WO2012088992A1 - Procédé de préparation d'une préparation médicale solide et préparation de médicament solide obtenue à partir dudit procédé - Google Patents

Procédé de préparation d'une préparation médicale solide et préparation de médicament solide obtenue à partir dudit procédé Download PDF

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WO2012088992A1
WO2012088992A1 PCT/CN2011/083285 CN2011083285W WO2012088992A1 WO 2012088992 A1 WO2012088992 A1 WO 2012088992A1 CN 2011083285 W CN2011083285 W CN 2011083285W WO 2012088992 A1 WO2012088992 A1 WO 2012088992A1
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water
insoluble
active ingredient
agent
pharmaceutical active
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PCT/CN2011/083285
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English (en)
Chinese (zh)
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郑斯骥
谭波
傅麟勇
袁少卿
曹智慧
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上海中西制药有限公司
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Publication of WO2012088992A1 publication Critical patent/WO2012088992A1/fr

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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
    • A61K9/1617—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • 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
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • 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
    • A61K31/54—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
    • A61K31/549—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 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of a solid pharmaceutical preparation and a obtained solid preparation of the medicament. Background technique
  • the particle size of the pharmaceutically active ingredient is closely related to the preparation process and quality of the solid preparation, and the reduction of the particle size is the key to improving the dissolution and content uniformity of the pharmaceutical preparation.
  • the particle size of a suitable pharmaceutically active ingredient is usually selected depending on the dissolution characteristics of the drug and the permeability of the biofilm. For example, if the solubility is poor, drug dissolution is a drug that absorbs the rate-limiting process, and a smaller particle size can be selected to promote drug absorption.
  • selective control of the particle size of the pharmaceutically active ingredient is often involved.
  • the universal pulverizer is a pulverizer widely used in the field of medicine.
  • the effect of crushing materials is mainly on impact force and shearing force. It is suitable for a variety of medium-hardness dry materials.
  • the average particle size after treatment is generally 100. About micrometers.
  • 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.
  • inhalation of a lower dose of sedative sleeping pills powder can quickly produce hypnotic effects.
  • these drugs are pulverized, it is highly prone to cause an operator's rapid hypnosis and cause a safety accident.
  • inhaling or contacting a certain amount of the drug powder can easily cause a serious drug reaction by the operator.
  • the average particle size reaches about 100 microns, and the dissolution characteristics of the prepared solid preparations are not satisfactory.
  • mechanical pulverization treatment for a high active pharmaceutically active ingredient having a low content (e.g., 5 wt%) in a solid preparation, it also relates to the problem of dispersion uniformity of its mixing with an auxiliary material.
  • a method of gradually diluting the pharmaceutically active ingredient and the auxiliary material in an equal amount is used to uniformly 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 uniformity?
  • stability is the focus of the quality of the solid preparation, including the chemical stability of the active ingredient, the content of impurities, the stability of the solid preparation, and the stability of dissolution during storage of the solid preparation, whether it is in the medicine Within the standard limits.
  • 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 acidic drug provides a simpler operation, less pollution, no such safety hazard, and can ensure that the prepared solid preparation has excellent dissolution characteristics.
  • A-BSoD Acid-Base Solventing-out Dispersion
  • the drug which is then returned to the solid state during the granulation process, avoids many of the drawbacks of mechanical comminution.
  • the inventors have unexpectedly found that the water-insoluble and/or poorly water-soluble acidic pharmaceutical solid preparation obtained by the method has excellent dissolution characteristics, stability, and content uniformity.
  • the method for preparing a pharmaceutical solid preparation of the present invention comprises the steps of: insoluble water and/or water
  • the soluble acidic pharmaceutical active ingredient is dissolved in an alkaline solution containing an alkalizing agent to prepare a medicated alkaline liquid; thereafter, the auxiliary material and the medicated alkaline liquid are uniformly mixed to perform wet granulation.
  • the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is selected from various existing pharmaceutically active ingredients satisfying the above properties, including an amphoteric active ingredient having both an acidic group and a basic group. .
  • the acidic pharmaceutically active ingredients are weak acid active ingredients.
  • the present invention preferably has a high activity and a low content in a solid preparation (generally 20% or less, preferably 10% or less, more preferably 5% or less, and a percentage by mass) of water-insoluble or poorly water-soluble acidity. Pharmaceutical active ingredient.
