.
  • agomelatine I, II, III, IV, V, and X have been discovered.
  • Agomelatine tablets are Clinically commonly used dosage forms, but in the preparation of crystalline X-type agomelatine tablets, the following difficulties exist:
  • Crystal X-type agomelatine bulk drug sensitive to pulverization, grinding, pressure, heat, etc., have different degrees Change to type II crystal.
  • the following is a sample of the crystal X-type raw material, which is pulverized, ground, and pressed (10 kg pressure) by DSC. Change (see Figures 1-4).
  • auxiliary materials microcrystalline cellulose such as common auxiliary materials, pregelatinized starch, etc. are not available, the main reason is Therefore, the above auxiliary materials can accelerate the transformation of the agomelatine crystal form; and convert to the type II.
  • the change in crystal form may cause infringement on the one hand, and may further lead to the bioavailability of the drug on the other hand. Inconsistent. Therefore, it is very important to solve the stability of the crystal form in the preparation process and preservation of the tablet.
  • the object of the present invention is to overcome the shortcomings and deficiencies of the prior art, and to provide a novel crystal X-type Agomei. Latin tablets and methods for preparing the same. To achieve this, the present invention provides the following technical solutions:
  • a stable crystalline X-type agomelatine tablet characterized by being crystalline X-type agomelatine raw material,
  • the composition of the protective agent and the medicinal auxiliary material wherein the crystalline X-type agomelatine raw material: the protective agent: the weight ratio of the medicinal auxiliary material is 1:0.1-1:0.1-10; the protective agent is polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose a mixture of one or more.
  • the crystalline X-type agomelatine tablet according to the present invention wherein the crystalline X-type agomelatine raw material refers to
  • the gemetadine material has a crystal X type of at least 85% or more, preferably 95% or more.
  • the crystalline X-type agomelatine tablet of the present invention is preferably composed of the following parts by weight:
  • the protective agent is one or more of polyvinylpyrrolidone, hydroxypropylmethylcellulose and hydroxypropylcellulose. a mixture; the pharmaceutical excipients are lactose, croscarmellose sodium, cross-linked polyvinylpyrrolidone, hard Fatty acid, magnesium stearate or silica.
  • the invention further discloses a preparation method of a crystalline X-type agomelatine tablet, which is carried out as follows:
  • the crystalline X-type agomelatine raw material of the present invention refers to the crystalline X-form of the agomelatine raw material is 85% or more. Preferably it is 95% or more.
  • the protective agent of the present invention is hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone k30 or A mixture of one or more of polyvinylpyrrolidone k90.
  • concentration of the protective agent is generally 5-40%, preferably 10-30% (w/w).
  • the pharmaceutical excipients of the present invention are lactose, croscarmellose sodium, crosslinked polyvinylpyrrolidone, and stearin. Acid, magnesium stearate or silica.
  • the invention mainly selects pure water as a solvent, and adds one or more protective agents, such as polyvinylpyrrolidone and hydroxypropyl Methyl cellulose, hydroxypropyl cellulose.
  • one or more protective agents such as polyvinylpyrrolidone and hydroxypropyl Methyl cellulose, hydroxypropyl cellulose.
  • one or more protective agents such
  • a preferred specific example of the present invention is: screening the crystalline X-type agomelatine (content of 85% or more) for use; Hydroxypropylmethylcellulose or polyvinylpyrrolidone k90 is stirred and dissolved in water (about 40 ° C), and allowed to cool to room temperature. Add crystal form X agomelatine and mix well to obtain a protective agent containing crystalline X-type agomelatine; then milk Sugar, part (1/2) of croscarmellose sodium is added to the wet mixing granulator to mix, and then added Gomellatine protective agent, granulation, swaying granulation mechanism granules; fluidized bed drying, granulation, calculation of yield; Mix the remaining pharmaceutical excipients in proportion and compress.
  • Another preferred specific example of the present invention is: selecting pure water as a solvent, and crystal X-type agomelatine (crystal form content) 99%) sieved for use; take hydroxypropylmethylcellulose, polyvinylpyrrolidone k30 after stirring and dissolving in water (about 40 ° C), let cool to room temperature, add crystal X-type agomelatine and stir to obtain crystal X-type agomelatine Protectant spare; then add lactose, part (1/2) of cross-linked polyvinylpyrrolidone to the wet mixing granulator Mixing well, adding a protective agent containing crystalline X-type agomelatine, making soft material, and swinging the granulation mechanism; The fluidized bed is dried, granulated, and the other auxiliary materials are added in proportion to be mixed and compressed.
  • Still another preferred specific example of the present invention is: selecting pure water as a solvent, and crystal X-type agomelatine (content 95%) Above) sieved for use; take hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone k30 in water After stirring and dissolving (about 40 ° C), let cool to room temperature, add crystal X-type agomelatine and mix well to obtain crystal X-type agomelatine's protective agent is used; then lactose, part (1/2) cross-linked polyvinylpyrrolidone Mix in a wet mixing granulator, and then add a protective agent containing crystalline X-type agomelatine to make a soft material.
  • the swing granulation mechanism granules; the fluidized bed is dried, the whole granules, the other auxiliary materials are added in proportion, and the tablets are compressed.
  • Ben The invention focuses on the following key issues:
  • Crystal X-type agomelatine is almost insoluble in water, soluble in methanol, ethanol, acetonitrile, DMSO, etc., further Bring changes in crystal form. Therefore, the selection is optimal in water, and the optimum ratio is about 0.5-4 times the amount of the raw material;
  • Crystal X-type agomelatine is sensitive to heat and pressure and unstable under high temperature and high pressure conditions.
  • the inventors examined lactose, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol 4000, polyvinylpyrrolidone k30, hydroxypropylmethylcellulose, hydroxypropylcellulose.
  • crystalline X-type agomelatine sodium carboxymethyl starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone, magnesium stearate, stearic acid, silica, talc and other auxiliary materials mixed with crystal X-type agomelatine ( 1:1);
  • the crystalline X-type agomelatine material was simultaneously placed at high temperature of 60 ° C, high humidity RH 92.5%, and light 4500 ⁇ 500 L X illuminance for 15 days, and its crystal form change was measured by DSC.
  • Polyvinylpyrrolidone k30, hydroxypropylmethylcellulose, polyethylene glycol, hydroxypropylcellulose were selected.
