WO2011079609A1 - 一种固体制剂的制备方法及所得固体制剂 - Google Patents

一种固体制剂的制备方法及所得固体制剂 Download PDF

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Publication number
WO2011079609A1
WO2011079609A1 PCT/CN2010/074706 CN2010074706W WO2011079609A1 WO 2011079609 A1 WO2011079609 A1 WO 2011079609A1 CN 2010074706 W CN2010074706 W CN 2010074706W WO 2011079609 A1 WO2011079609 A1 WO 2011079609A1
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water
insoluble
acid
active ingredient
pharmaceutically active
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PCT/CN2010/074706
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English (en)
French (fr)
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郑斯骥
谭波
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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 WO2011079609A1 publication Critical patent/WO2011079609A1/zh

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    • 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
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    • 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
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a preparation method of a solid preparation and the obtained solid preparation.
  • the particle size of the pharmaceutically active ingredient is closely related to the preparation process and quality of the solid preparation.
  • the particle size of a suitable pharmaceutically active ingredient is usually selected depending on the solubility characteristics of the drug and the permeability of the biofilm. For example, if it is poorly soluble, drug dissolution is a drug that absorbs the rate-limiting process, and a smaller particle size can be selected to promote drug absorption. For another example, if it is a less compressible drug, the compressibility can be improved by selecting a suitable particle size and adding a suitable excipient. Therefore, in the preparation process of a pharmaceutical solid preparation, selective control of the particle diameter of the pharmaceutically active ingredient is often involved. At present, most of the selection and control of the particle size of the pharmaceutically active ingredient are achieved by selecting different mechanical pulverization methods and pulverization process conditions.
  • the treatment method of mechanical pulverization has problems such as a lot of dust, a polluted environment, and a large loss.
  • it is easy to cause adverse reactions in the mechanical pulverization process, and there are serious safety hazards.
  • a considerable number of sedative and hypnotic drugs, such as dextrozopiclone and alprazolam have higher drug activity, and inhalation of lower doses of drug powder can quickly produce hypnotic effects.
  • smashing such drugs It is highly prone to adverse reactions that cause rapid hypnosis of the operator and cause a safety accident.
  • inhalation or contact with the drug powder can easily cause serious adverse drug reactions in the operator.
  • the conventional mechanical pulverization method e.g., using a conventional universal pulverizer
  • the average particle size generally reaches about 100 micrometers.
  • the dissolution characteristics of the solid preparation prepared by this method are not yet satisfactory.
  • the process of mechanical pulverization treatment for the high active pharmaceutical active ingredient which is low in the solid preparation (e.g., ⁇ 5 wt%), it also relates to the problem of dispersion homogeneity of the mixture with the auxiliary material.
  • a method of gradually diluting the pharmaceutically active ingredient and the auxiliary material in an equal amount is used to disperse the pharmaceutically active ingredient in the 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 needs. For example, can you guarantee? The better content is the hook.
  • stability is the focus of the quality of the solid preparation, including the chemical stability of the active ingredient, the content of the relevant substance (ie, impurities), the stability of the solid preparation, and the dissolution stability during storage of the solid preparation. Whether it is within the limits of the drug standard.
  • the technical problem to be solved by the present invention is to overcome the conventional method for preparing a solid preparation by mechanically pulverizing and controlling the particle size of the pharmaceutically active ingredient, which causes environmental pollution, has serious safety hazards, and has large loss, and the obtained solid pharmaceutical preparation
  • the dissolution characteristics are not ideally deficient, and for water-insoluble or poorly water-soluble alkaline drugs, it provides a simpler operation, less pollution, no such safety hazards, and can ensure excellent dissolution properties of the prepared solid preparations.
  • the preparation method of the stability and the content of the hook and the obtained solid preparation are not ideally deficient, and for water-insoluble or poorly water-soluble alkaline drugs, it provides a simpler operation, less pollution, no such safety hazards, and can ensure excellent dissolution properties of the prepared solid preparations.
  • the inventors have taken a different approach, uniquely using an acidic solution to dissolve a water-insoluble or poorly water-soluble alkaline drug, and then with the granulation process, the drug is returned to a solid state, thereby avoiding many defects of mechanical pulverization treatment, and
  • the present inventors have also unexpectedly found that the 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 a water-insoluble and/or water-insoluble basic pharmaceutically active ingredient in an acidic solution containing an acidifying agent to prepare a drug-containing acidic liquid, and then, the drug-containing acidic liquid and the auxiliary material are both Mix the hooks and perform wet granulation.
  • the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient is selected from various existing pharmaceutically active ingredients satisfying the above properties, including amphoteric drug activity having both an acidic group and a basic group. ingredient.
  • the basic pharmaceutically active ingredient is mostly a weak base active ingredient.
  • the present invention is particularly suitable for water insolubility and/or low in activity (generally 20% or less, preferably 5% or less, more preferably 1% or less, and percentage by mass) in a solid preparation.
  • a poorly water-soluble alkaline drug is particularly suitable for water insolubility and/or low in activity (generally 20% or less, preferably 5% or less, more preferably 1% or less, and percentage by mass) in a solid preparation.
  • the present invention is preferably, but not limited to, aripiprazole, dextrozopiclone, diazepam, estazolam, alprazolam, zopiclone, risperidone, agomelatine, yi Pantidone, paliperidone, perphenazine, digoxin, haloperidol, dipyridamole, olanzapine, mifepristone, carbimabazole, metoclopramide, minoxidil Or blood level.
  • aripiprazole dextrozopiclone, diazepam, estazolam, alprazolam, zopiclone, risperidone, agomelatine, yi Pantidone, paliperidone, perphenazine, digoxin, haloperidol, dipyridamole, olanzapine, mifepristone, carbimabazole, metoclopramide, minoxid
  • the basic pharmaceutically active ingredient accounts for the mass percentage of the wet granulated dry material. Further, in addition to the water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredient, other pharmaceutically active ingredients may be added to prepare a compound solid preparation such as a compound solid preparation of olanzapine and fluoxetine hydrochloride.
  • the acidifying agent means an acidic reagent which can dissolve a water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredient to form a drug-containing acidic liquid.
  • the acidulant should be a pharmaceutically acceptable agent that is compatible with water insoluble and/or poorly water soluble basic pharmaceutically active ingredients.
  • 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, tartaric acid, malic acid, hydrobromic acid, fumaric acid, succinic acid, maleic acid, lactic acid, acetic acid, sulfuric acid, nitric acid and phosphoric acid
  • hydrochloric acid citric acid, tartaric acid, malic acid, lactic acid or acetic acid.
  • the present invention particularly preferably has the following acidifying agent, which allows the solid preparation to have superior stability: when the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient is dextrozopicl, the tannin is selected. , tartaric acid, malic acid or hydrochloric acid, most preferably citric acid.
  • water-insoluble and/or water-insoluble basic pharmaceutically active ingredient When the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient is zopiclone, hydrochloric acid, malic acid, tartaric acid or citric acid is selected, and hydrochloric acid or tartaric acid is most preferred.
  • hydrochloric acid, decanoic acid or tartaric acid When the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient is dipyridamole, hydrochloric acid or citric acid is selected.
  • water-insoluble and/or water-insoluble basic pharmaceutically active ingredient is aripiprazole, hydrochloric acid, citric acid, malic acid or lactic acid is selected.
  • the acidifying agent is used in an amount at least a minimum amount which can completely dissolve the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient, preferably from 1 to 1.2 times, more preferably from 1 to 1.05. Times.
  • the amount of acidifying agent which can dissolve the water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredient is related to various factors such as the type of acidifying agent, the type of solvent, the water-insoluble and/or the solubility of the water-insoluble basic pharmaceutically active ingredient, The number of basic centers in the molecule, the number of hydrogen ions in the acidifying agent that can be combined with the basic center of the drug molecule, and the formulation conditions of the drug-containing acidic liquid are related.
  • the basic center refers to a group or a portion of the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient that can bind to hydrogen ions in the acidifying agent molecule. Therefore, the above minimum amount refers to the minimum amount of an acidulant which can be completely dissolved by a certain acid-insoluble and/or water-insoluble alkaline pharmaceutically active ingredient in the same solvent and drug-containing acidic liquid formulation conditions. .
  • the minimum amount can be determined by a simple conventional method: Under the conditions of the same solvent and the acid-containing solution, a certain amount of water-insoluble and/or poorly water-soluble alkaline drug active ingredient is dissolved by gradually increasing the amount of the acidifying agent. When it is completely dissolved, it is the minimum amount.
  • the inventors have found through extensive experiments that, in particular, the acidifying agent is insoluble with water.
  • the molar ratio of the active ingredient of the sexually and/or poorly water-soluble basic drug is generally 0.2 to 2.5, and most of it is 0.3 to 1.5.
  • the amount of the acidifying agent described below is particularly preferred in the present invention:
  • dextropicoside is selected in a molar amount of 0.8 to 1.1 times.
  • hydrochloric acid or tartaric acid having a molar amount of zopiclone of 0.95-1.1 is selected.
  • hydrochloric acid having a molar amount of lypoxone of 0.8 to 2.1 times or decanoic acid having a molar amount of lysine of 0.3 to 1.1 times
  • the tartaric acid having a molar amount of fluorenone is 0.25 to 1.1 times.
  • the dipyridamole molar amount is 0.7-1.2 times of hydrochloric acid, or the dipyridamole molar amount is 0.7-1.1 times of tannic acid.
  • hydrochloric acid having a molar amount of aripiprazole of 0.9 to 1.2 times or a molar amount of aripiprazole of 0.8 to 1.3 times is selected. , or aripiprazole molar amount of 0.8 to 1.1 times the malic acid.
  • the solvent in the acidic solution containing the acidifying agent may be water, an organic solvent or a mixture of water and an organic solvent, preferably water or a mixture of water and an organic solvent.
  • the solvent selected should be an ion dissociable solvent in the acidulant.
  • the acidifying agent is an inorganic substance
  • water or a mixed liquid of water and an organic solvent may be selected; and when the acidifying agent is an organic substance, it may be a mixed liquid of water, water and an organic solvent, or an organic solvent.
  • the pharmaceutically active ingredient is superior to the solubility in water in some organic solvents, it is preferred to select a mixture of water and the organic solvent to facilitate dissolution of the active ingredient of the drug, reduce the amount of the acidic solution, and facilitate subsequent preparation.
  • the organic solvent is selected according to the principle that its solubility to the pharmaceutically active ingredient is superior to water in a solvent acceptable for the pharmaceutical field, preferably a water-miscible organic solvent, such as water solubility commonly used in the pharmaceutical field.
  • An alcohol solvent such as ethanol, acetone, propylene glycol, glycerin, 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.
  • the amount of the solvent in the acidic solution is at least the minimum amount of the granulating liquid required for wet granulation, and is generally 5 to 100% by mass of the wet granulated dry material, preferably 10 to 50%.
  • some excipients such as a binder, a surfactant, a solubilizing agent, and a water-soluble carrier of the solid dispersion may be added.
  • the water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredient is dissolved in the acid-containing
  • one or more of a surfactant, a solubilizing agent and a water-soluble carrier of the solid dispersion are further added, and then the resulting drug-containing acidic liquid is subjected to a subsequent step, that is, The excipients are mixed and wet granulated.
  • the amount of the water-soluble carrier of the solid dispersion to be added at this time needs to be controlled.
