WO2016082705A1 - Matière particulaire de principe actif insoluble, préparation de matière particulaire et son procédé de préparation - Google Patents

Matière particulaire de principe actif insoluble, préparation de matière particulaire et son procédé de préparation Download PDF

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Publication number
WO2016082705A1
WO2016082705A1 PCT/CN2015/094889 CN2015094889W WO2016082705A1 WO 2016082705 A1 WO2016082705 A1 WO 2016082705A1 CN 2015094889 W CN2015094889 W CN 2015094889W WO 2016082705 A1 WO2016082705 A1 WO 2016082705A1
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Prior art keywords
acid
solution
active ingredient
preparation
sodium
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PCT/CN2015/094889
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English (en)
Chinese (zh)
Inventor
任福正
郑斯骥
景秋芳
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华东理工大学
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Publication of WO2016082705A1 publication Critical patent/WO2016082705A1/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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • 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

Definitions

  • the invention relates to a poorly soluble active ingredient microparticle, a microparticle preparation and a preparation method thereof. Background technique
  • the active ingredient also referred to as the active ingredient, refers to a monomeric compound having medical or physiological activity, which can be expressed by molecular formula and structural formula and having physical and chemical data.
  • a drug is also an active ingredient, and is a substance that can temporarily or permanently change or ascertain the physiological function and pathological state of the body, and has medical, diagnostic, preventive, and health-care effects, including natural drugs, chemical synthetic drugs, and biotechnological drugs. Active ingredients need to be formulated according to different requirements, different ways of use and different parts of use.
  • the active ingredient of the drug In the field of pharmaceutical preparations, after oral administration, the active ingredient of the drug must first be dissolved and then absorbed into the systemic circulation through the gastrointestinal mucosa.
  • the solubility of the active ingredient in aqueous solution is poorly soluble and easily soluble, and it is difficult to absorb and absorb easily when transported across the membrane.
  • researchers must design appropriate prescriptions and processes through a variety of means and techniques to allow the dissolution and absorption of active ingredients to meet therapeutic needs.
  • the dissolution rate of the active ingredient in the body is a rate limiting factor that affects the onset time, strength of action, and actual efficacy of the active ingredient. Therefore, the dissolution of the active ingredient is one of the main contents of the quality control of the preparation.
  • the Noyes-Whitney equation succinctly describes the factors that influence the dissolution rate of active ingredients.
  • effective measures for increasing the dissolution rate of the poorly soluble active ingredient include reducing the particle size of the active ingredient, increasing the dissolution area of the active ingredient, increasing the saturation solubility of the active ingredient, and the like.
  • the particle size of the active ingredient is closely related to the preparation process and quality of the solid pharmaceutical preparation.
  • the particle size of a suitable active ingredient is usually selected depending on the solubility characteristics of the active ingredient and the biofilm permeability. For example, if the solubility is poor, the dissolution of the active ingredient is the rate-limiting process, and a smaller particle size may be selected to promote absorption of the active ingredient. Therefore, in the preparation process of a pharmaceutical solid preparation, the selective control of the particle size of the active ingredient is often involved.
  • the commonly used pulverization methods for reducing the particle size of the active ingredient are mainly grinding method, impact pulverization method, jet pulverization method and wet high pressure homogenization method, etc., by selecting different pulverization methods and pulverization process conditions to achieve Selection control of the particle size of the active ingredient.
  • the solid dispersion method is also an effective method for improving the dissolution properties of the poorly soluble active ingredient preparation.
  • the solid dispersion method is to dissolve the active ingredient and a certain carrier material, such as povidone 30, in a suitable organic solvent, and evaporate the solvent under reduced pressure. A coprecipitate is obtained which, after sieving, gives a solid dispersion.
  • the solid dispersion method can significantly improve the dissolution effect of the poorly soluble active ingredient, but the operation process is complicated and the cost is high.
  • the solubility of the poorly soluble active ingredient can be significantly improved.
  • the amorphous form in the crystallization of the active ingredient has no lattice binding and large free energy, so the solubility and dissolution rate are larger than those of the crystalline form.
  • the preparation of the inclusion compound requires a specific excipient, which requires that the poorly soluble active ingredient and the inclusion material have matching properties, and the amount of the auxiliary material is large.
  • the amorphous type has instability in many cases, and it is easy to undergo crystal transformation or produce degradation products during the placement process.
  • CN102552161 discloses a method for preparing a solid pharmaceutical preparation, which comprises dissolving a water-insoluble and/or poorly water-soluble acidic pharmaceutical active ingredient in an alkaline solution containing an alkalizing agent to obtain a The alkaline solution is prepared; after that, the auxiliary material and the medicated alkaline liquid are uniformly mixed and subjected to wet granulation.
  • Ionic polymers can be used as pharmaceutical excipients or other fields, such as acrylic resins which are widely used.
  • Acrylic resins are a type of polymer composed of acrylic acid or methacrylic acid or their ester monomers, or with methyl groups.
  • Reducing the particle size of the poorly soluble active ingredient is an effective method for improving the dissolution properties of the poorly soluble active ingredient preparation, but the particles of the poorly soluble active ingredient (including nanoparticles, submicron particles and micro particles) and the particle size larger than 100 ⁇ m are difficult.
  • the particles of the poorly soluble active ingredient including nanoparticles, submicron particles and micro particles
  • the particle size larger than 100 ⁇ m are difficult.
  • the powder of soluble active ingredient it has the characteristics of large surface area, high surface energy and large proportion of surface atoms. There are surface effects, small size effects and macroscopic quantum tunneling effects to varying degrees.
  • some of the poorly soluble active ingredient particles obtained by a conventional method are caused by factors such as electrostatic force, agglomeration and nanobubbles.
  • the agglomeration of particles refers to the phenomenon that the primary particles are connected to each other during preparation, separation, treatment and placement, and a large particle cluster is formed by a plurality of particles.
  • the agglomeration of the particles generally includes soft agglomeration and hard agglomeration.
  • Soft agglomeration is mainly caused by van der Waals force and electrostatic attraction between the surface molecules or atoms of the microparticles. For example, some particles have a hydroxyl structure on the surface, and the attraction between the hydroxyl structures is greater than the repulsive force, and the particles adsorb each other.
  • Hard agglomeration is related to the chemical composition of the particles, chemical reactions and different preparation methods, such as intermolecular forces, electrostatic interactions, chemical bonds (hydrogen bonds), interactions between particles through the interface and solid phase reactions, and air or various media.
  • the agglomeration, dispersion and wettability of the particles depend on their surface composition, surface structure, surface properties and morphology, which in turn are related to the internal composition of the particles, surface adsorption, surface reactions, preparation processes and the environment in which the particles are located.
  • the properties of agglomeration, dispersibility, wettability and stability are the macroscopic manifestations of particle and particle surface and interface behavior under certain conditions. Summary of the invention
  • the technical problem solved by the invention is to overcome the defects of poor dissolution property of the poorly soluble active component, easy aggregation of particles, poor dispersion property and wet performance, and poor stability in the prior art, and provide a poorly soluble active component particle, Microparticle preparation and preparation method thereof.
  • the preparation method of the invention has the advantages of low pollution and loss, high safety and simple operation, and the prepared poorly soluble active ingredient has good dissolution property, good stability and wide application prospect.
  • the insoluble active component and the ionic polymer are co-precipitated (eutectoid) in the solvent system, which will cause a significant change in the properties of the poorly soluble active component eutectoid (composite particles). These properties include shape, specific surface area, wettability, dispersibility, crystallinity, and fluidity.
  • ionic polymers are mostly used as coating materials, and the inventors have found that: poorly soluble active ingredients and ionic polymers are precipitated by eutectoid analysis, which can greatly improve the particles of difficult-to-soluble active ingredients or are difficult to The dissolution property of the soluble active ingredient microparticle preparation can also change the release property of the poorly soluble active ingredient by different combinations and ratios, and provide a means for effectively regulating the release rate for developing various sustained release and controlled release preparations; poorly soluble activity
  • the composition and the ionic polymer can significantly improve the filterability when preparing the particles of the poorly soluble active ingredient, which is convenient for subsequent treatment, and can obviously improve the dispersibility and fluidity of the poorly soluble active ingredient particles, and is more suitable.
  • the active ingredient preparation; the poorly soluble active ingredient and the ionic polymer can also prevent agglomeration of the fine particles and improve the stability of the poorly soluble active ingredient microparticle preparation by means of eutectoid.
  • the present invention prepares a high-quality poorly soluble active ingredient microparticle or a poorly soluble active ingredient microparticle preparation by a simple method, and greatly improves the effect of using a poorly soluble active ingredient microparticle in a pharmaceutical preparation.
  • the present invention can be applied to related fields such as foods, health care products, veterinary drugs, and cosmetics, in addition to the pharmaceutical field.
  • the poorly soluble active ingredient may be a pharmaceutically active ingredient, or may be an active ingredient in a related field such as a food, a health care product, or a cosmetic.
  • the poorly soluble active ingredient generally means that it is poorly soluble in water and has a solubility in water of less than 5 g/100 ml or less than 5 ml/100 ml.
