WO2011079608A1 - 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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WO2011079608A1
WO2011079608A1 PCT/CN2010/074703 CN2010074703W WO2011079608A1 WO 2011079608 A1 WO2011079608 A1 WO 2011079608A1 CN 2010074703 W CN2010074703 W CN 2010074703W WO 2011079608 A1 WO2011079608 A1 WO 2011079608A1
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acid
water
agent
insoluble
alkalizing agent
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PCT/CN2010/074703
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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 WO2011079608A1 publication Critical patent/WO2011079608A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

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 (such as the conventional universal pulverizer) widely used at present, the average particle size generally reaches about 100 ⁇ m.
  • 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, is it possible to ensure a better content? For another example, stability is an important focus of the quality of solid preparations, including in solid preparations. During the storage period, whether the chemical stability of the active ingredient of the drug, the content of the relevant substance (ie, impurities), the stability of the solid preparation property, and the dissolution stability are 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 solubility is not ideal, and the water-insoluble or poorly water-soluble alkaline drug provides a simpler operation, less pollution, no aforementioned safety hazards, and ensures excellent dissolution of the prepared solid preparation.
  • the preparation method of the characteristics, stability and content, and the obtained solid preparation are examples of the characteristics, stability and content, and the obtained solid preparation.
  • the present inventors have taken a different approach, uniquely using an acidic solution to dissolve water-insoluble and/or poorly water-soluble alkaline drugs, and then reducing acidity during the preparation process, and returning the drug to a solid state, thereby avoiding mechanical pulverization treatment.
  • the inventors have also unexpectedly discovered 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 thereafter, an alkalizing agent, an auxiliary agent, and a The medicinal acid-containing acidic liquid is mixed and subjected to wet granulation; wherein the basifying agent is a reagent for lowering the acidity of the mixture of the alkalizing agent and the drug-containing acidic liquid with respect to the acidity of the drug-containing acidic liquid.
  • 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 preferably has a high activity and a low content in a solid preparation (generally 20% or less, preferably 5% or less, more preferably 1% or less, and a percentage by mass) of a water-insoluble or poorly water-soluble base. Sex drugs.
  • the present invention is preferably, but not limited to, dextrozopiclone, diazepam, estazolam, alprazolam, zopiclone, aripiprazole, risperidone, mifepristone, and perphenazine. Jing, Digoxin, Agomelatine, Iloperidone, Paliperidone, Olanzapine, Haloperidol, Dipyridamole, Carbimaazole, Metoclopramide, Minoxidil Or blood level.
  • the water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredient accounts for the quality of the wet granulated dry material during the preparation process. percentage.
  • Water-insoluble and/or poorly water-soluble alkaline drugs as needed
  • other pharmaceutically active ingredients may be added to prepare a compound solid preparation such as a combination solid preparation of olanzapine with fluoxetine hydrochloride, mifepristone and anordrin.
  • the acidifying agent means an acidic reagent which can completely dissolve the water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredient in an acidic solution containing an acidifying agent.
  • the acidulant should be a pharmaceutically acceptable agent that is compatible with water insoluble and/or poorly water soluble basic pharmaceutically active ingredients.
  • 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, tartaric acid, malic acid, fumaric acid, succinic acid, maleic acid, lactic acid, acetic acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, more preferably It is hydrochloric acid, citric acid, tartaric acid, malic acid, lactic acid, acetic acid or phosphoric acid. More specifically, the present invention particularly preferably has the following acidifying agent:
  • the acidifying agent is hydrochloric acid, citric acid, malic acid or tartaric acid, and most preferably hydrochloric acid.
  • the acidifying agent is citric acid, hydrochloric acid, malic acid or tartaric acid, and most preferably citric acid.
  • the acidifying agent is selected from the group consisting of hydrochloric acid, citric acid, malic acid or lactic acid, and most preferably hydrochloric acid or citric acid.
  • the acidifying agent is hydrochloric acid, decanoic acid or tartaric acid, and most preferably hydrochloric acid or citric acid.
  • the acidifying agent is hydrochloric acid or citric acid.
  • 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 1 to 1.5 times the minimum amount, and most preferably 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 poorly water-soluble basic drug activity in the acidifying agent.
  • the number of hydrogen ions combined with the basic center of the component and the preparation conditions (such as temperature) of the acid-containing solution 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 acidifying agent that can be dissolved by a certain acid-insoluble and/or water-insoluble basic pharmaceutically active ingredient in the same solvent and medicated acidic solution. The minimum amount can be determined by a simple conventional method: under the conditions of the same solvent and the acidic solution containing the drug, the amount of the acidifying agent is gradually increased to dissolve the certain amount. The water-insoluble and/or water-insoluble basic pharmaceutically active ingredient, when completely dissolved, is the minimum amount.
  • the present inventors have found out through a large number of experiments that, in particular, the molar ratio of the acidifying agent to the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient is generally from 0.1 to 2.5, and most preferably from 0.5 to 1.5, and the present invention is particularly preferred.
  • hydrochloric acid having a molar amount of 0.75 to 1.05 times, or a molar amount of 0.9 to 1.1 times of citric acid is particularly preferable.
  • citric acid having a molar amount of 0.9 to 1.1 times, or a salt acid having a molar amount of 0.95 to 1.2 times is particularly preferable.
  • hydrochloric acid having a molar amount of 0.9 to 1.2 times, or a molar amount of 0.8 to 1.3 times of citric acid, or malic acid having a molar amount of aripiprazole of 0.8 to 1.1 times is particularly preferable.
  • 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 0.8 to 2.1 times, or a decanoic acid having a molar amount of 0.3 to 1.1 times, or tartaric acid having a molar amount of 0.25 to 1.1 times is particularly preferable.
  • 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.
  • the solvent selected should be an ion dissociable solvent in the acidulant.
  • the acidifying agent is an inorganic substance, water or a mixture of water and an organic solvent may be selected; and when the acidifying agent is an organic substance, it may be a mixture of water, water and an organic solvent, or an organic solvent. If 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 granulation.
  • the organic solvent is selected according to the principle that its solubility in water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredients is superior to water in a solvent acceptable for the pharmaceutical field, preferably water-miscible.
  • An organic solvent such as a water-soluble alcohol solvent commonly used in the pharmaceutical field, such as ethanol, propylene glycol, glycerin, acetone, isopropanol and tert-butanol, preferably one or more of ethanol, acetone, propylene glycol and glycerol. Particularly preferred is ethanol.
  • the concentration of the organic solvent can be arbitrarily selected.
  • the amount of the solvent in the acidic solution is such that at least the drug is soluble, at least the minimum amount of granulating liquid required for wet granulation, generally 5 to 100% by mass of the dry granulated dry material, preferably 10 ⁇ 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 solubility of the surfactant, the solubilizing agent and the solid dispersion is added simultaneously with and/or after the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient is dissolved in the acidic solution containing the acidifying agent.
  • One or more of the carriers, and then the resulting drug-containing acidic liquid is subjected to a subsequent step, that is, mixed with the alkalizing agent and the auxiliary material Combined, wet granulation.
  • 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.
  • the present invention particularly preferably incorporates povidone, polyethylene glycol (preferably polyethylene glycol 400-8000), sodium lauryl sulfate, poloxamer, polyoxyethylene castor oil, Tween 80, stearic acid poly One or more of a hydrocarbon oxygen 40 ester, lactose, mannitol, sucrose, ⁇ -cyclodextrin, and maltitol.
  • the surfactant and/or solubilizer is preferably added in an amount of 0.05 to 5 times the mass of the water-insoluble and/or water-insoluble basic pharmaceutical active ingredient.