  • the amount of the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient is completely dissolved in the acidic solution containing the acidifying agent; the water-soluble carrier of the solid dispersion may be further added to the solution, when the amount is added When larger, the resulting drug-containing acidic solution may be in the form of a suspension or a viscous liquid.
  • Particularly preferred in the present invention are the addition of povidone, polyethylene glycol (preferably polyethylene glycol 400-8000), sodium lauryl sulfate, poloxamer, polyoxyethylene castor oil, Tween-80, stearic acid.
  • the surfactant and/or solubilizer is preferably added in an amount of 0.05 to 3 times the mass of the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient.
  • the water-soluble carrier of the solid dispersion is preferably added in an amount of from 1 to 20 times the mass of the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient.
  • one or more of the water-soluble carriers of the surfactant, solubilizer and solid dispersion added as described above, especially the water-soluble carrier of the solid dispersion, can render the resulting water insoluble and/or The dissolution property of the hardly soluble basic pharmaceutically active ingredient solid preparation is better.
  • the preparation temperature of the medicated acid solution can be appropriately raised by a conventional heating method such as a hot water bath to facilitate dissolution of the pharmaceutically active ingredient.
  • a conventional heating method such as a hot water bath
  • the temperature is preferably from 40 to 70 ° C, more preferably from 50 to 60 ° C.
  • the preferred increase is 30 to 50 °C.
  • the excipient may be selected from any of the excipients known in the art and widely used, such as fillers, binders, disintegrants, adsorbents, lubricants and the like.
  • the filler is preferably one or more of lactose, microcrystalline cellulose, starch, pregelatinized starch, mannitol, sucrose, magnesium oxide, calcium carbonate, magnesium carbonate and maltitol.
  • the binder is preferably one or more of hypromellose, povidone, methylcellulose and hydroxypropylcellulose.
  • the disintegrant is preferably one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and croscarmellose sodium.
  • the lubricant is preferably colloidal silica, sodium stearate, talc or magnesium stearate. The amount of the excipients can be selected according to conventional knowledge in the art.
  • the wet granulation can be carried out according to the conventional steps of the granulation method belonging to the wet granulation category in the art. And conditions, such as extrusion granulation (such as swing machine extrusion, spiral extrusion and rotary extrusion, etc.), agitation granulation, fluidized spray granulation and centrifugal spray granulation. For larger content in solid preparations (generally greater than 20%), or less soluble in acidic solutions containing acidifying agents, a larger amount of acidic solution is required to dissolve complete water-insoluble and/or poorly water-soluble alkaline drugs. As the active ingredient, a wet granulation process having a small restriction on the amount of the granulation solution, such as fluidized spray granulation or centrifugal spray granulation, may be selected.
  • the solid granule preparation can be directly obtained, or it can be used as a preparation intermediate, and further solid preparations such as tablets or capsules can be obtained through further conventional procedures.
  • the reagents and starting materials used are commercially available, and some of the drug substances can be prepared according to the existing literature methods. Further, the present invention also relates to a solid preparation prepared by the above method.
  • the preparation method of the present invention avoids the defects of serious pollution, large loss, and serious safety hazard caused by mechanical pulverization treatment.
  • the method is easy to operate, has a high safety factor, and is easy to be applied to industrial production.
  • the solid preparation prepared by the preparation method of the invention has a better content and a good stability.
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer.
  • the dosage form specification is based on the content of the active ingredient of the drug, such as 2 mg/tablet, which means that each tablet contains 2 mg of the active ingredient of the drug.
  • the unit of use is gram and the percentage is the mass percentage.
  • the mass percentage of the pharmaceutically active ingredient and the solvent is the mass percentage of the wet granulated dry material.
  • the amount of the solvent includes water in an aqueous solution of the acidifying agent. Comparative Example 1 and Examples 1 and 2 dextrozopiclone tablets (3 mg/tablet) formulation and preparation method
  • Example 6 and 7 risperidone tablets (1 mg / tablet) formula and preparation method
  • Heart acidifier citric acid monohydrate 0.59 (molar ratio to dextrozopiclone: 1.09) Mix dextrozopiclone, polyethylene glycol 6000, ethanol, citric acid and water into the preparation solution Add 50% of lactose to stir, prepare into a drug-containing acidic solution, add pre-mixed lactose and microcrystalline cellulose, stir granulate, add granules, add stearic acid sodium fumarate and talcum powder, mix Both are hooked and pressed.
  • Example 14 Formula of dextrozopiclone (2 mg/tablet) and preparation method Drug dextrozopidine 2 (3.0%, no pretreatment)
  • Acidifier DL-tartaric acid 0.8 (molar ratio to dextrozopiclone: 1.04)
  • the core of the film is film coated.
  • Acidifier DL-malic acid 0.65 (molar ratio to dextrozopiclone: 0.94)
  • the dextrozopidine clone, poloxamer, DL-malic acid and water are formulated into a drug-containing acidic liquid, and the mannitol and the microcrystalline cellulose are mixed, and the medicated acidic solution is added for stirring and granulation. After the wet granules are dried, the wet granules are dried. The whole granules were mixed with magnesium stearate, crospovidone and colloidal silica.
  • Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.
  • Example 16 Zopiclone Tablets (2.5 mg/tablet) Formulation and Preparation Method Zopiclone 2.5 (4.2%, no pretreatment) Mannitol 25, microcrystalline cellulose 30, poloxamer 1,
  • a drug-containing acidic solution prepared by warming at 70 ° C water bath
  • zopiclone, poloxamer 5% aqueous hydrochloric acid solution, 95% aqueous ethanol solution and water.
  • the mixture of mannitol and microcrystalline cellulose is added.
  • the drug-containing acidic liquid is stirred and granulated, and the wet granules are dried and then granulated, and magnesium stearate and colloidal silica are added and mixed, and then pressed.
  • the core of the film is film coated.
  • Example 17 Formulation and preparation method of zopiclone tablet (3.75 mg/tablet) Drug zopiclone 3.75 (3.4%, no pretreatment) Excipient lactose 70, sodium carboxymethyl starch 5, starch 30, hypromellose 0.4, Magnesium stearate 0.6, solvent water 22 (19.7%)
  • Tablet acidifier citric acid monohydrate 2.2 (molar ratio to zopiclone: 1.09)
  • the hypromellose is dispersed with hot water at 80 ° C, stirred with water, and mixed with zopiclone, prepared citric acid and water to prepare a drug-containing acidic solution, lactose, starch, 2/3 amount of sodium carboxymethyl starch and The process of sodium citrate is mixed and hooked, and the acidic liquid containing the drug is added to be stirred to form a soft material, which is squeezed and granulated. The wet granules are dried and then granulated, and magnesium stearate and 1/3 amount of sodium carboxymethyl starch are added. After pressing. Raw material film coating premix (stomach solution Opadry) 4.5, water 19
  • Example 18 Formulation and preparation method of zopiclone tablets (2.5 mg/tablet) Drug zopiclone 2.5 (3.7%, no pretreatment) Lactose 40, sucrose 2, starch 20, sodium carboxymethyl starch 2
  • Acidifier D-malic acid 0.88 (molar ratio to zopiclone: 1.02) Preparation of zopiclone, sucrose, D-malic acid and water into a medicated acidic solution (80 ° C water bath temperature preparation)
  • lactose and starch are mixed, added with acid solution for agitation granulation, wet granule drying process
  • Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.
  • Acidifier citrate monohydrate 0.17 (molar ratio to risperidone: 0.33)
  • the risperidone is mixed with citric acid, added with 75% aqueous solution of ethanol, mixed and stirred to dissolve, and added to the povidone ⁇ 30 while stirring, and dissolved to prepare a medicated acidic solution (60 ° C water bath warm preparation)
  • the wet granules are dried and then granulated, and magnesium stearate, colloidal silica and croscarmellose sodium are added, and the mixture is combined and pressed.
  • Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.
  • Heart acidifier DL-tartaric acid 0.18 (molar ratio to risperidone: 0.25)
  • the risperidone is mixed with DL-tartaric acid, added to a 75% aqueous solution of ethanol, mixed and stirred to dissolve, and prepared by adding polyethylene glycol 6000 and dissolving while stirring. It is formulated into a drug-containing acidic liquid, and the mannitol and the micro-process crystal cellulose are mixed and hooked, and the drug-containing acidic liquid is added for stirring and granulation, the wet granules are dried and then granulated, and magnesium stearate, colloidal silica and Cross-linked polyvinylpyrrolidone, mixed and hooked and pressed.
  • Raw material film coating premix (stomach solution Opadry) 5
  • Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.
  • Risperidone tablets (2mg/tablet) formula and preparation method risperidone 2 (1.8%, no pretreatment) sucrose 40, microcrystalline cellulose 60, cross-linked polyvinylpyrrolidone 4, excipients
  • Heart acidifier DL-tartaric acid 0.8 (molar ratio to risperidone: 1.09) Mix risperidone with DL-tartaric acid, add water, mix and stir to dissolve, add povidone K30 and dissolve with stirring, and prepare to contain The acidic solution of the medicine, the sucrose and microcrystalline cellulose are mixed and hooked, and the acidic liquid containing the medicine is added for stirring and granulation. The wet granules are dried and then granulated, and magnesium stearate, colloidal silica and crosslinked polyethylene are added. Pyrrolidone, mixed and hooked and compressed. Raw material film coating premix (stomach solution Opadry) 5, water 21
  • Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.
  • Risperidone tablets (lmg/tablet) formula and preparation method risperidone 1 0.8% adjuvant lactose 80, starch 30, sodium carboxymethyl starch 6, povidone-K30 3, magnesium stearate 0.7 solvent water 20 ( 16.7 %)
  • Risperidone is mixed with citric acid monohydrate, added with water, mixed and stirred to dissolve, and prepared to be added to povidone K30 and dissolved to form a drug-containing acidic solution, lactose, starch and 70% amount of process carboxymethyl
  • the starch and sodium are mixed, and the medicated acidic solution is added for stirring and granulation.
  • the wet granules are dried and then granulated.
  • Magnesium stearate and the remaining 30% of sodium carboxymethyl starch are added, and the mixture is combined and pressed.
  • Raw material film coating premix (stomach solution Opadry) 5
  • Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.
  • Example 24 Risperidone Tablets (3 mg/tablet) Formulation and Preparation Method Risperidone 3 (2.6%, no pretreatment) Lactose 80, microcrystalline cellulose 30, crosslinked polyvinylpyrrolidone 2, excipients
  • Acidifier citrate monohydrate 0.75 (molar ratio to risperidone: 0.49)
  • the risperidone is mixed with the citric acid monohydrate, and after adding water and Tween-80, the mixture is dissolved and dissolved to prepare a drug-containing acidic liquid. Mixing lactose and microcrystalline cellulose into multi-functional fluidized preparation
  • the peristaltic pump is sprayed on the above mixing process.
  • the granules were granulated, and colloidal silica, sodium stearyl fumarate and cross-linked polyvinylpyrrolidone were added to the obtained granules, and the mixture was mixed and pressed.
  • Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.
  • Povidone-K30 3 colloidal silica 0.2, magnesium stearate 0.8 Solvent 50% aqueous ethanol solution 18 ( 18.6%)
  • the risperidone is mixed with the 10%-DL aqueous solution of lactic acid, added with water, mixed and stirred to dissolve, and then added to the povidone K30 and dissolved to prepare a drug-containing acidic liquid, and the lactose and the microcrystalline fiber process are mixed.
  • the medicated acidic solution is added for stirring and granulation.
  • the wet granules are dried and then granulated, and magnesium stearate, colloidal silica and croscarmellose sodium are added, and the mixture is combined and pressed.
