WO2011079766A1 - Préparation solide d'aripiprazole et son procédé de production - Google Patents

Préparation solide d'aripiprazole et son procédé de production Download PDF

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Publication number
WO2011079766A1
WO2011079766A1 PCT/CN2010/080344 CN2010080344W WO2011079766A1 WO 2011079766 A1 WO2011079766 A1 WO 2011079766A1 CN 2010080344 W CN2010080344 W CN 2010080344W WO 2011079766 A1 WO2011079766 A1 WO 2011079766A1
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Prior art keywords
acid
aripiprazole
agent
acidifying agent
alkalizing agent
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PCT/CN2010/080344
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English (en)
Chinese (zh)
Inventor
郑斯骥
谭波
刘潇怡
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上海中西制药有限公司
上海中西三维药业有限公司
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Publication of WO2011079766A1 publication Critical patent/WO2011079766A1/fr

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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
    • A61K31/33—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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 belongs to the field of pharmaceutical preparations, and in particular relates to a solid preparation of aripiprazole and a preparation method thereof. Background technique
  • Aripiprazole chemical name 7- [4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)- Quinolinone, molecular weight 448.39, is a quinolinone derivative. It was developed by Otsuka, Japan, and was first approved by the US FDA in November 2002.
  • Aripiprazole is an atypical antipsychotic with presynaptic dopamine agonism and postsynaptic dopamine D 2 antagonists, with 5-11 butyl 1 £ receptor partial agonism and 5-1 ⁇ 2 receptor Body antagonism.
  • Aripiprazole is poorly water-soluble, so when preparing a solid preparation such as a tablet or a capsule, it needs to be pulverized to a certain degree of fineness to ensure rapid dissolution of the solid preparation after oral administration, and to ensure absorption rate and biological activity. Utilization.
  • the pulverization of aripiprazole is basically carried out by a mechanical pulverization method.
  • the mechanical pulverization treatment method has many defects such as dust, pollution, and loss.
  • the more serious problem is that due to the high drug activity of aripiprazole, it is very easy for the operator to inhale aripiprazole powder to cause adverse reactions such as headache and lethargy during mechanical pulverization. Long-term inhalation will cause more serious problems. as a result of.
  • the medicinal active ingredient is pulverized by a method of mechanical pulverization, and the pulverized powder is usually about 100 ⁇ m.
  • the dissolution characteristics of the solid preparation obtained by the pulverization treatment by this method are not satisfactory.
  • aripiprazole has a high activity and a low content in a solid preparation (generally 10 wt%)
  • the problem of dispersion uniformity mixed with an excipient is also involved.
  • a method of diluting the pharmaceutically active ingredient with an excipient in an equal amount by volume is used to uniformly disperse aripiprazole in a solid preparation.
  • the method is cumbersome in process operation, and also causes many problems such as dust, environmental pollution, large loss, and safety hazards in labor protection.
  • the preparation of solid preparations also needs to consider whether the various properties of the product can meet the requirements of the pharmaceutical field. For example, is it possible to ensure a better content uniformity?
  • stability is the focus of the quality of the solid preparation, including the chemical stability of the active ingredient of the active ingredient, the content of the relevant substance (ie, impurities), the stability of the solid preparation property, and the dissolution stability during the storage period of the solid preparation. Whether it is within the limits of the drug standard.
  • Chinese patent application CN1871007A discloses a method for preparing aseptic agraniprazole having an average particle size of less than 100 ⁇ m by impact spray crystallization, and the sterile aripiprazole prepared by the method is used for preparing aseptic frozen
  • the dried aripiprazole preparation can also be used to prepare an aripiprazole aqueous suspension preparation for injection.
  • CN101066267A discloses a method of obtaining a solid preparation by using recrystallization to obtain aripiprazole having an average particle diameter of not more than 50 ⁇ m, followed by filtration and drying, and mixing with an auxiliary material.