  • the water-soluble carrier of the solid dispersion is preferably added in an amount of from 1 to 10 times the mass of the water-insoluble and/or water-insoluble basic pharmaceutically active ingredient.
  • the solubility of the water-insoluble and/or poorly water-soluble basic pharmaceutically active ingredient in an acidic solution can be increased, and the amount of the solvent can be reduced to facilitate the operation of the subsequent granulation step.
  • one or more of the water-soluble carriers of the surfactant, the solubilizer and the solid dispersion are added as described above, in particular, the water-soluble carrier of the solid dispersion can make the dissolution characteristics of the obtained solid preparation. 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
  • water is used as the solvent, it is preferably raised to 40 to 80 °C.
  • the preferred increase is 40 to 70 °C.
  • ethanol is used as the solvent, 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 amount 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, starch, pregelatinized starch, mannitol, sucrose 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 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
  • An acid that is less acidic than a strongly acidic acidulant and that forms a buffer pair with it such as glycine and alanine.
  • the basifying agents should be pharmaceutically acceptable and compatible with water insoluble and/or poorly water soluble basic pharmaceutically active ingredients.
  • the present invention preferably comprises a combination of an acidifying agent and an alkalizing agent of the following type:
  • Type 1 The acidifying agent is an inorganic strong acid, and the alkalizing agent is an inorganic strong base such as hydrochloric acid and sodium hydroxide.
  • Type 2 The acidifying agent is an inorganic strong acid, and the alkalizing agent is an inorganic weak acid strong base salt such as hydrochloric acid and sodium carbonate, 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 decanoate, hydrochloric acid and sodium tartrate, hydrochloric acid and sodium acetate, or hydrochloric acid and sodium malate.
  • 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 buffer pairs of conjugated acid and base, such as tannic acid, tartaric acid a buffer pair consisting of one or more of malic acid, fumaric acid, succinic acid, maleic acid, lactic acid and acetic acid with its corresponding conjugate base, preferably one or more of the following buffer pairs: Citrate and sodium citrate, tartaric acid and sodium tartrate, malic acid and sodium malate, and acetic acid and sodium acetate.
  • 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 acidifying agent is an inorganic strong acid
  • the alkalizing agent is an inorganic strong base, an inorganic weak acid strong base salt or an organic weak acid strong base salt, such as phosphoric acid and sodium hydroxide, phosphoric acid and sodium carbonate, or phosphoric acid.
  • disodium hydrogen phosphate is an inorganic strong acid
  • the alkalizing agent is an inorganic strong base, an inorganic weak acid strong base salt or an organic weak acid strong base salt, such as phosphoric acid and sodium hydroxide, phosphoric acid and sodium carbonate, or phosphoric acid.
  • disodium hydrogen phosphate disodium hydrogen phosphate.
  • 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 acid solution.
  • the amount of the acidifying agent and the alkalizing agent satisfies the following relationship:
  • the value obtained by the formula 1 is from 0.01 to 1.5, more preferably from 0.3 to 1.2.
  • A is the total valence number of the alkalinizing agent molecule anion and the number of hydrogen ions in the alkalizing agent molecule;
  • B is the number of hydrogen ions in the acidifying agent molecule;
  • A/B is 1;
  • B is 1;
  • A is 1.
  • the invention is particularly preferred:
  • the formula 1 has a hydrochloric acid and sodium carbonate of 0.9 to 1.1, the formula 1 has a hydrochloric acid and sodium hydroxide of 0.9 to 1.05, or the citric acid and cerium of the formula 1 has a value of 0.4 to 1.2.
  • Sodium citrate Sodium citrate.
  • citric acid and sodium citrate having a value of formula 1 of 0.6 to 1.2, a hydrochloric acid and sodium carbonate having a value of 0.1 to 1 or a hydrochloric acid and a hydroxide having a value of 0.1 to 1 are particularly preferable. sodium.
  • hydrochloric acid and sodium hydroxide having a value of 0.01 to 1.1, or sodium citrate and sodium citrate of 0.1 to 1.3, or hydrochloric acid and sodium carbonate having a value of 0.2 to 1.0 are particularly preferable.
  • hydrochloric acid and sodium hydroxide having a value of 0.01 to 1.1, or sodium citrate and sodium citrate of 0.1 to 1.5, or hydrochloric acid and glycine having a value of 0.1 to 1.3 are particularly preferable.
  • sodium hydroxide and hydrochloric acid are most preferred in the present invention.
  • the solid preparation can still have better stability in the case where the amount of the alkalizing agent is small in the formulation, but does not affect the stability of the preparation. Under the appropriate increase of the amount of alkalizing agent to reduce the acidity, can reduce the migration of the active ingredient of the drug during the preparation process, and also facilitate the relaxation of the pH of the solid preparation.
  • the wet granulation can be carried out according to the conventional steps and conditions of various granulation methods in the art which are in the wet granulation category, such as extrusion granulation (such as swinging machine extrusion, spiral extrusion and rotary extrusion). Pressing, etc., stirring granulation, fluidized spray granulation, centrifugal spray granulation, and the like.
  • extrusion granulation such as swinging machine extrusion, spiral extrusion and rotary extrusion
  • Pressing, etc. stirring granulation, fluidized spray granulation, centrifugal spray granulation, and the like.
  • a larger amount of acidic solution is required to dissolve complete water-insoluble and/or poorly water-soluble alkaline drugs.
  • 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 specific operation mode of performing wet granulation by mixing the alkalizing agent, the auxiliary material and the drug-containing acidic liquid is selected from any one of the following modes: mode (1) The alkalizing agent or the alkalizing agent-containing solution and the auxiliary materials are mixed, and then mixed with the drug-containing acidic liquid to carry out extrusion granulation or stirring granulation; mode (2) the drug-containing acidic liquid and the alkalizing agent Or the alkalizing agent-containing solution is mixed to obtain a granulating liquid, and then the granulating liquid and the auxiliary material are subjected to extrusion granulation, agitation granulation, fluidized spray granulation or centrifugal spray granulation, etc.; 3) The drug-containing acidic liquid and auxiliary materials are both The mixture of the hooks is mixed with the alkalizing agent-containing solution, and subjected to extrusion granulation or agitation granulation.
  • the alkalizing agent-containing solution refers to a solution obtained by dissolving an alkalizing agent with a small amount of solvent according to a routine operation in the art to facilitate the step of mixing and hooking;
  • the solvent may be water, organic solvent or water and organic a mixture of solvents.
  • the organic solvent is the same as described above.
  • 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 positive progress of the present invention is that 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 apply to industrial production.
  • the solid preparation of the present invention has excellent dissolution characteristics, high bioavailability, small individual difference, and also has better stability and content uniformity.
  • 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 drug 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.
  • Example 7 Formula of dextrozopiclone capsule (3mg/granule) and preparation method thereof
  • Example 6 The pellets before the tableting of Example 6 were passed through a 30 mesh sieve and placed in a hard capsule.
  • Example 22 Formulation and preparation method of aripiprazole tablet (5 mg/tablet)
  • Example 23 Aripiprazole tablet (5 mg / tablet) formula and preparation method
  • Example 24 Formulation and preparation method of aripiprazole tablet (5 mg/tablet)
  • Example 25 Formulation and preparation method of aripiprazole tablet (5 mg/tablet)
  • Example 26 Formulation and preparation method of aripiprazole tablet (5 mg/tablet)
  • Example 27 Aripiprazole tablet (5 mg / tablet) formula and preparation method
  • Example 28 Formulation and preparation method of aripiprazole tablet (10 mg/tablet)
  • Example 29 Aripiprazole tablet (5 mg / tablet) formula and preparation method
  • Example 30 Formulation and preparation method of aripiprazole tablet (5 mg/tablet)
  • Example 32 Formulation and preparation method of aripiprazole orally disintegrating tablet (5 mg/tablet) Drug aripiprazole 5 (3.1%, no pretreatment) mannitol 120, microcrystalline cellulose 25, cross-linked polyvinylpyrrolidone 10, sodium lauryl sulfate 0.3, excipients
  • a 60% amount of mannitol, aspartame, microcrystalline cellulose and a 0.2% sodium hydroxide aqueous solution were stirred to form a mixed powder.