  • Raw material film coating premix (stomach solution Opadry) 5, water 21
  • Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.
  • Acidifier citrate monohydrate 0.46 (molar ratio to risperidone: 0.30)
  • the risperidone is mixed with citric acid monohydrate, added with water and Tween-80, mixed and stirred to prepare a drug-containing acidic solution. Mixing lactose and microcrystalline cellulose into multi-functional preparation
  • the peristaltic pump spray process is carried out while continuously stirring the drug-containing acid solution
  • the granules were granulated on the above mixed granules, and colloidal silica, sodium stearyl fumarate and crosslinked polyvinylpyrrolidone were added to the obtained granules, and the mixture was mixed and pressed.
  • Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition.
  • the process is a coating liquid, and the core is film-coated.
  • Example 27 Formulation and preparation of risperidone capsules (2 mg/granule) Drug Risperidone 2 (1.7%, no pretreatment) Lactose 50, microcrystalline cellulose 60, croscarmellose sodium 2.
  • Povidone-K30 3 magnesium stearate 0.6, colloidal silica 0.3 solvent water 15 ( 15.9%) acidifier 10% aqueous hydrochloric acid 3.7 (molar ratio to risperidone: 2.08) risperidone with 10
  • Mixing % hydrochloric acid aqueous solution adding water, mixing and stirring to dissolve, adding povidone K30 and dissolving while stirring, preparing to contain medicinal acidic liquid, mixing lactose and microcrystalline cellulose, adding the chemical solution
  • Soft material extrusion granulation, wet granules after drying, granules, magnesium stearate, colloidal silica and croscarmellose sodium are added, mixed and hooked, and then filled into hard capsules.
  • Example 28 Dipyridamole tablets (25 mg/tablet) formula and preparation method Drug dipyridamole 25 (10.3%, no pretreatment) Mannitol 80, microcrystalline cellulose 120, sodium carboxymethyl starch 5,
  • Acidifier citrate monohydrate 7.5 (molar ratio to dipyridamole: 0.72)
  • Dipyridamole is mixed with citric acid monohydrate, added to a 75% aqueous solution of ethanol, mixed and stirred to prepare a solution, and added to the povidone oxime 30 while stirring, and dissolved to prepare a medicated acidic liquid as a granulating liquid, Process lol and microcrystalline cellulose in a fluidized spray granulator, fluidized spray granulation, the obtained granules are granulated, and then mixed with sodium carboxymethyl starch, magnesium stearate and colloidal silica. Check the back and press.
  • Example 29 Dipyridamole tablets (25 mg/tablet) formulation and preparation method Drug Dipyridamole 25 (14.5%, no pretreatment)
  • Povidone- ⁇ 30 3 colloidal silica 0.3, magnesium stearate 0.6
  • the dipyridamole is mixed with a 75% aqueous solution of ethanol, added with a 10% aqueous solution of hydrochloric acid, mixed and stirred to prepare a solution, and the povidone 30 is added with stirring to prepare a drug-containing acidic liquid as a granulating liquid, and the lactose and the micro process crystal are added.
  • the cellulose flow-assisted spray granulator fluidized spray granulation is carried out, and the obtained granules are granulated, and then cross-linked polyvinylpyrrolidone, magnesium stearate and colloidal silica are added, and the mixture is combined and then pressed.
  • Example 30 Dipyridamole tablets (25 mg/tablet) formulation and preparation method Drug Dipyridamole 25 (14.5%, no pretreatment)
  • Povidone- ⁇ 30 3 colloidal silica 0.3, magnesium stearate 0.6
  • Acidifier citrate monohydrate 11.45 (molar ratio to dipyridamole: 1.1)
  • Dipyridamole is mixed with citric acid monohydrate, added to 80% ethanol aqueous solution, mixed and stirred to prepare a solution, and added to the povidone oxime 30 while stirring, to prepare a medicated acidic liquid as a granulating liquid, lactose, process
  • the microcrystalline cellulose is placed in a fluidized spray granulator, and subjected to fluidized spray granulation. After the granules are granulated, the crosslinked polyvinylpyrrolidone, magnesium stearate and colloidal silica are added and mixed. Tableting.
  • Example 31 Aripiprazole Tablets (10 mg/tablet) Formulation and Preparation Method Aripiprazole 10 (8.1%, no pretreatment) Lactose 60, microcrystalline cellulose 40, sodium carboxymethyl starch 6, polyethylene Alcohol 6000 2, accessories
  • the citric acid and polyethylene glycol 6000 are dissolved in a 60% aqueous solution of ethanol to prepare a drug-containing acidic solution, and the lactose, the microcrystalline cellulose, and the 70% amount of sodium carboxymethyl starch are mixed and added to the process containing the acidic acid solution. The mixture was stirred and granulated, and the wet granules were dried and then granulated.
  • Magnesium stearate, colloidal silica and the remaining 30% of sodium carboxymethyl starch were mixed and hung.
  • Example 31 The dried granules of Example 31 were passed through a 30 mesh sieve, and magnesium stearate and gum were added.
  • Starch sodium mixed into the hard capsules.
  • Example 33 Aripiprazole Tablets (5 mg/tablet) Formulation and Preparation Method Aripiprazole 5 (4.3%, no pretreatment) Excipients Lactose 70, Microcrystalline Cellulose 30, Sodium Carboxymethyl Starch 6, Poly" Ketone K30 2. Magnesium stearate 0.9 Solvent ethanol 20 (17.3%) Acidifier citrate monohydrate 1.7 (molar ratio to aripiprazole: 0.73) Add aripiprazole and citric acid to ethanol. Adding povidone K30 with stirring to prepare a drug-containing acidic solution (prepared by heating in a 50 ° C water bath), preparing lactose, microcrystalline cellulose, and 70% amount of carboxyformate
  • Acidifier DL-malic acid 1.64 (molar ratio to aripiprazole: 1.10)
  • aripiprazole and DL-malic acid Dissolve aripiprazole and DL-malic acid in 50% ethanol aqueous solution, heat to 40 in a water bath to prepare about °C, prepare a drug-containing acidic liquid, and mix the mannitol and microcrystalline cellulose into the multi-functional process stream.
  • a medicated acidic liquid is sprayed on the mixed auxiliary material by a peristaltic pump to granulate, and magnesium stearate and cross-linked polyvinylpyrrolidone are added to the obtained granules, and the mixture is combined and then pressed.
  • Example 37 Aripiprazole Tablets (5 mg/tablet) Formulation and Preparation Method Aripiprazole 5 (4.5%, no pretreatment)
  • Aripiprazole was placed in a 95% aqueous solution of ethanol, added with 20% DL-lactic acid aqueous solution, and dissolved to prepare a solution containing acidic acid.
  • the 20% lactose and microcrystalline cellulose were mixed and added.
  • the process liquid is stirred and granulated, and the wet granules are dried and then granulated, and magnesium stearate, colloidal silica and crosslinked polyvinylpyrrolidone are added and mixed, and then pressed.
  • Example 38 Formulation and preparation of aripiprazole tablets (10 mg/tablet) Drug Aripiprazole 10 (7.2%, no pretreatment)
  • Aripiprazole and DL-malic acid are placed in a 50% aqueous solution of ethanol, heated to about 50 ° C in a water bath, prepared to stir and dissolve, formulated into a drug-containing acidic solution, and lactose, microcrystalline cellulose and 70% amount of carboxymethyl
  • the starch sodium process is mixed and hooked, and the above-mentioned drug-containing acidic liquid is added for stirring and granulation.
  • the wet granules are dried and then granulated, and magnesium stearate and the remaining 30% of sodium carboxymethyl starch are mixed and hooked. Effect Example 1 Dissolution comparison test
  • Dissolution test method Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2005 edition two appendix XC third method), with water 200ml as solvent, the rotation speed is 50 rpm, operate according to law, and prepare a control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2005 edition two appendix IV A), the absorbance was measured at a wavelength of 304 nm, and the amount of dissolution per tablet was calculated. Dissolution (%)
  • Dissolution test method Take the sample and measure the dissolution method (Chinese Pharmacopoeia 2005 edition two appendix X C third method), use 200ml of water as solvent, rotate at 50 rpm, operate according to law, and prepare a control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2005 edition two appendix IV A), the absorbance was measured at a wavelength of 304 nm, and the amount of dissolution per tablet was calculated.
  • Dissolution test method Take the sample, according to the dissolution test method (Chinese Pharmacopoeia 2005 edition two appendix XC second method), with water 200ml as solvent, the rotation speed is 50 rpm, operate according to law, at 15, 30, 45 minutes Take 5 ml of the solution separately, replenish 5 ml, filter the sample, discard the initial filtrate, take the filtrate as a sample solution, and prepare a control solution. According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix V D), octadecylsilane bonded silica was used as a filler, and the amount of dissolution of each tablet was calculated.
  • the dissolution test method Choinese Pharmacopoeia 2005 edition two appendix XC second method
  • pH 4.0 acetate buffer 0.05mol / L acetic acid -0.05mol / L sodium acetate
  • octadecylsilane bonded silica was used as a filler; methanol-0.1% triethylamine solution (90: 10) as mobile phase; The detection wavelength is 255 nm. The amount of dissolution per tablet was calculated.
  • test samples were placed in high-density polyethylene plastic bottles, sealed, placed in an accelerated test chamber, and subjected to an accelerated test for 3 months at a temperature of 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%. Stability determination of related items.
  • Determination method Take the appropriate amount of this product (equivalent to 3mg of dextrozopicl), place it in a 250ml volumetric flask, add 0.02mol/L hydrochloric acid, shake the hook, filter, and take the filtrate as the test solution; The right amount of dexamethasone was used as a reference solution, and a solution containing 12 ⁇ ⁇ per ml of 0.02 mol/L hydrochloric acid was used as a control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2005 edition two appendix IV ⁇ ), the absorbance was measured at a wavelength of 304 nm, and the dissolution test method was calculated in the same manner as in the effect example 1).
  • Determination of related substances According to the high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix VD) determination, using octadecylsilane bonded silica as a filler, the chromatogram of the test solution and the control solution chromatogram according to the main The composition is calculated by the self-control method.
  • Method for determination of content Take appropriate amount of this product (equivalent to 3mg of zopiclone), place in a 250ml volumetric flask, add 0.02mol/L hydrochloric acid, shake the hook, filter, and take the filtrate as the test solution; A suitable amount of the reference substance was cloned, and a solution containing 12 ⁇ ⁇ per 1 ml was prepared using 0.02 mol/L hydrochloric acid as a control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2005 edition two appendix IV ⁇ ), the absorbance was measured at a wavelength of 304 nm, and the content was calculated.
  • the dissolution test method was the same as in the effect example 1 2).
  • 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 risperidone per ml, as the test solution, and prepare a control solution. According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix V D), octadecylsilane bonded silica was used as a filler and determined separately. The content is determined according to the external standard method, and the determination of the relevant substance is carried out according to the main component self-control method.
  • the dissolution test method was the same as in the effect example 1 (3).
  • 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.
  • aripiprazole solution per ml According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix V D), octadecylsilane bonded silica was used as a filler and determined separately.
  • the content is determined according to the external standard method, and the determination of the relevant substance is carried out according to the main component self-control method.
  • the dissolution test method was the same as in the effect example 1 (5). Traits Content (%) 45 minutes Dissolution (%) Related substances (%) Samples
  • the XE content of the appendix is checked, and the content of each tablet is determined.

