WO2012006965A1 - Comprimé dont les performances globales sont améliorées et son procédé de préparation - Google Patents

Comprimé dont les performances globales sont améliorées et son procédé de préparation Download PDF

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Publication number
WO2012006965A1
WO2012006965A1 PCT/CN2011/077211 CN2011077211W WO2012006965A1 WO 2012006965 A1 WO2012006965 A1 WO 2012006965A1 CN 2011077211 W CN2011077211 W CN 2011077211W WO 2012006965 A1 WO2012006965 A1 WO 2012006965A1
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WIPO (PCT)
Prior art keywords
tablet
binder
diluent
weight
water
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PCT/CN2011/077211
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English (en)
Chinese (zh)
Inventor
钟术光
Original Assignee
Zhong Shuguang
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Publication of WO2012006965A1 publication Critical patent/WO2012006965A1/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
    • A61K9/20—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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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 present invention relates to a tablet having improved overall performance. More specifically, a hydrophilic tablet having a higher mechanical properties and a higher porosity and a higher weather resistance.
  • the invention also relates to a process for the preparation of the tablet. Background of the invention
  • the porosity and mechanical strength of the tablet play a very important role in the tablet.
  • the high porosity facilitates the release of the drug in the tablet, especially the poorly soluble drug, especially the rapid disintegration/dissolution of the tablet in the mouth.
  • the high mechanical strength is conducive to the maintenance of the shape of the tablet during production, transportation, etc., to ensure the accuracy of a single dose, thus ensuring the safety of medication.
  • the high porosity of the tablet often leads to problems such as insufficient mechanical strength of the tablet, such as low hardness and poor friability, which may cause quality problems such as drop in drug loading (single dose), lobes, fragments, etc., and Further aggravating the influence of moisture, air (oxygen) and light on the tablet and reducing its stability; while the high mechanical strength of the tablet often leads to insufficient porosity of the tablet, tablet disintegration or slow dissolution of the drug, etc. problem.
  • the orally dissolvable tablet disclosed in JP-A-11-35451 medicinal ingredients, saccharides, and the like, and polyethylene glycols, lipids such as lanolin, lanolin alcohol, natural waxes such as carnauba wax, etc.
  • the melting point substance is mixed, the mixture is tableted at a low pressure, and the obtained tablet is heated at a temperature at which the low-melting point substance is melted, and then naturally cooled to characterize an orally dissolved tablet and a method for producing the same.
  • US Pat. No. 5,853,758 discloses a porous tablet: This tablet is prepared by using a lipid such as lanolin, lanolin alcohol, a natural wax such as carnauba wax, a natural or synthetic polymer such as PEG200 ⁇ 20000, malt. Dextrin, saccharide such as glucose, etc.
  • the preparation process is as follows: (a) bonding the meltability a combination of at least one excipient and a pharmaceutically active agent in a tablet, (b) melting the aforementioned meltable binder in the tablet, and (c) bonding the meltable bond The agent solidifies.
  • the above-mentioned technologies all have disadvantages such as insufficient mechanical strength, such as insufficient hardness and insufficient friability, and problems such as cracks and fragments are likely to occur during production and transportation. There is still much room for improvement in its mechanical properties.
  • the generally disclosed hydrophilicity of the meltable adhesive has a lower melting point, the formulation using the melting point as the binder may be melted in the case of indoor storage in which the air conditioner is not fully equipped. The tablet becomes soft, and the strength of the tablet and the disintegration time in the oral cavity are changed, and the weather resistance or the ability to withstand higher temperatures is deteriorated.
  • the lipophilic fusible binder having a relatively high melting point is not hydrophilic, and the above-mentioned preparation prepared for disintegration or drug dissolution is relatively slow. Hydrophilicity and weatherability are often not organically unified, but contradictory.
  • One object of the present invention is to provide a hydrophilic tablet having a high porosity and a high porosity which is further enhanced in mechanical properties and a process for producing the same.
  • a hydrophilic tablet having a high porosity and a high porosity which is further enhanced in mechanical properties and a process for producing the same.
  • the inventors conducted intensive studies and found that the mechanical properties of the porous tablet are largely related to the following factors: 1) the particles themselves bonded by the meltable binder Mechanical properties; 2), the mechanical properties of the meltable adhesive itself; 3) the adhesion or affinity between the particles bonded by the meltable adhesive and the meltable adhesive; 4) The ratio between the particulate material bound by the meltable binder and the meltable binder and the proportion of particulate matter bound by the meltable binder throughout the tablet.
  • the hydrophilicity of the particles bound by the meltable binder and the hydrophilicity of the meltable binder are significant or even decisive for the hydrophilicity of the formulation, and the melt densification of the meltable binder determines or primarily affects The weatherability of the formulation.
  • melt binders which usually have good hydrophilicity and lipophilicity
  • mechanical properties higher melting point lipophilic substances
  • the ratio drawn - mechanical properties (such as hardness or mash) phase diagram usually gives a convex or concave curve; after these treatments, lower melting hydrophilic polyethylene glycol ester or ether
  • the weather resistance or resistance to higher temperatures of substances such as surfactants and sugar ester surfactants is improved.
  • hydrophilic raw materials particularly soluble in water-crystalline auxiliary materials such as saccharides (crystalline particles or powders are generally not mechanically better than amorphous powders).
  • the above two meltable components are blended into the tablet raw materials and auxiliary materials, pressed or not pressed at a lower pressure, and then heated to melt the above two meltable components, and then cooled to make the above two kinds
  • the molten solidified product of the meltable component forms a crosslink between the above-mentioned hydrophilic raw material and a water-soluble crystalline auxiliary material such as a saccharide substance particle.
  • the hydrophilic and lipophilic polyethylene glycol ester or ether surfactant and the sugar ester surfactant are preferably adhered at one end to the hydrophilic raw material, particularly soluble in water.
  • a crystalline excipient such as a saccharide, the other end preferably binds a higher melting point lipophilic material.