  • the mixed powder and the medicated acidic liquid are stirred to form a soft material, extruded and granulated, and the wet granules are dried and granulated, and then colloidal silica, sodium stearate and crosslinked polyvinylpyrrolidone are added, and mixed. Both are hooked and pressed.
  • Example 33 Aripiprazole Orally Disintegrating Tablets (10 mg/tablet) Formulation and Preparation Method Aripiprazole 10 (4.4%, no pretreatment) Mannitol 140, microcrystalline cellulose 50, crosslinked polyvinylpyrrolidone 10 Excipients
  • Aripiprazole and citric acid monohydrate are dissolved in a 30% aqueous solution of ethanol, heated to 65 ° C in a water bath, stirred and dissolved to prepare a drug-containing acidic solution, mannitol, microcrystalline cellulose, Aspen
  • the balsamic process and sodium citrate are mixed and stirred, and the above solution is added to stir to form a soft material, which is extruded and granulated.
  • the wet granules are dried and then granulated. After adding magnesium stearate and cross-linked polyvinylpyrrolidone, the mixture is hooked. Tableting.
  • Example 34 Aripiprazole Capsule (5 mg / granule) formula and preparation method Drug aripiprazole 5 (4.2%, no pretreatment) Excipients lactose 76, microcrystalline cellulose 30, sodium carboxymethyl starch 6, magnesium stearate 0.9 Solvent 95% aqueous ethanol solution 20 (26.1%) Acidifier 5% hydrochloric acid Aqueous solution 11 (molar ratio to aripiprazole: 1.35) Alkaliner sodium carbonate 0.8 (formula 1 value: 1.00) Aripiprazole and 5% aqueous hydrochloric acid solution were added to a 95% aqueous solution of ethanol, stirred and dissolved, and prepared to contain The acidic solution of the medicine is prepared by mixing sodium carbonate, lactose, microcrystalline cellulose and 70% sodium carboxymethyl starch, adding the acidic liquid containing the medicine to stir the soft material, extruding and granulating, and drying the wet granules. The granule
  • Example 35 Formulation and preparation method of aripiprazole capsule (5 mg/granule) Drug aripiprazole 5 (4.2%, no pretreatment)
  • Excipient lactose 76 microcrystalline cellulose 30, sodium carboxymethyl starch 6, stearic acid
  • Magnesium 0.9 Solvent 95% ethanol aqueous solution 20 (26.3%)
  • Acidifier 5% hydrochloric acid aqueous solution 11 (molar ratio to aripiprazole: 1.35)
  • Alkaliner sodium carbonate 0.16 (Formula 1 value: 0.20)
  • Aripiprazole and 5 The aqueous solution of hydrochloric acid is added to a 95% aqueous solution of ethanol, stirred and dissolved, and prepared into a drug-containing acidic liquid, which is mixed with lactose, microcrystalline cellulose and 70% of sodium carboxymethyl starch, and then the process is dissolved in a small amount of water.
  • Sodium carbonate is mixed, stirred to make soft material,
  • Example 36 Formulation and preparation method of dextrozole fragment (2 mg/tablet) Drug dextrozopicl 2 (2.9%, no pretreatment)
  • Povidone K30 1, polyethylene glycol 6000 1 , magnesium stearate 0.3 Solvent Water 8, 95% aqueous ethanol solution 4 ( 17.6%)
  • Heart alkalizing agent L-sodium tartrate dihydrate 1 (formula 1 value: 0. 82)
  • 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.
  • Example 37 dextrozole fragment (lmg/tablet) formulation and preparation method
  • Lactose 40 microcrystalline cellulose 20, sodium carboxymethyl starch 2.5,
  • 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.
  • Example 38 Formulation and preparation method of dextrozole fragment (6 mg/tablet) Drug dextrozopicl 6 ( 10.2%, no pretreatment)
  • the dextrozopidine clone, povidone ⁇ 30, 5% aqueous hydrochloric acid and water are formulated into a drug-containing acidic preparation liquid, and a sodium carbonate solution (dissolved in a small amount of water) is added as a granulation liquid while stirring.
  • Lactose, microcrystalline process Cellulose in a fluidized spray granulator, fluidized spray granulation, granules after the addition of magnesium stearate and colloidal silica, mixed and hooked and pressed.
  • Process 6000 and the assorted titanium dioxide are formulated into a coating liquid, and the core is film-coated.
  • Lactose 340 microcrystalline cellulose 150, sodium carboxymethyl starch 7.5,
  • the medicinal acid solution was formulated by dextrozopiclone, povidone K30, tartaric acid, 95% aqueous ethanol solution and 50% water. Sodium carbonate is combined with 50% water to form a solution. Lactose, microcrystalline cellulose, preparation
  • the mixture While adding the acidic liquid containing the drug, the mixture is stirred to form a soft material, and the granules are squeezed and granulated. The wet granules are dried and then granulated, and magnesium stearate, colloidal silica and 1/3 amount of sodium carboxymethyl starch are added and mixed. sheet.
  • 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.
  • Example 40 dextrozole fragment (1 mg / tablet) formula and preparation method
  • Example 45 Formulation and preparation method of dextrozole fragment (1 mg/tablet)
  • Example 46 dextrozole fragment (2 mg / tablet) formula and preparation method
  • Povidone K30 polyethylene glycol 6000 1, magnesium stearate 0.3
  • Acidifier citric acid monohydrate 1.2 (molar ratio to zopiclone: 0.89)
  • Alkalizing agent disodium hydrogen phosphate dodecahydrate U (formula 1 value: 1.08)
  • the zoicone, the polyethylene glycol 6000, the povidone K30, the citric acid and the water are formulated into a drug-containing acidic liquid, the sucrose, the microcrystalline cellulose, the sodium carboxymethyl starch and the mixture are combined, and the preparation is carried out by adding the acidic liquid containing the drug.
  • the agitation granulation is continued, the wet granules are dried and then granulated, and the magnesium stearate is added and mixed, and then pressed.
  • 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 citric acid monohydrate 1.7 (molar ratio to zopiclone: 1.05)
  • Alkalizing agent sodium citrate dihydrate 0.8 (formula 1 value: 0.34)
  • the acid-containing solution is added for stirring and granulation.
  • the wet granules are dried and then granulated, and magnesium stearate and colloidal silica are added and mixed, and then pressed.
  • 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.
  • Example 50 Zopicone Tablets (2.5 mg/tablet) Formulation and Preparation Method
  • Example 57 Zopiclone Tablets (2.5 mg/tablet) Formulation and Preparation Method
  • Example 58 Zopiclone Tablets (2.5 mg/tablet) Formulation and Preparation Method
  • Example 60 risperidone tablets (1 mg / tablet) formula and preparation method
  • Example 64 risperidone tablets (1 mg / tablet) formula and preparation method
  • Example 66 risperidone tablets (2 mg / tablet) formula and preparation method
  • Example 67 risperidone tablets (1 mg / tablet) formula and preparation method
  • Example 68 risperidone tablets (1 mg / tablet) formula and preparation method
  • Example 72 Dipyridamole tablets (25 mg / tablet) formulation 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 570 ml, and the centrifugal pump speed is 1600 rpm.