  • the above method is cumbersome to operate, and for the preparation of solid preparations containing excipients, there are still problems such as environmental pollution, large loss, dust, and high labor protection requirements.
  • the technical problem to be solved by the present invention is to overcome the existing method for preparing a solid preparation of aripiprazole by mechanically pulverizing and controlling the particle size of aripiprazole, which causes environmental pollution and loss, and has serious safety hazards. Moreover, the dissolution characteristics of aripiprazole solid pharmaceutical preparations are not ideally deficient, and provide a simpler operation, less pollution, no aforementioned safety hazards, and can protect The solid preparation obtained by the invention has excellent preparation properties, stability and uniformity of content, and a solid preparation of aripiprazole prepared by the method.
  • the inventors have taken a different approach, uniquely dissolving aripiprazole with an acidic solution, and then returning the drug to a solid state during the granulation process, thereby avoiding many defects of mechanical pulverization treatment. Further, the inventors have unexpectedly found that the aripiprazole solid preparation prepared by the method has excellent dissolution characteristics, stability, and content uniformity.
  • the preparation method of the present invention comprises the steps of: dissolving aripiprazole in an acidic solution containing an acidifying agent to prepare a drug-containing acidic liquid; and then uniformly mixing the auxiliary material and the drug-containing acidic liquid to perform a wet process grain.
  • the aripiprazole is a poorly water-soluble weakly basic active drug, and the amount thereof is selected according to the conventional content of aripiprazole in a solid preparation, generally the mass percentage of the wet granulated dry material.
  • aripiprazole 1% to 20%, preferably 2% to 15%, and most preferably 2.5 to 9%.
  • other pharmaceutically active ingredients may be added as needed to prepare a solid formulation of aripiprazole.
  • the acidifying agent means an acidic reagent which can completely dissolve aripiprazole in an acidic solution containing an acidifying agent.
  • the acidulant should be a pharmaceutically acceptable agent compatible with aripiprazole.
  • the compatibility means coexistence without adverse effects.
  • the acidifying agent may be a single acidifying agent, or a composite acidifying agent composed of two or more components, and may be selected from various acids, such as one or more of inorganic strong acid, inorganic strong acid and organic weak acid.
  • hydrochloric acid citric acid, malic acid, lactic acid, hydrobromic acid, nitric acid, sulfuric acid, fumaric acid, succinic acid, maleic acid, acetic acid and phosphoric acid, more preferably Hydrochloric acid, citric acid, malic acid, lactic acid or phosphoric acid, most preferably hydrochloric acid, citric acid, malic acid or lactic acid.
  • the acidifying agent is used in an amount at least the minimum amount which can completely dissolve aripiprazole, preferably from 1 to 1.2 times, more preferably from 1 to 1.05 times the minimum amount.
  • the amount of acidifying agent that can dissolve aripiprazole is related to various factors such as the type of acidifying agent, the type of solvent (such as the concentration of an aqueous solution of an organic solvent), and the hydrogen ion in the acidifying agent that can be combined with the basic center of aripiprazole. The number, as well as the conditions for the preparation of the acidic solution containing the drug (such as temperature) and other factors.
  • the basic center means that the aripiprazole can be acidified A group or moiety in which a hydrogen ion binds in a molecule. Therefore, the above minimum amount refers to the minimum amount of a certain acidifier which can completely dissolve aripiprazole under the conditions of the same solvent and the drug-containing acidic solution.
  • the minimum amount can be determined by a simple conventional method: Aripiprazole is dissolved by gradually increasing the amount of the acidifying agent in the same solvent and the acidic solution containing the drug, and is the minimum amount when it is completely dissolved.
  • the molar ratio of the acidifying agent to aripiprazole is generally from 0.7 to 2.0, preferably from 0.9 to 1.3.
  • aripiprazole molar amount of 0.9 to 1.2 times hydrochloric acid or aripiprazole molar amount of 0.8 to 1.3 times of citric acid, or aripiprazole molar amount of 0.8 to 1.1 times of malic acid.