  • the present invention relates to a hydrophilic tablet having a higher porosity and a higher porosity, which is further enhanced in mechanical properties, the tablet comprising:
  • meltable binder which is preferably pharmaceutically acceptable, having a lower melting point than the above-mentioned water-soluble crystalline particulate or powdery diluent a meltable surfactant which is lower in solidity than the above active ingredient and which is solid at room temperature (melting point not lower than 25 ° C) and soluble in water;
  • meltable mechanical property enhancer is a pharmaceutically acceptable granule or powder having a melting point of not lower than 45 ° C and being more soluble in a water-soluble crystalline form
  • the unshaped diluent is preferably lower than the melting point of the above active ingredient but higher than the melting point of the above meltable binder, fat-soluble and water-insoluble, meltable and/or absent
  • the above-mentioned water-soluble crystalline particulate or powdery diluent and/or the above-mentioned active ingredient are bonded by the above-mentioned meltable binder and the cured melt of the above-mentioned mechanical property enhancer ⁇ Including the endpoint) (here "/" means a proportional relationship, equivalent to " ⁇ "), and the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent / (the above meltable binder)
  • the weight of the above-mentioned mechanical property enhancer + the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent is between 0.40 and 0.93 (inclusive) (here) /" indicates a proportional relationship, which is equivalent to " ⁇ "); and the ratio of the above-mentioned water-soluble crystalline particulate or powdery diluent to the total weight of the entire tablet is not less than 25%;
  • the present invention relates to a method for preparing a hydrophilic tablet having a higher porosity and a higher porosity and having a higher mechanical property, the method comprising three basic steps: (1), as follows The forming step described: in order to contain a granular or powdery diluent, a meltable binder, containing an active ingredient, a pharmaceutically acceptable water-soluble crystalline form,
  • the meltable mechanical performance enhancer and/or the tablet material without the pharmaceutically acceptable additive is in a substantially uniformly dispersed state of pharmacy and has a pharmaceutically acceptable morphological form (tablet), ie, maintains the tablet form
  • the above-mentioned meltable binder is preferably a pharmaceutically acceptable lower than the above-mentioned active ingredient having a melting point lower than that of the above-mentioned water-soluble crystalline particulate or powdery diluent a low meltable surfactant which is solid at room temperature (melting point not lower than 25 ° C) and soluble in water
  • the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent / (the above meltable binder
  • the weight + the weight of the above-mentioned mechanical property enhancer + the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent is between 0.40 and 0.93 (inclusive) (here "/ "representing a proportional relationship”; and the ratio of the above water-soluble crystalline particulate or powdery diluent to the total weight of the entire tablet is not less than 25%; and the above-mentioned molten binder and
  • the above mechanical property enhancer has a weight ratio of not less than 5% by weight based on the total weight of the whole tablet; when the above active ingredient and/or the above pharmaceutically acceptable additive is a water-soluble crystalline granular or powder In the case of an unexposed substance, the weight thereof is a total of the weight of the
  • the amount of the particulate or powdery diluent in the water-soluble crystalline state may be 0; (2), the heating process as described below: the process (1) a step of heating the obtained binder (C) and the mechanical property enhancer (D) by heating the obtained tablet molded article to a temperature higher than a melting temperature (including a melting temperature) of the meltable mechanical property enhancer;
  • a cooling step as follows: a step of solidifying the melted binder (C) and the above-mentioned mechanical property enhancer (D) in the tablet molded article obtained in the step (2).
  • tablette refers to a flat or slightly convex, disc-shaped, rod-like, branched shape made of a pressurized or other non-pressurized process containing one or more active ingredients.
  • the internal components of the pellets, lumps, cones, or other pharmaceutically acceptable shapes are substantially uniformly dispersed, and the solid dosage forms are mainly for internal use, and can also be used externally, and capsules prepared by further processing on this basis and others
  • a pharmaceutically acceptable dosage form, in the present invention, the "tablet” is preferably a rapidly disintegrating/dissolving tablet in the oral cavity.
  • rapidly disintegrating/dissolving the tablet in the mouth means that the tablet is not ingested for taking the tablet, and the saliva is substantially only within 1 minute (preferably within about 30 seconds, preferably in the oral cavity). A tablet that disintegrates/dissolves within about 10 seconds.
  • porous refers to the porous structure of a tablet, typically having a porosity of from about 10 to about 95%, desirably from about 20 to about 80%, more desirably from about 30 to about 50%. meaning.
  • Porcity as used in the present invention means the ratio of the volume of pores in the microparticles in the tablet to the volume of the interparticle voids to the volume of the tablet, usually expressed as a percentage.
  • melting point refers to the temperature at which a substance is converted from a solid state to a liquid state.
  • melting range particularly when comparing the melting points of the two substances, in the present invention, the starting point of the melting point is specifically referred to.
  • melttable means that the substance can be melted at a temperature not higher than 150 ° C, especially not higher than 120 ° C, particularly not higher than 10 CTC.
  • mechanical performance enhancer means that the solid melt or tablet mechanical properties such as increased hardness, tensile strength or Ejection Force can be improved, and mashing can be reduced. Substances such as Friabiity.
  • mechanical performance parameter refers to a parameter that reflects the mechanical properties of a tablet, including but not limited to hardness (hardness), fragrantness (tensi le strength), tensile strength (tensi le strength), push film. Ejection Force.
  • water-soluble or water-soluble as used in the present invention means that the equilibrium dissolved amount of the substance in water (temperature 25 ° C) or warm water (temperature 37 ° C) is not less than 33 m g /l ml ( Solute/water), preferably not lower than 100 mg/lml (solute/water), more preferably not lower than 200 mg/lml (solute/water), optimally not lower than 500 mg/lml (solute /water).
  • lipid-soluble and insoluble in water means that the substance is soluble or dispersible in one or more of such as vegetable oil, natural fat, mineral oil or petroleum ether, benzene, diethyl ether, carbon tetrachloride, etc.