  • Test method Take 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:
  • Test Purpose The particle size of aripiprazole in the aripiprazole particles of Comparative Examples 1 to 2 and Examples 1 to 2 was compared.
  • D 1Q , D 5Q and D 9Q are the corresponding particle sizes when the cumulative particle size distribution percentage reaches 10%, 50% and 90%, respectively.
  • the aripiprazole particles in the aripiprazole particles obtained in Examples 1 and 2 of the present invention have a smaller particle diameter than the comparative examples 1 and 2, and are advantageous for the dissolution of the pharmaceutically active ingredient.
  • 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
  • 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 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, 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.
  • 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 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 a proper amount of aripiprazole solution per ml
  • 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 2 (1).
  • 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 is measured at the wavelength of 304 nm, and the calculation is performed.
  • Determination of related substances According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix VD) determination, using octadecylsilane bonded silica as a filler; with acetonitrile -0.05mol / L ammonium sulfate solution (40:60 ) is the mobile phase; the detection wavelength is 304 nm, and the chromatogram of the test solution and the chromatogram of the control solution are calculated according to the main component self-control method.
  • Dissolution test method The same effect as in Example 2 (2).
  • 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.
  • Determination of related substances According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix V D) determination, using octadecylsilane bonded silica as a filler, the detection wavelength is 304nm.
  • the chromatogram of the test solution and the control solution chromatogram were calculated according to the principal component self-control method.
  • the dissolution test method was the same as in Test Example 2 (3).
  • Implementation traits 3 (%) 30 minutes dissolution (%) Related substances (%)
  • 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 Test Example 2 (4).
  • Determination of the content Take the appropriate amount of sample (equivalent to dipyridamole 50mg), placed in a 100ml volumetric flask, add 0.01mol / L hydrochloric acid solution, shake to dipyridamole, diluted with 0.01mol / L hydrochloric acid solution To the scale, shake the hook, filter, add O.Olmol / L hydrochloric acid solution to quantitatively dilute the solution containing dipyridamole lOug per ml, as the test solution by UV-visible spectrophotometry (Chinese Pharmacopoeia 2005 edition two Appendix IV A), absorbance is measured at a wavelength of 283 nm.
  • Determination of the relevant substances Take the appropriate amount of the sample, make a solution containing dipyridamole 1.0 mg per ml with methanol, as the test solution, and prepare a solution containing dipyridamole lOug per ml as a control solution. .
  • high performance liquid chromatography Choinese Pharmacopoeia 2005 edition two appendix VD
  • octadecylsilane bonded silica as a filler
  • the length was 288 nm, which was measured separately, and calculated according to the main component self-control method.

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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微米左右。 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性等不够理想的缺陷，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和 / 或水难溶性碱性药物， 之后在制备过程中降低酸性， 并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， 本发明人还意外的发现， 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， 将碱化剂、 辅料和所述的含药酸性液 均勾的混合， 进行湿法制粒； 其中， 所述的碱化剂为使碱化剂与含药酸性液的混合液的 酸性相对于含药酸性液的酸性降低的试剂。
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。 本发明优选活性较高、 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） 的水不溶性或水难溶性碱性药物。 更具体的， 本发明优选但不限于右旋 佐匹克隆、 地西泮、 艾司唑仑、 阿普唑仑、 佐匹克隆、 阿立哌唑、 利醅酮、 米非司酮、 奋乃静、 狄戈辛、 阿戈美拉汀、 伊潘立酮、 帕潘立酮、 奥氮平、 氟哌啶醇、 双嘧达莫、 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、 米非司酮与双炔失碳酯的复方固体制剂。