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Description

一种固体制剂的制备方法及所得固体制剂
技术领域
本发明属于药物制剂领域， 具体涉及一种固体制剂的制备方法及所得固体制剂。
背景技术
在药物制剂领域， 药物活性成分的粒径对固体制剂的制备过程和质量密切相关。 在 具体的药物制剂的制备工艺中， 通常依据药物的溶解特性和生物膜通透性， 来选择合适 的药物活性成分的粒径。 例如， 若属于溶解性较差， 药物溶出是吸收限速过程的药物， 可选择较小的粒径， 以促进药物的吸收。 再例如， 若属于可压性较差的药物， 可通过选 择合适的粒径， 以及加入适宜的辅料来改善其可压性。 因此， 在药物固体制剂的制备工 艺中， 时常涉及到对药物活性成分的粒径的选择控制。 目前， 大多通过选择不同的机械 粉碎方法及粉碎工艺条件， 以实现对药物活性成分粒径的选择控制。
但是， 机械粉碎的处理方法存在粉尘多、 污染环境和损耗大等问题。 对于一些高活 性药物， 还容易在机械粉碎过程中， 使操作人员产生不良反应， 存在严重的安全隐患。 例如， 相当多的镇静安眠药物， 如右旋佐匹克隆、 阿普唑仑等药物活性较高， 吸入较低 剂量的药物粉末即可快速产生催眠效果， 在对这类药物进行粉碎处理时， 极易发生致操 作人员快速催眠的不良反应， 引发安全事故。 再例如， 在对一些高活性的激素或抗肿瘤 等药物进行粉碎处理时， 吸入或接触药物粉末， 极易使操作人员产生严重的药物不良反 应。
并且， 目前广泛使用的普通机械粉碎方法（如采用常用的万能粉碎机）， 平均粒径一 般达到 100左右微米。 由该方法处理制得的固体制剂的溶出特性尚不够理想。
在机械粉碎处理的工艺中， 对于在固体制剂中含量较低 （如≤5wt%) 的高活性药物 活性成分， 还涉及其与辅料混合的分散均勾性问题。 通常， 采用将药物活性成分与辅料 等量稀释逐步扩大的方法， 以使药物活性成分在固体制剂中分散均勾。 但该方法工艺操 作繁琐， 同样会产生粉尘多、 污染环境、 损耗大和劳动防护存在安全隐患等诸多问题。
此外， 固体制剂的制备还需考虑产品的各种性能是否能满足需要。 例如， 是否能保 证较佳的含量均勾度。 再例如， 稳定性是固体制剂质量的考察重点， 其包括在固体制剂 贮存期内， 药物活性成分的化学稳定性、 有关物质 （即杂质） 的含量、 固体制剂性状稳 定性、 以及溶出稳定性等， 是否处在药品标准限度内。
因此， 针对上述现有技术的缺陷， 亟待寻求一种既可避免机械粉碎处理方法的上述 缺陷， 又可保证固体制剂各种性能优良的制备方法。
发明内容
本发明所要解决的技术问题是为了克服现有的固体制剂制备方法通过机械粉碎的 方式选择控制药物活性成分的粒径， 会造成环境污染， 存在严重的安全隐患， 损耗大， 且所得固体药物制剂的溶出特性不够理想的缺陷，而针对水不溶性或水难溶性碱性药物， 提供一种操作更简便， 污染更小， 没有前述安全隐患， 且能保证所制得的固体制剂具有 优异的溶出特性、 稳定性和含量均勾度的制备方法及所得固体制剂。
为解决上述技术问题， 本发明人另辟蹊径， 独特的采用酸性溶液溶解水不溶性或水 难溶性碱性药物， 之后随制粒过程， 使药物回复固体状态， 从而避免了机械粉碎处理的 诸多缺陷， 并且， 本发明人还意外发现， 该方法所制得的固体制剂具有优异的溶出特性、 稳定性和含量均勾度。
本发明的制备方法包括如下步骤： 将水不溶性和 /或水难溶性碱性药物活性成分溶于 含酸化剂的酸性溶液中， 制得含药酸性液， 之后， 将含药酸性液和辅料均勾的混合， 进 行湿法制粒。
本发明中， 所述的水不溶性和 /或水难溶性碱性药物活性成分选自现有的各种符合上 述性质的药物活性成分， 包括同时具有酸性基团和碱性基团的两性药物活性成分。 本领 域中， 所述的碱性药物活性成分大都为弱碱类药物活性成分。 本发明尤其适用于活性较 高、 在固体制剂中含量较低 （一般为 20%以下， 较佳的为 5%以下， 更佳的为 1%以下， 百分比为质量百分比） 的水不溶性和 /或水难溶性碱性药物。 更具体的， 本发明优选但不 限于阿立哌唑、 右旋佐匹克隆、 地西泮、 艾司唑仑、 阿普唑仑、 佐匹克隆、 利醅酮、 阿 戈美拉汀、 伊潘立酮、 帕潘立酮、 奋乃静、 狄戈辛、 氟哌啶醇、 双嘧达莫、 奥氮平、 米 非司酮、 卡比马唑、 甲氧氯普胺、 米诺地尔或利血平。 根据水不溶性和 /或水难溶性碱性 药物活性成分在固体制剂中的常规含量， 即可确定制备过程中， 水不溶性和 /或水难溶性 碱性药物活性成分占湿法制粒干物料的质量百分比。 根据需要， 除水不溶性和 /或水难溶 性碱性药物活性成分之外， 还可加入其他药物活性成分， 制备为复方固体制剂， 如奥氮 平与盐酸氟西汀的复方固体制剂。
本发明中，所述的酸化剂是指能使水不溶性和 /或水难溶性碱性药物活性成分溶解形 成含药酸性液的酸性试剂。 根据本领域常识， 所述的酸化剂应为药学上可接受的， 且与 水不溶性和 /或水难溶性碱性药物活性成分相配伍的试剂。 所述的酸化剂可为单一的酸化 剂， 也可为两种以上成分组成的复合酸化剂， 可选自各种酸， 如无机强酸、 无机中强酸 和有机弱酸中的一种或多种， 较佳的选自盐酸、 枸橼酸、 酒石酸、 苹果酸、 氢溴酸、 富 马酸、 琥珀酸、 马来酸、 乳酸、 醋酸、 硫酸、 硝酸和磷酸中的一种或多种， 更佳的为盐 酸、 枸橼酸、 酒石酸、 苹果酸、 乳酸或醋酸。 更具体的， 本发明特别优选下述酸化剂， 可使得固体制剂具有较优的稳定性： 当水不溶性和 /或水难溶性碱性药物活性成分为右旋 佐匹克隆时， 选择枸橼酸、 酒石酸、 苹果酸或盐酸， 最优选枸橼酸。 当水不溶性和 /或水 难溶性碱性药物活性成分为佐匹克隆时， 选择盐酸、 苹果酸、 酒石酸或枸橼酸， 最优选 盐酸或酒石酸。 当水不溶性和 /或水难溶性碱性药物活性成分为利醅酮时， 选择盐酸、 枸 橼酸或酒石酸。 当水不溶性和 /或水难溶性碱性药物活性成分为双嘧达莫时， 选择盐酸或 枸橼酸。 当水不溶性和 /或水难溶性碱性药物活性成分为阿立哌唑时， 选择盐酸、枸橼酸、 苹果酸或乳酸。
所述的酸化剂的用量至少为能使水不溶性和 /或水难溶性碱性药物活性成分完全溶 解的最小量， 较佳的为此最小量的 1~1.2倍， 更佳的为 1~1.05倍。 可溶解水不溶性和 /或 水难溶性碱性药物活性成分的酸化剂的量与诸多因素有关， 如酸化剂种类、 溶剂种类、 水不溶性和 /或水难溶性碱性药物活性成分的溶解性、 其分子中的碱性中心数、 酸化剂中 可与药物分子的碱性中心相结合的氢离子数、 以及含药酸性液配制条件有关。 其中， 所 述的碱性中心是指水不溶性和 /或水难溶性碱性药物活性成分中可与酸化剂分子中氢离 子结合的基团或部位。 因此， 上述最小量是指在同一溶剂和含药酸性液配制条件下， 对 某种水不溶性和 /或水难溶性碱性药物活性成分而言， 某种酸化剂可将其完全溶解的最小 量。 通过简单的常规方法即可确定该最小量： 在同一溶剂和含药酸性液配制条件下， 采 用逐渐增大某种酸化剂的用量溶解某种水不溶性和 /或水难溶性碱性药物活性成分， 刚好 完全溶解时， 即为最小量。 本发明人经大量实验摸索得出， 具体而言， 酸化剂与水不溶 性和 /或水难溶性碱性药物活性成分的摩尔比值一般为 0.2~2.5， 大多为 0.3~1.5。 本发明 特别优选下述酸化剂的用量：
当水不溶性和 /或水难溶性碱性药物活性成分为右旋佐匹克隆时，选择右旋佐匹克隆 摩尔量 0.8~1.1倍的枸橼酸。
当水不溶性和 /或水难溶性碱性药物活性成分为佐匹克隆时， 选择佐匹克隆摩尔量 0.95-1.1倍的盐酸或酒石酸。
当水不溶性和 /或水难溶性碱性药物活性成分为利醅酮时， 选择利醅酮摩尔量 0.8-2.1倍的盐酸， 或利醅酮摩尔量 0.3~1.1倍的枸橼酸， 或利醅酮摩尔量 0.25~1.1倍的 酒石酸。
当水不溶性和 /或水难溶性碱性药物活性成分为双嘧达莫时， 选择双嘧达莫摩尔量 0.7-1.2倍的盐酸， 或双嘧达莫摩尔量 0.7~1.1倍的枸橼酸。
当水不溶性和 /或水难溶性碱性药物活性成分为阿立哌唑时， 选择阿立哌唑摩尔量 0.9~1.2倍的盐酸， 或阿立哌唑摩尔量 0.8~1.3倍的枸橼酸， 或阿立哌唑摩尔量 0.8~1.1倍 的苹果酸。
本发明中， 所述的含酸化剂的酸性溶液中的溶剂可为水、 有机溶剂或者水和有机溶 剂的混合液， 优选水或水和有机溶剂的混合液。 根据本领域常识， 选择的溶剂应为酸化 剂中离子可解离的溶剂。 例如， 酸化剂为无机物时， 可选择水或水和有机溶剂的混合液; 酸化剂为有机物时， 可为水、 水和有机溶剂的混合液、 或者有机溶剂。 若药物活性成分 在某些有机溶剂中有优于在水中的溶解性， 则较佳的选择水与该有机溶剂的混合液， 以 利于药物活性成分的溶解， 减少酸性溶液的用量， 利于后续制粒步骤的操作。 所述的有 机溶剂根据其对药物活性成分的溶解性优于水的原则在药剂领域可接受的溶剂中进行选 择， 较佳的为能与水混溶的有机溶剂， 如药剂领域常用的水溶性醇类溶剂， 如乙醇、 丙 酮、 丙二醇、 丙三醇、 异丙醇和叔丁醇等， 优选乙醇、 丙酮、 丙二醇和丙三醇中的一种 或多种， 特别优选乙醇。 水与有机溶剂的混合液中， 有机溶剂的用量可任意选择。 所述 的酸性溶液中溶剂的用量至少为湿法制粒所需制粒液最小量， 一般为湿法制粒干物料的 质量百分比 5~100%， 较佳的为 10~50%。