  • the water-soluble meltable binder is one-tenth of the equilibrium dissolved amount in water at the same temperature, preferably not more than one-thirtieth, more preferably not more than one-hundredth, most The best place is no more than one thousandth.
  • equilibrium dissolved amount means an amount required to dissolve a substance in a unit volume of a solvent and reach equilibrium (saturation) under certain conditions such as a certain temperature.
  • dispersion means a process in which a substance is dispersed in a molecular state and/or an ionic state or a surfactant in a micelle state and/or a molecular state and/or an ionic state in a dispersion medium, i.e., a solvent.
  • active ingredient means any substance as it Detectable biological effects when administered to a living body include any physiological, diagnostic, prophylactic or pharmacological effects. This term is intended to include, but is not limited to, any pharmaceutically, therapeutic, prophylactic, nutritional material.
  • a as used in the present invention means at least one, and may be one type or two or more types.
  • pharmaceutically acceptable as used in the present invention means that it can be mixed with each other in the preparation without adverse effects on each other without deteriorating the stability and/or efficacy of the preparation and is suitable for topical or systemic administration.
  • the diluent used in the present invention it is required to be a crystalline or granulated substance which is soluble in water (as defined above), which should be easily formed into a tablet and made into tablets. It should disintegrate or dissolve rapidly in the mouth.
  • the diluent used in the present invention is preferably in the form of a cubic crystal or a finely divided crystalline particle or powder.
  • the diluent used in the present invention is preferably a particulate or powdery form in a water-soluble crystalline state, more preferably a water-soluble crystalline substance.
  • Examples of the diluent which can be used in the present invention are crystalline saccharides, sodium oxide, potassium chloride, soluble amino acids and mixtures thereof, with saccharides being more preferred.
  • the saccharides useful in the present invention include, but are not limited to, crystalline erythritol, glucose, isomalt, lactitol, lactose, maltitol, maltose, mannitol, sucrose, trehalose, xylitol, fructose, Raffinose, conjugated sugars, oligosaccharides, and mixtures thereof.
  • a crystalline particulate or powdered d diluent for use in the present invention advantageously enhances the mechanical properties of the tablet due to its relatively high mechanical properties, particularly relative to amorphous powder.
  • the water-soluble diluent facilitates its affinity or binding force with the hydrophilic meltable binder, which is advantageous for improving the mechanical properties of the tablet.
  • the blending amount of the above diluent used in the present invention may be appropriately adjusted depending on the amount of the drug and/or the size of the tablet, but generally the above-mentioned water-soluble crystalline granular or powder-form diluent usually accounts for
  • the proportion of the entire tablet is not less than 25% (wt/wt), more preferably not less than 34% (wt/wt) and not more than 80% (wt/wt), and most preferably not less than 40% ( The wt% is not more than 70% (wt/wt), and the above weight percentage is based on the total weight of the tablet. This is because the higher amount of the above diluent is added to enhance the hydrophilicity, particularly the mechanical properties of the tablet.
  • the meltable binder (hereinafter referred to as a molten binder) according to the present invention is preferably a pharmaceutically acceptable low-particle granule or powder-like diluent having a melting point higher than that of the above-mentioned water-soluble crystalline form.
  • a meltable surfactant which is lower than the above-mentioned active ingredient and which is solid at a normal temperature (melting point of not lower than 25 ° C) and soluble in water.
  • the melting point of the above molten binder is preferably at least 10 ° C (inclusive), more preferably at least 20 ° C (inclusive) lower than the melting point of the active ingredient.
  • the meltable binder used in the present invention usually has a melting point of 25 to 10 CTC (inclusive), preferably 35 to 80 ° C (inclusive), more preferably 40 to 80 ° C (inclusive).
  • the melting point of the above molten binder is usually not lower than 25 ° C because the mixing of the components is usually carried out at this temperature and the binder should maintain a solid form at this mixing temperature.
  • the melting temperature of the above molten binder is generally not Above 100 ° C, because the binder should melt at a temperature at which the activity of the pharmaceutically active component is not adversely affected. For example, the binder should be melted at a temperature below the decomposition of the pharmaceutically active component and any excipients contained therein.
  • meltable binders suitable for use in the present invention include, but are not limited to, the following pharmaceutically acceptable meltable surfaces which are solid at room temperature (melting point not lower than 25 ° C) and soluble in water
  • active agent are, but not limited to, polyoxyethylene Alkyl Ethers surfactants, polyoxyethylene castor oil derivatives
  • polyoxyethylene decyl ether surfactants which can be used in the present invention are as follows: Volpo S10
  • polyoxyethylene castor oil derivative surfactants which can be used in the present invention are as follows: polyethylene glycol (60) hydrogenated castor oil (Polyoxyl 60 hydrogenated castor oi l) (mp, 40 ° C), polyethylene glycol (40) Hydroxyl 40 hydrogenated castor oi l (mp, 30 ° C), and mixtures thereof.
  • polyoxyethylene sorbitan fatty acid ester surfactant which can be used in the present invention are: polysorbate 61 (mp, 35 - 49 ° C), polysorbate 65, and a mixture thereof.
  • Examples of ethoxylated fatty acid or polyoxyethylene stearate surfactants which can be used in the present invention are: polyoxyethylene (12) stearate (mp, 37 ° C), polyoxyethylene (20) Stearate (mp, 28 ° C), polyoxyethylene (40) stearate (mp, 38 ° C), polyoxyethylene (50) stearate (mp, 52 ° C), polyoxygen Ethylene (100) stearate (mp, 46 ° C), polyoxyethylene (32) distearate (mp, 45 ° C), polyoxyethylene (150) distearate (mp, 53 - 57 ° C), and mixtures thereof.
  • ethoxylated fatty alcohol or polyoxyethylene laurate surfactant which can be used in the present invention are, for example, polyoxyethylene (23) laurate (mp, 38 to 40 ° C).