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完全溶 解于含酸化剂的酸性溶液中的酸性试剂。 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。 本发明中， 所述 的配伍是指可共存， 无不良影响。 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、 富马酸、 琥珀酸、 马来酸、 乳酸、 醋酸、 氢溴酸、 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、 醋酸或磷酸。 更具体的， 本发明特别优选下述酸化剂：
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， 所述的酸化剂为盐 酸、 枸橼酸、 苹果酸或酒石酸， 最佳的为盐酸。
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， 所述的酸化剂为枸橼 酸、 盐酸、 苹果酸或酒石酸， 最佳的为枸橼酸。
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， 所述的酸化剂为选自盐 酸、 枸橼酸、 苹果酸或乳酸， 最佳的为盐酸或枸橼酸。
当水不溶性和 /或水难溶性碱性药物活性成分为利培酮时， 所述的酸化剂为盐酸、 枸 橼酸或酒石酸， 最佳的为盐酸或枸橼酸。
当水不溶性和 /或水难溶性碱性药物活性成分为双嘧达莫时， 所述的酸化剂为盐酸或 枸橼酸。
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 1~1.5倍， 最佳的为 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、 酸化剂中可与水不溶性和 /或水难溶性碱性药物活性成分的碱性中心相结合的氢离子数、 以及含药酸性液配制条件 （如温度） 等有关。 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 尔比一般为 0.1~2.5， 大多为 0.5~1.5， 本发明特别优选下述用量的酸化剂：
对于右旋佐匹克隆， 特别优选其摩尔量 0.75~1.05倍的盐酸， 或其摩尔量 0.9~1.1倍 的枸橼酸。
对于佐匹克隆， 特别优选其摩尔量 0.9~1.1倍的枸橼酸， 或其摩尔量 0.95~1.2倍的盐 酸。
对于阿立哌唑， 特别优选其摩尔量 0.9~1.2倍的盐酸， 或其摩尔量 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。
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。
对于利培酮， 特别优选其摩尔量 0.8~2.1倍的盐酸， 或其摩尔量 0.3~1.1倍的枸橼酸， 或其摩尔量 0.25~1.1倍的酒石酸。
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。 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， 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、 丙二醇、 丙三醇、 丙酮、 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， 有机溶剂的浓度可任意选择。 所述的酸性溶 液中溶剂的用量以至少使得药物可溶解， 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， 即与碱化剂和辅料均勾混 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、 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 0.05~5 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 1~10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 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。 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。 所述的辅料的含量可按照本领域常规知识进行选 择。 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， 所述的碱化剂是指能使碱化剂与含药酸性液的混合液的酸性相对于含药 酸性液的酸性降低的试剂。 例如， 无机强碱 （如氢氧化钠）、 弱酸强碱盐 （如碳酸钠、 磷 酸氢二钠， 以及有机弱酸的共轭碱 （如枸橼酸钠、 酒石酸钠、 苹果酸钠和醋酸钠））， 或 酸性低于强酸性酸化剂， 且能与其形成缓冲对的酸（如甘氨酸和丙氨酸）。 根据本领域常 识， 所述的碱化剂都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。
较佳的， 本发明优选下述类型的酸化剂和碱化剂的组合：
类型 1 : 所述的酸化剂为无机强酸， 所述的碱化剂为无机强碱， 如盐酸和氢氧化钠。 类型 2: 所述的酸化剂为无机强酸， 所述的碱化剂为无机弱酸强碱盐， 如盐酸和碳 酸钠， 盐酸和磷酸氢二钠。
类型 3 : 所述的酸化剂为无机强酸， 所述的碱化剂为有机弱酸强碱盐， 如盐酸和枸 橼酸钠， 盐酸和酒石酸钠， 盐酸和醋酸钠， 或盐酸和苹果酸钠。
类型 4: 所述的酸化剂为有机弱酸， 所述的碱化剂为该有机弱酸的共轭碱， 酸化剂 和碱化剂组成互为共轭酸碱的缓冲对， 例如枸橼酸、 酒石酸、 苹果酸、 富马酸、 琥珀酸、 马来酸、 乳酸和醋酸中的一种或多种与其相应的共轭碱组成的缓冲对， 优选下述缓冲对 中的一种或多种： 枸橼酸和枸橼酸钠， 酒石酸和酒石酸钠， 苹果酸和苹果酸钠， 以及醋 酸和醋酸钠。
类型 5 : 所述的酸化剂为有机弱酸， 所述的碱化剂为无机强碱或无机弱酸强碱盐， 酸化剂和碱化剂形成缓冲对， 如枸橼酸和碳酸钠， 苹果酸和碳酸钠， 苹果酸和磷酸氢二 钠， 或枸橼酸和磷酸氢二钠。
类型 6: 所述的酸化剂为无机强酸， 所述的碱化剂为弱酸， 且能与其形成缓冲对的 酸， 例如， 盐酸和甘氨酸， 或盐酸和丙氨酸。
类型 7: 所述的酸化剂为无机中强酸， 所述的碱化剂为无机强碱、 无机弱酸强碱盐或 有机弱酸强碱盐， 如磷酸和氢氧化钠、 磷酸和碳酸钠， 或磷酸和磷酸氢二钠。
所述的碱化剂的量为至少能使碱化剂与含药酸性液的混合液的酸性相对于含药酸 性液的酸性降低的量。 较佳的， 酸化剂与碱化剂的用量满足下述关系： 式 1 所得值为 0.01-1.5 , 更佳的为 0.3~1.2。
(碱化剂摩尔数 X A) I (酸化剂摩尔数 X B ) 式 1
其中， 当酸化剂和碱化剂为类型 1、 2或 5时， A为碱化剂分子阴离子总价态数一碱化剂 分子中的氢离子数；
当酸化剂和碱化剂为类型 1、 2、 3或 6时， B为酸化剂分子中的氢离子数； 当酸化剂和碱化剂为类型 4时， A/B为 1 ;
当酸化剂和碱化剂为类型 5时， B为 1 ;
当酸化剂和碱化剂为类型 3或 6时， A为 1。
本发明特别优选：
对于右旋佐匹克隆，特别优选式 1值为 0.9~ 1.1 的盐酸和碳酸钠，式 1值为 0.9~1.05 的盐酸和氢氧化钠， 或式 1值为 0.4~ 1.2 的枸橼酸和枸橼酸钠。
对于佐匹克隆，特别优选式 1值为 0.6~1.2 的枸橼酸和枸橼酸钠，式 1值为 0.1~ 1 的 盐酸和碳酸钠， 或式 1值为 0.1~1的盐酸和氢氧化钠。
对于阿立哌唑， 特别优选式 1值为 0.01~1.1的盐酸和氢氧化钠， 或 0.1~1.3的枸橼 酸和枸橼酸钠， 或式 1值为 0.2~1.0的盐酸和碳酸钠。
对于利培酮， 特别优选式 1值为 0.01~1.1的盐酸和氢氧化钠， 或 0.1~1.5的枸橼酸和 枸橼酸钠， 或式 1值为 0.1~1.3的盐酸和甘氨酸。
对于双嘧达莫， 本发明最优选氢氧化钠与盐酸。
对于某些水不溶性和 /或水难溶性碱性药物活性成分， 在配方中碱化剂用量很少的情 况下， 固体制剂仍然可具有较佳的稳定性， 但在不影响制剂稳定性的前提下， 适当增加 碱化剂用量降低酸性， 能减少药物活性成分在制备过程中的迁移， 也利于缓和固体制剂 的酸碱度。
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各种制粒方法的常规 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。对于在固体制剂中剂量较大（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。
较佳的， 所述的将碱化剂、 辅料和所述的含药酸性液均勾的混合， 进行湿法制粒的 具体操作方式选自下述方式中的任一种： 方式（1 )将碱化剂或含碱化剂的溶液和辅料均 勾混合， 再与含药酸性液均勾混合， 进行挤压制粒或搅拌制粒； 方式 （2)将含药酸性液 与， 碱化剂或含碱化剂的溶液均勾的混合， 得制粒液， 之后再将该制粒液与辅料进行挤 压制粒、 搅拌制粒、 流化喷雾制粒或离心喷雾制粒等； 方式 （3 )将含药酸性液与辅料均 勾的混合， 之后再与含碱化剂的溶液均勾的混合， 进行挤压制粒或搅拌制粒。 所述的含 碱化剂的溶液是指， 按本领域常规操作， 用少量溶剂溶解碱化剂所得的溶液， 以方便进 行混勾步骤； 所述的溶剂可为水、 有机溶剂或水和有机溶剂的混合液。 所述的有机溶剂 同前述。