  • the solvent in the acidic solution containing the acidifying agent may be an organic solvent or a mixture of water and an organic solvent, preferably a mixture of water and an organic solvent.
  • the organic solvent is selected according to the principle that its solubility to aripiprazole is better than water in a solvent acceptable for the pharmaceutical field, preferably a water-miscible organic solvent, such as water-soluble commonly used in the pharmaceutical field.
  • a solvent such as ethanol, propylene glycol, glycerin, acetone, isopropanol or t-butanol is preferably one or more selected from the group consisting of ethanol, acetone, propylene glycol and glycerin, and ethanol is particularly preferred.
  • the amount of the organic solvent can be arbitrarily selected.
  • concentration of ethanol is preferably from 30% by weight to 95% by mass, more preferably from 50% to 75% by mass.
  • the amount of the solvent in the acidic solution is based on at least the minimum amount of granulating liquid required for wet granulation, and is usually from 5 to 100% by mass, preferably from 10 to 75% by mass of the dry granulated dry material.
  • the solvent in the acid solution containing the acidifier, is a 50% to 75% by mass aqueous solution of ethanol, and the amount of the solvent is 8% to 60% by mass of the dry granulated dry material.
  • the acidifying agent is hydrochloric acid having a molar amount of aripiprazole of 0.9 to 1.2 times.
  • some excipients such as a binder, a surfactant, a solubilizing agent, and a water-soluble carrier of the solid dispersion may be added.
  • a binder e.g., a surfactant, a solubilizing agent, and a water-soluble carrier of the solid dispersion
  • one or more of the water-soluble carrier of the surfactant, the solubilizing agent and the solid dispersion are added simultaneously with and/or after the aripiprazole is dissolved in the acidic solution containing the acidifying agent.
  • the resulting drug-containing acidic liquid is then subjected to a subsequent step, that is, uniformly mixed with the auxiliary material, and subjected to wet granulation.
  • the water-soluble carrier of the solid dispersion is simultaneously with aripiprazole
  • the amount of the water-soluble carrier of the solid dispersion to be added at this time is controlled to be less than the amount which can ensure that aripiprazole is completely dissolved in the acidic solution containing the acidifying agent;
  • a water-soluble carrier of the solid dispersion When the solution is added a water-soluble carrier of the solid dispersion, and when the amount added is large, the resulting drug-containing acidic liquid may be in the form of a suspension or a viscous liquid.
  • the present invention particularly preferably incorporates povidone, polyethylene glycol (preferably polyethylene glycol 400-8000), sodium dodecyl sulfate, poloxamer, polyoxyethylene castor oil, Tween 80, stearic acid poly One or more of alkoxy 40 ester, lactose, mannitol, sucrose, hydroxypropyl ⁇ -cyclodextrin, &-cyclodextrin and maltitol.
  • the surfactant and/or solubilizer is preferably added in an amount of 0.05 to 2 times the mass of aripiprazole.
  • the water-soluble carrier of the solid dispersion is preferably added in an amount of from 1 to 10 times the mass of aripiprazole.
  • the solubility of aripiprazole in an acidic solution can be increased, and the amount of the solvent can be reduced to facilitate the subsequent granulation step operation.
  • one or more of the water-soluble carrier of the surfactant, the solubilizing agent and the solid dispersion, especially the water-soluble carrier of the solid dispersion can be used to obtain the aripiprazole solid obtained by the above operation. The dissolution characteristics of the formulation are better.
  • the temperature may be raised by a heating means such as a hot water bath to facilitate the dissolution of aripiprazole.
  • a heating means such as a hot water bath to facilitate the dissolution of aripiprazole.
  • an aqueous ethanol solution it is preferably heated to 40 ° C to 70 ° C, more preferably 50 to 65 ° C.