  • Test method According to the prescription in the following table, take the appropriate amount of protective agent to make a 5% solution; as a granulation Protective agent; crystal X-type agomelatine and lactose, part (1/2) cross-linked polyvinylpyrrolidone mixed, added to (SHR-6 Type) rapid wet granulator, mixed granulation for 2 min, transferred to the swing granulation mechanism granules (screen 833 ⁇ m), via (WBF-2 Type) multi-functional fluidized bed (inlet air temperature 45 ° C, boiling bed temperature 30 ° C) dry, calculate the yield; add according to the prescription Part (1/2) of cross-linked polyvinylpyrrolidone, magnesium stearate, stearic acid, silica; using a diameter of 7.5mm Stamping sheet. The tablets were subjected to DSC scanning and the purity of the crystal form X was calculated by normalization.
  • Method 1 The protective agent is mixed with agomelatine and then added with lactose.
  • Method 2 Agomelatine is mixed with lactose and then added with a protective agent.
  • Test 1 Polyvinylpyrrolidone k30 was selected as a protective agent to examine the protective effects at different concentrations. Following up For the prescription, take the appropriate amount of polyvinylpyrrolidone k30, and arrange it into 5%, 10%, 15%, 20% solution, according to the above method. Prepare tablets. The crystal X-type purity of the tablets was determined as follows:
  • Test 2 Hydroxypropyl cellulose was selected as a protective agent to examine the protective effects at different concentrations. According to the above prescription, A suitable amount of hydroxypropylcellulose was prepared and placed in a 5%, 10%, 15%, 20% solution, and tablets were prepared as described above. Measuring piece The crystal X-type purity results of the agent are as follows:
  • Test 3 Hydroxypropylmethylcellulose was selected as a protective agent to examine the protective effects at different concentrations. According to the above The tablets were prepared according to the above method by taking appropriate amounts of hydroxypropylmethylcellulose and disposing them into 5%, 10%, 15%, and 20% solutions. The crystal X-type purity of the tablets was determined as follows:
  • Test 4 Select polyvinylpyrrolidone k30 and hydroxypropyl cellulose as protective agents to investigate the protection of different concentrations. Protection. According to the above prescription, take the appropriate amount of polyvinylpyrrolidone k30 and hydroxypropylcellulose (the ratio is 1:1). The tablets were prepared as described above in a 5%, 10%, 15%, 20% solution. Determination of the crystal X-type purity of the tablet results under:
  • Test 5 Select hydroxypropyl cellulose and hydroxypropyl methyl cellulose as protective agents to investigate the protection of different concentrations. use. According to the above prescription, take hydroxypropylcellulose, hydroxypropylmethylcellulose in an appropriate amount (a ratio of 1:1), configured to 5%, 10%, 15%, 20% solution, tablets were prepared as described above. The crystal X-type purity of the tablets was determined as follows:
  • Test 6 Select hydroxypropylmethylcellulose and polyvinylpyrrolidone k30 as protective agents to investigate different concentrations Protective effects. According to the above prescription, take the appropriate amount of hydroxypropylmethylcellulose and polyvinylpyrrolidone k30 (the ratio is 1:1).
  • the tablets were prepared as described above in a 5%, 10%, 15%, 20% solution. Determination of the crystal X-type purity of the tablet results under:
  • the best effect is to use mixed protective agents, among which hydroxypropylmethylcellulose and polyvinylpyrimidine are the best choice.
  • Pyrrolidone k30 the use of 15% concentration, 20% concentration (too much viscosity) soft material preparation is relatively easy, more Conducive to industrial production.
  • the conditions for the determination of dissolution according to the dissolution test method (Chinese Pharmacopoeia 2010 edition two appendix XC, the second method), 900ml 0.1M hydrochloric acid as solvent, the rotation speed is 50 rev / min, according to the law, after 5, 10, 15, 20, 30, 45 In minutes, 10 ml of each sample was taken and replenished in time, filtered, and the filtrate was taken as the test solution.
  • Another precision weighing control Appropriate amount add 95% ethanol solution to make a solution containing 1.25mg of agomelatine per 1ml, precision measurement 1ml set 50ml In the measuring flask, add 0.1 mol/L to the mark and shake well to prepare a reference solution.
  • the package uses a polyethylene bottle with a desiccant. Place in RH 75%, 40 ° C conditions and RH 60%, 30 ° C conditions. The crystal form is used as an evaluation index. The results are as follows:
  • the protective agent selected for use in the present invention is a commonly used pharmaceutical excipient in the preparation, such as hydroxypropyl cellulose, hydroxypropyl Methylcellulose, polyvinylpyrrolidone, is added by first adding the crystalline X-type agomelatine to a certain concentration. The aqueous solution of the protective agent is thoroughly mixed and stirred uniformly to prepare a protective agent containing crystalline X-type agomelatine. Then with other The medicinal excipients are mixed and granulated, and finally the agomelatine tablet is prepared to ensure that the crystal form X does not change.
  • a commonly used pharmaceutical excipient in the preparation such as hydroxypropyl cellulose, hydroxypropyl Methylcellulose, polyvinylpyrrolidone
  • the crystalline X-type agomelatine tablet prepared by the invention can fully ensure that the crystal form X is not in the preparation process of the tablet. A change has occurred.
  • the tablet form and the related substance have good stability in the tablet preparation process disclosed in the present invention.
  • Figure 2AG is a DSC pattern of the crystal X-type raw material after pulverization
  • Figure 5AG is a DSC diagram of the crystalline X-type protected material after tableting
  • Figure 10 is a comparison of dissolution profiles in pH 4.5 acetate buffer
  • Crystalline type X agomelatine is sieved according to the above weight; hydroxypropylmethylcellulose, polyvinylpyrrole The alkanone k30 is stirred and dissolved in water, allowed to cool to room temperature, and added to the crystal X-type agomelatine; Gomeratin's protective agent is used; the protective agent containing crystalline X-type goomelatine is added to the lactose-containing portion (1/2)
  • the granulation mechanism is granulated (screen 833 ⁇ m); obtained wet granules; dried by fluidized bed (inlet air temperature 45 ° C, boiling bed temperature 30 ° C), control moisture 2%; whole grain; calculate the yield, add other remaining auxiliary materials, mix, and use a punch with a diameter of 7.5 mm.