在制备含药酸性液时， 可加入一些辅料， 如粘合剂、 表面活性剂、 增溶剂和固体分 散体的水溶性载体等。 较佳的， 在将水不溶性和 /或水难溶性碱性药物活性成分溶于含酸 化剂的酸性溶液中的同时和 /或之后， 还加入表面活性剂、 增溶剂和固体分散体的水溶性 载体中的一种或多种， 然后将所得含药酸性液进行后续步骤， 即与辅料均勾混合， 进行 湿法制粒。 其中， 将固体分散体的水溶性载体与水不溶性和 /或水难溶性碱性药物活性成 分同时加入含酸化剂的酸性溶液中时， 此时加入的固体分散体的水溶性载体的量需控制 在能保证水不溶性和 /或水难溶性碱性药物活性成分完全溶解于含酸化剂的酸性溶液中 的量以下； 之后还可以再向该溶液中加入固体分散体的水溶性载体， 当加入量较大时， 所得含药酸性液可能为悬浊液或粘稠液形式。本发明特别优选加入聚维酮、聚乙二醇（优 选聚乙二醇 400-8000)、 十二烷基硫酸钠、 泊洛沙姆、 聚氧乙烯蓖麻油、 吐温 -80、 硬脂 酸聚烃氧 40酯、 β-环糊精、 乳糖、 甘露醇、 蔗糖和麦芽糖醇中的一种或多种。 所述的表 面活性剂和 /或增溶剂的加入量较佳的为水不溶性和 /或水难溶性碱性药物活性成分质量 的 0.05~3倍。所述的固体分散体的水溶性载体的加入量较佳的为水不溶性和 /或水难溶性 碱性药物活性成分质量的 1~20倍。 按上述操作加入表面活性剂和 /或增溶剂， 可增加水 不溶性和 /或水难溶性碱性药物活性成分在酸性溶液中的溶解度， 减少溶剂用量， 利于后 续制粒步骤的操作。 更值得一提的是， 按上述操作加入表面活性剂、 增溶剂和固体分散 体的水溶性载体中的一种或多种， 尤其是固体分散体的水溶性载体可使所得水不溶性和 / 或水难溶性碱性药物活性成分固体制剂的溶出特性更佳。
较佳的， 在制备含药酸性液时， 可以通过热水浴等常规加热方法， 适当升高含药酸 性液的配制温度， 以利于药物活性成分的溶解。 以水为溶剂时， 较佳的升高至 40~80°C。 以水和有机溶剂的混合溶液为溶剂时， 较佳的升高为 40~70°C， 更佳的为 50~60°C。 以乙 醇为溶剂时， 较佳的升高为 30~50°C。
本发明中， 所述的辅料可选自本领域任何已知的并广泛使用的辅料， 如填充剂、 粘 合剂、 崩解剂、 吸附剂和润滑剂等等。 其中， 所述的填充剂较佳的为乳糖、 微晶纤维素、 淀粉、 预胶化淀粉、 甘露醇、 蔗糖、 氧化镁、 碳酸钙、 碳酸镁和麦芽糖醇中的一种或多 种。 所述的粘合剂较佳的为羟丙甲纤维素、 聚维酮、 甲基纤维素和羟丙纤维素中的一种 或多种。 所说的崩解剂较佳的为羧甲淀粉钠、 低取代羟丙纤维素、 交联聚乙烯吡咯烷酮 和交联羧甲基纤维素钠中的一种或多种。 所述的润滑剂较佳的为胶态二氧化硅、 硬脂酸 富马酸钠、 滑石粉或硬脂酸镁。 所述的辅料的含量可按照本领域常规知识进行选择。
本发明中， 所述的湿法制粒可按照本领域属于湿法制粒范畴的制粒方法的常规步骤 和条件进行， 如挤压制粒 （如摇摆机挤压、 螺旋挤压和旋转挤压等）、 搅拌制粒、 流化喷 雾制粒和离心喷雾制粒等。对于在固体制剂中含量较大（一般大于 20%)， 或在含酸化剂 的酸性溶液中溶解度较小， 需较大量的酸性溶液才可溶解完全的水不溶性和 /或水难溶性 碱性药物活性成分， 可选择对制粒溶液量限制小的湿法制粒工艺， 如流化喷雾制粒或离 心喷雾制粒。
湿法制粒完成后， 可直接得到固体颗粒制剂， 也可作为制剂中间体， 经进一步的常 规步骤， 制得片剂或胶囊剂等其他形式的固体制剂。
本发明中， 上述各优选条件， 可在符合本领域常识的基础上任意组合， 即可得本发 明各较佳实例。
本发明中， 所用试剂和原料可通过市售可得， 部分原料药可按照现有文献方法制备。 进一步的， 本发明还涉及由上述方法制得的固体制剂。
本发明的积极进步效果在于：
( 1 )本发明的制备方法避免了机械粉碎处理所带来的污染严重、损耗大和安全隐患 严重的缺陷。 该方法操作简便易行， 安全系数高， 易应用于工业化生产。
(2)本发明的制备方法制得的固体制剂的溶出特性较现有技术有显著的提高， 生物 利用度高， 个体差异小。
( 3 ) 本发明的制备方法制得的固体制剂具有较佳的含量均勾度和较好的稳定性。 具体实施方式
下面用实施例来进一步说明本发明， 但本发明并不受其限制。
下列实施例中未注明具体条件的实验方法， 通常按照常规条件， 或按照制造厂商所 建议的条件。 剂型规格以药物活性成分含量计， 如 2mg/片， 是指每片中含药物活性成分 2mg。 用量单位为克， 百分比为质量百分比。 药物活性成分和溶剂的质量百分比为占湿 法制粒干物料的质量百分比。 其中， 溶剂的用量包括酸化剂的水溶液中的水。 对比实施例 1与实施例 1和 2 右旋佐匹克隆片剂（3mg/片）配方及制备方法
Figure imgf000008_0001
对比实施例 2与实施例 3和 4 佐匹克隆片剂配方及制备方法
Figure imgf000009_0001
对比实施例 3与实施例 5 利培酮片剂（lmg/片）配方及制备方法
Figure imgf000010_0001
实施例 6和 7 利培酮片剂 ( lmg/片 )配方及制备方法
Figure imgf000011_0001
对比实施例 4与实施例 8 双嘧达莫片剂（25mg/片）配方及制备方法
Figure imgf000012_0001
对比实施例 5与实施例 9 阿立哌唑片剂（5mg/片）配方及制备方法
Figure imgf000013_0001
实施例 10和 11 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000014_0001
右旋佐匹克隆片 （2mg/片）配方及制备方法
Figure imgf000015_0001
右旋佐匹克隆片 （2mg/片）配方及制备方法 药物 右旋佐匹克隆 1 ( 1.4%， 无预处理） 乳糖 40、 微晶纤维素 25、 聚乙二醇 6000 1、
辅料
硬脂酸富马酸钠 0.5、 滑石粉 1.5
溶剂 水 6、 乙醇 5 ( 15.8%)
片
心 酸化剂 枸橼酸一水合物 0.59 (与右旋佐匹克隆的摩尔比值： 1.09) 将右旋佐匹克隆、 聚乙二醇 6000、 乙醇、 枸橼酸和水混勾， 向 制备 溶液中加入 50%量的乳糖搅拌， 配制成含药酸性液， 再加入预先混 工艺 合的乳糖和微晶纤维素， 进行搅拌制粒， 颗粒干燥后加入硬脂酸富 马酸钠和滑石粉， 混合均勾后压片。
原料 羟丙甲纤维素 1.8、 聚乙二醇 6000 0.3、 二氧化钛 0.4、 水 15 包
将羟丙甲纤维素用 80°C热水分散后加水搅拌溶解， 加入聚乙二 衣 制备工艺
醇 6000和勾化好的二氧化钛， 配成包衣液， 对片芯进行薄膜包衣。 实施例 14 右旋佐匹克隆片 （2mg/片）配方及制备方法 药物 右旋佐匹克隆 2 (3.0%, 无预处理）
蔗糖 25、 微晶纤维素 30、 淀粉 5、 羧甲淀粉钠 2、 辅料
聚维酮 K30 1、 聚乙二醇 6000 1 、 硬脂酸镁 0.3 溶剂 水 8、 95%乙醇水溶液 4 ( 17.9%)
片
酸化剂 DL-酒石酸 0.8 (与右旋佐匹克隆摩尔比值： 1.04) 心
将右旋佐匹克隆、 聚乙二醇 6000、 聚维酮 K30、 DL-酒石酸、 95% 制备 乙醇水溶液和水配制成含药酸性液， 蔗糖、 微晶纤维素、 淀粉和羧甲 工艺 淀粉钠混合均勾，加入含药酸性液进行搅拌制成软材，挤压制粒，湿颗 粒干燥后整粒， 加入硬脂酸镁混合均勾后压片。 原料 薄膜包衣预混料 （胃溶欧巴代） 3、 水 13
包
在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配 衣 制备工艺
成包衣液， 对片芯进行薄膜包衣。
实施例 15 右旋佐匹克隆片 （2mg/片）配方及制备方法
药物 右旋佐匹克隆 2 (3.3%, 无预处理）
甘露醇 25、 微晶纤维素 30、 泊洛沙姆 1、 硬脂酸镁 0.3、 辅料
胶态二氧化硅 0.2、 交联聚维酮 2
溶剂 水 11 ( 16.4%)
片
酸化剂 DL-苹果酸 0.65 (与右旋佐匹克隆摩尔比值： 0.94) 心
将右旋佐匹克隆、 泊洛沙姆、 DL-苹果酸和水配制成含药酸性液， 甘露醇、 微晶纤维素混合均勾， 加入含药酸性液进行搅拌制粒， 湿颗 粒干燥后整粒， 加入硬脂酸镁、 交联聚维酮和胶态二氧化硅混合均勾 后压片。
原料 薄膜包衣预混料 （胃溶欧巴代） 2.2、 水 10
包
制备 在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配成 衣
工艺 包衣液， 对片芯进行薄膜包衣。 实施例 16 佐匹克隆片 （2.5毫克 /片）配方及制备方法 药物 佐匹克隆 2.5 (4.2%, 无预处理） 甘露醇 25、 微晶纤维素 30、 泊洛沙姆 1、
辅料
硬脂酸镁 0.3、 胶态二氧化硅 0.2
溶剂 95%乙醇水溶液 3、 水 9 (28.5%)
片
心 酸化剂 5%盐酸水溶液 4.5 (与佐匹克隆的摩尔比值： 0.96)
将佐匹克隆、泊洛沙姆、 5%盐酸水溶液、 95%乙醇水溶液和水配制 制备 成含药酸性液（70°C水浴温热配制）， 甘露醇和微晶纤维素混合均勾， 工艺 加入含药酸性液进行搅拌制粒， 湿颗粒干燥后整粒， 加入硬脂酸镁和 胶态二氧化硅混合均勾后压片。
原料 薄膜包衣预混料 （胃溶欧巴代） 2.2、 水 10
包
在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配 衣 制备工艺
成包衣液， 对片芯进行薄膜包衣。
实施例 17 佐匹克隆片 （3.75mg/片）配方及制备方法 药物 佐匹克隆 3.75 ( 3.4%, 无预处理） 辅料 乳糖 70、 羧甲淀粉钠 5、 淀粉 30、 羟丙甲纤维素 0.4、 硬脂酸镁 0.6、 溶剂 水 22 (19.7%)
片 酸化剂 枸橼酸一水合物 2.2 (与佐匹克隆的摩尔比值： 1.09) 心