  • the excipient may be selected from any of the excipients known and widely used in the art, such as fillers, binders, disintegrants, lubricants and the like.
  • the content of the excipients can be selected according to the conventional knowledge in the art.
  • the filler is preferably one or more of lactose, microcrystalline cellulose, pregelatinized starch, starch, mannitol, sucrose, and maltitol.
  • the binder is preferably one or more of hypromellose, povidone and methylcellulose.
  • the disintegrant is preferably one or more of sodium carboxymethyl starch, hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone and croscarmellose sodium.
  • the lubricant is preferably colloidal silica, sodium stearate fumarate, talc or magnesium stearate.
  • the amount of the excipients can be selected according to the conventional knowledge in the art.
  • the alkalizing agent refers to a reagent capable of lowering the acidity of the mixed solution of the alkalizing agent and the drug-containing acidic liquid with respect to the acidity of the drug-containing acidic liquid.
  • inorganic strong bases such as sodium hydroxide
  • weak acid strong base salts such as sodium carbonate, disodium hydrogen phosphate
  • organic weak acid conjugate bases such as sodium citrate, sodium tartrate, sodium malate and sodium acetate
  • the basifying agent should be a pharmaceutically acceptable agent compatible with aripiprazole.
  • the present invention preferably comprises a combination of an acidifying agent and an alkalizing agent of the following type:
  • the acidifying agent is an inorganic strong acid
  • the alkalizing agent is an inorganic strong base such as hydrochloric acid and sodium hydroxide.
  • the acidifying agent is an inorganic strong acid
  • the alkalizing agent is an inorganic weak acid strong base salt such as hydrochloric acid and sodium carbonate, or hydrochloric acid and disodium hydrogen phosphate.
  • the acidifying agent is an inorganic strong acid
  • the alkalizing agent is an organic weak acid strong base salt such as hydrochloric acid and sodium citrate, hydrochloric acid and sodium tartrate, hydrochloric acid and sodium malate, or hydrochloric acid and sodium acetate.
  • Type 4 the acidifying agent is an organic weak acid
  • the alkalizing agent is a conjugate base of the organic weak acid
  • the acidifying agent and the alkalizing agent are mutually buffered pairs of conjugated acid and base, such as tannic acid, rich A buffer pair consisting of horse acid, succinic acid, maleic acid, acetic acid or malic acid with its corresponding conjugate base, preferably citric acid and sodium citrate.
  • the acidifying agent is an organic weak acid
  • the alkalizing agent is an inorganic strong base or an inorganic weak acid strong base salt
  • the acidifying agent and the alkalizing agent form a buffer pair, such as capric acid and sodium carbonate, malic acid and Sodium carbonate, malic acid and disodium hydrogen phosphate, or citric acid and disodium hydrogen phosphate.
  • the acidifying agent is an inorganic strong acid
  • the alkalizing agent is a weak acid and can form a buffer pair with an acid, for example, hydrochloric acid and glycine, or hydrochloric acid and alanine.
  • the amount of the alkalizing agent is such an amount that at least the acidity of the mixed solution of the alkalizing agent and the drug-containing acidic liquid is lowered with respect to the acidity of the drug-containing acidic liquid.
  • the amount of the acidifying agent and the alkalizing agent is as follows: The value obtained by Formula 1 is from 0.01 to 1.5, more preferably from 0.1 to 1.2. (molar number of alkalizing agent XA) I (molar number of acidifying agent XB) Formula 1 wherein, when the acidifying agent and the alkalizing agent are of type 1, 2 or 5, A is the alkalizing agent The number of hydrogen ions in the molecule of the agent;
  • B is the number of hydrogen ions in the acidifying agent molecule
  • A/B is 1;
  • B is 1;
  • A is 1.
  • hydrochloric acid and sodium hydroxide having a value of formula 1 of 0.01 to 1.1, or citric acid and sodium citrate having a value of formula 1 of 0.1 to 1.3, or hydrochloric acid and sodium carbonate having a value of 0.2 to 1.0 of formula 1 .