  • the present invention is preferably, but not limited to, glipizide, folic acid, bumetanide, diclofenac, isocarbopurine, benzfluorothiazide, p-fluorothiazide, methotrexate, vitamin H , hexaerythritol, indapamide, furosemide, thioguanine, allopurinol, gliclazone, simvastatin, leflunomide, hydrochlorothiazide or phenobarbital.
  • the mass percentage of the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in the wet-processed dry material can be determined during the preparation.
  • other pharmaceutically active ingredients may be added to prepare a compound solid preparation.
  • the alkalizing agent refers to a reagent capable of completely dissolving a water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in an alkaline solution containing an alkalizing agent.
  • the basifying agent should be a pharmaceutically acceptable agent compatible with water insoluble and/or poorly water soluble acidic pharmaceutical active ingredients.
  • the compatibility means coexistence without adverse effects.
  • the alkalizing agent may be a single alkalizing agent or a complex alkalizing agent composed of two or more components, and may be selected from various bases such as inorganic bases and/or organic bases, strong bases and/or weakeners.
  • the base is preferably selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, meglumine, diethanolamine and triethanolamine.
  • the basifying agent described below is particularly preferred in the present invention:
  • the alkalizing agent is sodium hydroxide, potassium hydroxide or sodium ethoxide, most preferably sodium hydroxide.
  • the alkalization is sodium hydroxide or potassium hydroxide, and the most preferred is sodium hydroxide.
  • the alkalizing agent is sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium carbonate or potassium carbonate, and most preferably sodium hydroxide or carbonic acid. sodium.
  • the alkalizing agent is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
  • the alkalizing agent is sodium hydroxide or potassium hydroxide.
  • the alkalizing agent is used in an amount at least the minimum amount which can completely dissolve the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient, preferably 1 to 1.5 times the minimum amount, and most preferably 1 to 1.05. Times.
  • the amount of the alkalizing agent which can dissolve the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is related to various factors such as the type of alkalizing agent, the type of solvent, the water-insoluble and/or poorly water-soluble acidic drug in the alkalizing agent.
  • the number of negative ions combined with the acid center of the active ingredient and the preparation conditions of the medicated alkaline solution (such as temperature, time, feeding sequence, stirring method) and the like.
  • the acidic center means a group or a portion of the water-insoluble and/or water-insoluble acidic drug active ingredient which can bind to a negative ion in the alkalizing agent molecule. Therefore, the above minimum amount refers to the minimum amount of an alkalizing agent which can be dissolved by a certain alkali-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient under the same solvent and medicated alkaline solution. The minimum amount can be determined by a simple conventional method: in the same solvent and the medicated alkaline solution, the amount of the alkalizing agent is gradually increased to dissolve a certain water-insoluble and/or poorly water-soluble acidic drug. The active ingredient, when completely dissolved, is the minimum amount.
  • the present inventors have found through a large number of experiments that, in particular, the molar ratio of the alkalizing agent to the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient is generally from 0.1 to 2.5, and most of from 0.9 to 1.5, and the present invention is particularly preferred.
  • sodium hydroxide or sodium ethoxide having a molar amount of 0.7 to 1.1 times is particularly preferred.
  • sodium hydroxide having a molar amount of 0.95 to 1.1 times is particularly preferable.
  • sodium hydroxide having a molar amount of 1.8 to 2.1 times or a molar amount of 0.95 to 1.1 is particularly preferable. Times sodium carbonate or potassium carbonate.
  • sodium hydroxide having a molar amount of 1.4 to 1.6 times or sodium carbonate having a molar amount of 0.85 to 1.1 times is particularly preferable.
  • sodium hydroxide having a molar amount of 0.9 to 1.6 times is particularly preferable.
  • the solvent in the alkalizing agent-containing alkaline solution 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 alkalizing agent.
  • the alkalizing agent is an inorganic substance, water or a mixed liquid of water and an organic solvent may be selected; and when the alkalizing 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, and to reduce the amount of alkalizing agent or solvent, which is advantageous for The operation of the subsequent granulation step.
  • the organic solvent is selected according to the principle that its solubility in water-insoluble and/or poorly water-soluble acidic pharmaceutically active ingredients is superior to water in a solvent acceptable for the pharmaceutical field, preferably organically miscible with water.