将羟丙甲纤维素用 80°C热水分散后加水搅拌溶解， 与佐匹克隆、 制备 枸橼酸和水配制成含药酸性液， 乳糖、 淀粉、 2/3量的羧甲淀粉钠和 工艺 枸橼酸钠混合均勾，加入含药酸性液进行搅拌制成软材，挤压制粒，湿 颗粒干燥后整粒，加入硬脂酸镁和 1/3量羧甲淀粉钠混合均勾后压片。 原料 薄膜包衣预混料 （胃溶欧巴代） 4.5、 水 19
包
在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配 衣 制备工艺
成包衣液， 对片芯进行薄膜包衣。 实施例 18 佐匹克隆片 （2.5mg/片）配方及制备方法 药物 佐匹克隆 2.5 ( 3.7%, 无预处理） 乳糖 40、 蔗糖 2、 淀粉 20、 羧甲淀粉钠 2、
辅料
硬脂酸镁 0.3、 胶态二氧化硅 0.1
片 溶剂
心
酸化剂 D-苹果酸 0.88 (与佐匹克隆的摩尔比值： 1.02) 将佐匹克隆、 蔗糖、 D -苹果酸和水配制成含药酸性液（80°C水浴温 制备
热）， 乳糖和淀粉混合均勾， 加入含药酸性液进行搅拌制粒， 湿颗粒干燥 工艺
后整粒， 加入硬脂酸镁、 羧甲淀粉钠和胶态二氧化硅混合均勾后压片。 原料 薄膜包衣预混料 （胃溶欧巴代） 2.5、 水 11
包
制备 在水中边搅拌边加入欧巴代粉末，加完后继续搅拌 45分钟，配成包 衣
工艺 衣液， 对片芯进行薄膜包衣。
实施例 19 利培酮片 （lmg/片）配方及制备方法 药物 利培酮 1 ( 0.9%， 无预处理） 乳糖 50、 微晶纤维素 60、 交联羧甲基纤维素钠 2、 辅料
聚维酮 -K30 1.2、 硬脂酸镁 0.6、 胶态二氧化硅 0.3 溶剂 75%乙醇水溶液 25 (21.7%)
片
酸化剂 枸橼酸一水合物 0.17 (与利培酮的摩尔比值： 0.33 ) 心
将利培酮与枸橼酸混合， 加入 75%乙醇水溶液后混合搅拌溶解， 边搅拌边加入聚维酮 Κ30并溶解， 配制成含药酸性液 （60°C水浴温热 制备
配制），将乳糖、微晶纤维素混合均勾，加入含药酸性液进行搅拌制粒， 工艺
湿颗粒干燥后整粒， 加入硬脂酸镁、 胶态二氧化硅和交联羧甲基纤维 素钠， 混合均勾后压片。
原料 薄膜包衣预混料 （胃溶欧巴代） 5、 水 21
包
制备 在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配成 衣
工艺 包衣液， 对片芯进行薄膜包衣。 实施例 20 利培酮片 （2mg/片）配方及制备方法 药物 利培酮 2 ( 1.7%, 无预处理） 甘露醇 50、 微晶纤维素 60、 交联聚维酮 2、
辅料
聚乙二醇 6000 2、 硬脂酸镁 0.6、 胶态二氧化硅 0.3 溶剂 75%乙醇水溶液 25 (21.4%)
片
心 酸化剂 DL-酒石酸 0.18 (与利培酮的摩尔比值： 0.25 ) 将利培酮与 DL-酒石酸混合，加入 75%乙醇水溶液后混合搅拌溶解， 制备 边搅拌边加入聚乙二醇 6000并溶解， 配制成含药酸性液， 将甘露醇、微 工艺 晶纤维素混合均勾，加入含药酸性液进行搅拌制粒，湿颗粒干燥后整粒， 加入硬脂酸镁、胶态二氧化硅和交联聚乙烯吡咯烷酮，混合均勾后压片。 原料 薄膜包衣预混料 （胃溶欧巴代） 5、 水 21
包
制备 在水中边搅拌边加入欧巴代粉末，加完后继续搅拌 45分钟，配成包 衣
工艺 衣液， 对片芯进行薄膜包衣。
利培酮片 （2mg/片）配方及制备方法 药物 利培酮 2 (1.8%, 无预处理） 蔗糖 40、 微晶纤维素 60、 交联聚乙烯吡咯烷酮 4、 辅料
聚维酮 -K30 3、 胶态二氧化硅 0.2、 硬脂酸镁 0.6 溶剂
片
心 酸化剂 DL-酒石酸 0.8 (与利培酮的摩尔比值： 1.09) 将利培酮与 DL-酒石酸混合， 加入水后混合搅拌溶解， 边搅拌边 制备 加入聚维酮 K30并溶解， 配制成含药酸性液， 将蔗糖、 微晶纤维素混 工艺 合均勾， 加入含药酸性液进行搅拌制粒， 湿颗粒干燥后整粒， 加入硬 脂酸镁、 胶态二氧化硅和交联聚乙烯吡咯烷酮， 混合均勾后压片。 原料 薄膜包衣预混料 （胃溶欧巴代） 5、 水 21
包
制备 在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配成 衣
工艺 包衣液， 对片芯进行薄膜包衣。 利培酮片 （lmg/片）配方及制备方法
Figure imgf000020_0001
利培酮片 （lmg/片）配方及制备方法 药物 利培酮 1 0.8% 辅料 乳糖 80、 淀粉 30、 羧甲淀粉钠 6、 聚维酮 -K30 3、 硬脂酸镁 0.7 溶剂 水 20 ( 16.7%)
片 酸化剂 枸橼酸一水合物 0.36 (与利培酮的摩尔比值： 0.70) 心
利培酮与枸橼酸一水合物混合， 加入水后混合搅拌溶解， 边搅拌边 制备 加入聚维酮 K30并溶解， 配制成含药酸性液， 将乳糖、淀粉和 70%量的 工艺 羧甲淀粉钠混合均勾， 加入含药酸性液进行搅拌制粒， 湿颗粒干燥后整 粒， 加入硬脂酸镁和剩余 30%量羧甲基淀粉钠， 混合均勾后压片。 原料 薄膜包衣预混料 （胃溶欧巴代） 5、 水 21
包
制备 在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配成 衣
工艺 包衣液， 对片芯进行薄膜包衣。 实施例 24利培酮片 （3mg/片）配方及制备方法 药物 利培酮 3 (2.6%, 无预处理） 乳糖 80、 微晶纤维素 30、 交联聚乙烯吡咯烷酮 2、 辅料
吐温 -80 0.3、 胶态二氧化硅 0.3、 硬脂酸富马酸钠 0.6 溶剂 水 70 ( 59.9%)
片
酸化剂 枸橼酸一水合物 0.75 (与利培酮的摩尔比值： 0.49) 心
将利培酮与枸橼酸一水合物混合， 加入水和吐温 -80 后混合搅拌溶 解， 配制成含药酸性液。 将乳糖和微晶纤维素混合均勾置于多功能流化 制备
喷雾制粒机中， 将含药酸性液持续搅拌的同时， 用蠕动泵喷于上述混合 工艺
辅料上制粒， 在制得的颗粒中加入胶态二氧化硅、 硬脂酸富马酸钠和交 联聚乙烯吡咯烷酮， 混合均勾后压片。
原料 薄膜包衣预混料 （胃溶欧巴代） 5、 水 21
包
制备 在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配成 衣
工艺 包衣液， 对片芯进行薄膜包衣。 实施例 25 利培酮片 （lmg/片）配方及制备方法 药物 利培酮 1 ( 0.9%， 无预处理） 乳糖 50、 微晶纤维素 60、 交联羧甲基纤维素钠 2、 辅料
聚维酮 -K30 3、 胶态二氧化硅 0.2、 硬脂酸镁 0.8 溶剂 50%乙醇水溶液 18 ( 18.6%)
片
心 酸化剂 10%DL-乳酸水溶液 3.8 (与利培酮的摩尔比值： 1.73 )
将利培酮与 10%-DL乳酸水溶液混合， 加入水后混合搅拌溶解， 边 制备 搅拌边加入聚维酮 K30并溶解， 配制成含药酸性液， 将乳糖、微晶纤维 工艺 素混合均勾， 加入含药酸性液进行搅拌制粒， 湿颗粒干燥后整粒， 加入 硬脂酸镁、 胶态二氧化硅和交联羧甲基纤维素钠， 混合均勾后压片。 原料 薄膜包衣预混料 （胃溶欧巴代） 5、 水 21
包
制备 在水中边搅拌边加入欧巴代粉末， 加完后继续搅拌 45分钟， 配成 衣
工艺 包衣液， 对片芯进行薄膜包衣。 实施例 26利培酮片 （3mg/片）配方及制备方法 药物 利培酮 3 (2.6%, 无预处理） 乳糖 80、 微晶纤维素 30、 交联聚乙烯吡咯烷酮 2、 辅料
吐温 -80 0.3、 胶态二氧化硅 0.3、 硬脂酸富马酸钠 0.6 溶剂 水 17 ( 14.6%)
片
酸化剂 枸橼酸一水合物 0.46 (与利培酮的摩尔比值： 0.30) 心
将利培酮与枸橼酸一水合物混合，加入水和吐温 -80后混合搅拌 溶解， 配制成含药酸性液。 将乳糖和微晶纤维素混合均勾置于多功 制备
能流化喷雾制粒机中， 将含药酸性液持续搅拌的同时， 用蠕动泵喷 工艺
于上述混合辅料上制粒， 在制得的颗粒中加入胶态二氧化硅、 硬脂 酸富马酸钠和交联聚乙烯吡咯烷酮， 混合均勾后压片。
原料 薄膜包衣预混料 （胃溶欧巴代） 5、 水 21 包
制备 在水中边搅拌边加入欧巴代粉末，加完后继续搅拌 45分钟，配 衣
工艺 成包衣液， 对片芯进行薄膜包衣。
实施例 27 利培酮胶囊（2mg/粒）配方及制备方法 药物 利培酮 2 ( 1.7%, 无预处理） 乳糖 50、 微晶纤维素 60、 交联羧甲基纤维素钠 2、
辅料
聚维酮 -K30 3、 硬脂酸镁 0.6、 胶态二氧化硅 0.3 溶剂 水 15 ( 15.9%) 酸化剂 10%盐酸水溶液 3.7 (与利培酮的摩尔比值： 2.08 ) 将利培酮与 10%盐酸水溶液混合， 加入水后混合搅拌溶解， 边搅拌边 制备 加入聚维酮 K30并溶解， 配制成含药酸性液， 将乳糖、 微晶纤维素混合均 工艺 勾， 加入含药酸性液制成软材， 挤压制粒， 湿颗粒干燥后整粒， 加入硬脂 酸镁、 胶态二氧化硅和交联羧甲基纤维素钠， 混合均勾后装入硬胶囊。 实施例 28 双嘧达莫片 （25mg/片）配方及制备方法 药物 双嘧达莫 25 ( 10.3% ， 无预处理） 甘露醇 80、 微晶纤维素 120、 羧甲淀粉钠 5、
辅料
聚维酮 -K30 3、 硬脂酸镁 0.6、 胶态二氧化硅 0.6
溶剂 75%乙醇水溶液 150 ( 62.1%)
酸化剂 枸橼酸一水合物 7.5 (与双嘧达莫的摩尔比值： 0.72)