  • the present invention solves the above technical problems by the following technical solutions.
  • the present invention provides a method for preparing microparticles of poorly soluble active ingredient, comprising the steps of: dissolving a poorly soluble active ingredient and an ionic polymer in an alkaline solution or an acidic solution, and then mixing the alkaline solution and the acidic solution, By changing the pH of the solution, the poorly soluble active ingredient and the ionic polymer which were originally dissolved in the solution are co-precipitated from the mixed solution to form fine particles.
  • the poorly soluble active ingredient comprises an acidic poorly soluble active ingredient and a basic poorly soluble active ingredient
  • the alkaline solution is prepared by adding an alkalizing agent or a pH buffering agent to the solvent
  • the acidic solution It is prepared by adding an acidifying agent or a pH buffering reagent to the solvent.
  • the invention provides a preparation method of microparticles of poorly soluble active ingredient, which comprises the following steps:
  • the acidic solution and/or the alkaline solution are dissolved in the ionic polymer preferably in any of the following manners:
  • Method 1 co-dissolving the acidic poorly soluble active ingredient and the ionic polymer in an alkaline solution, and then mixing with the acidic solution;
  • the acidic poorly soluble active ingredient is dissolved in an alkaline solution, and then mixed with an acidic solution in which the ionic polymer is dissolved;
  • the acidic poorly soluble active ingredient and the partial ionic polymer are dissolved together in an alkaline solution, and then mixed with an acidic solution in which the remaining amount of the ionic polymer is dissolved.
  • the relationship between the partial ionic polymer and the balance ionic polymer is The same ionic polymer may be added in portions, or different ionic polymers may be added separately.
  • the acidic poorly soluble active ingredient refers to a poorly soluble active ingredient which can be dissolved in an alkaline solution in a related field such as pharmacy, preferably including but not limited to ibuprofen, estradiol, estriol, Lepyrazine, folic acid, bumetanide, mefenamic acid, aprepitant, dehydrocholic acid, heparin, phenylbutazone, ganglioside, naproxen, tofatib, 7- Hydroxy-4-methylcoumarin, aspirin, sulfasalazine, acyclovir, ganciclovir, salsalate, diflunisal, indomethacin, sulindac, ketoprofen, Fenbufen, phenylbutazone, flurbiprofen, furosemide, triiodothyronine, cefazolin, lansoprazole, flumethacin, pikamilon,
  • all of the above-mentioned acidic poorly soluble active ingredients may be used as derivatives or conjugates thereof, including but not limited to isomers, epimers, diastereomers or Racemic mixture.
  • the ionic polymer preferably comprises an anionic polymer and/or a cationic polymer, and is generally soluble in an acidic solution or an alkaline solution.
  • the anionic polymer preferably includes, but is not limited to, a (meth) acrylate polymer, a (meth) acrylate copolymer, a polyethylene polymer, a polyethylene copolymer, an acid-substituted cellulose ester, a carboxy group.
  • the (meth) acrylate copolymer is preferably An acrylate copolymer containing methacrylic acid or methyl methacrylate and ethyl acrylate containing an acidic group or containing a tertiary amine group, including but not limited to Eudragit L100, Eudragit S100, Eudragit L30D L, Eudragit L100-55, Eudragit FS 100, Eudragit FS30D, domestic polyacrylic resin II, domestic One or more of polyacrylic resin III, domestic polyacrylic resin IV and Eudragit EPO.
  • the ionic polymer is preferably used in an amount of
  • the alkaline solution is prepared by adding an alkalizing agent or a pH buffer to the solvent;
  • the acidic solution is prepared by adding an acidifying agent or a pH buffer to the solvent.
  • the alkalizing agent may be a single base or a complex base composed of two or more components, and generally includes one or more of an inorganic strong base, a weak acid strong base salt and an organic base;
  • the inorganic strong base preferably includes sodium hydroxide and/or potassium hydroxide
  • the weak acid strong base salt is preferably one or more of sodium carbonate, potassium carbonate and disodium hydrogen phosphate.
  • the base is preferably one or more of meglumine, ethylenediamine, arginine and lysine.
  • the alkalizing agent is more preferably one or more of sodium hydroxide, sodium carbonate, disodium hydrogen phosphate, meglumine, ethylenediamine and arginine.
  • the alkalizing agent is preferably added in the form of an aqueous alkalizing agent, and the concentration of the aqueous alkalizing agent solution is preferably from 1 to 20% by weight.
  • the acidifying agent may be a single acid or a complex acid composed of two or more components, and the acidifying agent is preferably hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, nitric acid, hydrobromic acid, and Malay.
  • the acidifying agent is preferably hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, nitric acid, hydrobromic acid, and Malay.
  • phosphoric acid acetic acid, maleic acid, tartaric acid, and citric acid.
  • the acidifying agent is preferably added in the form of an aqueous acidulant solution, and the concentration of the aqueous acidifying agent solution is preferably from 1 to 20% by weight.
  • the pH buffer refers to a solution prepared by different pH buffering reagents and solvents, and can be various pH buffers conventionally used in the art, generally refers to strong acid and organic weak acid, weak acid and salt thereof, weak acid and basic salt, A combination of a strong base with an organic weak acid, a strong acid and a weak base, a strong base and a weak acid.
  • the pH buffer is preferably hydrochloric acid-glycine buffer, hydrochloric acid-sodium hydroxide-capric acid buffer, sodium hydroxide-capric acid buffer, hydrochloric acid-sodium citrate buffer, sodium hydroxide -Glycine buffer, citrate-sodium citrate buffer, malic acid-sodium malate buffer, tartaric acid-sodium tartrate buffer, acetic acid-sodium acetate buffer, lactic acid-sodium lactate buffer, phthalic acid- Hydrochloric acid buffer, sodium phosphate-sodium phosphate buffer, disodium hydrogen phosphate-decanoic acid buffer, potassium dihydrogen phosphate-sodium hydroxide buffer, disodium hydrogen phosphate-sodium dihydrogen phosphate buffer, citric acid-phosphoric acid Hydrogen disodium buffer or sodium carbonate-sodium bicarbonate buffer.
  • the pH buffer is more preferably hydrochloric acid-glycine buffer, hydrochloric acid-sodium hydroxide-capric acid buffer, hydrochloric acid-sodium citrate buffer, sodium hydroxide-citrate buffer, sodium hydroxide - Glycine buffer, sodium citrate-sodium citrate buffer, sodium carbonate-sodium bicarbonate buffer or disodium hydrogen phosphate-sodium dihydrogen phosphate buffer.
  • the solvent is preferably water and/or an organic solvent, more preferably water.
  • the organic solvent can be based on The solubility of the acid-insoluble active ingredient is superior to that of water, and is selected among solvents acceptable in the pharmaceutical field, preferably a water-miscible organic solvent, such as a water-soluble alcohol solvent commonly used in the pharmaceutical field.
  • a water-miscible organic solvent such as a water-soluble alcohol solvent commonly used in the pharmaceutical field.
  • ethanol propylene glycol, glycerol, ethylene glycol, isopropanol and benzyl alcohol, preferably ethanol.
  • the amount of the organic solvent can be arbitrarily selected.
  • the mass of the solvent is at least 3 to 300 times, preferably 5 to 200 times the mass of the acidic poorly soluble active ingredient, which is completely soluble in the acidic poorly soluble active ingredient.
  • the acidic poorly soluble active ingredient is dissolved in an alkaline solution, and the ionic polymer is dissolved in an alkaline solution and/or an acidic solution, and then the alkaline solution and the acidic solution are mixed.
  • the previously dissolved acidic poorly soluble active ingredient and the ionic polymer are subjected to eutectoid formation in a mixed solution to prepare an acid poorly soluble active ingredient eutectoid suspension.
  • the addition and dissolution of the ionic polymer can be carried out in various different manners, and is not limited to the above-described manner, and the above-described manner can be arbitrarily combined on the basis of common knowledge in the art, such as: acidic poorly soluble activity
  • the component and the ionic polymer are respectively dissolved in an alkaline solution, and the two are mixed and then subjected to subsequent operations; for example, the acidic poorly soluble active component is dissolved in an alkaline solution together with a plurality of ionic polymers, and then subjected to subsequent operations, etc. .
  • the acidic poorly soluble active ingredient is dissolved in an alkaline solution
  • the ionic polymer is dissolved in an alkaline solution and/or an acidic solution
  • the alkaline solution and the acidic solution are mixed to change the pH of the solution, thereby
  • the poorly soluble active ingredient and the ionic polymer are co-precipitated in the mixed solution.
  • the acidic poorly soluble active ingredient and the ionic polymer can be sufficiently co-eproduced by controlling the pH of the mixed solution.
  • the pH of the solution containing the acidic poorly soluble active ingredient is preferably 2.0 8.0, more preferably 3.0 7.0.
  • the mixing may be carried out in various liquid-liquid or liquid-solid mixing modes including, but not limited to, one or more of mechanical agitation, gas flow, liquid jet, and ultrasound.
  • mechanical stirring method various stirring devices, stirring blades of different shapes, and agitation speeds may be selected, and the stirring speed is to make the system quickly and uniformly disperse, preferably the linear speed of the agitator is 50-500.