  • a solvent such as a water-soluble alcohol solvent commonly used in the pharmaceutical field, such as ethanol, propylene glycol, glycerol, acetone, isopropanol or 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 alkaline 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-insoluble and/or water-insoluble acidic pharmaceutically active ingredient is dissolved in the alkaline solution containing the alkalizing agent while and/or after, the water-soluble solution of the surfactant, the solubilizing agent and the solid dispersion is further added.
  • One or more of the carrier materials are then subjected to a subsequent step of uniformly mixing the excipients with the excipients for wet granulation.
  • the amount of the water-soluble carrier of the solid dispersion to be added at this time is required. Controlled to ensure that the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredients are completely dissolved in the alkaline agent-containing alkaline The amount in the solution is below; after that, a water-soluble carrier of the solid dispersion may be further added to the solution, and when the amount added is large, the obtained drug-containing acidic liquid 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 dodecyl sulfate, poloxamer, polyoxyethylene castor oil, Tween (preferably Tween 80). And one or more of polyoxyl 40 stearate, lactose, mannitol, sucrose, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin and maltitol.
  • the surfactant and/or solubilizer is preferably added in an amount of 0.05 to 5 times, more preferably 0.05 to 2 times, the mass of the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient.
  • the water-soluble carrier of the solid dispersion is preferably added in an amount of from 0.5 to 20 times, more preferably from 0.5 to 2 times, the mass of the water-insoluble and/or water-insoluble acidic pharmaceutical active ingredient.
  • a surfactant and/or a solubilizing agent as described above, the solubility of the water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in an alkaline solution can be increased, the amount of the solvent can be reduced, and the operation of the subsequent granulation step can be facilitated.
  • 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.
  • the preparation temperature of the medicated alkaline solution may 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 and widely used in the art, such as fillers, binders, disintegrants, adsorbents, lubricants and the like.
  • the amount of the excipients can be selected according to routine or prior 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 magnesium stearate, micronized silica gel (colloidal silica), talc or sodium stearate.
  • the acidifying agent is added to lower the alkalinity of the mixture of the acidifying agent and the medicated alkaline solution with respect to the alkalinity of the medicated alkaline solution.
  • the acidulant should be a pharmaceutically acceptable agent compatible with water insoluble and/or poorly water soluble acidic pharmaceutical active ingredients.
  • the present invention is preferably a combination of an alkalizing agent and an acidifying agent of the following type: the alkalizing agent is an inorganic strong base, an organic strong base or an inorganic medium strong base, and the acidifying agent is an inorganic strong acid (such as hydrochloric acid).
  • the amount of the acidifying agent is such an amount that at least the alkalinity of the mixture of the acidifying agent and the medicated alkaline liquid is lowered relative to the alkalinity of the medicated alkaline liquid.
  • the amount of the alkalizing agent and the acidifying agent satisfies the following relationship:
  • the value obtained by the formula 1 is 0.01 to 1.5, preferably 0.2 to 1.1, more preferably 0.9 to 1.1.
  • the present invention particularly preferably has a combination of the following alkalizing agent and acidifying agent of the formula 1 having a value of 0.9 to 1.1: sodium hydroxide and hydrochloric acid, potassium hydroxide and hydrochloric acid, sodium ethoxide and hydrochloric acid, sodium carbonate and hydrochloric acid, and potassium carbonate and hydrochloric acid. .
  • the addition of an acidifying agent is more advantageous for the stability of the solid preparation.
  • the solid preparation can still have better stability without adding an acidifying agent or an acidifying agent in the formulation, but does not affect the preparation. Under the premise of stability, appropriately increasing the amount of acidifier to reduce alkalinity can help to alleviate the pH of solid preparations.
  • the wet granulation can be carried out according to the conventional steps and conditions of various granulation methods in the field of wet granulation in the art, such as extrusion granulation (such as swinging machine extrusion, spiral extrusion or rotary extrusion). Pressing, etc., stirring granulation, fluidized spray granulation or centrifugal spray granulation.
  • extrusion granulation such as swinging machine extrusion, spiral extrusion or rotary extrusion. Pressing, etc., stirring granulation, fluidized spray granulation or centrifugal spray granulation.