  • polyoxyethylene-polyoxypropylene alcohol copolymers which can be used in the present invention are poloxamer 188 (melting point 52 to 57 ° C), poloxamer 237 (melting point 49 ° C), poloxamer 338 (melting point 57 °) C), poloxamer 407 (melting point 52 to 57 ° C).
  • meltable sugar ester surfactant which is solid at room temperature (melting point not lower than 25 ° C) and soluble in water can also be used in the present invention, such as: sucrose monostearate (melting point 53 to 57 °) C), sucrose monopalmitate (mp, 43 ⁇ 48 ° C).
  • the meltable mechanical property enhancer (hereinafter referred to as mechanical property enhancer) according to the present invention is pharmaceutically acceptable, has a melting point of not lower than 45 ° C and is lower than the above-mentioned diluent, and is also lower than the above-mentioned active ingredient.
  • a fat-soluble, water-insoluble, meltable material that is higher than the above meltable binder.
  • the equilibrium dissolution amount of the above mechanical property enhancer in water (temperature 25 ° C) or warm water (temperature 37 ° C) generally does not exceed the equilibrium dissolution of the above water-soluble meltable binder in water at the same temperature
  • the above meltable mechanical property enhancer is preferably pharmaceutically acceptable, has a melting point of not less than 50 ° C and is at least 5 ° C lower than the above-mentioned diluent and is at least 5 ° C (inclusive) and more meltable.
  • the melting point is preferably not lower than 60 ° C, more preferably not lower than 70 ° C, most preferably not lower than 80 ° C, but preferably not higher than 120 ° C, more preferably not higher than ioo °c ;
  • the melting point of the above mechanical property enhancer is preferably at least 10 ° C (inclusive), more preferably at least 20 ° C lower (inclusive) than the melting point of the above diluent and the above active ingredient;
  • the melting point is preferably at least 10 ° C (inclusive), more preferably at least 20 ° C (inclusive), and most preferably at least 30 ° C (inclusive) above the melting point of the molten binder.
  • Meltable mechanical property enhancers useful in the present invention include, but are not limited to, pharmaceutically acceptable fat-soluble and water-insoluble meltable animal and vegetable oils, semi-synthetic fats, having a melting point of not lower than 45 ° C, Higher hydrocarbons, natural or artificial waxes, higher fatty acids, higher fatty acid esters, higher mercapto alcohols, and mixtures thereof, preferred exemplary compounds of which include, but are not limited to, stearic acid (melting point about 54 ° C), ethylene Alcohol monostearate (melting point 54 ⁇ 57 ° C), diethylene glycol distearate (melting point 54 ⁇ 55 ° C), microcrystalline wax (melting point 54 ⁇ 102 ° C), glyceryl tristearic acid Ester (melting point 55 ° C), stearyl alcohol (melting point 55 ⁇ 60 ° C), glyceryl monostearate (melting point 55 ⁇ 60 ° C), glycerol monodecanoate (melting point 56 ⁇ 57 ° C
  • stearic acid and hydrogenated castor oil are more preferred because they are harder in texture and are advantageous for improving the mechanical properties of the tablet.
  • Hydrogenated castor oil is particularly preferred because it also has a high melting point, which is advantageous for improving or improving the tablet.
  • the mechanical properties are especially weather resistant.
  • meltable mechanical property enhancers include, but are not limited to, fat-soluble and water-insoluble lactic acid fatty acid propylene glycol esters, lactic acid fatty acid glycerides, fatty acid lactyl esters having a melting point of not lower than 45 ° C, and Particularly preferred are the above-mentioned hard substances, particularly those having a hardness of not less than 70% of the hardness of hydrogenated castor oil.
  • the advantages of the "melt binder” and the “mechanical performance enhancer” which are preferably at least 10 ° C lower than the melting point of the diluent and active ingredient, more preferably at least 20 ° C lower, are: When the substance is completely melted, only a small amount or a small amount of the above diluent and active ingredient are melted, and a large amount of the above diluent and active ingredient exist in the original form, which is advantageous for improving the strength of the solid melt and the tablet without affecting The disintegration performance of the tablet.
  • Mechanisms of the invention is a meltable substance having a melting point of not lower than 45 ° C or 50 ° C or higher and higher than the above meltable binder, and has the advantages of: facilitating the tablet to withstand higher Temperature and improve the mechanical properties of solid melts and tablets.
  • “Mechanical performance enhancer” is a fat-soluble and water-insoluble substance, which not only contributes to the action of bridging a soluble molten binder but also contributes to the function and does not reduce the water-soluble meltable bond. The adhesion of the agent (ie, a water-soluble surfactant) to a water-soluble crystalline particulate or powdery diluent.
  • the ratio of the molten binder to the mechanical performance enhancer ie, the weight of the mechanical performance enhancer / (the weight of the molten binder + the weight of the mechanical performance enhancer)
  • the mechanical performance parameter values are plotted on the ordinate - mechanical properties (such as hardness or mash).
  • the phase diagram is usually a curve with a large convex or concave width (see Figure 1-2 of Example 1). ).
  • the compatibility of the molten binder with the mechanical performance enhancer is good, and the above-mentioned phase diagram has a convex or concave amplitude, and the maximum value appearing in the figure is Yuda (or small) (which is the most preferable value of the present invention).
  • the proportional relationship between the amount of the molten binder and the mechanical performance enhancer of the present invention is Taking the proportion of the middle section, and because the mechanical property enhancer is too high, the formulation has high lipophilicity and poor hydrophilicity, and the proportional relationship between the amount of the molten binder and the mechanical performance enhancer is further taken before the pro In addition, the proportion of the molten binder which is too high in proportion makes the formulation less resistant to weathering.
  • the ratio of the amount of the above-mentioned molten binder to the above-mentioned mechanical property enhancer is preferably:
  • the ratio of the weight ratio of the above-mentioned sizing agent (the above-mentioned sizing agent + the above-mentioned mechanical property-enhancing agent) is between 0.25 and 0.70 (weight ratio) (including the end point), preferably from 0.35 to 0.60 (weight ratio) Between (including the endpoints), more preferably between 0.40 and 0.55 (by weight) (inclusive).