  • ultrasonic assisted mode it is also possible to use ultrasonic assisted mode at the same time, or use various homogenizers to mix and disperse.
  • various solutions of the acidic poorly soluble active ingredient and/or the ionic polymer solution are generally prepared at room temperature, or may be appropriately raised by a conventional heating method such as a hot water bath or the like as needed.
  • the temperature at the time of preparation and mixing is stabilized to facilitate the dissolution of the acidic poorly soluble active ingredient.
  • the mixing temperature is preferably raised to 40 to 90 °C.
  • the mixing temperature is preferably raised to 30 to 70 °C.
  • the mixing temperature is preferably increased to 30 to 50 °C.
  • post-treatment can be carried out according to the routine in the art, and the post-treatment is preferably carried out by the following steps: co-precipitation to obtain an eutectoid of the poorly soluble active component and the ionic polymer
  • the suspension of the substance can be removed by removing the solvent.
  • the solvent to be removed may be a method generally used in the art, preferably a filter washing and drying method. Solvent evaporation method, spray drying method, fluidized bed drying method or freeze drying method.
  • a bridging solvent to the eutectoid suspension to form an eutectoid to form spherical particles under stirring
  • the bridging solvent includes, but is not limited to, chloroform, dichloromethane, Isopropyl acetate, ethyl acetate, isobutyl acetate, methyl acetate, ethyl formate, tert-butyl methyl ether, toluene, dimethyl sulfoxide, dimethylformamide, methanol, ethanol, n-propanol, isopropyl One or more of an alcohol, n-butanol, sec-butanol, dioxane, and acetone.
  • the aqueous solution of different concentrations of ethanol is preferably 0 to 60% by weight of an aqueous solution of ethanol, and the amount thereof is not particularly required.
  • the above-mentioned water or ethanol aqueous solution may also be adjusted with a pH adjusting agent according to the nature and needs of the eutectoid.
  • the pH adjusting agent is pharmaceutically acceptable, including an acidifying agent and alkalization as described above. And pH buffer.
  • the mixture of the step may be subjected to a dispersion treatment with a colloid mill or a homogenizer as needed to further disperse the educt or reduce the particle size of the eutectoid before separating the eutectoid.
  • the filtration washing and drying method is to filter, dry or filter, wash and dry the eluate suspension of the acidic poorly soluble active ingredient and the ionic polymer to obtain fine particles of the acid poorly soluble active ingredient.
  • the washing is preferably carried out by using water or a 0 ⁇ 30% aqueous solution of ethanol, and the number of washings is generally 1 to 5 times.
  • the drying can be carried out by a drying method conventional in the art, such as static drying or dynamic drying. Wherein, the static drying is dried in a normal oven or under reduced pressure, and the temperature is generally 40 to 100 ° C (preferably 50 to 70 ° C), and dried for 1 to 12 hours (preferably 3 to 8 hours), and dried under reduced pressure.
  • the vacuum condition is preferably from 450 mmHg to 76 mmHg, more preferably 150 mmHg.
  • the dynamic drying is carried out, for example, at 50 to 80 ° C (preferably 60 to 70 ° C) in a double cone vacuum drying mixer for 2 to 6 hours (preferably 3 to 5 hours).
  • the present invention also provides an acidic poorly soluble active ingredient microparticle obtained by the above preparation method.
  • the present invention also provides an acidic poorly soluble active ingredient microparticle preparation comprising the above-mentioned acidic poorly soluble active ingredient microparticles and adjuvants acceptable in pharmacy or respective fields; and also including the above-mentioned acidic poorly soluble active ingredient microparticles, other active ingredients and medicaments Learning or acceptable excipients in their respective fields.
  • the present invention also provides a method for preparing the above-mentioned acidic poorly soluble active ingredient microparticle preparation, which can adopt any of the following methods:
  • Method 1 mixing the eutectoid suspension with an auxiliary material to prepare a preparation
  • the second step the eutectoid suspension is filtered or filtered, washed, filtered to obtain a wet eutectoid, and the wet eutectate is mixed with the auxiliary material to prepare a preparation;
  • the third method mixing the acidic poorly soluble active ingredient microparticles with an auxiliary material, and preparing a preparation
  • Method 4 dissolving the acid-insoluble active ingredient and the ionic polymer in an alkaline solution, uniformly mixing with the auxiliary material, mixing with the acidic solution, co-precipitating, performing extrusion granulation or stirring granulation, and then preparing the preparation ;
  • Method 5 Dissolving the acid-insoluble active ingredient and the ionic polymer in an alkaline solution, uniformly mixing with some auxiliary materials, mixing with the acidic solution, co-precipitating, adding the remaining auxiliary materials, performing extrusion granulation, stirring Granulation, fluidized spray granulation or centrifugal spray granulation, and then prepared into a preparation;
  • Method 6 Dissolving the acid-insoluble active ingredient in an alkaline solution, uniformly mixing with the auxiliary material, mixing with the ionic polymer solution dissolved in the acidic solution, co-precipitating, performing extrusion granulation or stirring granulation, and then Preparation method;
  • Method 7 Dissolving the acid-insoluble active ingredient in an alkaline solution, uniformly mixing with some auxiliary materials, mixing with the ionic polymer solution dissolved in the acidic solution, co-precipitating, and adding the remaining auxiliary materials.
  • the preparation is carried out by extrusion granulation, agitation granulation, fluidized spray granulation or centrifugal spray granulation.
  • the preparation of the fine particle preparation containing the acidic poorly soluble active ingredient can be carried out by various methods and by the method of pharmacy or the respective fields, and is not limited to the above-described manner, and the above modes can be arbitrarily combined on the basis of common knowledge in the respective fields.
  • auxiliary material when the auxiliary material is added, pharmaceutically acceptable excipients may be added in different steps of different stages as needed, for example, in the stage of forming a poorly soluble active ingredient eutectoid suspension by eutectoid method, or The poorly soluble active ingredient eutectoid suspension is post-treated or prepared at the stage of preparation, or in the combined preparation process to prepare a stage containing a poorly soluble active ingredient eutectoid preparation.
  • the auxiliary material preferably comprises one or more of a co-dispersant, a water-soluble carrier, a stabilizer, a filler, a binder, a disintegrant, an adsorbent, and a lubricant.
  • the co-dispersant preferably comprises a surfactant and/or a solubilizer.
  • the co-dispersant used in the present invention is more preferably povidone (PVP), poloxamer, water-soluble vitamin E, polyethylene glycol (PEG), hypromellose (HPMC), methyl cellulose ( One or more of MC), hydroxypropylcellulose (HPC), Tween, polyoxyethylene hydrogenated castor oil, sucrose ester, and polyoxyl 40 stearate.
  • the mass of the co-dispersing agent is preferably from 0.1 to 5 times, more preferably from 0.1 to 3 times the mass of the poorly soluble active ingredient.
  • the water-soluble carrier is preferably lactose, mannitol, sucrose, sorbitol, xylitol, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin and
  • maltitol are particularly preferably one or more of lactose, mannitol, sucrose, and ⁇ -cyclodextrin.
  • the stabilizer is preferably sodium metabisulfite, sodium hydrogen sulfite, sodium sulfite, sodium thiosulfate, L-cysteine, sodium vitamin C, vitamin C, tert-butyl-p-hydroxyanisole, dibutylhydroxyl
  • BHT toluene
  • ascorbyl palmitate and propyl gallate.
  • the filler is preferably one or more of lactose, microcrystalline cellulose, starch, pregelatinized starch, mannitol, sorbitol, sucrose, and maltitol.
  • the binder is preferably one of hypromellose, povidone, methylcellulose and hydroxypropylcellulose. Or a variety.
  • the disintegrant is preferably one of sodium carboxymethyl starch, hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, and croscarmellose calcium or A variety.
  • the adsorbent is preferably one or more of calcium sulfate, calcium hydrogen phosphate, and micronized silica gel (colloidal silica).
  • the lubricant is preferably magnesium stearate, micronized silica gel (colloidal silica), magnesium trisilicate, powdered polyethylene glycol, talc, stearic acid and sodium stearyl fumarate. One or more of them.
  • the direct pressure mannitol includes, but is not limited to, PEARLITOL® (mannitol); the direct pressure microcrystalline cellulose includes, but is not limited to, AVICEL® PH-102 F, AVICEL® PH-102 SCG* and AVICEL® PH One or more of the -200 F microcrystalline cellulose series; the direct pressed lactose includes, but is not limited to, anhydrous direct pressed lactose (DT) and/or fast flowing anhydrous direct pressed lactose (DTHV); Direct compression compounds such as, but not limited to, Ludipress® (physically mixed with medicinal lactose, PVP K30, PVPP), Ludipress® LCE (mixed with medicinal lactose and PVP K30), Ludiflash® (from mannitol) , PVP K30, PVPP physically mixed), Cellactose® 80 (lactose and powdered cellulose complex), MicroceLaclOO (lactose and microcrystalline
  • various blank particles containing no active ingredients can be prepared in advance, and then uniformly mixed with the fine particles, and the particle size of the blank particles is controlled to be more than 80% in the range of 100-800 micrometers, preferably controlled. More than 80% is in the 150-500 micron range to ensure mixing, flow and uniformity of particulate formulation.