  • the acidic pharmaceutically active ingredient may be selected from a wet granulation process in which the amount of the granulation solution is limited, such as fluidized spray granulation or centrifugal spray
  • the acidifying agent or the acidifying agent-containing solution and the auxiliary material are uniformly mixed, and then uniformly mixed with the medicated alkaline liquid, and subjected to extrusion granulation or stirring granulation; and (2) the medicated alkaline liquid and the acidifying agent or The solution of the acidifying agent is uniformly 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; and the method (3) will contain The alkaline solution of the drug is uniformly mixed with the auxiliary material, and then uniformly mixed with the solution containing the acidifying agent, and subjected to extrusion granulation or stirring granulation; and (4) the medicated alkaline liquid and the auxiliary material of 1/3 or less And the acidifying agent or the acidifying agent-containing solution is uniformly mixed
  • the excipients in the 1/3 or less of the excipients are preferably water-soluble excipients.
  • the 1/3 or less of the above may be usually 1/4 to 1/10 or less.
  • the acidifier-containing solution refers to a solution obtained by dissolving an acidifying agent with a small amount of solvent according to a routine operation in the art to facilitate the mixing step; the solvent may be water, an organic solvent or water and an organic solvent. Mixture.
  • the organic solvent is the same as described above.
  • the solid granule preparation can be directly obtained, or can be used as a preparation intermediate, and further solid preparations such as tablets or capsules can be obtained through further conventional steps.
  • the present invention also relates to a solid preparation prepared by the above method.
  • the reagents and starting materials used are commercially available.
  • the positive progress of the invention is that the preparation method of the invention avoids the defects of serious pollution, large loss and serious safety hazard caused by mechanical pulverization treatment, and achieves reduction of water insolubility and/or poor water solubility during granulation.
  • the method is easy to operate, has a high safety factor, and is easy to be applied to industrial production.
  • the solid active preparation of the present invention has a small particle size, excellent dissolution characteristics, high bioavailability, small individual difference, and also good stability and content uniformity. detailed description
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with 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 an acidifying agent and an alkalizing agent.
  • the coating material is a premix of the gastric coating material - Opadry. Comparative Example 1 and Example 1 Indapamide particle formulation and preparation method (Indapamide molecular weight: 365.83)
  • Example 4 Indapamide granule formula and preparation method
  • Example 5 Indapamide Tablets (2.5 mg/tablet) Formulation and Preparation Method
  • magnesium stearate and talc powder are added to form a soft material, which is extruded and granulated, and the wet granules are dried.
  • the mixture was added to the Opadry in the water while stirring, and magnesium stearate and talc powder were added and then compressed. Powder, continue to stir for 45 minutes after the addition, add Opadry powder in water while stirring, add the coating solution of 19% concentration, continue to stir for 45 minutes after the core, and prepare the film with 19wt% concentration. Coating.
  • the coating liquid is film coated on the core.
  • Example 10 Indapamide Capsule (2.5 mg/granule) Formulation and Preparation Method The particles before the tableting of Example 6 were passed through a 30 mesh sieve, uniformly mixed, and then filled. Comparative Example 3 Glipizide granule formulation and preparation method (glipizide molecular weight 445.54)
  • Example 13 Drug glipizide 2.5 (2.3%, micronized treatment) Glipizide 2.5 (2.2%, no pretreatment) Lactose 100, povidone K30 2, lactose lactose 100, polydimensional Ketone ⁇ 30 2, magnesium stearate 0.5, accessories
  • the sodium sulphate solution is formulated into a medicated alkaline solution, and 25% of the sugar is added and uniformly mixed, and the povidone ⁇ 30 is added.
  • lactose The amount of lactose is stirred evenly, and 10% salt is added with stirring to prepare an aqueous solution for stirring to form a soft material.
  • the aqueous acid solution is added to the 75% amount of lactose and stirred to process the granules.
  • the wet granules are dried and then granulated.
  • Example 15 glipizide tablets (5 mg / tablet) formula and preparation method
  • Example 16 glipizide capsule (2.5 mg / granule) formula and preparation method The granules before the tableting of Example 14 were passed through a 30 mesh sieve, and the mixture was uniformly mixed and then filled.