  • Crystalline type X agomelatine is sieved according to the above weight; hydroxypropyl cellulose, polyvinylpyrrolidine Ketone k30 is stirred and dissolved in water, allowed to cool to room temperature, and added with crystal X-type agomelatine to obtain a crystal X-type Ago
  • the protective agent of melastin is reserved; the protective agent containing crystalline X-type agomelatine is added to the lactose-containing portion (1/2)
  • the granulation mechanism is granulated (screen) 833 ⁇ m); obtained wet granules; dried by fluidized bed (inlet air temperature 45 ° C, boiling bed temperature 30 ° C), control moisture 2%; whole grain; calculate the yield, add other remaining auxiliary materials, mix, and use a punch with a diameter of 7.5 mm.
  • Crystalline type X agomelatine is sieved according to the above weight; hydroxypropylmethylcellulose, polyvinylpyrrole The alkanone k30 is stirred and dissolved in water, allowed to cool to room temperature, and added to the crystal X-type agomelatine; Gomeratin's protective agent is used; the protective agent containing crystalline X-type agomelatine is added to the lactose-containing portion (1/2) In a mixed granulator of croscarmellose sodium, after wet granulation for 2 min, the granulation mechanism is granulated (screen) 833 ⁇ m); obtained wet granules; dried by fluidized bed (inlet air temperature 45 ° C, boiling bed temperature 30 ° C), control moisture 2%; whole grain; calculate the yield, add other remaining auxiliary materials, mix, and use a punch with a diameter of 7.5 mm.
  • Crystalline type X agomelatine is sieved for use according to the above weight; hydroxypropylmethyl cellulose is taken and stirred in water Dissolve, let cool to room temperature, add crystal X-type agomelatine and stir well; get protective agent containing crystal X-type agomelatine Adding a protective agent containing crystalline X-type agomelatine to lactose-containing, partially (1/2) cross-linked polyvinylpyrrolidine
  • the granulation mechanism (screen 833 ⁇ m) is obtained by a rocking granulation mechanism; Granule; dried by fluidized bed (inlet air temperature 45 ° C, boiling bed temperature 30 ° C), control moisture is about 2%; whole grain; calculation Yield, add other remaining excipients, mix, and use a punch with a diameter of 7.5 mm.
  • Crystalline type X agomelatine is sieved for use according to the above weight; polyvinylpyrrolidone k90 is stirred in water Dissolve and dissolve, let cool to room temperature, add crystal form X agomelatine and mix well; get protective agent containing crystalline X-type agomelatine Stand-by; adding a protective agent containing crystalline X-type agomelatine to lactose-containing, partially (1/2) croscarmellose fiber
  • the mixed granulator of sodium after wet granulation for 2 min, the granulation mechanism (screen 833 ⁇ m) was shaken; Granule; dried by fluidized bed (inlet air temperature 45 ° C, boiling bed temperature 30 ° C), control moisture is about 2%; whole grain; Calculate the yield, add other remaining excipients, mix, and use a punch with a diameter of 7.5 mm.
  • Crystalline type X agomelatine is sieved for use according to the above weight; hydroxypropyl cellulose is stirred and dissolved in water, Allow to cool to room temperature, add crystal form X agomelatine and mix well; get a protective agent containing crystalline X-type agomelatine; A protective agent containing crystalline X-type agomelatine is added to a mixture containing lactose and a portion (1/2) of cross-linked polyvinylpyrrolidone In the granulator, after wet granulation for 2 min, the granulation mechanism (screen 833 ⁇ m) was obtained by a rocking granulation mechanism; wet granules were obtained; Fluidized bed drying (inlet air temperature 45 ° C, boiling bed temperature 30 ° C), control moisture is about 2%; whole grain; calculate yield, Add other remaining excipients, mix and use a 7.5mm diameter punch.
  • Crystalline type X agomelatine is sieved according to the above weight; hydroxypropyl cellulose, hydroxypropyl methyl fiber And polyvinylpyrrolidone K30 is stirred and dissolved in water, allowed to cool to room temperature, and added to the crystal X-type agomelatine; Obtaining a protective agent containing crystalline X-type agomelatine; adding a protective agent containing crystalline X-type agomelatine to the milk containing In a mixed granulator of sugar and partial (1/2) cross-linked polyvinylpyrrolidone, after wet granulation for 2 min, it is subjected to rocking granulation.
  • Mechanism granules (screen 833 ⁇ m); wet granules; fluidized bed drying (inlet air temperature 45 ° C, boiling bed temperature 30 ° C), Control the moisture content to about 2%; whole grain; calculate the yield, add other remaining auxiliary materials, mix, use a diameter of 7.5mm Head compression.