  • the preparation may be in various forms conventionally used in the respective fields, preferably a solid preparation, a suspension or a controlled release preparation.
  • suspending agents including suspending agents, wetting agents, preservatives, flavoring agents and solvents.
  • the suspending agent is preferably selected from the group consisting of xanthan gum, gum arabic, povidone, tragacanth, sodium alginate, glycerol, sucrose, mannitol, sorbitol, methylcellulose, hydroxypropyl One or more of methylcellulose, sodium carboxymethyl starch, sodium carboxymethylcellulose, and bentonite;
  • the wetting agent is preferably selected from the group consisting of Tween 80, polyoxyethylene fatty alcohol ether (benzyl Ze), one or more of polyoxyethylene fatty acid (selling), poloxamer, and sodium decyl sulfate.
  • the solvent is usually water or a mixed solution of water and an alcohol, and the alcohol is generally one or more of propylene glycol, benzyl alcohol and ethanol.
  • the solvent is used in an amount to make up the weight percentage of the suspension to 100%.
  • Preservatives and/or flavoring agents may also be included in the suspension, and the preservative is preferably selected from the group consisting of preservatives.
  • the flavoring agent is preferably selected from the group consisting of One or more of aspartame, stevioside, and flavor.
  • the invention also provides a preparation method of the basic poorly soluble active ingredient microparticles, comprising the following steps:
  • the acidic solution and/or the alkaline solution are dissolved in the ionic polymer preferably in any of the following manners:
  • the alkaline poorly soluble active ingredient and the partial ionic polymer are co-dissolved in an acidic solution, and then mixed with an alkaline solution in which the remaining amount of the ionic polymer is dissolved.
  • the basic poorly soluble active ingredient refers to a poorly soluble activity which can be dissolved in an acidic solution in the art.
  • Ingredients preferably including domperidone, risperidone, zopiclone, diazepam, berberine, estazolam, huperzine A, alprazolam, clozapine, olanzapine, glucosamine, Terbinafine, aripiprazole, cefotiamide, amiodarone, levofloxacin, cinnarizine, flunarizine, mifepristone, perphenazine, digoxin, azithromycin, trimethoprim , Benzofuran, Phenylpyridinium, Lamotrigine, Acotamine, Chlorpromazine, Nemoride, Celecoxib, Tofatib, Gfitinib, Nilotinib, Er Lotitinib, imatinib, bosut
  • all of the above-mentioned basic poorly soluble active ingredients may be used as derivatives or conjugates thereof, including but not limited to isomers, epimers, and diastereomers of the active ingredient. Or a racemic mixture.
  • the ionic polymer preferably comprises an anionic polymer and/or a cationic polymer.
  • the anionic polymer preferably includes, but is not limited to, a (meth) acrylate polymer, a (meth) acrylate copolymer, a polyethylene polymer, a polyethylene copolymer, an acid-substituted cellulose ester, a carboxy group.
  • the alkaline solution is prepared by adding an alkalizing agent or a pH buffer to the solvent;
  • the acidic solution is prepared by adding an acidifying agent or a pH buffer to the solvent.
  • the alkalizing agent may be a single base or a complex base composed of two or more components, and generally includes one or more of an inorganic strong base, a weak acid strong base salt and an organic base;
  • the inorganic strong base preferably includes sodium hydroxide and/or potassium hydroxide
  • the weak acid strong base salt is preferably one or more of sodium carbonate, potassium carbonate and disodium hydrogen phosphate.
  • the base is preferably one or more of meglumine, ethylenediamine, arginine and lysine.
  • the alkalizing agent is more preferably one or more of sodium hydroxide, sodium carbonate, disodium hydrogen phosphate, meglumine, ethylenediamine and arginine.
  • the alkalizing agent is preferably added in the form of an aqueous alkalizing agent, and the concentration of the aqueous alkalizing agent solution is preferably from 1 to 20% by weight.
  • the pH buffer is more preferably hydrochloric acid-glycine buffer, hydrochloric acid-sodium hydroxide-capric acid buffer, hydrochloric acid-sodium citrate buffer, sodium hydroxide-citrate buffer, sodium hydroxide - Glycine buffer, sodium citrate-sodium citrate buffer, sodium carbonate-sodium bicarbonate buffer or disodium hydrogen phosphate-sodium dihydrogen phosphate buffer.
  • the solvent is preferably water and/or an organic solvent, more preferably water.
  • the organic solvent may be selected in a solvent acceptable for the pharmaceutical field according to the principle that its solubility to the basic poorly soluble active ingredient is superior to water, preferably a water-miscible organic solvent such as pharmacy.
  • a water-soluble alcohol solvent commonly used in the field such as one or more of ethanol, propylene glycol, glycerin, ethylene glycol, isopropanol and benzyl alcohol, preferably ethanol.
  • the amount of the organic solvent can be arbitrarily selected.
  • the solvent is used in an amount sufficient to completely dissolve the basic poorly soluble active ingredient, and is usually from 3 to 300 times, preferably from 5 to 200 times the mass of the basic poorly soluble active ingredient.
  • the alkaline poorly soluble active ingredient is dissolved in an acidic solution
  • the ionic polymer is dissolved in an acidic solution and/or an alkaline solution
  • the acidic solution and the alkaline solution are mixed to change the pH of the solution, thereby
  • the alkaline poorly soluble active ingredient and the ionic polymer are co-precipitated in the mixed solution.
  • the alkaline poorly soluble active ingredient and the ionic polymer can be sufficiently eutectoidally controlled by controlling the pH of the mixed solution.
  • the pH of the solution containing the basic poorly soluble active ingredient is preferably 5.0 10.0, more preferably 6.0 9.0.
  • the mixing may be carried out in various liquid-liquid or liquid-solid mixing modes including, but not limited to, one or more of mechanical agitation, gas flow, liquid jet, and ultrasound.
  • mechanical stirring method various stirring devices, stirring blades of different shapes, and agitation speeds may be selected, and the stirring speed is to make the system quickly and uniformly disperse, preferably the linear speed of the agitator is 50-500.
  • ultrasonic assisted mode it is also possible to use ultrasonic assisted mode at the same time, or use various homogenizers to mix and disperse.
  • post-treatment can be carried out according to the routine in the art, and the post-treatment is preferably carried out by the following steps: co-precipitation to obtain a total of the basic poorly soluble active ingredient and the ionic polymer
  • the suspension of the analyte can be removed by removing the solvent.
  • the solvent to be removed may be a method generally used in the art, and is preferably a filter washing and drying method, a solvent evaporation method, a spray drying method, a fluidized bed drying method or a freeze drying method.
  • a bridging solvent to the eutectoid suspension to form an eutectoid to form spherical particles under stirring
  • the bridging solvent includes, but is not limited to, chloroform, dichloromethane, Isopropyl acetate, ethyl acetate, isobutyl acetate, methyl acetate, ethyl formate, tert-butyl methyl ether, toluene, dimethyl sulfoxide, dimethylformamide, methanol, ethanol, n-propanol, isopropyl One or more of an alcohol, n-butanol, sec-butanol, dioxane, and acetone.
  • the mixture of the step may be subjected to a dispersion treatment with a colloid mill or a homogenizer as needed to further disperse the educt or reduce the particle size of the eutectoid before separating the eutectoid.
  • the filtration washing and drying method is to filter, dry or filter, wash and dry the eutectoid suspension of the poorly soluble active ingredient and the ionic polymer.
  • the washing is preferably carried out by using water or a 0 to 30% by weight aqueous solution of ethanol, and the number of washings is generally 1 to 5 times.
  • the drying can be carried out by conventional drying in the art.
  • the method is carried out, such as static drying or dynamic drying. Wherein, the static drying is dried in a normal oven or under reduced pressure, and the temperature is generally 40 to 100 ° C (preferably 50 to 70 ° C), dried for 1 to 12 hours (preferably 3 to 8 hours), and dried under reduced pressure.
  • the vacuum condition is preferably from 450 mmHg to 76 mmHg, more preferably 150 mmHg.
  • the dynamic drying is carried out by drying in a double cone vacuum drying mixer at 50 to 80 ° C (preferably 60 to 70 ° C) for 2 to 6 hours (preferably 3 to 5 hours).
  • the present invention also provides a basic poorly soluble active ingredient microparticle preparation comprising the above-mentioned basic poorly soluble active ingredient microparticles and adjuvants; also comprising the above basic poorly soluble active ingredient microparticles, other active ingredients and pharmacy or respective fields Accepted accessories.
  • the second step the eutectoid suspension is filtered or filtered, washed, filtered to obtain a wet eutectoid, and the wet eutectate is mixed with the auxiliary material to prepare a preparation;
  • the third method is: mixing the alkaline poorly soluble active ingredient microparticles with an auxiliary material to prepare a preparation;
  • Method 4 dissolving the alkaline poorly soluble active ingredient and the ionic polymer in an acidic solution, uniformly mixing with the auxiliary material, mixing with the alkaline solution, coprecipitating, performing extrusion granulation or stirring granulation, and then preparing Formulation
  • Method 6 dissolving the alkali-insoluble active ingredient in an acidic solution, uniformly mixing with the auxiliary material, mixing with the ionic polymer solution dissolved in the alkaline solution, co-precipitating, performing extrusion granulation or stirring granulation, The preparation is prepared.