  • the active ingredient to be used in the present invention may be any pharmaceutically or nutritionally therapeutic or preventive substance, and is not particularly limited. Examples of active ingredients useful in the present invention are listed below: A central nervous system drug:
  • a central stimulant idebenone, benzopyridin, piracetam, pyrithione, vinpocetine, dimethylformin, aniracetam, meclofenoxate, caffeine, modafinil , pentylenetetrazol.
  • An analgesic chlorpheniramine, buprenorphine, dihydroetorphine, florofinine, bicuculline, codeine, rotundine, morphine, ergotamine, meptazin, methadone, nai Fructus, pethidine, pirimidin, oxycodone, hydromorphol, tramadol, sumatriptan, tetrahydropalmatine, dextropropoxyphene, dextromethorphan, levonorol, left mala amine.
  • An antipyretic analgesic aspirin, acetaminophen, phenacetin, hydroxybzon, thiaramite, magnesium salicylate, imidazole salicylate, isopropyl antipyrine.
  • An anti-inflammatory analgesic aminclofen, acemetacin, azaprozin, ampoxicam, augusin, olsalazine, benolyl ester, pirfen, ibuprofen, buxila Ming, aceclofenac, butyl hydroxy acid, diflunisal, fenbufen, flurbiprofen, flufenamic acid, citrictin, cyclohexanoic acid, mefenamic acid, meclofena Acid, gold thioglucose, auranofin, leflunomide, chlorpheniric acid, loxoprofen, aristolochic acid, meloxicam, mesalazine, nabumetone, naproxen, ni Fluoric acid, etodolac, zaltoprofen, guaiac blue hydrocarbon, etofenamate, escitoxicam, ketoprofen
  • An anti-gout drug glucosamine, benzbromarone, allopurinol, colchicine, probenecid, etimabazole.
  • An anti-shock paralysis drug trihexyphenidate, biperiden, dorepeptide, entacapone, adamantamine, carbidopa, quetiapine, rasagiline, memantine, selegiline, Tokapeng, bromocriptine, levodopa, mobilis, moxifensin, palitide, donepezil.
  • Primary antipsychotic drugs alipidide, anibirdolol, azaipone, ampicillate, amisulpride, oxaporone, oxaflurazine, oxybuterazine, prochlorperazine, Fluphenazine, haloperidol, droperidol, flupentixol, flupristen, risperidone, linacazole, thiopril, thioridazine, clozapine, clopipapine, Clopidogrel, clopidogrel, loxapine, mazapamine, nemiride, piperazine, pimozide, pramipexole, rimopride, sulpiride, penfluridol, zo Telpine, epoprazol, olanzapine.
  • An anti-anxiety drug alprazolam, estazolam, buspirone, flazodazole, lorazepam, clomiprazole, metaxalone, beta chlorophenidate, etidazolam, Fludisazine.
  • An antidepressant amitriptyline, amoxapine, bupropion, opipramol, desipramine, dexmedeline, fluvoxamine, fluoxetine, carbipipamine, Clomipramine, maprotiline, mianserin, paroxetine, methylphenidate, protriptyline, trimipramine, sertraline, St. John's wort extract, veroshaqin, wenla Fasin, sibutramine, citalopram, isocarbomer.
  • An antiepileptic drug oxcarbazepine, bequesamine, phenytoin, valproic acid and its sodium, magnesium salt, methyl ethyl ketone, carbamazepine, casinitide, lamotrigine, riluzole, primidone , Topiramate, esadiazepine, ethecoxibine, etoposide, ethosuxamine, zonisamide, tiagabin, mefentoin.
  • a sedative, hypnotic, anticonvulsant and others oxazuron, barbital, phenobarbital, glutamine, quetiapine, niazophenone, gastrodin, bromoisoval, relying on Mimidate, acetyl gastrodin, zaleplon, zopiclone, zolpidem, betahistine, vincamine, flunarizine, flumethenone, fluentil, cyclomandelate, pentoxifylline , meglumine dihydroergotamine, rizatriptan, mesalamine, naratriptan, nicotinol, nigralin, kallikrein, niacin, iripusone, eletriptan , epoprostenol, isoprozol, papaverine, zolmitriptan, levetiracetam.
  • An autonomic nervous system drug arololol, aplolol, atenolol, esmolol, benzaltropine, bisoprolol, scopolamine, metoprolol tartrate, carteolol, carvey Dilo, Labetalol, Metoprolol, Moplelol, Moxicelli, Nadolol, Anisodamine, Celilol, Cetalol, Thiololol, Tamsulosin , sotalol, yohimbine, anisodine, carvedilol, tamsulosin, tropicamide, bromopropylamine.
  • a circulatory system drug is a circulatory system drug
  • One calcium antagonist anipamil, benidipine, benidipine, bepridil, valparaprin, faripamil, cinnarizine, lacidipine, manidipine, thiophane, dimension Lapami, right Vera Paimi.
  • a drug for the treatment of chronic cardiac insufficiency budexin, digoxin, denomamine, venom glycosides, dobutamine, docarbaamine, paclitaxel, milrinone, enoxacin , Zuo Xi Meng Dan, Ali Fei Jun.
  • An antiarrhythmic drug aprilin, amiodarone, pyridoxine, propiamine, flecainide, quinidine, modicani, orexizine, procainamide, propa Ketone, ivabradine, itraconi, tocic bromide, mexiletine, stenicai.
  • a drug for preventing and treating angina pectoris oxyxitox, isosorbide mononitrate, ligustrazine, diltiazem, tetrabutyl nitrite, hysopidine, cyclophosphamide, levopraz, musk ketone, dipyridamole, pentaerythritol Nitrate, nitroglycerin, imoramin, etanoterone, cyclic adenosine.