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Abstract

一种稳定的晶X型阿戈美拉汀片剂及其制备方法。该方法包括选择一种或多种保护剂加入纯水中，搅拌，加热到35-40°C溶解至清，放冷至室温，加入晶X型阿戈美拉汀，搅拌均匀，得到含有晶X型阿戈美拉汀的保护剂备用；然后将部分药用辅料混合均匀后再加入含有晶X型阿戈美拉汀的保护剂，经湿法混合制粒和干燥后，得到含晶X型阿戈美拉汀的颗粒；最后按比例加入其余药用辅料混匀，压片。

Description

一种稳定的晶X型阿戈美拉汀片剂及其制备方法 技术领域
本发明属于药物制剂技术领域，涉及一种晶X型阿戈美拉汀片剂及其制备方法。
技术背景
阿戈美拉汀-褪黑激素类精神疾病类药物。褪黑素类似物阿戈美拉汀 (agomelatine)，既是首个褪黑素受体激动剂，也是5-羟色胺2C(5-HT2C)受体拮抗剂。 动物试验与临床研究表明该药有抗抑郁、抗焦虑、调整睡眠节律及调节生物钟作用，同 时其不良反应少，对性功能无不良影响，也未见撤药反应。
首个褪黑素受体激动剂agomelatine(Valdoxan)为褪黑素类似物，它同时也是5一 羟色胺2C(5-HT2C)受体拮抗剂。褪黑素与其受体MT1和MT2的亲和力Ki分别为 8.85x10 -11及2.63x10 -11，阿戈美拉汀与其相似，对克隆的人褪黑素受体MT1和MT2也有 高度的亲和力(Ki分别为6.15x10 -11及2.68x10 -11)。临床研究表明，阿戈美拉汀对抑郁 症患者有较好的疗效，且不良反应非常少。
阿戈美拉汀抗抑郁的确切机制目前尚未明确。单纯的5-HT2C受体阻断剂并无抗抑 郁作用。阿戈美拉汀能阻断5-HT2C受体，然而动物试验显示褪黑素也有少量的抗抑郁 作用，并有研究发现应激与褪黑素分泌有关，但人体服用褪黑素并未见明显的抗抑郁作 用。
另有研究表明，阿戈美拉汀抗抑郁的机制可能与增加海马部位神经元的可塑性及神 经元增生有关。以免疫染色的方法测定成年大鼠脑部神经细胞的增生、再生及死亡，结 果发现，阿戈美拉汀长期(3周)给药可增加海马腹侧齿状回细胞增生及神经元再生，而 这一部位与情绪反映有关。但在急性或亚急性给药时(4小时或9周)未见类似情况。继 续延长给药后，整个齿状回区域均出现细胞增生及神经元再生，表明阿戈美拉汀可不同 程度地增加海马的神经再生，从而产生新的颗粒细胞。
阿戈美拉汀由Servier公司开发研制，目前已上市销售。化学结构：
Figure PCTCN2014000526-appb-000001
目前已发现了阿戈美拉汀I、II、III、IV、V、X等多种晶型。阿戈美拉汀片剂为 临床上常用的剂型，但在晶X型的阿戈美拉汀片剂制备过程中存在如下的难点：
(1)晶X型阿戈美拉汀原料药，对粉碎、研磨、压力、热等敏感，均有不同程度的 转变为II型结晶。以下是晶X型原料粉碎、研磨、压片(10kg压力)通过DSC测定其 变化(见附图1～4)。
Figure PCTCN2014000526-appb-000002
结果表明：晶X型阿戈美拉汀原料在粉碎、研磨、压片的过程中晶型有明显的变化， 转化为II型结晶。
(2)辅料选择面窄：像常用辅料微晶纤维素、预胶化淀粉等均不可用，主要原因在 于，上述辅料能加速阿戈美拉汀晶型的转变；转化为II型。
因此，采用常规制粒压片工艺均不能保证晶X型稳定。原料和辅料直接压片或干法 制粒压片，晶型立即会发生转变；用普通湿法制粒工艺，转变更为明显。
首先，法国瑟维尔实验室的专利申请CN200510071611.6，其中关于晶II型的合成 工艺及药物组合物在2007年获得中国专利授权，其晶II型阿戈美拉汀得到保护。中国 专利CN101781226A介绍了晶X型制备方法。通过此方法制备得到的晶X型阿戈美拉汀， 在实际的片剂制备过程中晶X型极易转化成II型，进一步稳定性试验也存在转化为II 型的可能(我们制备的样品片剂在加速2个月后经粉末衍射检查：原料药几乎全部转化 为II型)。
晶型的变化，一方面可能造成侵权，另一方面可能进一步带来药物在生物利用度上 的不一致。因此解决晶型在片剂制备过程及保存中的稳定性是非常重要的。
发明内容
本发明的目的在于克服现有技术的缺点与不足，提供了一种新型的晶X型阿戈美 拉汀片剂及其该片剂的制备方法。为实现此目的，本发明提供如下的技术方案：
一种稳定的晶X型阿戈美拉汀片剂，其特征在于它是由晶X型阿戈美拉汀原料、保 护剂、药用辅料组成；其中晶X型阿戈美拉汀原料：保护剂：药用辅料的重量份数比为 1∶0.1-1∶0.1-10；所述的保护剂为聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基纤维 素一种或多种的混合物。
本发明所述的晶X型阿戈美拉汀片剂，其中所述的晶X型阿戈美拉汀原料指的是阿 戈美拉汀原料中晶X型至少为85％以上，优选95％以上。
本发明优选所述的晶X型阿戈美拉汀片剂，它是由下述重量份数的原料组成：
Figure PCTCN2014000526-appb-000003
所述的保护剂为聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基纤维素一种或多种 的混合物；所述的药用辅料为乳糖、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、硬 脂酸、硬脂酸镁或二氧化硅。
本发明进一步公开了晶X型阿戈美拉汀片剂的制备方法，按如下的步骤进行：
(a)选择一种或多种保护剂加入纯水中，搅拌，加热到35-40℃溶解至清，放冷 至室温，加入晶X型阿戈美拉汀，搅拌均匀，得到含有晶X型阿戈美拉汀的保护剂备用； 其中晶X型阿戈美拉汀原料与保护剂的重量份数比为1∶0.1-1；水的加入量为晶X型 阿戈美拉汀重量的0.5-4倍；