  • Example 17 Folic acid granule formula and preparation method (folic acid molecular weight 441.4) ) Comparative Example 5 and Example 18 Folic acid granule formulation and preparation method (folic acid molecular weight 441.4)
  • Example 24 Folic acid tablet (5 mg / tablet) formula and preparation method
  • Example 28 Methotrexate tablets (2.5 mg / tablet) formula and preparation method
  • Example 37 Benzyl fluorothiazide tablets (2.5 mg / tablet) formulation and preparation method
  • Example 38 Benzyl fluorothiazide particle formulation and preparation method
  • Example 39 Benzyl fluorothiazide tablets (5 mg / tablet) formulation and preparation method
  • Example 40 Indapamide Tablets (2.5 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 570ml, and the centrifugal pump has a rotation speed of 1600rpm.
  • Test method Take about 2g of particles, 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.
  • D10, D50 and D90 are the corresponding particle sizes when the cumulative particle size distribution percentage reaches 10%, 50% and 90%, respectively.
  • the intrinsic average particle size of indapamide in the indapamide particles obtained by the method of the present invention is reduced to 8.5 to 21.8% of the particle diameter of the drug substance, reaching 4.78 to 12.25 ⁇ m.
  • the average volume fraction of folic acid in the folic acid granules obtained by the method of the present invention is reduced to 15.9 to 34.6% of the particle size of the raw material treated with the fine powder, and is 0.89 to 1.94 ⁇ m.
  • the volume average particle diameter of methotrexate in the methotrexate particles obtained by the method of the present invention is reduced to 5.2 to 10.9% of the particle diameter of the drug substance, which is 4.43 to 9.37 ⁇ m.
  • Dissolution method Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the dissolution solution 900 ml, take 0.2mol / l potassium dihydrogen phosphate solution 250ml, add 0.2mol / KOH
  • the sodium solution was diluted with water to 1000 ml of 118 m, the pH was adjusted to 6.8, the rotation speed was 100 rpm, and the control solution was prepared according to the law.
  • the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A)
  • the absorbance was measured at a wavelength of 240 nm, and the amount of dissolution per tablet was calculated.
  • Dissolution method (1) Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the eluate is phosphate buffer (pH 7.4) 500ml, the rotation speed is 100 rpm , operate according to law, and prepare a control solution. According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance was measured at a wavelength of 222 nm, and the amount of dissolution per tablet was calculated.
  • Dissolution method (2) Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the eluate is water 500ml, the rotation speed is 100 rpm, operate according to the law, and prepare the control solution . According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance was measured at a wavelength of 222 nm, and the amount of dissolution per tablet was calculated.
  • Dissolution method (1) Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the eluate is phosphate buffer (pH 6.8) buffer 900ml, the rotation speed is every minute 100 rpm, operate according to law, and prepare a control solution. According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance is measured at a wavelength of 281 nm, and the dissolution of each tablet is calculated.
  • Dissolution method (2) Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), the eluate is 900ml of water, the rotation speed is 100 rpm, operate according to the law, and prepare the control solution . According to the spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance was measured at a wavelength of 281 nm, and the amount of dissolution per tablet was calculated. Dissolution (%)
  • test samples were placed in high-density polyethylene plastic bottles, sealed, placed in an accelerated inspection box, 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.
  • Method for determining the substance Protect from light. Take the appropriate amount of fine powder, add appropriate amount of mobile phase, shake in a hot water bath for 5 minutes, dissolve indapamide, dilute with mobile phase to make a solution containing about 0.5 mg of indapamide per 1 ml, filter After that, the filtrate was taken as the test sample. According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix V D), octadecyl silicon germanium bonded silica was used as a filler and determined separately. Calculated according to the area normalization method.
  • the dissolution test method was the same as in the effect example 2.
  • Determination of content uniformity Take 1 tablet of this product, place it in the milk, add appropriate amount of ethanol, grind, and transfer it to 100ml volumetric flask with ethanol, shake it, dissolve indapamide, dilute with ethanol to scale Shake well, filter, and accurately measure 10ml of the filtrate. Place in a 50ml volumetric flask, dilute to the mark with ethanol, shake well, take the reference solution under the solution and the content determination, and observe the UV-visible spectrophotometry. Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance is measured at a wavelength of 242 nm, calculated.
  • Determination of content uniformity Take 1 piece of this product, grind it, add phosphate buffer (pH 7.4), grind it in an appropriate amount, and transfer it to a 200ml volumetric flask with phosphate buffer (pH 7.4). Shake well. , filtered, take the filtrate as the test solution; take the appropriate amount of glipizide reference substance, the same method to make a solution containing about 25 per 1ml, as a reference solution. The above two solutions were taken, and the absorbance was measured at a wavelength of 275 nm, and calculated.