  • the wet granulation can be carried out according to conventional steps and conditions of various granulation methods in the art which are in the wet granulation category, such as extrusion granulation (e.g., rocker extrusion, spiral extrusion and rotation). Extrusion, etc., agitation granulation, fluidized spray granulation, and centrifugal spray granulation.
  • extrusion granulation e.g., rocker extrusion, spiral extrusion and rotation
  • Extrusion, etc. agitation granulation, fluidized spray granulation, and centrifugal spray granulation.
  • an alkalizing agent When an alkalizing agent is used, it is preferred to carry out the specific operation in any of the following manners: mode (1) uniformly mixing the alkalizing agent or the alkalizing agent-containing solution and the auxiliary material, and then uniformly mixing the drug-containing acidic liquid Mixing, performing extrusion granulation or agitation granulation; mode (2) uniformly mixing the medicated acidic solution with an alkalizing agent or an alkalizing agent-containing solution to obtain a granulating liquid, and then granulating the granulating liquid Excipients are subjected to extrusion granulation, agitation granulation, fluidized spray granulation or centrifugal spray granulation, etc.; mode (3) uniformly mixing the medicated acidic liquid with the auxiliary material, and then uniformly mixing with the alkalizing agent-containing solution Extrusion granulation or agitation granulation; mode (4) uniformly mixing the medicated acidic liquid with less than 1/3 of the auxiliary material, and the alkalizing agent or the alkalizing
  • the excipients in the 1/3 or less of the excipients are preferably water-soluble excipients.
  • the 1/3 or less of the above may be usually 1/5 to 1/10 or less.
  • the alkalizing agent-containing solution refers to a solution obtained by dissolving an alkalizing agent in a small amount of solvent according to a routine operation in the art to facilitate mixing; the solvent may be water or water. Mix with organic solvents Liquid.
  • the organic solvent is the same as described above.
  • the aripiprazole solid granule preparation can be directly obtained, or can be used as a preparation intermediate, and a tablet (including aripiprazole orally disintegrating tablet) or a capsule can be obtained through a conventional sputum.
  • a tablet including aripiprazole orally disintegrating tablet
  • a capsule can be obtained through a conventional sputum.
  • the reagents and raw materials used are commercially available.
  • the present invention also relates to a solid preparation of aripiprazole prepared by the above method.
  • the positive effect of the invention is as follows: (1) The preparation method of the invention avoids the defects of serious pollution, large loss and serious safety hazard caused by mechanical pulverization treatment of aripiprazole, and the operation is simple and easy, and the safety factor is high. , easy to apply to industrial production. (2) The dissolution property of the solid preparation of aripiprazole prepared by the preparation method of the present invention is remarkably improved as compared with the prior art, and the bioavailability is high and the individual difference is small. (3) The solid preparation of aripiprazole prepared by the preparation method of the present invention has better stability and content uniformity.
  • Fig. 1 is a graph showing the dissolution profiles of aripiprazole orally disintegrating tablets prepared in Comparative Example 4 and Example 6 respectively. detailed description
  • the dosage form specification is aripiprazole content, such as 5 mg/tablet, which means that each tablet contains 5 mg of aripiprazole.
  • the unit of use is gram and the percentage is the mass percentage.
  • the mass percentage of aripiprazole and solvent is the mass percentage of the wet granulated dry material.