(b)将部分药用辅料混匀，然后加入含有晶X型阿戈美拉汀的保护剂，混合制粒， 得到含晶X型阿戈美拉汀的颗粒；所述的部分药用辅料为乳糖、交联羧甲基纤维素钠或 交联聚乙烯吡咯烷酮；
(c)按比例加入其余药用辅料混匀，压片；其中所述的保护剂为聚乙烯吡咯烷酮、 羟丙基甲基纤维素、羟丙基纤维素一种或多种的混合物。
本发明所述的晶X型阿戈美拉汀原料指的是阿戈美拉汀原料中晶X型为85％以上， 优选95％以上。
本发明所述的保护剂为羟丙甲基纤维素、羟丙基纤维素、聚乙烯吡咯烷酮k30或 聚乙烯吡咯烷酮k90的一种或多种的混合物。保护剂的浓度一般为5-40％，优选10-30％ (w/w)。例如5-20％的羟丙甲基纤维素、5-20％羟丙基纤维素、5-20％聚乙烯吡咯烷酮 k30或5-20％聚乙烯吡咯烷酮k90。
本发明所述的药用辅料为乳糖、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、硬脂 酸、硬脂酸镁或二氧化硅。
本发明主要选择纯水为溶剂，加入一种或多种保护剂，例如聚乙烯吡咯烷酮、羟丙 基甲基纤维素、羟丙基纤维素。搅拌，加热到35-40℃溶解至清，放冷至室温，加入晶 X型阿戈美拉汀，搅拌均匀，得到含有晶X型阿戈美拉汀的保护剂备用；然后将部分药 用辅料混匀，例如乳糖、交联羧甲基纤维素钠或交联聚乙烯吡咯烷酮，再加入含有晶X 型阿戈美拉汀的保护剂，湿法混合制粒，干燥，得到含晶X型阿戈美拉汀的颗粒；最后 按比例加入其余药用辅料混匀，压片。
本发明一个优选的特例是：将晶X型阿戈美拉汀(含量85％以上)过筛备用；取 羟丙甲基纤维素或聚乙烯吡咯烷酮k90在水中搅拌溶解后(约40℃)，放冷至室温， 加入晶X型阿戈美拉汀搅匀，得到含有晶X型阿戈美拉汀的保护剂备用；然后将乳 糖、部分(1/2)交联羧甲基纤维素钠加入湿法混合制粒机中混匀，再加入含有阿 戈美拉汀的保护剂，制粒，经摇摆制粒机制粒；流化床干燥，整粒，计算收率；按 比例加入其余药用辅料混匀，压片。
本发明另一个优选的特例是：选择纯水为溶剂，将晶X型阿戈美拉汀(晶型含量 99％)过筛备用；取羟丙甲基纤维素、聚乙烯吡咯烷酮k30在水中搅拌溶解后(约 40℃)，放冷至室温，加入晶X型阿戈美拉汀搅匀，得到含有晶X型阿戈美拉汀的 保护剂备用；然后将乳糖、部分(1/2)交联聚乙烯吡咯烷酮加入湿法混合制粒机 中混匀，再加入含有晶X型阿戈美拉汀的保护剂，制软材，经摇摆制粒机制粒； 流化床干燥，整粒，按比例加入其余辅料混匀，压片。
本发明再一个优选的特例是：选择纯水为溶剂，将晶X型阿戈美拉汀(含量95％ 以上)过筛备用；取羟丙基纤维素、羟丙甲基纤维素、聚乙烯吡咯烷酮k30在水 中搅拌溶解后(约40℃)，放冷至室温，加入晶X型阿戈美拉汀搅匀，得到含有晶 X型阿戈美拉汀的保护剂备用；然后将乳糖、部分(1/2)交联聚乙烯吡咯烷酮加 入湿法混合制粒机中混匀，再加入含有晶X型阿戈美拉汀的保护剂，制软材，经 摇摆制粒机制粒；流化床干燥，整粒，按比例加入其余辅料混匀，压片。为此，本 发明重点考察了如下的关键问题：
(1)溶剂选择：
晶X型阿戈美拉汀几乎不溶于水，在甲醇、乙醇、乙腈、DMSO等中易溶，进一步 带来晶型的变化。因此，选择在水中制备最佳，最佳比例加入量约为原料的0.5-4倍；
(2)药用辅料的选择：
晶X型阿戈美拉汀对热与压力较为敏感，在高温和高压条件下不稳定。为此，本发 明人考察了乳糖、甘露醇、磷酸氢钙、微晶纤维素、预胶化淀粉、聚乙二醇4000、聚 乙烯吡咯烷酮k30、羟丙甲基纤维素、羟丙基纤维素、羧甲基淀粉钠、交联羧甲基纤维 素钠、交联聚乙烯吡咯烷酮、硬脂酸镁、硬脂酸、二氧化硅、滑石粉等辅料与晶X型阿 戈美拉汀混合(1∶1)；晶X型阿戈美拉汀原料同时在高温60℃、高湿RH92.5％、光照4500 ±500L X照度下放置15天后，采用DSC测定其晶型变化。
结果：预胶化淀粉对测定干扰，其中微晶纤维素有明显的晶型转变促进作用。结合 上市品使用的辅料，我们选用乳糖、聚乙烯吡咯烷酮、羟丙甲基纤维素、羟丙基纤维素、 羧甲基淀粉钠、交联聚乙烯吡咯烷酮、硬脂酸、硬脂酸镁、二氧化硅等作为试验用的辅 料。
(3)保护剂的选择：
选择聚乙烯吡咯烷酮k30、羟丙甲基纤维素、聚乙二醇、羟丙基纤维素。
试验方法：按照以下表中处方，取保护剂适量，制成5％的溶液；作为制粒用的保 护剂；晶X型阿戈美拉汀和乳糖、部分(1/2)交联聚乙烯吡咯烷酮混合，加入到(SHR-6 型)快速湿法制粒机，混合制粒2min后转移到摇摆制粒机制粒(筛网833μm)，经(WBF-2 型)多功能流化床(进风温度45℃，沸床温度30℃)干燥，计算收率；按照处方量加 入部分(1/2)交联聚乙烯吡咯烷酮、硬脂酸镁、硬脂酸、二氧化硅；采用直径为7.5mm 冲压片。片剂经DSC扫描，归一法计算晶X型的纯度。
处方表
成分 重量(g)
晶X型阿戈美拉汀 25
乳糖 92
保护剂 纯水或5％保护剂，20ml
交联聚乙烯吡咯烷酮 9
硬脂酸镁 1.3
硬脂酸 2.6
二氧化硅 0.3
结果如下表：
Figure PCTCN2014000526-appb-000004
结果表明：聚乙烯吡咯烷酮k30、羟丙基纤维素、羟丙甲基纤维素均有保护作用； 聚乙二醇有促进晶型转化作用。
3.1保护剂加入方法试验
方法1：保护剂与阿戈美拉汀混合均匀后再加入乳糖。
方法2：阿戈美拉汀与乳糖混合后再加入保护剂。
采用聚乙烯吡咯烷酮k30(浓度为10％)为保护剂，照方法1、2制备得到片剂；测 定片剂的晶X型纯度结果如下：
Figure PCTCN2014000526-appb-000005
结果表明：方法1的效果更好。
3.2保护剂用量用法试验
试验1：选取聚乙烯吡咯烷酮k30作为保护剂，考察不同浓度的保护作用。按照上 述处方，取聚乙烯吡咯烷酮k30适量，配置成5％、10％、15％、20％溶液，照上述方法制 备片剂。测定片剂的晶X型纯度结果如下：
Figure PCTCN2014000526-appb-000006
结果表明：随着聚乙烯吡咯烷酮k30的浓度提高，晶型的变化减少。