  • Method 7 Dissolving the alkaline poorly soluble active ingredient in an acidic solution, uniformly mixing with some auxiliary materials, and then mixing with the ionic polymer solution dissolved in the alkaline solution, coprecipitating, and then adding the balance The excipients are subjected to extrusion granulation, agitation granulation, fluidized spray granulation or centrifugal spray granulation to prepare a preparation.
  • auxiliary material when the auxiliary material is added, pharmaceutically acceptable excipients may be added in different steps of different stages as needed, for example, in the stage of forming a poorly soluble active ingredient eutectoid suspension by eutectoid method, or The poorly soluble active ingredient eutectoid suspension is post-treated or prepared at the stage of preparation, or in the combined preparation process to prepare a stage containing a poorly soluble active ingredient eutectoid preparation.
  • the auxiliary material preferably comprises one or more of a co-dispersant, a water-soluble carrier, a stabilizer, a filler, a binder, a disintegrant, an adsorbent, and a lubricant.
  • the stabilizer is preferably sodium metabisulfite, sodium hydrogen sulfite, sodium sulfite, sodium thiosulfate, L-cysteine, sodium vitamin C, vitamin C, tert-butyl-p-hydroxyanisole, dibutylhydroxyl
  • BHT toluene
  • ascorbyl palmitate and propyl gallate.
  • the disintegrant is preferably one of sodium carboxymethyl starch, hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, and croscarmellose calcium or A variety.
  • the adsorbent is preferably one or more of calcium sulfate, calcium hydrogen phosphate, and micronized silica gel (colloidal silica).
  • the lubricant is preferably magnesium stearate, micronized silica gel (colloidal silica), magnesium trisilicate, powdered polyethylene glycol, talc, stearic acid and sodium stearyl fumarate. One or more of them.
  • the direct pressure mannitol includes but is not limited to PEARLITOL® (mannitol); said direct pressure microcrystalline cellulose includes but is not limited to one of AVICEL® PH-102 F, AVICEL® PH-102 SCG* and AVICEL® PH-200 F microcrystalline cellulose series
  • the direct compression lactose includes, but is not limited to, anhydrous direct lactose (DT) and/or fast flowing anhydrous lactose (DTHV), etc.;
  • the direct compression composite includes but is not limited to Ludipress® (physically mixed with medicinal lactose, PVP K30, PVPP), Ludipress® LCE (mixed with medicinal lactose and PVP K30), Ludiflash® (physically mixed with mannitol, PVP K30, PVPP), Cellactose ®80 (Lactose and Powdered Cellulose Complex), MicroceLaclOO
  • the form of the preparation may be various dosage forms conventional in the art, preferably a solid preparation, a suspension or a controlled release preparation.
  • Particle size is the most basic property of microparticles. Reducing the particle size of poorly soluble active ingredients is an effective way to improve the dissolution properties of poorly soluble active ingredient preparations.
  • the shape of the microparticles is generally irregular and needs to be defined by geometric or physical concepts.
  • the particle size of the particles There are various methods for measuring the particle diameter of the particles such as optical microscopy, electron microscopy, laser scattering, Coulter counting, sedimentation, adsorption, and the like. At present, a laser particle size analyzer is commonly used to determine the particle size of poorly soluble drug particles, which employs Furanhofer diffraction and Mie scattering principles.
  • Reducing the particle size of the poorly soluble active ingredient is an effective method for improving the dissolution properties of the poorly soluble active ingredient preparation.
  • the particle size is small and the dissolution rate is improved.
  • some of the poorly soluble active ingredient particles obtained by conventional methods have problems such as surface energy, electrostatic force and agglomeration, which are difficult to mix with other materials, poor dispersion, poor wetting and poor stability. If the technical problem is not properly solved, the effect of using the poorly soluble active ingredient particles in the preparation will be reduced, and the other properties of the particles must be paid attention to while reducing the particle size. In order to improve the dissolution level of the poorly soluble active ingredient particles, it is more meaningful to improve the surface properties of the particles than to merely reduce the particle size.
  • a major feature of the present invention is that the specific surface area of the poorly soluble active ingredient particles is greatly increased.
  • the reagents and starting materials used in the present invention are commercially available.
  • the present invention forms a poorly soluble active component eutectoid (composite microparticles) by changing the pH value of the solution, so that the poorly soluble active ingredient and the ionic polymer originally dissolved in the solution are co-precipitated from the solution, so that the poorly soluble activity
  • the properties of the ingredients are significantly changed, the dissolution properties of the poorly soluble active ingredient particles and the active ingredient microparticle preparations are greatly improved; the release properties of the poorly soluble active ingredients can be changed, and the effective release rate is provided for the development of various slow and controlled release preparations.
  • the method can obviously improve the filterability when preparing the particles of the poorly soluble active ingredient, facilitate the subsequent treatment, and can obviously improve the dispersibility and fluidity of the poorly soluble active ingredient particles, and is more suitable for further processing to obtain a high quality active ingredient preparation. It also prevents agglomeration of the particles and improves the stability of the poorly soluble active ingredient microparticle preparation.
  • the eutectoid solution of the poorly soluble active ingredient and the ionic polymer is tightly integrated with the preparation process, and the poorly soluble active ingredient microparticle preparation is integrally prepared.
  • the prepared poorly soluble active ingredient preparation has excellent dissolution characteristics, high bioavailability, small individual difference, and also has better stability and content uniformity.
  • the pH-eutectoid method of the present invention can be used without removing the organic solvent or using the organic solvent in a large amount, and can be removed by filtration or directly combined with the preparation process, and the operation process is simple and the solid dispersion is avoided.
  • Figure 1 is a comparison of dissolution profiles of domperidone microparticles.
  • Figure 4 is a comparison of the dissolution curves of glipizide microparticles.
  • Figure 5 is a comparison of the dissolution curves of indomethacin microparticles.
  • Figure 6 is a comparison of the dissolution curves of folic acid tablets.
  • Figure 7 is a graph showing the release profile of three batches of mefenamic acid sustained release tablets.
  • Figure 8 is a particle surface morphology diagram of domionalone sample 1A (a), comparative 1A (b) and domperidone raw material sample (c) (magnified by scanning electron microscope 5000 times;).
  • Figure 9 is a graph showing the surface morphology of the samples of mefenamic acid samples 3A (a), contrast 3B (b) and comparative 3C (c) (scanning electron microscope magnification 10000 times;).
  • Figure 10 is a surface morphology diagram of domperidone sample 1A, wherein (a) is a 0-day sample, (b) is placed at room temperature for 6 months, (c) is placed under accelerated conditions for 6 months (scanning electron microscope magnification 5000 times) ).
  • Figure 11 is a comparison of the dissolution curves of glipizide microparticles.
  • the content indicates the percentage content.
  • the indicated amount of the formulation refers to the amount of the main drug specified in the formulation of the unit dose, which is usually indicated on the specification of the dosage form.
  • the percentage indicated by the formulation is the percentage of each sample content and the labeled amount, indicating the degree of deviation from the labeled amount, generally specified at 90%-110%, 93%-107% or 95%-105%.
  • Resin Eudragit EPO 0.15g after it is dissolved, filter the solution; add 7.0% sodium hydroxide solution to the solution at a rate of 0.75ml / min, control the pH of the solution to 7.2 and continue to stir for 30 min, pump The eutectoid was filtered, washed three times with water, dried at 40 ° C for 48 h, and then gently ground. After passing through a 80 mesh sieve, a sample (denoted as 1 A) was obtained, and the content was 99.79%.
  • Comparative 1A Washed with water 3 times, After drying at 40 ° C for 48 h, it was gently ground and passed through a 80 mesh sieve to obtain a sample (denoted as Comparative 1A) with a content of 99.67%.
  • Three kinds of domperidone microparticles were prepared by the above method as comparison. It was recorded that the PVP K30 was added to 9 g in the sample of Comparative 1B, and other conditions were unchanged; it was recorded that the sample of Comparative 1C was added with polyethylene glycol 6000 1.5g instead of PVP K30. All other conditions were unchanged; PVP K30 was not added to the sample recorded as 1D, and the other conditions were unchanged.
  • the contents of Comparative 1B, Comparative 1C and Comparative 1D samples were 99.56%, 99.47% and P 99.73%, respectively.
  • the lg estradiol was dispersed in 120 ml of 30% ethanol, dispersed using a stirrer at a linear velocity of 250 m/min, and then 0.5 g of acrylic future L100 was added thereto and dispersed to 15 ml/min.
  • S100 was dissolved, and a hydrochloric acid solution having a concentration of 10% was added to the solution until the pH of the solution was 4.0, and an eutectoid suspension was obtained.
  • the eutectoid was obtained by suction filtration, washed twice with water, and dried under reduced pressure at 50 °C. h, a sample (denoted as 6A) was obtained after passing through a mesh of 80 mesh, and the content was 100.1%.