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： 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。 本发明的固体制剂具有优异的溶出特性， 生物利用度高， 个体差异小， 且还 具有较佳的稳定性和含量均勾度。
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 括酸化剂和碱化剂的水溶液中的水。
对比实施例 1~2和实施例 1~2 阿立哌唑颗粒剂配方及制备方法
Figure imgf000010_0001
对比实施例 3和实施例 3和 4 阿立哌唑片剂（5mg/片）配方及制备方法
Figure imgf000011_0001
对比实施例 4和 5 阿立哌唑口腔崩解片 （5mg/片）配方及制备方法
Figure imgf000012_0001
对比实施例 5与实施例 6 右旋佐匹克隆片 （3mg/片）配方及制备方法
Figure imgf000013_0001
实施例 7 右旋佐匹克隆胶囊 (3mg/粒）配方及制备方法
取实施例 6压片前的颗粒过 30目筛， 装入硬胶囊内。
实施例 8和 9 右旋佐匹克隆片配方及制备方法
Figure imgf000014_0001
实施例 10和 11 右旋佐匹克隆片配方及制备方法
Figure imgf000015_0001
对比实施例 6与实施例 12和 13 佐匹克隆片配方及制备方法
Figure imgf000016_0001
实施例 14和 15 佐匹克隆片 （2.5mg/片）配方及制备方法
Figure imgf000017_0001
实施例 16和 17 佐匹克隆片 （2.5mg/片）配方及制备方法
Figure imgf000018_0001
对比实施例 7和实施例 18 利培酮片剂（lmg/片）配方及制备方法
Figure imgf000019_0001
实施例 19和 20 利培酮片 ( lmg/片）配方及制备方法
Figure imgf000020_0001
对比实施例 8与实施例 21 双嘧达莫片 （25mg/片）配方及制备方法
Figure imgf000021_0001
实施例 22 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000022_0001
实施例 23 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000022_0002
实施例 24 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000023_0001
实施例 25 阿立哌唑片 （5毫克 /片）配方及制备方法
Figure imgf000023_0002
实施例 26 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000024_0001
实施例 27 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000024_0002
实施例 28 阿立哌唑片 （10mg/片）配方及制备方法
Figure imgf000025_0001
实施例 29 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000025_0002
实施例 30 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000026_0001
实施例 31 阿立哌唑片 （5mg/片）配方及制备方法
Figure imgf000026_0002
实施例 32 阿立哌唑口腔崩解片 （5毫克 /片）配方及制备方法 药物 阿立哌唑 5 ( 3.1%, 无预处理） 甘露醇 120、微晶纤维素 25、交联聚乙烯吡咯烷酮 10、十二烷基硫酸钠 0.3、 辅料
阿斯巴甜 0.8、 硬脂酸富马酸钠 1.2、 胶态二氧化硅 0.3 溶剂 95% 乙醇水溶液 18 ( 15.0%) 酸化剂 10%盐酸水溶液 4.1 (与阿立哌唑摩尔比值： 1.01 ) 碱化剂 0.2%氢氧化钠水溶液 2.3 (式 1值 0.01 ) 将阿立哌唑和和十二烷基硫酸钠分散 95%乙醇水溶液中，加入 10%盐酸 水溶液， 水浴加热至 65 °C左右， 搅拌溶解， 加入 40%量的甘露醇， 配制成 制备 含药酸性液。 将 60%量的甘露醇、 阿斯巴甜、 微晶纤维素与 0.2%氢氧化钠 工艺 水溶液搅拌均勾制成混合粉料。 将该混合粉料与含药酸性液搅拌制成软材， 挤压制粒， 湿颗粒干燥后整粒， 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。 实施例 33 阿立哌唑口腔崩解片 （10mg/片）配方及制备方法 药物 阿立哌唑 10 (4.4%, 无预处理） 甘露醇 140、 微晶纤维素 50、 交联聚乙烯吡咯烷酮 10、 辅料
阿斯巴甜 1、 硬脂酸镁 0.9 溶剂 30%乙醇水溶液 20 ( 8.9% ) 酸化剂 枸橼酸一水合物 4.7 (与阿立哌唑摩尔比值： 1.00) 碱化剂 枸橼酸钠二水合物 8.6 (式 1值 1.31 )
将阿立哌唑和枸橼酸一水合物溶于 30%乙醇水溶液中， 水浴加热至 65 制备 °C左右， 搅拌溶解， 配制成含药酸性液， 将甘露醇， 微晶纤维素、 阿斯巴甜 工艺 和枸橼酸钠搅拌混合均勾， 加入上述溶液进行搅拌制成软材， 挤压制粒， 湿 颗粒干燥后整粒， 加入硬脂酸镁和交联聚乙烯吡咯烷酮混合均勾后压片。
实施例 34 阿立哌唑胶囊（5mg/粒）配方及制备方法 药物 阿立哌唑 5 (4.2%, 无预处理） 辅料 乳糖 76、 微晶纤维素 30、 羧甲淀粉钠 6、 硬脂酸镁 0.9 溶剂 95%乙醇水溶液 20 (26.1%) 酸化剂 5%盐酸水溶液 11 (与阿立哌唑摩尔比值： 1.35 ) 碱化剂 碳酸钠 0.8 (式 1值： 1.00) 将阿立哌唑和 5%盐酸水溶液加入 95%乙醇水溶液中， 搅拌溶解， 配制 制备 成含药酸性液， 将碳酸钠、 乳糖、 微晶纤维素和 70%量的羧甲淀粉钠混合均 工艺 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 入硬脂酸镁和剩余 30%量羧甲淀粉钠混合均勾后装胶囊。
实施例 35 阿立哌唑胶囊（5mg/粒）配方及制备方法 药物 阿立哌唑 5 (4.2%, 无预处理） 辅料 乳糖 76、 微晶纤维素 30、 羧甲淀粉钠 6、 硬脂酸镁 0.9 溶剂 95%乙醇水溶液 20 (26.3%) 酸化剂 5%盐酸水溶液 11 (与阿立哌唑摩尔比值： 1.35 ) 碱化剂 碳酸钠 0.16 (式 1值： 0.20) 将阿立哌唑和 5%盐酸水溶液加入 95%乙醇水溶液中， 搅拌溶解， 配制 制备 成含药酸性液， 与乳糖、微晶纤维素和 70%量的羧甲淀粉钠混合均勾， 之后 工艺 再与溶于少量水的碳酸钠混合， 搅拌制成软材， 挤压制粒， 湿颗粒干燥后整 粒， 加入硬脂酸镁和剩余 30%量羧甲淀粉钠混合均勾后装胶囊。
实施例 36 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 (2.9%, 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 ( 17.6%)
片 酸化剂 L-酒石酸 0.8 (与右旋佐匹克隆摩尔比值： 1.04)
心 碱化剂 L-酒石酸钠二水合物 1 (式 1值： 0. 82)
将右旋佐匹克隆、聚乙二醇 6000、 聚维酮 K30、 酒石酸、 95%乙醇水 制备工 溶液和水配制成含药酸性液， 蔗糖、 微晶纤维素、 淀粉、 羧甲淀粉钠和酒 艺 石酸钠混合均勾， 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， 加入硬脂酸镁混合均勾后压片。
原料 薄膜包衣预混料 （胃溶欧巴代） 2.4、 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， 配成包 衣
工艺 衣液， 对片芯进行薄膜包衣。 实施例 37 右旋佐匹克隆片 (lmg/片）配方及制备方法
药物 右旋佐匹克隆 1 ( 1.5%， 无预处理）
乳糖 40、 微晶纤维素 20、 羧甲淀粉钠 2.5、
辅料
羟丙甲纤维素 0.5、 硬脂酸镁 0.3
溶剂 水 11 ( 16.6%)
片 酸化剂 枸橼酸一水合物 0.65 (与右旋佐匹克隆摩尔比值： 1.2) 心 碱化剂 枸橼酸钠二水合物 1.14 (式 1值： 1.25 )
将羟丙甲纤维素用 80°C热水分散后加水搅拌溶解，与右旋佐匹克隆、 制备 枸橼酸和余下的水配制成含药酸性液， 乳糖、 微晶纤维素、 2/3量的羧甲 工艺 淀粉钠和枸橼酸钠混合均勾， 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 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） 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 38 右旋佐匹克隆片 (6mg/片）配方及制备方法 药物 右旋佐匹克隆 6 ( 10.2%, 无预处理）
乳糖 30、 微晶纤维素 20、 聚维酮 K30 2、
辅料
硬脂酸镁 0.25、 胶态二氧化硅 0.15
溶剂 水 19 (49.8%)
片 酸化剂 5%盐酸水溶液 11 (与右旋佐匹克隆摩尔比值： 0.98 ) 心 碱化剂 碳酸钠 0.16 (式 1值： 0.2)
将右旋佐匹克隆、 聚维酮 Κ30、 5%盐酸水溶液和水配制成含药酸性 制备 液,边搅拌边加入碳酸钠溶液 （溶于少量水中）， 作为制粒液。 乳糖、 微晶 工艺 纤维素置流化喷雾制粒机中，进行流化喷雾制粒，颗粒整粒后加入硬脂酸 镁和胶态二氧化硅， 混合均勾后压片。