试验2：选取羟丙基纤维素作为保护剂，考察不同浓度的保护作用。按照上述处方， 取羟丙基纤维素适量，配置成5％、10％、15％、20％溶液，照上述方法制备片剂。测定片 剂的晶X型纯度结果如下：
Figure PCTCN2014000526-appb-000007
结果表明：随着羟丙基纤维素的浓度提高，晶型的变化减少。
试验3：选取羟丙甲基纤维素作为保护剂，考察不同浓度的保护作用。按照上述处 方，取羟丙甲基纤维素适量，配置成5％、10％、15％、20％溶液，照上述方法制备片剂。 测定片剂的晶X型纯度结果如下：
Figure PCTCN2014000526-appb-000008
结果表明：羟丙甲基纤维素保护作用最强，5％的浓度就能达到90％以上随着羟丙甲 基纤维素的浓度提高，晶型的变化减少。
试验4：选取聚乙烯吡咯烷酮k30、羟丙基纤维素作为保护剂，考察不同浓度的保 护作用。按照上述处方，取聚乙烯吡咯烷酮k30、羟丙基纤维素适量(比例为1∶1)， 配置成5％、10％、15％、20％溶液，照上述方法制备片剂。测定片剂的晶X型纯度结果如 下：
Figure PCTCN2014000526-appb-000009
结果表明：随着聚乙烯吡咯烷酮k30和羟丙基纤维素的浓度提高，晶型的变化减少。
试验5：选取羟丙基纤维素、羟丙甲基纤维素作为保护剂，考察不同浓度的保护作 用。按照上述处方，取羟丙基纤维素、羟丙甲基纤维素适量(比例为1∶1)，配置成5％、 10％、15％、20％溶液，照上述方法制备片剂。测定片剂的晶X型纯度结果如下：
Figure PCTCN2014000526-appb-000010
结果表明：随着羟丙基纤维素和羟丙甲基纤维素的浓度提高，晶型的变化减少。
试验6：选取羟丙甲基纤维素、聚乙烯吡咯烷酮k30作为保护剂，考察不同浓度的 保护作用。按照上述处方，取羟丙甲基纤维素、聚乙烯吡咯烷酮k30适量(比例为1∶1)， 配置成5％、10％、15％、20％溶液，照上述方法制备片剂。测定片剂的晶X型纯度结果如 下：
结果表明：随着聚乙烯吡咯烷酮k30和羟丙甲基纤维素的浓度提高，晶型的变化减 少，当浓度达到15％时，晶X型阿戈美拉汀几乎没有改变。
综上所述，采用混合保护剂效果最好，其中最优选择羟丙甲基纤维素与聚乙烯吡 咯烷酮k30。其中，采用15％的浓度，较20％浓度(粘度太大)软材制备相对容易，更 利于工业化大生产。
4.体外溶出度试验：
阿戈美拉汀(晶X型)固体制剂与上市品的体外溶出曲线对比试验：
溶出度的测定条件：照溶出度测定法(中国药典2010年版二部附录XC，第二法)， 以900ml0.1M盐酸为溶剂，转速为50转/分，依法操作，经5、10、15、20、30、45 分钟，分别取样10ml并及时补液，滤过，取续滤液作为供试品溶液。另精密称取对照 品适量，加95％乙醇溶液制成每1ml含1.25mg阿戈美拉汀的溶液，精密量取1ml置50ml 量瓶中，加0.1mol/L稀释至刻度，摇匀，作为对照品溶液。
分别取供试品溶液和对照品溶液，照分光光度法(中国药典2010年版二部附录IVA) 在276nm的波长处测定吸收度，外标法计算每片溶出量。
同时计算相似因子f 2值，结果如下：
自制在水中的溶出度(％)
时间(min) 1 2 3 4 5 6 均值
5 34.6 34.4 33.6 35.7 31.7 34.0 34.0
10 62.5 63.3 61.1 64.5 63.6 63.5 63.1
15 80.7 80.4 79.5 81.2 81.0 81.2 80.7
20 87.3 88.5 87.9 90.9 89.9 89.1 88.9
30 93.4 94.6 94.0 95.4 94.4 94.1 94.3
45 95.5 94.9 95.0 96.0 95.4 95.1 95.3
片在0.1mol/L盐酸中的溶出度(％)
时间(min) 1 2 3 4 5 6 均值
5 33.3 34.4 33.8 34.3 32.8 34.6 33.9
10 64.5 66.1 62.4 66.9 64.1 64.6 64.8
15 79.4 82.0 81.0 83.9 83.4 83.8 82.3
20 87.7 89.8 87.0 90.6 90.3 89.5 89.1
30 93.6 94.6 93.9 95.5 95.7 95.9 94.9
45 97.1 95.8 95.2 96.8 97.2 95.8 96.3
自制片在pH4.5醋酸盐缓冲液中的溶出度(％)
时间(min) 1 2 3 4 5 6 均值
5 39.4 38.0 37.0 37.3 37.0 36.7 37.6
10 66.3 65.6 67.5 64.8 64.5 66.6 65.9
15 81.1 81.7 81.9 79.9 81.1 83.0 81.5
20 90.3 90.5 91.9 88.4 88.8 90.5 90.1
30 94.5 96.3 96.8 94.4 94.1 95.3 95.2
45 97.3 98.4 99.3 96.7 98.2 97.3 97.9
自制片在pH6.8磷酸盐缓冲液中的溶出度(％)
时间(min) 1 2 3 4 5 6 均值
5 39.1 34.8 34.4 33.5 34.9 35.4 35.4
10 62.6 63.2 62.7 62.2 64.3 63.5 63.1
15 80.4 80.1 77.7 76.8 78.6 78.2 78.6
20 89.8 88.6 88.3 85.5 89.1 87.3 88.1
30 95.4 93.4 91.2 93.0 94.1 92.9 93.3
45 97.9 96.4 95.8 96.1 96.4 93.6 96.0
自制片在0.5％SDS溶液中的溶出度(％)
时间(min) 1 2 3 4 5 6 均值
5 77.7 75.5 76.4 75.8 75.6 73.9 75.8