  • the amount of the solvent includes water in an aqueous solution of an acidifying agent and an alkalizing agent. Comparative Example 1-2 and Example 1-2 Aripiprazole granule formulation and preparation method
  • Example 5 Aripiprazole tablet (5m g / tablet) formula and preparation method
  • Example 9 Formulation and preparation method of aripiprazole tablet (10m g / tablet)
  • Example 10 Formulation and preparation method of aripiprazole tablet (5 mg/tablet)
  • Example 11 Aripiprazole tablet (10m g / tablet) formula and preparation method
  • Example 12 Aripiprazole tablet (5m g / tablet) formula and preparation method
  • Example 13 Aripiprazole tablet (10m g / tablet) formula and preparation method
  • Example 14 Aripiprazole tablet (5m g / tablet) formulation and preparation method
  • Example 15 Formulation and preparation method of aripiprazole tablet (5 mg/tablet)
  • Example 16 Aripiprazole tablet (5m g / tablet) formula and preparation method
  • Example 18 Aripiprazole tablet (5m g / tablet) formulation and preparation method
  • Example 19 Aripiprazole Tablets (5m g / tablet) Formulation and Preparation Method
  • Example 20 Aripiprazole Tablets (5 mg/tablet) Formulation and Preparation Method
  • Example 22 Formulation and preparation method of aripiprazole orally disintegrating tablet (5 mg/tablet)
  • Example 23 Aripiprazole tablet (5m g / tablet) formula and preparation method
  • Example 24 Aripiprazole tablet (10m g / tablet) formula and preparation method
  • Example 25 Aripiprazole Tablets (5m g / tablet) Formulation and Preparation Method
  • Example 26 Aripiprazole Orally Disintegrating Tablets (10m g / tablet) Formulation and Preparation Method
  • Example 27 Aripiprazole tablet (5m g / tablet) formulation and preparation method
  • Example 29 Aripiprazole tablet (5m g / tablet) formula and preparation method
  • Example 30 Formulation and preparation method of aripiprazole tablet (5m g / tablet)
  • Example 31 Aripiprazole Tablets (5m g / tablet) Formulation and Preparation Method
  • Example 32 Aripiprazole tablet (5m g / tablet) formula and preparation method
  • Test equipment BT-9300S laser particle size distribution instrument; BT-800 automatic cycle injection system.
  • Test conditions The medium in the circulating injection system is water, the volume is about 570ml, and the centrifugal pump has a rotation speed of 1600rpm.
  • Test method Take about 2g of granules, add to the circulating injection system, make the absorbance of the system reach about 15%, turn on the ultrasonic dispersion for 3 minutes, and test the sample for 6 consecutive times to obtain the average particle size:
  • D 1Q , D 5Q and D 9Q are the corresponding particle sizes for the cumulative particle size distribution percentages of 10%, 50% and 90%, respectively.
  • Determination of the content and related substances Take the appropriate amount of the sample, dissolve it with ultrasonic vibration of the mobile phase, prepare a proper amount of aripiprazole solution per ml, and use it as a test solution, and prepare a control solution.
  • high performance liquid chromatography Choinese Pharmacopoeia 2005 edition two appendix VD
  • 18 ⁇ ⁇ silicon germanium bonded silica as a filler
  • methanol-0.1% triethylamine solution 90: 10
  • the detection wavelength is 255 nm
  • the content is determined according to the external standard method.
  • the determination of the relevant substances is carried out according to the main component self-control method, and the result data is recorded in the following table.

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Abstract

La présente invention a pour objet un procédé de production d'une préparation solide d'aripiprazole et la préparation produite par ledit procédé. Le procédé comprend : la dissolution d'aripiprazole dans la solution acide contenant un agent acidifiant pour obtenir un liquide acide du médicament ; ensuite, le mélange homogène des adjuvants et dudit liquide acide du médicament, puis la réalisation d'une granulation humide.
PCT/CN2010/080344 2009-12-29 2010-12-28 Préparation solide d'aripiprazole et son procédé de production WO2011079766A1 (fr)

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CN106074415B (zh) * 2016-07-22 2018-10-30 南京正大天晴制药有限公司 一种阿立哌唑片剂及其制备方法
CN109419772B (zh) * 2017-08-23 2021-03-09 北京罗诺强施医药技术研发中心有限公司 经鼻给药治疗精神疾病的方法和药物组合物
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