原料 羟丙甲纤维素 2、 聚乙二醇 6000 0.4、 二氧化钛 0.5、 水 17 包
制备 将羟丙甲纤维素用 80 °C热水分散后加水搅拌溶解， 加入聚乙二醇 衣
工艺 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 39 右旋佐匹克隆片 (lmg/片）配方及制备方法
药物 右旋佐匹克隆 1 ( 0.2%， 无预处理）
乳糖 340、 微晶纤维素 150、 羧甲淀粉钠 7.5、
辅料
聚维酮 K30 5、 硬脂酸镁 3、 胶态二氧化硅 1.5
酸化剂 5%盐酸水溶液 1.6 (与右旋佐匹克隆摩尔比值： 0.85 ) 碱化剂 碳酸钠 0.09 (式 1值： 0.77)
片
溶剂 水 90、 95%乙醇水溶液 20 (21.7%)
心
将右旋佐匹克隆、聚维酮 K30、 酒石酸、 95%乙醇水溶液和 50%量水 配制成含药酸性液。 碳酸钠与 50%量水配成溶液。 乳糖、 微晶纤维素、 制备工
2/3量的羧甲淀粉钠混合均勾， 加入碳酸钠溶液搅拌一段时间后， 边搅拌 艺
边加入含药酸性液继续搅拌制成软材， 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 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） 20、 水 85
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 40右旋佐匹克隆片 (lmg/片）配方及制备方法
Figure imgf000031_0001
实施例 42 右旋佐匹克隆片 (2mg/片）配方及制备方法
Figure imgf000032_0001
实施例 43 右旋佐匹克隆片 (2mg/片)
Figure imgf000032_0002
实施例 44 右旋佐匹克隆片 (2mg/片)
Figure imgf000033_0001
实施例 45 右旋佐匹克隆片 (lmg/片）配方及制备方法
Figure imgf000033_0002
实施例 46右旋佐匹克隆片 （2mg/片）配方及制备方法
Figure imgf000034_0001
实施 1列 48 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 ( 3.6%, 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 11 ( 15.9%)
酸化剂 枸橼酸一水合物 1.2 (与佐匹克隆摩尔比值： 0.89) 片
碱化剂 磷酸氢二钠十二水合物 U (式 1值： 1.08 )
心
将佐匹克隆、聚乙二醇 6000、聚维酮 K30、枸橼酸和水配制成含药 酸性液， 蔗糖、 微晶纤维素、 羧甲淀粉钠和混合均勾， 加入含药酸性液 制备
进行搅拌制粒， 边搅拌边加入磷酸氢二钠溶液（磷酸氢二钠溶于少量水 工艺
中）， 继续进行搅拌制粒， 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） 2.4、 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， 配成包 衣
工艺 衣液， 对片芯进行薄膜包衣。
实施例 49佐匹克隆片 (3毫克 /片）配方及制备方法
药物 佐匹克隆 3 (2.9%, 无预处理）
甘露醇 60、 微晶纤维素 30、 羟丙纤维素 5、 聚维酮 Κ30 1、 辅料
羟丙甲纤维素 0.33、 胶态二氧化硅 0.2、 硬脂酸镁 0.6 溶剂 水 22 (21.4%)
酸化剂 枸橼酸一水合物 1.7 (与佐匹克隆摩尔比值： 1.05 ) 片
碱化剂 枸橼酸钠二水合物 0.8 (式 1值： 0.34)
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、聚 维酮 K30、 枸橼酸和水配制成含药酸性液， 甘露醇、 微晶纤维素、 羟丙 制备
纤维素混合均勾， 加入枸橼酸钠溶液 （枸橼酸钠溶于少量水中） 搅拌， 工艺
再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） 4、 水 18
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 50佐匹克隆片 （2.5毫克 /片）配方及制备方法
Figure imgf000036_0001
实施例 52佐匹克隆片 （2.5毫克 /片）配方及制备方法
Figure imgf000037_0001
实施例 54 佐匹克隆片 （2.5毫克 /片）配方及制备方法
Figure imgf000038_0001
实施例 56 佐匹克隆片 （2.5毫克 /片）配方及制备方法
Figure imgf000039_0001
实施例 57 佐匹克隆片 （2.5毫克 /片）配方及制备方法
Figure imgf000039_0002
实施例 58 佐匹克隆片 （2.5毫克 /片）配方及制备方法
Figure imgf000040_0001
实施例 60利培酮片 （lmg/片）配方及制备方法
Figure imgf000041_0001
实施例 61 利培酮胶囊（2mg/粒）配方及制备方法
Figure imgf000041_0002
实施例 62利培酮片 （lmg/片）配方及制备方法
Figure imgf000042_0001
实施例 64利培酮片 （lmg/片）配方及制备方法
Figure imgf000043_0001
实施例 66利培酮片 （2mg/片）配方及制备方法
Figure imgf000044_0001
实施例 67利培酮片 （lmg/片）配方及制备方法
Figure imgf000044_0002
实施例 68利培酮片 （lmg/片）配方及制备方法
Figure imgf000045_0001
实施例 70 利培酮片 （lmg/片）配方及制备方法
Figure imgf000046_0001
实施例 72双嘧达莫片 （25mg/片）配方及制备方法
Figure imgf000047_0001
双嘧达莫片 （25mg/片）配方及制备方法
Figure imgf000047_0002
效果实施例 1 粒径比较试验
测试仪器: BT-9300S激光粒度分布仪； BT-800自动循环进样系统。
测试条件:循环进样系统中的介质为水，体积为 570ml左右，离心泵转速为 1600rpm。 测试方法： 取颗粒 2g， 加入循环进样系统， 使系统吸光度达到 15%左右， 开启超声 分散 3分钟， 连续 6次采样测试， 得到粒径平均值：
测试目的： 比较对比实施例 1~2和实施例 1~2的阿立哌唑颗粒中阿立哌唑的粒径。
Figure imgf000048_0001
注： D1Q、 D5Q和 D9Q分别是累计粒度分布百分数达到 10%、 50%和 90%时所对应的粒 径。
由上对比可见， 与对比实施例 1和 2相比， 本发明实施例 1和 2获得的阿立哌唑颗 粒中的阿立哌唑的粒径更小， 利于药物活性成分的溶出。 效果实施例 2 溶出度比较试验
( 1 )对比实施例 3和 4， 以及实施例 3~5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 255nm， 计算出 每片的溶出量。 溶出度 （％)
实施例
5分 10分 20分 30分 45分
对比 3 25.6 56.1 84.1 94.4 97.3
3 34.5 67.3 90.7 95.2 98.5
4 35.1 66.4 91.0 96.9 99.7 对比 4 27.7 35.0 40.5 45.0 50.4
5 46.7 60.2 78.0 86.0 93.7
(2) 对比实施例 5、 实施例 6~11的右旋佐匹克隆制剂的溶出度比较
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 imgf000049_0001
(3) 对比实施例 6、 实施例 12~17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。 溶出度 （％)
实施例
10分 20分 30分 40分 对比 6 40.1 64.6 89.3 94.9
12 60.6 91.4 98.5 99.7
13 64.0 90.2 100.2 100.6
14 71.3 93.1 100.6 100.5
15 70.9 93.6 99.8 99.6
16 64.7 90.2 100.3 100.1
17 73.6 94.1 99.8 99.7
(4) 对比实施例 7与实施例 18~20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。
Figure imgf000050_0001
(5) 对比实施例 8与实施例 21 的双嘧达莫片的溶出度比较
溶出度测定方法： 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。 溶出度 （％)
实施例
5min 15 min 30 min
对比 8 75.3 87.1 89.7
21 85.9 95.4 97.0 效果实施例 3 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 3和实施例 3~4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。 溶出度测试方法 同效果实施例 2中 （1 )。
Figure imgf000051_0001
(2) 对比实施例 5、 实施例 6~9和 11的右旋佐匹克隆制剂的稳定性比较