10 96.8 97.1 97.3 95.8 95.7 96.8 96.6
15 99.7 100.1 99.2 98.3 98.7 98.8 99.1
20 101.4 99.3 98.8 99.4 98.9 99.4 99.5
30 100.9 99.1 98.9 98.7 100.0 100.3 99.6
45 101.3 100.0 99.8 100.6 99.5 99.5 100.1
上市品在水中的溶出度(％)
Figure PCTCN2014000526-appb-000012
上市品在0.1mol/L盐酸中的溶出度(％)
Figure PCTCN2014000526-appb-000013
Figure PCTCN2014000526-appb-000014
上市品在pH4.5缓冲液中的溶出度(％)
Figure PCTCN2014000526-appb-000015
上市品在pH6.8缓冲液中的溶出度(％)
Figure PCTCN2014000526-appb-000016
上市品在0.5％十二烷基硫酸钠溶液中的溶出度(％)
Figure PCTCN2014000526-appb-000017
自制品与上市品溶出曲线比较结果
Figure PCTCN2014000526-appb-000018
结果表明，自制品上市品在以上各种介质中的f 2值均大于50，说明体外溶出非常 接近。
5.稳定性考察：
参照上述试验6：采用羟丙甲基纤维素、聚乙烯吡咯烷酮k30作为保护剂，浓度为 15％，按照处方工艺制备片剂。
5.1工艺过程中稳定性
以晶型和有关物质为评价指标，采用DSC法测定片剂的晶型纯度；有关物质的测定： 采用进口药品标准，HPLC法；其结果如下：
本发明制备的晶X型阿戈美拉汀片结果(％)
项目 有关物质(％) 晶型纯度(％)
原料 0.42 100
含原料颗粒 0.44 100
片剂 0.43 100
结果表明：制剂过程中晶型和有关物质几乎没有变化，工艺过程良好。
5.2影响因素试验
我们结合本发明的制剂考察：在高温60℃、高湿RH92.5％、高温高湿(40℃、RH75％) 敞口放置30天，其结果如下：
影响因素试验结果(％)
Figure PCTCN2014000526-appb-000019
结果表明：有关物质没有增加；晶X型制剂与单纯原料相比，晶型的稳定性明显提高。
5.3加速试验
包装使用聚乙烯瓶，内加干燥剂。放置在RH75％，40℃条件和RH60％，30℃条件。 以晶型为评价指标。结果如下：
Figure PCTCN2014000526-appb-000020
结果表明：在RH75％，40℃条件下，晶型发生改变；RH60％，30℃条件下，晶型稳 定，提示片剂应在阴凉处放置。
本发明所公开的晶X型阿戈美拉汀片剂与现有技术相比所具有的显著特点在于：
(1)本发明所选用的保护剂为制剂中的常用药用辅料，例如羟丙基纤维素、羟丙 甲基纤维素、聚乙烯比咯烷酮，其加入方法是：先将晶X型阿戈美拉汀与一定浓度的保 护剂水溶液充分混合搅拌均匀，制成含有晶X型阿戈美拉汀的保护剂。然后再与其他的 药用辅料混合制粒，最后制成保证晶X型不发生任何变化的阿戈美拉汀片剂。
(2)本发明所制备的晶X型阿戈美拉汀片剂能充分保证晶X型在片剂制备过程中不 发生变化。
(3)本发明所公开的片剂制备工艺完全能够适应大规模工业化生产的需要。
(4)本发明所公开的片剂制备工艺中片剂的晶型和有关物质的稳定性良好。
附图说明：
图1AG晶X型原料DSC图；
图2AG晶X型原料粉碎后DSC图；
图3AG晶X型原料研磨后DSC图；
图4AG晶X型原料压片后DSC图；
图5AG晶X型保护后原料压片后DSC图；
图6AG晶X型原料(含杂晶)DSC图；
图7AG晶X型(含杂晶)保护后原料压片后DSC图；
图8.在水中溶出曲线对比；
图9.在0.1N盐酸0.1mol/L中溶出曲线对比；
图10在pH4.5醋酸盐缓冲液中溶出曲线对比；
图11.在pH6.8磷酸盐缓冲液中溶出曲线对比；
图12.在0.5％十二烷基硫酸钠中溶出曲线对比。
具体实施方式：
为了简单和清楚的目的，下文恰当的省略了公知技术的描述，以免那些不必要的细 节影响对本技术方案的描述。以下结合实例对本发明做进一步的说明。其中阿戈美拉汀 (晶X型含量为85％以上)的制备参考中国专利CN101781226A；所用其它辅料均有市售。
实施例1：
Figure PCTCN2014000526-appb-000021
Figure PCTCN2014000526-appb-000022
工艺：按上述重量将晶X型阿戈美拉汀过筛备用；取羟丙甲基纤维素、聚乙烯吡咯 烷酮k30在水中搅拌溶解，放冷至室温，加入晶X型阿戈美拉汀搅匀；得到含晶X型阿 戈美拉汀的保护剂备用；将含有晶X型阿戈美拉汀的保护剂加入到含有乳糖、部分(1/2) 交联聚乙烯吡咯烷酮的混合制粒机中，湿法制粒2min后，经摇摆制粒机制粒(筛网 833μm)；得到湿颗粒；经流化床干燥(进风温度45℃，沸床温度30℃)，控制水分约 为2％；整粒；计算收率，加入其他剩余辅料，混匀，使用直径为7.5mm冲头压片。
实施例2
工艺：按上述重量将晶X型阿戈美拉汀过筛备用；取羟丙基纤维素、聚乙烯吡咯烷 酮k30在水中搅拌溶解，放冷至室温，加入晶X型阿戈美拉汀搅匀；得到含晶X型阿戈 美拉汀的保护剂备用；将含晶X型阿戈美拉汀的保护剂加入到含有乳糖、部分(1/2) 交联羧甲基纤维素钠的混合制粒机中，湿法制粒2min后，经摇摆制粒机制粒(筛网 833μm)；得到湿颗粒；经流化床干燥(进风温度45℃，沸床温度30℃)，控制水分约 为2％；整粒；计算收率，加入其他剩余辅料，混匀，使用直径为7.5mm冲头压片。
实施例3
Figure PCTCN2014000526-appb-000024