  • the suspension is added to the above mixed powder for rapid stirring and granulation, and the wet granules are dried. After the whole granules, 1.5 g of magnesium stearate was added, and 3 g of crospovidone was uniformly mixed, and the tablets were compressed according to the specifications of 2.5 mg of methotrexate/tablet.
  • the granules were extruded by a 20-mesh sieve, and the wet granules were dried and granulated, and 1.5 g of magnesium stearate, 0.3 g of micronized silica gel and 4 g of sodium carboxymethyl starch were added and uniformly mixed, and the tablets were tableted in a size of 5 mg of folic acid/tablet.
  • mannitol 60 g of mannitol, 80 g of microcrystalline cellulose, 10 g of starch and 10 g of hydroxypropyl cellulose were uniformly mixed, and 2 g of risperidone, 0.2 g of acrylic acid Eudragit EPO, 30 g of water, l. lg glycine and 2.0 g of 0% hydrochloric acid aqueous solution were mixed.
  • the solution was prepared together, and 2.3 g of 10% aqueous sodium hydroxide solution was added under a mixing condition of a 150 m/min linear speed stirrer to prepare a risperidone eutectoid suspension, and the suspension was added to the above. The mixture is quickly stirred and granulated.
  • the wet granules are dried and then granulated.
  • 1.5 g of magnesium stearate, 0.3 g of micronized silica gel and 3 g of croscarmellose sodium are added and uniformly mixed, and pressed according to the specification of 1 mg risperidone/tablet.
  • Into the core Add the film-coated premix (stomach-soluble Opadry) powder in water while stirring. After the addition, continue to stir for 45 minutes, and prepare a film coating liquid with a solid content of 18% to coat the core. The clothing layer gained about 3%.
  • Example 11 Domperidone tablets (5 mg / tablet)
  • Example 1 5 g of the sample 1A prepared in Example 1 was mixed with 5 g of microcrystalline cellulose (pH 102 F), passed through a 80 mesh sieve, and further mixed with 60 g of anhydrous lactose (DT), 30 g of microcrystalline cellulose (pH 102 F), 5 g of sodium carboxymethyl starch, 0.3 g of microsilica gel and 1.2 g of magnesium stearate were mixed and sieved through a 40 mesh sieve, and the mixture was uniformly mixed and then compressed.
  • DT anhydrous lactose
  • Example 12 Mefenamic acid sustained-release tablets (500 mg/tablet)
  • Example 3 50 g of mefenamic acid and 5 g of acrylic resin Eudragit L100 were prepared as in Example 3, and mixed with 16 g of lactose, 16 g of HPMC K4M, passed through a 80 mesh sieve, and then uniformly mixed with 4 g of magnesium stearate. , tablet at 500mg/table size. Three batches were prepared separately, and the release curves of the three batches are shown in Fig. 7.
  • Example 1 The aqueous eutectin obtained by washing 3 times in Example 1 (Acrylic Eudragit EPO 1.5 g formulation) was filtered, and 20 g of lactose, 20 g of microcrystalline cellulose and an appropriate amount of 3% hypromellose aqueous solution were combined. The mixture was quickly stirred and granulated. The wet granules were dried and then granulated. 0.5 g of magnesium stearate, 1.5 g of cross-linked polyvinylpyrrolidone and O.lg micronized silica gel were added and uniformly mixed, and the tablets were compressed according to the specifications of 10 mg of domperidone/tablet.
  • the eutectoid was obtained by filtration, washed with water for 5 times, and dried under reduced pressure at 55 ° C for 5 hours ; it was gently ground in a mortar and passed through a sieve of 80 mesh to obtain gambogic acid microparticles.
  • 0.5 g of new gambogic acid and 0.25 g of acrylic resin L100 were dispersed in 20 ml of a 30% aqueous solution of ethanol, and then a 10% strength arginine solution was added until complete dissolution.
  • a dilute hydrochloric acid solution having a concentration of 8% at a rate of 5 ml/min to a pH of about 4.5 at a line speed of 180 m/min.
  • the eutectoid was obtained by filtration, washed with water for 5 times, and dried under reduced pressure at 55 ° C for 5 hours ; it was gently ground in a mortar, and after 80 mesh sieve, the new gambogic acid microparticles were obtained.
  • the aqueous eutectin was mixed with 10 g of lactose, 20 g of microcrystalline cellulose and an appropriate amount of 5% hypromellose aqueous solution to form a soft material, and granulated by extrusion.
  • the wet granules were dried and granulated, and 0.3 g of magnesium stearate, 1.5 g of sodium carboxymethyl starch and 0.1 g of microsilica gel were added and uniformly mixed, and the tablets were compressed according to the specifications of 40 mg of telmisartan/tablet.
  • the eutectoid was obtained by suction filtration, washed twice with water, and the sample was dried under reduced pressure at 50 ° C for 5 h. After passing through a mesh of 80 mesh, a sample (reported as 25 A) was obtained, and the content was 99.33%. In addition, without using ultrasound, other samples were prepared as described above (denoted as 25B) with a content of 99.51%.
  • Comparative 7A After passing through a mesh of 80 mesh, a sample (indicated as Comparative 7A) was obtained, and the content was 99.78%. In addition, without using ultrasound, other samples were prepared as described above (denoted as Comparative 7B) with a content of 99.91%.
  • Example 26 According to the preparation method of Example 26, 0.5 g of urethane resin Eudragit L100 was replaced with 2.5 g of hydroxypropylmethylcellulose acetate succinate (AS-HF) to obtain a sample (indicated as 28A) in an amount of 103.07%.
  • AS-HF hydroxypropylmethylcellulose acetate succinate
  • the glipizide microcrystalline material was used as a comparison 8 .
  • Example 29 According to the preparation method of Example 29, 0.15 g of acrylic acid resin Eudragit 0.15 g of S100 was replaced with 0.15 g of hydroxypropylmethylcellulose acetate succinate (AS-HF) to obtain a sample (indicated as 30A) in an amount of 98.1%. The sample had a dissolution rate of greater than 90% in a pH 6.8 phosphate buffer for 10 minutes.
  • AS-HF hydroxypropylmethylcellulose acetate succinate
  • Example 31 Hydrochlorothiazide particles Disperse 10 g of hydrochlorothiazide and lg acrylic resin Eudragit L100 in 100 ml of water, disperse it at a line speed of 200 m/min using a stirrer, and add a 10% sodium hydroxide solution to dissolve hydrochlorothiazide and acrylic Eutec L100.
  • a hydrochloric acid solution having a concentration of 10% was added until the pH of the solution was 4.0, and an eutectoid suspension was obtained.
  • the eutectoid was obtained by suction filtration, washed twice with water, and dried under reduced pressure at 50 ° C for 5 h.
  • a sample (denoted as 31 A) was obtained after passing through a mesh of 80 mesh, and the content was 97.35%.
  • the hydrochlorothiazide material was used as a comparison 10 .
  • Example 33 Losartan Potassium Hydrochlorothiazide Tablets (50 mg of losartan potassium, 12.5 mg of hydrochlorothiazide/tablet) 10 g of losartan potassium, 2.5 g of the microparticles obtained in Example 7, 14 g of pregelatinized starch, 6 g of lactose and 4 g were taken.
  • Microcrystalline cellulose is uniformly mixed, using 2% hypromellose (5 mPa.s) as a binder, wet granulation, drying, whole granules, adding 0.35 g of magnesium stearate and mixing evenly, according to 50 mg of chlorin Tablets of potassium sulphate, 12.5 mg hydrochlorothiazide/tablet, and the sample was recorded as 33A.
  • 400g blank pellet core was weighed as the starting material, and the above-mentioned drug-suspended solution was applied to the fluidized bed; the air volume was 60 m3/hr, the temperature was 50-45 °C, and the atomization pressure was At 2000 mbar, the product temperature is controlled at 35-38 °C.
  • Preparation of coating solution Weigh the enteric material L 100 about 110 g, and slowly add about 600 g of ethanol. To the remaining about 300 g of ethanol, triethyl citrate and talc were added in an appropriate amount, and thoroughly homogenized for 10 minutes using a high-speed emulsion homogenizer. The suspension was filtered through a 100 mesh screen, slowly poured into a solution of L100 ethanol, and formulated into a coating solution, which was coated by a bottom spray method in a stirring manner.
  • Fluidized bed coating parameters spray rate 2.5-3.5 g/min, inlet air temperature 30-35 °C, air inlet volume 55-65 m 3 /h, bed temperature 28-30 ° C, atomization pressure 1500 m bar. After coating, it is dried in an oven at 40 ° C for 2 h to obtain enteric pellets.
  • Dissolution test method Take the appropriate amount of sample (equivalent to domperidone 10mg), according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), with pH 6.0 phosphate buffer 900 ml as the dissolution medium, the rotation speed is 50 rpm, operate according to the law, take 5ml of solution at the set time, replenish 5ml, filter the sample, discard the initial filtrate, take the filtrate as the sample solution, and prepare the control solution.
  • the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 20010 edition, Appendix II A), the absorbance is measured at a wavelength of 283 nm, and the amount of dissolution of the sample is calculated.