将双嘧达莫与枸橼酸一水合物混合， 加入 75%乙醇水溶液后混合搅拌溶 制备 解， 边搅拌边加入聚维酮 Κ30并溶解， 配制成含药酸性液作为制粒液， 将甘 工艺 露醇和微晶纤维素置流化喷雾制粒机中， 进行流化喷雾制粒， 制得的颗粒整 粒后， 加入羧甲淀粉钠、 硬脂酸镁和胶态二氧化硅后混合均勾后压片。 实施例 29 双嘧达莫片 （25mg/片）配方及制备方法 药物 双嘧达莫 25 ( 14.5%, 无预处理）
乳糖 60、 微晶纤维素 80、 交联聚乙烯吡咯烷酮 3、
辅料
聚维酮 -Κ30 3、 胶态二氧化硅 0.3、 硬脂酸镁 0.6
溶剂 75%乙醇水溶液 120 (77.7%)
酸化剂 10%盐酸水溶液 13.5 (与双嘧达莫的摩尔比值： 0.75 )
将双嘧达莫与 75%乙醇水溶液混合， 加入 10%盐酸水溶液后混合搅拌溶 制备 解， 边搅拌边加入聚维酮 Κ30， 配制成含药酸性液作为制粒液， 将乳糖、 微 工艺 晶纤维素置流化喷雾制粒机中， 进行流化喷雾制粒， 制得的颗粒整粒后， 加 入交联聚乙烯吡咯烷酮、 硬脂酸镁和胶态二氧化硅后混合均勾后压片。 实施例 30 双嘧达莫片 （25mg/片）配方及制备方法 药物 双嘧达莫 25 ( 14.5%, 无预处理）
乳糖 60、 微晶纤维素 80、 交联聚乙烯吡咯烷酮 3、
辅料
聚维酮 -Κ30 3、 胶态二氧化硅 0.3、 硬脂酸镁 0.6
溶剂 80%乙醇水溶液 120 (77.7%)
酸化剂 枸橼酸一水合物 11.45 (与双嘧达莫的摩尔比值： 1.1 )
将双嘧达莫与与枸橼酸一水合物混合， 加入 80%乙醇水溶液后混合搅拌 制备 溶解， 边搅拌边加入聚维酮 Κ30， 配制成含药酸性液作为制粒液， 将乳糖、 工艺 微晶纤维素置流化喷雾制粒机中， 进行流化喷雾制粒， 制得的颗粒整粒后， 加入交联聚乙烯吡咯烷酮、 硬脂酸镁和胶态二氧化硅后混合均勾后压片。 实施例 31 阿立哌唑片 （10毫克 /片）配方及制备方法 药物 阿立哌唑 10 ( 8.1%, 无预处理） 乳糖 60、 微晶纤维素 40、 羧甲淀粉钠 6、 聚乙二醇 6000 2、 辅料
硬脂酸镁 0.6、 胶态二氧化硅 0.6 溶剂 60%乙醇水溶液 30 (24.2%) 酸化剂 枸橼酸一水合物 5 (与阿立哌唑的摩尔比值： 1.07) 将阿立哌唑、 枸橼酸和聚乙二醇 6000溶解于 60%乙醇水溶液中， 配制 制备 成含药酸性液， 将乳糖、 微晶纤维素、 70%量的羧甲淀粉钠混合均勾， 加入 工艺 含药酸性液进行搅拌制粒， 湿颗粒干燥后整粒， 加入硬脂酸镁、胶态二氧化 硅和剩余 30%量羧甲基淀粉钠混合均勾后压片。
实施例 32 阿立哌唑胶囊（10mg/粒））配方及制备方法
取实施例 31的干燥颗粒过 30 目筛， 加入硬脂酸镁、 胶
淀粉钠， 混合均勾装入硬胶囊内。
实施例 33 阿立哌唑片 （5毫克 /片）配方及制备方法 药物 阿立哌唑 5 (4.3%, 无预处理） 辅料 乳糖 70、 微晶纤维素 30、 羧甲淀粉钠 6、 聚维酮 K30 2、 硬脂酸镁 0.9 溶剂 乙醇 20 ( 17.3%) 酸化剂 枸橼酸一水合物 1.7 (与阿立哌唑的摩尔比值： 0.73 ) 将阿立哌唑、 枸橼酸加入乙醇， 边搅拌边加入聚维酮 K30， 配制成含 药酸性液（用 50°C水浴温热配制）， 将乳糖、 微晶纤维素、 70%量的羧甲淀 制备工艺
粉钠混合均勾， 加入含药酸性液制成软材， 挤压制粒， 湿颗粒干燥后整粒， 加入硬脂酸镁和剩余 30%量羧甲淀粉钠混合均勾后压片。 实施例 34阿立哌唑片 （5毫克 /片）配方及制备方法
Figure imgf000025_0001
实施例 35 阿立哌唑片 （10毫克 /片）配方及制备方法
Figure imgf000025_0002
实施例 36 阿立哌唑片 （5mg/片）配方及制备方法 药物 阿立哌唑 5 (4.4%, 无预处理）
辅料 乳糖 60、 微晶纤维素 40、 交联聚乙烯吡咯烷酮 6、 硬脂酸镁 0.6 溶剂 50%乙醇水溶液 85 ( 75.1%)
酸化剂 DL-苹果酸 1.64 (与阿立哌唑摩尔比值: 1.10)
将阿立哌唑、 DL-苹果酸溶解于 50%乙醇水溶液中， 水浴加热至 40 制备 °C左右， 配制成含药酸性液， 将甘露醇和微晶纤维素混合均勾置于多功能 工艺 流化喷雾制粒机中， 用蠕动泵将含药酸性液喷于上述混合辅料上制粒， 在 制得的颗粒中加入硬脂酸镁和交联聚乙烯吡咯烷酮， 混合均勾后压片。 实施例 37 阿立哌唑片 （5mg/片）配方及制备方法 药物 阿立哌唑 5 ( 4.5%, 无预处理）
乳糖 70、 微晶纤维素 30、 交联聚乙烯吡咯烷酮 6、
辅料
硬脂酸镁 0.6、 胶态二氧化硅 0.3
溶剂 95%乙醇水溶液 15 ( 22.3% ) 酸化剂 20%DL-乳酸 10 (与阿立哌唑摩尔比值： 1.99 )
将阿立哌唑置于 95%乙醇水溶液中， 加入 20%DL-乳酸水溶液， 搅拌溶 制备 解， 配制成含药酸性液， 将 20%乳糖和微晶纤维素混合均勾， 加入含药酸性 工艺 液进行搅拌制粒， 湿颗粒干燥后整粒， 加入硬脂酸镁、 胶态二氧化硅和交联 聚乙烯吡咯烷酮混合均勾后压片。 实施例 38 阿立哌唑片 （10mg/片）配方及制备方法 药物 阿立哌唑 10 ( 7.2%, 无预处理）
辅料 乳糖 80、 微晶纤维素 40、 羧甲淀粉钠 6、 硬脂酸镁 0.6
溶剂 50%乙醇水溶液 30 ( 21.5% ) 酸化剂 DL-苹果酸 2.4 (与阿立哌唑摩尔比值： 0.80 )
将阿立哌唑和 DL-苹果酸置 50%乙醇水溶液中，水浴加热至 50°C左右， 制备 搅拌溶解， 配制成含药酸性液， 将乳糖、 微晶纤维素和 70%量的羧甲淀粉钠 工艺 混合均勾， 并加入上述含药酸性液进行搅拌制粒， 湿颗粒干燥后整粒， 加入 硬脂酸镁和剩余 30%量羧甲淀粉钠混合均勾后压片。 效果实施例 1 溶出度比较试验
1)对比实施例 1和实施例 1和 2的右旋佐匹克隆片的溶出度比较
溶出度试验方法： 取样品， 照溶出度测定法 （中国药典 2005年版二部附录 X C 第 三法）， 以水 200ml为溶剂， 转速为每分钟 50转， 依法操作， 并配制对照溶液。 按紫外- 可见分光光度法（中国药典 2005年版二部附录 IV A)， 在 304nm的波长处分别测定吸光 度， 计算出每片的溶出量。 溶出度 （％)
样品
10分 20分 30分 40分 对比 1 45.7 67.9 89.1 94.6
1 63.5 90.2 99.2 100.5
2 61.7 88.4 99.1 99.8
2)对比实施例 2和实施例 3和 4的佐匹克隆片的溶出度比较
溶出度试验方法： 取样品， 照溶出度测定法 （中国药典 2005年版二部附录 X C 第 三法）， 以水 200ml为溶剂， 转速为每分钟 50转， 依法操作， 并配制对照溶液。 按紫外- 可见分光光度法（中国药典 2005年版二部附录 IV A)， 在 304nm的波长处分别测定吸光 度， 计算出每片的溶出量。
Figure imgf000027_0001
3)对比实施例 3和实施例 5~7的利培酮片的溶出度比较
溶出度测试方法： 取样品， 照溶出度测定法 （中国药典 2005年版二部附录 X C 第 二法）， 以水 200ml为溶剂， 转速为每分钟 50转， 依法操作， 在 15、 30、 45分钟分别取 溶液 5ml， 补液 5ml， 将样品滤过， 弃去初滤液， 取续滤液作为样品溶液， 并配制对照溶 液。 照高效液相色谱法 （中国药典 2005年版二部附录 V D)， 用十八烷基硅烷键合硅胶 为填充剂， 分别测定， 计算出每片的溶出量。
溶出度 （％)
样品
15分 30分 45分
对比 3 50.2 75.1 96.5
5 75.9 96.9 98.7
6 80.3 97.5 99.5
7 70.5 89.3 97.0 4)对比实施例 4和实施例 8的双嘧达莫片的溶出度比较
溶出度的测定方法：取样品， 照溶出度测定法（中国药典 2005年版二部附录 X C 第 一法）， 以 pH4.0的醋酸盐缓冲液 （0.05mol/L醋酸 -0.05mol/L醋酸钠 =16.4: 3.6) 900ml 为溶剂， 转速为每分钟 50转， 依法操作， 按紫外-可见分光光度法 （中国药典 2005年版 二部附录 IV A)， 在 283nm的波长处分别测定吸光度， 计算出每片的溶出量。
Figure imgf000028_0001
5)对比实施例 5和实施例 9~11的阿立哌唑片的溶出度比较
溶出度试验方法： 取样品， 照溶出度测定法 （中国药典 2005年版二部附录 X C 第 二法）， 以 pH4.0的醋酸盐缓冲液 （0.05mol/L醋酸 -0.05mol/L醋酸钠 =16.4: 3.6) 500ml 为溶剂， 转速为每分钟 50转， 依法操作， 分别在 5、 10、 20、 30、 45分钟取溶液 5ml， 补入 5ml溶出介质至溶出杯中， 将样品滤过， 取续滤液作为样品溶液， 并配制对照溶液。 照高效液相色谱法（中国药典 2005年版二部附录 V D)分别测定， 用十八烷基硅烷键合 硅胶为填充剂； 以甲醇 -0.1%三乙胺溶液 （90: 10) 为流动相； 检测波长为 255 nm。 计算 出每片的溶出量。
溶出度 （％)
样品
5分 10分 20分 30分 45分 对比 5 25.6 56.1 84.1 94.4 97.3
9 33.1 63.9 90.1 95.7 98.0
10 32.9 64.3 88.7 95.1 98.7
11 42.5 70.1 92.0 99.6 99.2 效果实施例 2 稳定性加速试验
将试验样品分别置高密度聚乙烯塑料瓶中， 密封， 放入加速考察箱中， 于温度 40°C ±2°C， 相对湿度 75%±5%条件进行 3个月的加速试验后， 进行相关项目的稳定性测定。