工艺：按上述重量将晶X型阿戈美拉汀过筛备用；取羟丙甲基纤维素、聚乙烯吡咯 烷酮k30在水中搅拌溶解，放冷至室温，加入晶X型阿戈美拉汀搅匀；得到含晶X型阿 戈美拉汀的保护剂备用；将含晶X型阿戈美拉汀的保护剂加入到含有乳糖、部分(1/2) 交联羧甲基纤维素钠的混合制粒机中，湿法制粒2min后，经摇摆制粒机制粒(筛网 833μm)；得到湿颗粒；经流化床干燥(进风温度45℃，沸床温度30℃)，控制水分约 为2％；整粒；计算收率，加入其他剩余辅料，混匀，使用直径为7.5mm冲头压片。
实施例4
Figure PCTCN2014000526-appb-000025
工艺：按上述重量将晶X型阿戈美拉汀过筛备用；取羟丙甲基纤维素，在水中搅拌 溶解，放冷至室温，加入晶X型阿戈美拉汀搅匀；得到含晶X型阿戈美拉汀的保护剂备 用；将含晶X型阿戈美拉汀的保护剂加入到含有乳糖、部分(1/2)交联聚乙烯吡咯烷 酮的混合制粒机中，湿法制粒2min后，经摇摆制粒机制粒(筛网833μm)；得到湿颗 粒；经流化床干燥(进风温度45℃，沸床温度30℃)，控制水分约为2％；整粒；计算 收率，加入其他剩余辅料，混匀，使用直径为7.5mm冲头压片。
实施例5
Figure PCTCN2014000526-appb-000026
工艺：按上述重量将晶X型阿戈美拉汀过筛备用；取聚乙烯吡咯烷酮k90在水中搅 拌溶解，放冷至室温，加入晶X型阿戈美拉汀搅匀；得到含晶X型阿戈美拉汀的保护剂 备用；将含晶X型阿戈美拉汀的保护剂加入到含有乳糖、部分(1/2)交联羧甲基纤维 素钠的混合制粒机中，湿法制粒2min后，经摇摆制粒机制粒(筛网833μm)；得到湿 颗粒；经流化床干燥(进风温度45℃，沸床温度30℃)，控制水分约为2％；整粒；计 算收率，加入其他剩余辅料，混匀，使用直径为7.5mm冲头压片。
实施例6
Figure PCTCN2014000526-appb-000027
工艺：按上述重量将晶X型阿戈美拉汀过筛备用；取羟丙基纤维素在水中搅拌溶解， 放冷至室温，加入晶X型阿戈美拉汀搅匀；得到含晶X型阿戈美拉汀的保护剂备用；将 含晶X型阿戈美拉汀的保护剂加入到含有乳糖、部分(1/2)交联聚乙烯吡咯烷酮的混 合制粒机中，湿法制粒2min后，经摇摆制粒机制粒(筛网833μm)；得到湿颗粒；经 流化床干燥(进风温度45℃，沸床温度30℃)，控制水分约为2％；整粒；计算收率， 加入其他剩余辅料，混匀，使用直径为7.5mm冲头压片。
实施例7
Figure PCTCN2014000526-appb-000028
工艺：按上述重量将晶X型阿戈美拉汀过筛备用；取羟丙基纤维素、羟丙甲基纤维 素、聚乙烯吡咯烷酮K30在水中搅拌溶解，放冷至室温，加入晶X型阿戈美拉汀搅匀； 得到含晶X型阿戈美拉汀的保护剂备用；将含晶X型阿戈美拉汀的保护剂加入到含有乳 糖、部分(1/2)交联聚乙烯吡咯烷酮的混合制粒机中，湿法制粒2min后，经摇摆制粒 机制粒(筛网833μm)；得到湿颗粒；经流化床干燥(进风温度45℃，沸床温度30℃)， 控制水分约为2％；整粒；计算收率，加入其他剩余辅料，混匀，使用直径为7.5mm冲 头压片。

Claims (10)

  1. 一种稳定的晶X型阿戈美拉汀片剂，其特征在于它是由晶X型阿戈美拉汀原料、 保护剂、药用辅料组成；其中晶X型阿戈美拉汀原料：保护剂：药用辅料的重量份数比 为1∶0.1-1∶0.1-10；所述的保护剂为聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基 纤维素一种或多种的混合物。
  2. 权利要求1所述的晶X型阿戈美拉汀片剂，其中所述的晶X型阿戈美拉汀原料 指的是阿戈美拉汀原料中晶X型至少为85％以上。
  3. 权利要求1所述的晶X型阿戈美拉汀片剂，其中所述的晶X型阿戈美拉汀原料 指的是阿戈美拉汀原料中晶X型至少为95％以上。
  4. 权利要求1所述的晶X型阿戈美拉汀片剂，它是由下述重量份数的原料组成：
    Figure PCTCN2014000526-appb-100001
    所述的保护剂为聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基纤维素一种或多种 的混合物；所述的药用辅料为乳糖、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、硬 脂酸、硬脂酸镁或二氧化硅。
  5. 权利要求1-4任一项所述晶X型阿戈美拉汀片剂的制备方法，其特征在于 按如下的步骤进行：
    (a)选择一种或多种保护剂加入纯水中，搅拌，加热到35-40℃溶解至清，放冷 至室温，加入晶X型阿戈美拉汀，搅拌均匀，得到含有晶X型阿戈美拉汀的保护剂备用； 其中晶X型阿戈美拉汀原料与保护剂的重量份数比为1∶0.1-1；水的加入量为晶X型 阿戈美拉汀重量的0.5-4倍；
    (b)将部分药用辅料混匀，然后加入含有晶X型阿戈美拉汀的保护剂，混合制粒， 得到含晶X型阿戈美拉汀的颗粒；所述的部分药用辅料为乳糖、交联羧甲基纤维素钠或 交联聚乙烯吡咯烷酮；
    (c)按比例加入其余药用辅料混匀，压片；其中所述的保护剂为聚乙烯吡咯烷酮、 羟丙基甲基纤维素、羟丙基纤维素一种或多种的混合物。
  6. 权利要求5所述的制备方法，其中所述的晶X型阿戈美拉汀原料指的是阿戈美 拉汀原料中晶X型为85％以上。
  7. 权利要求5所述的制备方法，其中所述的晶X型阿戈美拉汀原料指的是阿戈美 拉汀原料中晶X型为95％以上。
  8. 权利要求5所述的制备方法，其中的保护剂为羟丙甲基纤维素、羟丙基纤维素、 聚乙烯吡咯烷酮k30或聚乙烯吡咯烷酮k90的一种或多种的混合物。
  9. 权利要求8所述的制备方法，其中的保护剂浓度为5-40％(w/w)。
  10. 权利要求5所述的制备方法，其中所述的药用辅料为乳糖、交联羧甲基纤维素 钠、交联聚乙烯吡咯烷酮、硬脂酸、硬脂酸镁或二氧化硅。
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