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 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； 以乙腈 -0.05mol/L硫酸铵溶液 （40:60) 为流动相； 检测波长为 304nm， 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。
溶出度测试方法： 同效果实施例 2中 （2)。
Figure imgf000052_0001
(3) 对比实施例 6、 实施例 12、 13和 15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。
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， 检测波长为 304nm。 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。
溶出度测试方法同试验实施例 2中 （3 )。 实施 性状 3里 (%) 30分钟溶出度 （％) 有关物质 （％) 例 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 6 白色片 白色片 99.1 98.8 89.3 87.1 0.09 0.60
12 白色片 白色片 99.7 99.3 98.5 99.1 0.11 0.51
13 白色片 白色片 101.4 100.7 100.2 99.8 0.10 0.48
15 白色片 白色片 99.1 99.5 99.8 99.1 0.09 0.50
(4) 对比实施例 7和实施例 18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。
溶出度测试方法同试验实施例 2中 （4)。
Figure imgf000053_0001
(5) 对比实施例 8和实施例 21的双嘧达莫片的稳定性比较
含量的测定方法： 取样品适量 （相当于双嘧达莫 50mg)， 置 100ml 容量瓶中， 加 0.01mol/L盐酸溶液适量， 振摇使双嘧达莫溶解， 用 0.01mol/L盐酸溶液稀释至刻度， 摇 勾， 滤过， 加 O.Olmol/L盐酸溶液定量稀释成每 ml中含双嘧达莫 lOug的溶液， 作为供试 品溶液照紫外-可见分光光度法 （中国药典 2005年版二部附录 IV A)， 在 283nm波长处 测定吸光度。
有关物质的测定方法： 取样品适量， 用甲醇制成每 ml中含双嘧达莫 l .Omg的溶液， 作为供试品溶液， 并配制每 ml中含双嘧达莫 lOug的溶液作为对照溶液。 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， 检测波 长为 288nm， 分别测定， 按照主成分自身对照法进行计算。
Figure imgf000054_0001
效果实施例 4 含量均勾度实验
Figure imgf000054_0002

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， 将碱化剂、 辅料和所述的含药酸性液均勾的混合， 进行湿法制粒； 其中， 所述的碱化剂为使碱化剂 与含药酸性液的混合液的酸性相对于含药酸性液的酸性降低的试剂。
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 物活性成分为右旋佐匹克隆、 地西泮、 艾司唑仑、 阿普唑仑、 佐匹克隆、 阿立哌唑、 利 醅酮、 米非司酮、 奋乃静、 狄戈辛、 伊潘立酮、 帕潘立酮、 奥氮平、 氟哌啶醇、 双嘧达 莫、 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、 硫酸、 硝酸、 富马酸、 琥珀 酸、 马来酸、 乳酸、 醋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、 醋酸或磷酸。
5、 如权利要求 1~4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 1~1.5 倍， 更佳的为 1-1.05倍。
6、 如权利要求 1~4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为 0.1~2.5， 更佳的为 0.5~1.5。
7、 如权利要求 1~6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、有机溶剂或者水和有机溶剂的混合液， 且酸化剂中离子在该溶剂中可解离； 所述的有机溶剂为水不溶性和 /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药剂领域常用的水溶性醇类溶剂， 更佳的为乙醇、 丙二醇、 丙三醇、 丙酮、 异丙醇和叔丁醇中的一种或多种， 最佳的为乙醇。
8、 如权利要求 1~7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%， 较佳的为 10~50%。
9、 如权利要求 1~8 任一项所述的方法， 其特征在于： 在所述的将水不溶性和 /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， 即与碱化剂和辅料均勾混合， 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； 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、 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、 乳糖、 甘露醇、 蔗糖、 β -环糊精和麦芽糖醇中的一种或多种。
10、 如权利要求 9任一项所述的方法， 其特征在于： 所述的表面活性剂和 /或增溶剂 的加入量为水不溶性和 /或水难溶性碱性药物活性成分质量的 0.05~5倍；所述的固体分散 体的水溶性载体的加入量为水不溶性和 /或水难溶性碱性药物活性成分质量的 1~10倍。
11、如权利要求 1~10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， 以水为溶剂时， 升高含药酸性液温度至 40~80°C ; 以水和有机溶剂的混合溶液为溶剂时， 升高含药酸性液温度至 40~70°C； 以乙醇为溶剂时， 升高含药酸性液温度至 30~50°C。
12、 如权利要求 1~11任一项所述的方法， 其特征在于： 所述的碱化剂为无机强碱、 弱酸强碱盐、 有机弱酸的共轭碱、 或酸性低于强酸性酸化剂， 且能与其形成缓冲对的酸， 较佳的为氢氧化钠、 碳酸钠、 磷酸氢二钠、 枸橼酸钠、 酒石酸钠、 苹果酸钠、 醋酸 钠、 甘氨酸和丙氨酸中的一种或多种。
13、 如权利要求 1~11 任一项所述的方法， 其特征在于： 所述的酸化剂和碱化剂为 下述类型中的任一种：
类型 1 : 所述的酸化剂为无机强酸， 所述的碱化剂为无机强碱；
类型 2: 所述的酸化剂为无机强酸， 所述的碱化剂为无机弱酸强碱盐；
类型 3 : 所述的酸化剂为无机强酸， 所述的碱化剂为有机弱酸强碱盐；
类型 4: 所述的酸化剂为有机弱酸， 所述的碱化剂为该有机弱酸的共轭碱； 类型 5 : 所述的酸化剂为有机弱酸， 所述的碱化剂为无机强碱或无机弱酸强碱盐； 和 类型 6: 所述的酸化剂为无机强酸， 所述的碱化剂为弱酸， 且能与其形成缓冲对的 酸； 类型 7: 所述的酸化剂为无机中强酸， 所述的碱化剂为无机强碱、无机弱酸强碱盐或 有机弱酸强碱盐；
较佳的， 所述的酸化剂和碱化剂为： 盐酸和氢氧化钠， 盐酸和碳酸钠， 盐酸和磷酸 氢二钠， 盐酸和枸橼酸钠， 盐酸和酒石酸钠， 盐酸和苹果酸钠， 盐酸和醋酸钠， 枸橼酸 和枸橼酸钠， 酒石酸和酒石酸钠， 苹果酸和苹果酸钠， 醋酸和醋酸钠， 枸橼酸和碳酸钠， 苹果酸和碳酸钠、 苹果酸与磷酸氢二钠， 枸橼酸和磷酸氢二钠、 盐酸和甘氨酸， 盐酸和 丙氨酸， 磷酸和氢氧化钠、 磷酸和碳酸钠， 或磷酸和磷酸氢二钠。
14、 如权利要求 13所述的方法， 其特征在于： 所述的酸化剂与碱化剂的用量满足 下述关系： 式 1所得值为 0.01~1.5， 更佳的为 0.3~1.2;
(碱化剂摩尔数 X A) I (酸化剂摩尔数 X B ) 式 1
其中， 当酸化剂和碱化剂为类型 1、 2或 5时， A为碱化剂分子阴离子总价态数一碱化剂 分子中的氢离子数；
当酸化剂和碱化剂为类型 1、 2、 3或 6时， B为酸化剂分子中的氢离子数； 当酸化剂和碱化剂为类型 4时， A/B为 1 ;
当酸化剂和碱化剂为类型 5时， B为 1 ;
当酸化剂和碱化剂为类型 3或 6时， A为 1。
15、 如权利要求 1~14任一项所述的方法， 其特征在于： 所述的将碱化剂、 辅料和所 述的含药酸性液均勾的混合， 进行湿法制粒的具体操作方式选自下述方式中的任一种： 方式 （1 ) 将碱化剂或含碱化剂的溶液和辅料均勾混合， 再与含药酸性液均勾混合， 进行挤压制粒或搅拌制粒；
方式 （2 )将含药酸性液与， 碱化剂或含碱化剂的溶液均勾的混合， 得制粒液， 之后 再将该制粒液与辅料进行挤压制粒、 搅拌制粒、 流化喷雾制粒或离心喷雾制粒等；
方式 （3 ) 将含药酸性液与辅料均勾的混合， 之后再与含碱化剂的溶液均勾的混合， 进行挤压制粒或搅拌制粒。
16、 如权利要求 1~15任一项所述的方法， 其特征在于： 将如权利要求 1~16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。
17、 如权利要求 1~16任一项所述的方法制得的固体制剂。
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