  • Dissolution test method Take the appropriate amount of sample (equivalent to 5mg of estradiol), according to the dissolution test method (Chinese Pharmacopoeia 2010 edition two appendix XC third method), with 0.1% sodium decyl sulfate aqueous solution 200 ml as dissolution Medium, rotation speed is 100 rpm, operate according to law, take 5ml solution at the set time, replenish 5ml, filter the sample, discard The initial filtrate was removed, and the filtrate was taken as a sample solution, and a control solution was prepared. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 20010 edition two appendix IV A), the absorbance was measured at a wavelength of 282 nm, and the elution amount of the sample was calculated.
  • Example 2 Comparison of dissolution is shown in Figure 2 Comparison of estradiol microparticle dissolution curves (2A, 2B, comparison 2A, comparison 2B, comparison 2C).
  • Dissolution test method Take the appropriate amount of sample (equivalent to 25 mg of mefenamic acid), according to the dissolution test method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), dissolve in 1000 ml phosphate buffer pH 7.6 Medium, the rotation speed is 50 rpm, operate according to the law, take 10ml of solution at the set time, replenish 10ml, filter the sample, discard the initial filtrate, take the filtrate as the sample solution, and prepare the control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 20010 edition, Appendix II A), the absorbance is measured at a wavelength of 286 nm, and the amount of dissolution of the sample is calculated.
  • the dissolution test method Choinese Pharmacopoeia 2010 edition two appendix XC second method
  • Example 25 and Comparative Example 7 The dissolution rates of Example 25 and Comparative Example 7: the dissolution rates of sample 25A and comparative 7A at 10 min were 95.1% and 25.5%, respectively, the dissolution at 45 min was 98.3% and 52.5%, respectively; the sample 25B was compared with 10 min of comparison 7B. The dissolution rates were 92.7% and 18.5%, respectively, and the dissolution rates at 45 min were 96.5% and 42.1%, respectively.
  • Dissolution test method Take the appropriate amount of sample (equivalent to glipizide 5mg or 5mg tablets), according to dissolution test (Chinese Pharmacopoeia 2010 edition two appendix XC second method), phosphate buffer 900 with pH6.0 Ml is the dissolution medium, the rotation speed is 50 rpm, operate according to the law, take 6ml of solution at the set time, replenish 6ml, filter the sample, discard the initial filtrate, take the filtrate as the sample solution, and prepare the control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 20010 edition, Appendix II A), the absorbance is measured at a wavelength of 275 nm, and the amount of dissolution of the sample is calculated.
  • Example 4 Comparison of dissolution is shown in Figure 4 Comparison of the dissolution profiles of glipizide microparticles (4A, 4B, C and Comparative 4).
  • Example 22 The dissolution of glipizide tablets at 30 min was 90.2%.
  • Dissolution test method 2 Take the appropriate amount of the sample (equivalent to glipizide 5mg), according to the dissolution test (Chinese Pharmacopoeia 2010 edition two appendix XC second method), to pH 6.8 900 ml of phosphate buffer is the dissolution medium, the rotation speed is 50 rpm, operate according to the law, take 6ml of solution at the set time, replenish 6ml, filter the sample, discard the primary filtrate, and take the filtrate as the sample solution. A control solution was prepared. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 20010 edition, Appendix II A), the absorbance is measured at a wavelength of 275 nm, and the amount of dissolution of the sample is calculated.
  • Comparison of dissolution rates of Examples 26, 27 and 28 is shown in Figure 11. Comparison of dissolution profiles of glipizide particles (26A, 27A, 28 A and contrast 8) are shown.
  • Dissolution test method Take the appropriate amount of the sample (equivalent to indomethacin 25mg), according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), dissolved in 100 mM phosphate buffer pH 6.8 Medium, rotation speed is 50 rpm, operate according to law, take 6ml solution at the set time, replenish 6ml, filter the sample, discard the initial filtrate, take the filtrate as the sample solution, and prepare the control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 20010 edition II attached IV A), the absorbance is measured at a wavelength of 320 nm, and the elution amount of the sample is calculated.
  • Dissolution test method Take the sample and measure the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix X C second method), use 900 ml of water as the dissolution medium, rotate at 100 rpm, operate according to law, and prepare a control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance is measured at a wavelength of 281 nm, and the elution amount of the sample is calculated.
  • Example 9 and Comparative Example 6 Comparison of dissolution rates is shown in Fig. 6. Comparison of dissolution profiles of folic acid tablets (Example 9, Comparative 6A and Comparative 6B).
  • Determination of release method Take the sample, according to the release method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), with pH7.6 phosphate buffer (containing 0.5% Tween 80) 1000ml as the release medium, the rotation speed is 50 rpm, operate according to the law, sample 10ml at 1, 2, 4, 6, 8, 10, 12h, replenish 10ml, filter the sample, discard the primary filtrate, and dilute the filtrate to the appropriate concentration, as a sample The solution was prepared and a control solution was prepared. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 20010 edition two appendix IV A), the absorbance is measured at a wavelength of 286 nm, and the cumulative release of the sample is calculated.
  • the release method Choinese Pharmacopoeia 2010 edition two appendix XC second method
  • pH7.6 phosphate buffer containing 0.5% Tween 80
  • Example 12 Comparison of dissolution is shown in the release profile of the three batches of mefenamic acid sustained release tablets.
  • Dissolution test method Take the appropriate amount of sample (about 10mg of hydrochlorothiazide), according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), with 0.1m O l / L hydrochloric acid 1000 ml as the dissolution medium, The rotation speed is 100 rpm, operate according to the law, take 10ml of solution at the set time, replenish 10ml, filter the sample, discard the initial filtrate, take the filtrate as the sample solution, and prepare the control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 20010 edition two appendix IV A), the absorbance was measured at a wavelength of 272 nm, and the elution amount of the sample was calculated.
  • Example 31 and Comparative Examples 9, 10 are shown in Figure 12 for the comparison of the dissolution profiles of hydrochlorothiazide microparticles (31A, Comparative 9 and Comparative 10). Effect Example 2 Comparison of surface morphology of particles
  • Measurement Determine the magnification, observe, and select the appropriate position to take a scanning electron microscope photograph.
  • Domperidone microparticles The surface morphology of the sample of Example 1 in Example 1A (a), Comparative Example 1 Comparative 1A (b) and domionate raw material (c) is shown in Fig. 8.
  • Domperidone microparticles Comparing the microscopic shape stability of the sample 1A in Example 1, the scanning electron micrograph is shown in Fig. 10, wherein (a) is a sample of 0 day, (b) is left at room temperature for 6 months, (c) Place for 6 months under accelerated conditions.
  • test samples were placed in high density polyethylene plastic bottles and sealed. 1) Put it into the accelerated inspection box and carry out the 6-month accelerated test at a temperature of 40 °C ⁇ 2 °C, relative humidity of 75% ⁇ 5%, 2) into the accelerated test chamber at a temperature of 25 ° C ⁇ A 6-month accelerated test was carried out at 2 ° C and a relative humidity of 75% ⁇ 5%. The stability of the relevant project was determined after the accelerated test.
  • Determination method Take the appropriate amount of sample (equivalent to domperidone 25mg), put it in a 50 ml volumetric flask, add 30 ml of absolute ethanol, and dissolve it completely by ultrasound. After cooling to room temperature, make up to volume with absolute ethanol and shake well. That is, much more phenyl ketone sample stock solution. Precisely measure 1 ml of the stock solution, place it in a 25 ml volumetric flask, dilute to a pH 6.0 phosphate buffer solution, shake it and filter it to obtain a test solution, and prepare a reference solution for UV-visible spectrophotometry. The method (Chinese Pharmacopoeia 2010 edition two appendix IV A), the absorbance was measured at a wavelength of 283 nm, and the sample content was calculated.
  • the dissolution test method was the same as the effect example 1.
  • Determination method Take the appropriate amount of sample (equivalent to 20mg of estradiol), place it in a 25ml volumetric flask, add 15ml of absolute ethanol, dissolve it by ultrasound, and then cool it to room temperature, then make up to volume with absolute ethanol, shake well Estradiol sample stock solution was obtained. Precisely measure 1 ml of the stock solution, place it in a 25 ml volumetric flask, and make up to volume with 0.1% sodium sulfonate solution. Shake well to obtain the test solution. Also prepare a reference solution, UV-visible Spectrophotometry (Chinese Pharmacopoeia 2010 Edition, Part II, Appendix IV A), absorbance was measured at a wavelength of 282 nm, and the sample content was calculated.
  • UV-visible Spectrophotometry Choinese Pharmacopoeia 2010 Edition, Part II, Appendix IV A
  • the dissolution test method was the same as the effect example 1.
  • Sample 2A was placed in a high density polyethylene plastic bottle and sealed. It was 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%. The dissolution rate was 96.2% at 45 min after the accelerated test.
  • Method for determination Take appropriate amount of sample (equivalent to 25 mg of mefenamic acid), place in a 50 ml volumetric flask, add 30 ml of absolute ethanol, dissolve it by sonication, and after cooling to room temperature, make up to volume with absolute ethanol and shake well. A solution of mefenamic acid sample is obtained.