  • Peripheral vasodilator apovinamine, vincamine, pinacidil, vinpocet, vinorelbine, dagapamil, buflomedil, fasudil, golopamil, hydralazine , kalazine, minoxidil, nicorandil, naproxil, tripidil, diterpenoid, urapidil, bromo-vincoamine, nicotinic acid inositol, enalappine, isopropanol, Isosaramine, poppy peony, valvadil, left emolim, zoelepine.
  • a blood pressure lowering drug alfuzosin, alapril, analipide, amlodipine, betaxetidine, benazepril, octapeptide, bunazosin, diazepam, dilapid Lee, Delilorol, Butyzolamine, Doxazosin, Irbesartan, Felodipine, Fosinopril, Tetrandrine, Methyldopa, Daidzein, Tartrate Tartrate, Card Topily, candesartan, quinapril, clonidine, lisinopril, ramipril, limonidine, lishepine, spiropril, lofexidine, mecaramine, Nilvadipine, nicardipine, nimodipine, nitrendipine, nisoldipine, pagilin, perindopril, trandolapril, terazosin, temocap
  • a regulation of blood lipids and anti-atherosclerosis drugs atorvastatin, acixil, phenylpropanolamine, benzepressin, bezafibrate, pyracarbyl ester, benzyl chloride, darvastatin , elastase, dopamine, docepramine, fenofibrate, fluvastatin, ciprofibrate, gemfibrozil, colestipol, cholestyramine, kevastatin, clebate, lysine Bate, clofibrate, clofibrate, lovastatin, mevastatin, nicaratin, niketabate, pravastatin, probucol, cerivastatin, simvastatin, linoleum Acid, polydextrose, dextrothyroxine, hyodeoxycholic acid.
  • a respiratory system drug aminophylline, ambroxol, oxycin, oxicillin, benproperine, bitoterol, benzonatate, pyrbuterol, sodium zoate, dimethoate Ester, putotropine, erdosteine, fenoterol, forcodine, hexolin, clenbuterol, chlorobutano, mabuterol, montelukast, picotazide Lin, terbutaline, guaifenesin, guaiacol sulfonate, zaloterol, levopropoxyphene, isomirier, acetylcysteine, ketotifen, terbutaline, Trolotrol, epradolone, terpineol.
  • a digestive system drug is a digestive system drug
  • An antacid and a peptic ulcer drug omeprazole, balsalazide, ornoprost, enprostin, famotidine, galac aluminum, bismuth potassium citrate, lansoprazole, Rabeprazole, sucralfate, aluminum-magnesium plus, barium aluminate, magnesium aluminum carbonate, rosaprost, roxatidine, misoprostol, nizatidine, pirenzepine, Pronoto, Pantoprazole, Traxapat, Sophorone, Tirenoxapine, Vitamin U, Isoladine, Ekabit.
  • a gastrointestinal antispasmodic drug adifenin.
  • a helper digestive drug oxcarbin, trypsin amylase, citric acid, carnitine, pepsin, cisapride, trypsin, trypsin, pancreatic lipase.
  • An antiemetic, emetic, and gastrointestinal drug ondansetron, domperidone, granisetron, metoclopramide, clopirol, tolztron, itopride, bergenin, sulpiride , quercetin, lystron, lintobili, mojistan, mosapride.
  • a hepatobiliary disease adjuvant medication olamimet, chenodeoxycholic acid, non-bupropanol, anthranil trioxide, inositol, inosine, biphenyl diester, leucovorin, tiopronin, lipoic acid, horse Loctinate, glucurolactone, oleanolic acid, hydroxymethyl coumarin, hydroxymethanolamine, dehydrocholic acid, sodium dehydrocholate, deoxycholic acid, lactulose, silybin, silymarin , ceaniol, adenosylmethionine, ursodeoxycholic acid, sodium protoporphyrin.
  • a urinary system drug amiloride, azosemide, triamterene, bethiazine, poritizine, bumetanide, pyrrhotanib, furosemide, cyclopentazine, cloxasolone , spirronone, melilone, spironolactone, mefsett, lysine , indapamide, epilizide, eszolate, ethenic acid, sodium citrate, etazozoline, thiazide, acetazolamide, isopropyl iodide, isopamine, Desmopressin, diclofenac, teprenone, metyrapone.
  • a drug that affects the blood and hematopoietic system sarpogrelate, bis-coumarin, ethyl acetophenone, warfarin, benzoquinone, acenocoumarol, ferrous sulfate, ferrous gluconate, ar Calcium folate, folic acid, iron dextran, mecobalamin, ferrous fumarate, iron glucoheptone, sodium ferulate, nucleotides, anethole, valerate, squalyl alcohol, chloramine, aca Dixin, anagrelide, aprostin, ozagrel, beraprost, picogreline, dalgregre, dazooxaphene, furoic acid, limatoprost, clopidogrel, rolagrel, imidazole , motodipine, narfagre, pamidrex, alprostadil, trox rutin, ticlopidine, tribe
  • Primary antihistamines avastin, alimazine, astemizole, oxapramine, oxomamycin, diphenhydramine, benzoguanamine, propionylazine, bupizine, tea benzene Hamming, promethazine tea, azelastine, diflupromide, dolastatin, doxylamine, embramin, febrinamide, fexofenadine, dimethylformidine , loratadine, clemastine, cloperastine, chlorpheniramine maleate, mepyrazine, meclozine, mequitazine, niprazine, cyproheptadine, stastatin, Ebastine, estramustine, epilin, bromophenamine, zafirlukast, levocabastine.
  • An allergic reaction medium release agent and others azastatin, amlexanox, lodosamide, tranilast, cromolyn, cetirizine, zapastast, plucomi, pu Hydrazine, his zastel.
  • An adrenocortical hormone and adrenocorticotropic hormone difluxate, dexamethasone, methylprednisolone, prednisone, cortisone, triamcinolone.