  • Determination of content uniformity Take 1 piece of this product, place it in a 25ml volumetric flask, add about 15ml of 0.5% ammonia solution, heat in a hot water bath for 20 minutes, shake it to dissolve the folic acid, let cool, dilute with water to the scale Shake, filter, and take the filtrate as the test solution, according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix VD), using 18 ⁇ ⁇ silicon germanium bonded silica as a filler, record the chromatogram
  • Another folic acid reference substance determined by the same method, according to the external standard method to calculate the content of the peak area, should be consistent with (Chinese Pharmacopoeia 2010 edition two appendix XE).
  • Determination of content uniformity Take 1 tablet of this product, place it in a mortar, grind it, add 0.4% sodium hydroxide solution, grind it, and transfer it to a 25ml volumetric flask with 0.4% sodium hydroxide solution, shake it thoroughly.

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  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

La présente invention concerne un procédé de préparation d'une préparation médicale solide et une préparation de médicament solide obtenue à partir dudit procédé. Ledit procédé de préparation utilise une technique de dispersion de dissolution de substances acides/alcalines comprenant les étapes suivantes : dissolution d'un principe actif médical acide indissoluble et/ou insoluble dans l'eau dans une solution alcaline contenant un agent alcalifiant, pour produire une solution alcaline contenant un médicament ; puis mélange uniforme d'un matériau auxiliaire et de la solution alcaline contenant un médicament pour réaliser une granulation par voie humide. Ledit procédé permet d'éviter les inconvénients provoqués par un traitement de broyage mécanique ‑ tels que pollution grave, pertes importantes et risques potentiels d'accidents ‑, l'effet de réduction de la taille de particule des principes actifs médicaux indissolubles et/ou insolubles dans l'eau pouvant être obtenu durant la préparation, et le solide produit possédant d'excellentes caractéristiques en termes de capacités à dissoudre des substances, de stabilité et d'uniformité de teneur.
PCT/CN2011/083285 2010-12-28 2011-12-01 Procédé de préparation d'une préparation médicale solide et préparation de médicament solide obtenue à partir dudit procédé WO2012088992A1 (fr)

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CN201010619883.6A CN102552161B (zh) 2010-12-28 2010-12-28 一种药物固体制剂的制备方法及所得药物固体制剂
CN201010619883.6 2010-12-28

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CN103462918B (zh) * 2013-09-22 2015-12-02 南京正宽医药科技有限公司 一种盐酸伐昔洛韦片剂及其制备方法
CN103520122B (zh) * 2013-10-25 2015-06-17 海南通用康力制药有限公司 一种注射用布美他尼冻干粉针制剂制备方法
CN107714653B (zh) * 2017-11-27 2022-01-28 济南新科医药科技有限公司 一种稳定的可溶性甲氨蝶呤颗粒剂
CN107823160B (zh) * 2017-12-02 2020-04-14 广东世信药业有限公司 一种用于抗痛风的固体分散制剂及其制备方法

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CN1615123A (zh) * 2002-01-16 2005-05-11 贝林格尔英格海姆法玛两合公司 含有替米沙坦和利尿剂的双层药片及其制备方法
CN1720027A (zh) * 2002-11-29 2006-01-11 詹森药业有限公司 含有碱性或酸性药物化合物、表面活性剂以及生理上可接受的水溶性酸或碱的药物组合物
US20060057073A1 (en) * 2002-11-08 2006-03-16 Pari Gmbh Wet granulation process
CN101312714A (zh) * 2005-11-22 2008-11-26 特瓦制药工业有限公司 替米沙坦的药用组合物

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
CN1615123A (zh) * 2002-01-16 2005-05-11 贝林格尔英格海姆法玛两合公司 含有替米沙坦和利尿剂的双层药片及其制备方法
US20060057073A1 (en) * 2002-11-08 2006-03-16 Pari Gmbh Wet granulation process
CN1720027A (zh) * 2002-11-29 2006-01-11 詹森药业有限公司 含有碱性或酸性药物化合物、表面活性剂以及生理上可接受的水溶性酸或碱的药物组合物
CN101312714A (zh) * 2005-11-22 2008-11-26 特瓦制药工业有限公司 替米沙坦的药用组合物

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