  • the dissolution test method was the same as the effect example 1.
  • Determination method Take the appropriate amount of sample (equivalent to glipizide 5mg), put it in a 10 ml volumetric flask, add methanol to dissolve, dilute to volume, shake well, then get the glipizide sample stock solution. Precisely measure 0.5ml of the stock solution and place 25 ml volumetric flask In the medium, the volume of the dissolution medium is adjusted to a pH of 6.0 in phosphate buffer solution, and the mixture is shaken and filtered to obtain a test solution.
  • the glipizide reference solution was prepared by the same method, and the absorbance was measured at the wavelength of 275 nm according to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), and the sample content was calculated.
  • the dissolution test method was the same as the effect example 1.
  • Example 4 of the present invention sample 4A (prepared by pH-eutectoid method, glipizide: HPMCP was 1:0.5) lOmin and 45 min dissolution were 90.3% and 91.5%, which was significantly better than glipizide microcrystals. 4.3% and 9.5% of the raw material (sample comparison 4).
  • the particle size of the sample comparison 4 (D 10 , D 50 and D 90 are 1.507 ⁇ , 3.456 ⁇ and 11.604 ⁇ , respectively) is smaller than the particle size of the sample 4 ⁇ particles (D 10 , D 50 and D 90 are 4.742 ⁇ , 12.335, respectively). ⁇ and 24.906 ⁇ ), however, exhibited a rather low dissolution.
  • the gemizide and the ionic polymer HPMCP were subjected to pH-eutectoidization in a solvent system, and the properties of the formed eutectoid particles were significantly changed, although the particle size of the sample 4A was larger than that of the sample comparison 4,
  • the dissolution rate of lOmin is 21.0 times that of sample comparison 4
  • the dissolution rate of 45 minutes is 9.6 times that of sample comparison 4.
  • Sample 4A was placed in a high density polyethylene plastic bottle and sealed. It was 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%. The dissolution rate was 92.1% at 45 min after the accelerated test.
  • Determination method Take the appropriate amount of the sample (equivalent to 20 mg of indomethacin), place it in a 50 ml volumetric flask, add ethanol to dissolve, dilute to volume, and shake well to obtain the indomethacin sample stock solution. Precisely measure 0.5 ml of the stock solution, set a volume of 10 ml volumetric flask with ethanol, and shake it to obtain a test solution.
  • the indomethacin reference solution was prepared by the same method, and the absorbance was measured at a wavelength of 320 nm according to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), and the sample content was calculated.
  • Example 5 The sample 5 of Example 5 was placed in a high-density polyethylene plastic bottle and sealed. It was 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%. The dissolution rate was 95.2% at 30 minutes after the accelerated test.
  • Determination method Take the appropriate amount of sample (equivalent to hydrochlorothiazide 10mg), put it in a 50 ml volumetric flask, add anhydrous ethanol to dissolve, dilute to volume, and shake well to obtain hydrochlorothiazide sample stock solution. Precisely measure 2.5 ml of the stock solution into a 50 ml volumetric flask, and make up to volume with O.lmol/L hydrochloric acid. Shake well to obtain the test solution.
  • hydrochlorothiazide reference solution was prepared by the same method, and the absorbance was measured at the wavelength of 272 nm according to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A), and the sample content was calculated.
  • Sample 31A was placed in a high density polyethylene plastic bottle and sealed. It was placed in an accelerated test chamber and subjected to a 6-month accelerated test at a temperature of 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%.
  • Domperidone microparticle test group suspension test suspension: Weigh a certain amount of the 1A sample in Example 1, and add water to disperse to prepare a test group suspension with a domperidone concentration of 2.5 mg/ml; domperidone tablets control group mixed Suspension: take Commercially available domperidone tablets (morphines) Several tablets (each containing 10 mg) were gently ground and mixed with water to prepare a control suspension with a domperidone concentration of 2.5 mg/ml.
  • morphines domperidone tablets
  • Plasma samples were processed and determined by HPLC-MS/MS.
  • the ion source is an electrospray ionization source (ESI source), positive ion detection; spray voltage is 4200 V; heating capillary temperature is 300 °C; sheath gas (N2) pressure 35 Arb; auxiliary gas (N2) pressure lO Arb; collision gas (Ar) pressure 1.2 mTorr; collision induced dissociation (CID) voltage is 30 eV; scanning method is selective reaction monitoring (SRM), and the ion reaction for quantitative analysis is m/z 426 ⁇ m/ z 175 (domperidone) and m/z 432 ⁇ m/zl81 (D6-domionate); scan time is 0.15 s.
  • ESI source electrospray ionization source
  • spray voltage is 4200 V
  • heating capillary temperature is 300 °C
  • sheath gas (N2) pressure 35 Arb auxiliary gas (N2) pressure lO Arb
  • collision gas (Ar) pressure 1.2 mTorr collision gas
  • Mefenamic acid microparticle test group suspension Weigh a certain amount of 3A mefenamic acid microparticles prepared in Example 3, add water Dispersed, prepared into a suspension of test group with a concentration of mefenamic acid of 25 mg/ml; a suspension of mefenamic acid dispersible tablets: a batch of commercially available mefenamic acid dispersible tablets (each containing a dose) For 10 mg), gently grind and disperse in water to prepare a control suspension with a mefenamic acid concentration of 25 mg/ml.
  • Dosing regimen Randomly divided into 2 groups, 3 in each group, cross-administered every other week, the dose was 50mg, fasted for 12 hours before the experiment, free drinking water, intragastric administration, administration for 2 h After uniform eating.
  • Plasma samples were processed and determined by HPLC.
  • Micromeritics Tristar II 3020 (Micromeritic Instrument Corporation)
  • the sample was degassed at 90 ° C for 1 h, then degassed at 150 ° C for 2 h, then subjected to nitrogen adsorption and desorption measurements.
  • the P/P0 was calculated in the range of 0.05-0.2 by the Brunauer-Emmett-Teller method. Specific surface area c
  • Example 1 of the present invention the dissolution rate of the sample 1A (prepared by pH-eutectoid method, domperidone: Eudragit EPO was 1:0.5) was 96.5%.
  • the addition of the water-soluble co-dispersant PVP K30 or PEG 6000 also improved the dissolution of the microparticles.
  • domperidone: PVP K30 or domperidone: PEG 6000 were also 1:0.5 (compared with 1A and contrast).
  • the dissolution rate was 56.8% and 41.8% at 45 min, respectively. Only when domperidone: PVPK30 reached 1:3 (compared to 1B), the dissolution rate reached 96.6% at 45 min.
  • sample 1A The specific surface area of sample 1A was 8.2338 m 2 /g, which was 19.28 times that of the domperidone raw material, which was 1.67 times that of the comparative 1B sample; the pore volume of the sample 1A was 0.015215 m 3 /g, which was 22.85 times that of the domperidone raw material; 1.32 times.
  • the surface morphology of 1A microparticles differs greatly from the surface morphology of the comparative 1A and domperidone materials.
  • the dissolution of 1A microparticles and the surface morphology of the microparticles are good. The results are shown in Fig. 1, Fig. 8 and Fig. 10, and the content of domperidone microparticles and dissolution stability. (6 months) Data comparison table.
  • sample 3A prepared by pH-eutectoid method, mefenamic acid: Eudragit L100 was 1:0.1
  • the addition of the water-soluble co-dispersing agent PVP K30 also improved the dissolution rate of the microparticles, but the amount of addition must be large, compared with 3A (methylphenofate: PVPK30 is 1:1) Compared with 3B (mefenamic acid: PVPK30 is 1: 3), the dissolution rates of the microparticles lOmin and 45min are 11.8% and 42.5%, 47.2% and 70.3%, respectively.
  • the PVPK30 addition amount is 3A sample, the Utech L100 is added. The amount is 30 times, but it is far below the dissolution level of the 3A sample. Experiments have shown that increasing the amount of PVPK30 on the basis of mefenamic acid: PVPK30 of 1:3 does not further increase the level of particle dissolution.
  • Sample 3A has a specific surface area of 15.1962 m 2 /g, which is 7.46 times that of mefenamic acid.
  • the porosity is 14.4070, which is 7.72 times that of mefenamic acid.
  • the surface morphology of 3A particles is compared with that of 3B and 3C. Large, 3A particle dissolution stability is good, the results are shown in Figure 3 and Figure 9, and mefenamic acid particle content and dissolution stability (40 ° C

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Abstract

La présente invention concerne une matière particulaire de principe actif insoluble, une préparation de matière particulaire et son procédé de préparation. Le procédé de préparation de la matière particulaire comprend les étapes suivantes consistant à : dissoudre un principe actif insoluble et un polymère ionique dans une solution alcaline ou une solution acide, puis mélanger la solution alcaline et la solution acide, et co-précipiter le principe actif insoluble et le polymère ionique dissous au départ dans la solution à partir de la solution mixte pour former la matière particulaire en changeant la valeur du pH de la solution.
PCT/CN2015/094889 2014-11-27 2015-11-18 Matière particulaire de principe actif insoluble, préparation de matière particulaire et son procédé de préparation WO2016082705A1 (fr)

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