  • a sex hormone and gonadotropin bicalutamide, estrone, estriol, medroxyprogesterone acetate, danazol, prazzab, flutamide, diethylstilbestrol, hexaerythritol, diethylstilbestrol, Megestrol, medroxyprogesterone, raloxifene, nilutamide, gestrinone, toremifene, stanozolol, norgestrel.
  • An islet hormone and other drugs that affect blood sugar acarbose, pioglitazone, metformin, voglibose, glibenclamide, glibenclamide, glipizide, glibenclamide, glibenclamide, Glequinolidone, glimepiride, gliclazide, tolbutamide, miglitol, troglitazone, repaglinide, tolazamide.
  • a thyroid hormone drug and an antithyroid drug oltipreline, botinidrine, nitrexine, liothyronine, dibromotyrosine, thyropropionate, thyroidine, thyroglobulin, montetine Relin, miprazole, diiodotyrosine, telazocine, levothyroxine, levothyroxine sodium, aminothiazole, propylthiouracil, iodothiouracil, methylthiouracil, methimazole, Carbazole, thiazoline.
  • a penicillin amoxicillin, ampicillin, bamcillin, oxacillin, flucloxacillin, hetacillin, cyclohexillin, sulfacillin, carbocillin, cloxacillin, lenazocillin, nafcillin , pirazicillin, pimecillin, penicillium, sultamicillin, diclocillin, and acesulfame.
  • a cephalosporin chlorocarbon cephalosporin, cephalexin, cefprozil, cefpodoxime, ceftibuten, cefaclor, cefixime, cefradine, cefradine, ceftriaxone, cefadroxil, cefafloxacin, Ceftriaxone, cefdinir.
  • a beta-lactamase inhibitor clavulanic acid, sulbactam, brombata.
  • An aminoglycoside paromomycin, kanamycin, gentamicin, neomycin.
  • One tetracyclines and others dimecycline, doxycycline, indomethacin, metacycline, minocycline, oxytetracycline, tetracycline, chloramphenicol.
  • a other antibacterial agent levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, polymyxin, clindamycin, lincomycin, fosfomycin, micammycin, Stomycin, yellow vine, berberine, gentian, houttuyfonate sodium.
  • Primary anti-tuberculosis drugs pyrazinamide, sodium salicylic acid, sodium salicylate, propionamide, cycloserine, rifamp Butin, rifapentine, rifampicin, ethambutol, isoniazid.
  • An antifungal drug flucytosine, fluconazole, griseofulvin, miconazole, itraconazole, ketoconazole, nystatin.
  • An antiviral drug acyclovir, famciclovir, valaciclovir, lamivudine, ribavirin, morpholinium, zidovudine, deoxyfluorouridine, didanosine, zhaxi coast.
  • An anti-tumor drug busulfan, cyclophosphamide, lomustine, semustine, thioguanine, guanidine, idarubicin, aminoglutethimide, tamoxifen, anastrozole, c Carbachol, cantharidin, capecitabine, letrozole, melphalan.
  • a drug that affects the body's immune function akitali, propacetam, azathioprine, imidazolyn, tacrolimus.
  • a protein DNase, alginate, superoxide dismutase and lipase, peptide, oligopeptide.
  • a diet pill Amiris, amfepramone, amphetamine, amphetamine, oltipamine, fenfluramine, phenyltol, benzethetamine, propylhexidine, p-chloro Phentermine, non-Nyles, fenbufen, fluramine, fenmetrazine, fenpres, phentermine, furfurex.
  • One other drug finasteride, alendronate, alosetron, orlistat, eric acid, epalrestat, tolterodine, torista, herbal extracts.
  • the actives useful in the present invention include the pharmaceutically acceptable salt forms, free acid forms, free base forms, hydrates, various crystal forms, and optical isomers of the following active ingredients.
  • the invention is more suitable for active components with poor compressibility, such as poorly viscous drugs (examples such as bismuth carbon silver, ferrous sulfate, sulfur quinine and bromobenzine), and highly viscous drugs (such as protein: Yeast tablets and multi-enzyme tablets, Chinese herbal extracts), more flexible drugs such as Chinese herbal medicine powder.
  • poorly viscous drugs examples such as bismuth carbon silver, ferrous sulfate, sulfur quinine and bromobenzine
  • highly viscous drugs such as protein: Yeast tablets and multi-enzyme tablets, Chinese herbal extracts
  • more flexible drugs such as Chinese herbal medicine powder.
  • the amount of the active ingredient to be added is generally not particularly limited as long as it is therapeutically safe and effective, but it is preferably a safe and effective dose or more, and a tablet of 80% w/w or less or less based on the weight of the tablet.
  • the weight is more preferably the weight of the tablet above 50% w/w above the safe and effective dose. Since the present invention can attain sufficient tablet strength while maintaining the original porous structure, the amount of drug incorporation relative to the weight of the tablet can be increased.
  • the average particle diameter is 250 ⁇ m or less due to the unsmooth feeling in disintegration in the oral cavity.
  • the drug may be pulverized in advance with an appropriate pulverizer apparatus to an average particle diameter of from about 1 to about 200 ⁇ m, preferably pulverized to an average particle diameter of from about 5 to about 100 ⁇ m, more preferably to about 5 Up to a size of about 30 ⁇ m.
  • the active ingredient having poor stability it may be coated with a polymer film-forming material, wax or the like.
  • the active ingredient for volatile and chemical instability can be encapsulated with cyclodextrin and its derivatives.
  • a coating material include a water-insoluble polymer, a gastric-soluble polymer, an enteric polymer, or a waxy substance as a polymer material.
  • pharmaceutically acceptable additive means that the solid preparation contains one or more solid or liquid substances which can be mixed with each other without interaction without reducing the stability and/or effectiveness of the solid preparation.
  • a pharmaceutical auxiliary material (including its encapsulated compound) for topical or systemic administration.