1 ) 对比实施例 1和实施例 1的右旋佐匹克隆片的稳定性比较
含量测定方法： 取本品适量 （相当于右旋佐匹克隆 3mg)， 置 250ml 量瓶中， 加 0.02mol/L盐酸适量， 摇勾， 滤过， 取续滤液作为供试品溶液； 另取右旋佐匹克隆对照品 适量， 用 0.02mol/L盐酸制成每 lml中含 12μ§的溶液， 作为对照溶液。照紫外-可见分光 光度法（中国药典 2005年版二部附录 IV Α)， 在 304nm的波长处分别测定吸光度， 计算 溶出度试验方法同效果实施例 1中 1 )。
有关物质测定方法： 照高效液相色谱法 （中国药典 2005年版二部附录 V D) 测定， 用十八烷基硅烷键合硅胶为填充剂， 供试品溶液的色谱图与对照溶液色谱图按照主成分 自身对照法进行计算。
Figure imgf000029_0001
2) 对比实施例 2和实施例 3的佐匹克隆片的稳定性比较
含量测定方法： 取本品适量（相当于佐匹克隆 3mg)， 置 250ml量瓶中， 加 0.02mol/L 盐酸适量，摇勾，滤过，取续滤液作为供试品溶液；另取佐匹克隆对照品适量，用 0.02mol/L 盐酸制成每 1ml中含 12μ§的溶液， 作为对照溶液。 照紫外-可见分光光度法 （中国药典 2005年版二部附录 IV Α)， 在 304nm的波长处分别测定吸光度， 计算含量。
溶出度试验方法同效果实施例 1中 2)。
有关物质测定方法： 照高效液相色谱法 （中国药典 2005年版二部附录 V D) 测定， 用十八烷基硅烷键合硅胶为填充剂， 供试品溶液的色谱图与对照溶液色谱图按照主成分 自身对照法进行计算。 性状 含量 (%) 30分钟溶出度（％) 有关物质 （％) 样品
加速前 加速后 加速前 加速后 加速前 加速后 加速前 加速后 对比 2 白色片 白色片 100.1 99.8 87.7 84.9 0.11 0.57
3 白色片 白色片 99.5 99.4 99.5 99.4 0.10 0.55
3) 对比实施例 3和实施例 5的利培酮片的稳定性比较
含量和有关物质的测定方法： 取样品适量， 用流动相超声振摇使溶解， 制成每 ml 中含利培酮适量的溶液， 作为供试品溶液， 并配制对照溶液。 照高效液相色谱法 （中国 药典 2005年版二部附录 V D)， 用十八烷基硅烷键合硅胶为填充剂， 分别测定。 含量的 测定按照外标法， 有关物质的测定按照主成分自身对照法进行计算。
溶出度试验方法同效果实施例 1中 3 )。
Figure imgf000030_0001
4) 对比实施例 5和实施例 9和 11的阿立哌唑片的稳定性比较
含量和有关物质的测定方法： 取样品适量， 用流动相超声振摇使溶解， 制成每 ml 中含阿立哌唑适量的溶液， 作为供试品溶液， 并配制对照溶液。 照高效液相色谱法 （中 国药典 2005年版二部附录 V D)， 用十八烷基硅烷键合硅胶为填充剂， 分别测定。 含量 的测定按照外标法， 有关物质的测定按照主成分自身对照法进行计算。 溶出度试验方法 同效果实施例 1中 5 )。 性状 含量 (%) 45分钟溶出度（％) 有关物质 （％) 样品
加速前 加速后 加速前 加速后 加速前 加速后 加速前 加速后 对比 5 白色片 白色片 99.2 99.6 97.3 94.4 0.16 0.20
9 白色片 白色片 99.5 99.4 98.0 97.5 0.18 0.22
11 白色片 白色片 100.2 100.0 99.2 98.0 0.14 0.24 效果实施例 3 含量均勾度实验
照中国药典 2005年版附录 XE 含量均勾度检查法， 测定每片的含量（含量测定方法
Figure imgf000031_0001

Claims

权利要求
1、 一种固体制剂的制备方法， 其特征在于其包括如下步骤： 将水不溶性和 /或水难 溶性碱性药物活性成分溶于含酸化剂的酸性溶液中， 制得含药酸性液， 之后， 将含药酸 性液和辅料均勾的混合， 进行湿法制粒。
2、 如权利要求 1 所述的方法， 其特征在于： 所述的水不溶性和 /或水难溶性碱性药 物活性成分为在固体制剂中含量为 20%以下， 较佳的为 5%以下， 更佳的为 1%以下的水 不溶性和 /或水难溶性碱性药物。
3、 如权利要求 1 所述的方法， 其特征在于： 所述的水不溶性和 /或水难溶性碱性药 物活性成分为阿立哌唑、 右旋佐匹克隆、 地西泮、 艾司唑仑、 阿普唑仑、 佐匹克隆、 利 醅酮、 阿戈美拉汀、 伊潘立酮、 帕潘立酮、 奋乃静、 狄戈辛、 氟哌啶醇、 双嘧达莫、 奥 氮平、 米非司酮、 卡比马唑、 甲氧氯普胺、 米诺地尔或利血平。
4、 如权利要求 1~3任一项所述的方法， 其特征在于： 所述的酸化剂为无机强酸、 无机中强酸和有机弱酸中的一种或多种，
较佳的选自盐酸、 枸橼酸、 酒石酸、 苹果酸、 氢溴酸、 富马酸、 琥珀酸、 马来酸、 乳酸、 醋酸、 硫酸、 硝酸和磷酸中的一种或多种，
更佳的为盐酸、 枸橼酸、 酒石酸、 苹果酸、 乳酸或醋酸。
5、 如权利要求 1所述的方法， 其特征在于：
所述的水不溶性和 /或水难溶性碱性药物活性成分为右旋佐匹克隆时，所述的酸化剂 为枸橼酸、 酒石酸、 苹果酸或盐酸；
所述的水不溶性和 /或水难溶性碱性药物活性成分为佐匹克隆时，所述的酸化剂为盐 酸、 苹果酸、 酒石酸或枸橼酸；
所述的水不溶性和 /或水难溶性碱性药物活性成分为利醅酮时， 所述的酸化剂为盐 酸、 枸橼酸或酒石酸；
所述的水不溶性和 /或水难溶性碱性药物活性成分为双嘧达莫时，所述的酸化剂为盐 酸或枸橼酸；
所述的水不溶性和 /或水难溶性碱性药物活性成分为阿立哌唑时，所述的酸化剂为盐 酸、 枸橼酸、 苹果酸或乳酸。
6、 如权利要求 1~5任一项所述的方法， 其特征在于： 所述的酸化剂的用量为， 能 使水不溶性和 /或水难溶性碱性药物活性成分完全溶解的最小量的 1~1.2 倍， 更佳的为 1-1.05倍。
7、 如权利要求 1~5任一项所述的方法， 其特征在于： 所述的酸化剂与水不溶性和 / 或水难溶性碱性药物活性成分的摩尔比值为 0.2~2.5， 更佳的为 0.3~1.5。
8、 如权利要求 1所述的方法， 其特征在于：
所述的水不溶性和 /或水难溶性碱性药物活性成分为右旋佐匹克隆时，所述的酸化剂 为右旋佐匹克隆摩尔量 0.8~1.1倍的枸橼酸；
所述的水不溶性和 /或水难溶性碱性药物活性成分为佐匹克隆时，所述的酸化剂为佐 匹克隆摩尔量 0.95~1.1倍的盐酸或酒石酸；
所述的水不溶性和 /或水难溶性碱性药物活性成分为利醅酮时，所述的酸化剂为利醅 酮摩尔量 0.8~2.1倍的盐酸，或利醅酮摩尔量 0.3~1.1倍的枸橼酸，或利醅酮摩尔量 0.25~1.1 倍的酒石酸；
当水不溶性和 /或水难溶性碱性药物活性成分为双嘧达莫时，所述的酸化剂为双嘧达 莫摩尔量 0.7~1.2倍的盐酸， 或双嘧达莫摩尔量 0.7~1.1倍的枸橼酸；
所述的水不溶性和 /或水难溶性碱性药物活性成分为阿立哌唑时，所述的酸化剂为阿 立哌唑摩尔量 0.9~1.2倍的盐酸， 或阿立哌唑摩尔量 0.8~1.3倍的枸橼酸， 或阿立哌唑摩 尔量 0.8~1.1倍的苹果酸。
9、 如权利要求 1~8任一项所述的方法， 其特征在于： 所述的含酸化剂的酸性溶液 中的溶剂为水、 水和有机溶剂的混合液、 或者有机溶剂， 且酸化剂中离子在该溶剂中可 解离； 所述的有机溶剂为对水不溶性和 /或水难溶性碱性药物活性成分的溶解性优于水的 药剂领域可接受的溶剂；
所述的有机溶剂较佳的为乙醇、 丙二醇、 丙三醇、 丙酮、 异丙醇和叔丁醇中的一种 或多种， 更佳的为乙醇。
10、 如权利要求 1~9任一项所述的方法， 其特征在于： 所述的酸性溶液中溶剂的用 量为湿法制粒干物料的质量百分比 5~100%， 更佳的为 10~50%。
11、 如权利要求 ι~ιο 任一项所述的方法， 其特征在于： 在将水不溶性和 /或水难溶 性碱性药物活性成分溶于含酸化剂的酸性溶液中的同时和 /或之后， 还加入表面活性剂、 增溶剂和固体分散体的水溶性载体中的一种或多种， 然后将所得含药酸性液进行后续步 骤， 即与辅料均勾混合， 进行湿法制粒；
所述的表面活性剂、 增溶剂和固体分散体的水溶性载体中的一种或多种较佳的为聚 维酮、 聚乙二醇 400-8000、 十二烷基硫酸钠、 泊洛沙姆、 聚氧乙烯蓖麻油、 吐温 -80、 硬 脂酸聚烃氧 40酯、 羟丙甲纤维素、 甲基纤维素、 羟丙纤维素、 乳糖、 甘露醇、 蔗糖、 β- 环糊精和麦芽糖醇中的一种或多种；
所述的表面活性剂和 /或增溶剂的加入量较佳的为水不溶性和 /或水难溶性碱性药物 活性成分质量的 0.05~3倍；
所述的固体分散体的水溶性载体的加入量较佳的为水不溶性和 /或水难溶性碱性药 物活性成分质量的 1~20倍。
12、如权利要求 1~11任一项所述的方法，其特征在于：在制备所述的含药酸性液时， 按照下述操作进行溶液配制： 当以水为溶剂时， 升温至 40~80°C ; 当以水和有机溶剂的 混合溶液为溶剂时， 升温至 40~70°C， 更佳的升温至 50~60°C ; 当以乙醇为溶剂时， 升高 温度至 30~50°C。
13、 如权利要求 1~12任一项所述的方法， 其特征在于： 所述的湿法制粒为挤压制 粒、 搅拌制粒、 流化喷雾制粒或离心喷雾制粒； 所述的挤压制粒为摇摆机挤压制粒、 螺 旋挤压制粒或旋转挤压制粒。
14、 如权利要求 1~13任一项所述的方法， 其特征在于： 将如权利要求 1~13任一项 所述的方法制得的固体颗粒， 经进一步的常规步骤， 制得片剂或胶囊剂。
15、 如权利要求 1~14任一项所述的方法制得的固体制剂。
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