  • the selection of the additive and the amount thereof to be used in the present invention are determined according to the specific dosage form, the actual state of the solid preparation, the preparation method, and the subjective requirements, etc., and are not completely limited to the limitations herein.
  • various excipients which can be used as an additive are not particularly limited as long as they are pharmaceutically acceptable.
  • disintegrators for example, there are disintegrators, binders, lubricants, plasticizers, sweeteners, fragrances, colorants, sour sauces, foaming agents, stabilizers, and the like.
  • Such additives may be used in combination of one or more kinds.
  • sour materials there are, for example, citric acid, tartaric acid, malic acid and the like.
  • foaming agents for example, baking soda or the like.
  • Stabilizers can be selected for various studies on drugs. These additives can be appropriately added in an appropriate amount, and one type or two or more types can be used in combination.
  • the ratio of the weight of the above water-soluble crystalline particulate or powdery diluent to the weight of the molten binder and the mechanical strength enhancer also affects the mechanical properties of the tablet to a large extent.
  • the ratio is the above soluble
  • the weight of the particulate or powdery diluent in the crystalline state of water / (the weight of the above molten binder + the weight of the above mechanical property enhancer + the above-mentioned water-soluble crystalline form of granular or powdery
  • the weight of the diluent is plotted on the abscissa and the ratio of the measured mechanical properties to the ordinate - the mechanical properties (such as hardness or mash) phase diagram is usually convex or concave. Curve (see Figures 3-4 of Example 2).
  • the above-mentioned molten binder has good affinity with the above-mentioned water-soluble component, and the above-mentioned phase diagram has a convex or concave amplitude, and the maximum value of Yu Da (or small) appears in the figure (which is the present invention) Most preferred values);
  • the most significant values appearing in the graph are generally offset toward the water soluble component having a higher melting point.
  • the ratio of the above-mentioned proportional relationship in the present invention is taken as the ratio of the middle segment, and relatively A high proportion of the above-mentioned water-soluble crystalline particulate or powdery diluent is advantageous for improving the hydrophilicity and mechanical properties of the tablet, so that the above-mentioned proportional relationship in the present invention is further taken in the middle of the back (
  • the ratio of the hydrophilic segment that is, the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent / (the weight of the above molten binder + the weight of the above mechanical property enhancer + the above soluble Between 0. 50 and 0. 87 (inclusive), preferably between 0. 40 and 0.87 (inclusive), More preferably between 0.55 and 0.80 (inclusive).
  • the proportion of the above water-soluble crystalline particulate or powdery diluent in the above tablet in the total weight of the tablet also affects the mechanical properties and hydrophilicity of the tablet to a large extent.
  • the above ratio of the total amount of the molten binder to the mechanical performance enhancer in the entire tablet also affects the mechanical properties of the tablet to a large extent.
  • other components in the tablet formulation water-insoluble crystalline material or non-melting curing agent
  • the weight of the above-mentioned water-soluble crystalline granular or powdery diluent / (weight of the above molten binder + mechanical properties mentioned above)
  • the weight of the reinforcing agent + the weight of the above-mentioned water-soluble crystalline granular or powdery diluent is the ratio of the abscissa and the measured mechanical property parameter value to the ordinate - mechanical property parameter (such as hardness or mash) phase diagram (see Figures 3-4 of Example 2), the above water-soluble crystalline particulate or powder-form diluent in the above tablet accounts for the entire weight
  • the ratio of the total weight of the tablet is not less than 25% (wt/wt), more preferably not less than 34%
  • the mechanical performance enhancer accounts for not less than 5% (wt/wt), more preferably not less than 8%, of the entire tablet.
  • the weight of the granulated or powdered diluent is used to calculate the above relevant ratio based on the total weight.
  • the above-mentioned active ingredient and/or the above pharmaceutically acceptable additive is a particulate or powdery substance in a water-soluble crystalline state
  • the above-mentioned water-soluble crystalline granular or powdery form The amount of diluent can be zero.
  • the present invention also relates to a method for producing a hydrophilic tablet having a high porosity and a high porosity which is further enhanced by the above mechanical properties. The relevant preparation steps will be described in detail below.
  • the present process is to make the above-mentioned preparation raw materials of the present invention: a diluent, an active ingredient, a molten binder, a mechanical property enhancer and an additive are substantially uniformly dispersed in a pharmaceutical state and have a pharmaceutically acceptable space form. That is, the tablet form is not particularly limited unless otherwise.
  • the preparation raw materials of the present invention are prepared by the following preparation methods, for example, physical mixing, wet granulation, dry granulation, spray drying, fluidized bed granulation, stirring granulation, rotary granulation, and melt cooling pulverization.
  • granulation by various methods such as casting, rolling granulation, or combining the active ingredient-free pellet or the active ingredient-containing granule with powder or granule; or the pair containing about 100% of the bioactive substance powder and
  • the crystal or the above-mentioned shaped product is coated and granulated by spreading, spraying or the like; or after the above process is completed, further formed into a sheet by a pressing process; or the mixed preparation of the original raw material is directly compressed, and the dry powder is compressed; or The uniform preparation of the raw materials is melted, cast into tablets, or sintered, extruded, and subsequently rounded, or directly into pellets or tablets (for example, through a flat plate), or further processed after the above process is completed. tablet.
  • the molten binder and the mechanical performance enhancer are evenly distributed. Dispersed on the surface of the formed body, the fluidized bed granulation method was satisfactory.
  • a diluent, an active ingredient, a molten binder, a mechanical property enhancer is dissolved and/or suspended in a pharmaceutically acceptable solvent as an adhesive spray , coating and / or granulation, after the above process is completed, further into tablets.
  • the thickness of the coating is between 1 and 100 ⁇ m, preferably between 10 and 50 ⁇ m. In a common tablet, the thickness corresponds to the use of 0.5 to 5% by weight of the polymer, and may be appropriately increased or decreased in a specific application.
  • a pressing process is often employed. Such a pressing process is usually carried out by a tableting machine after the lubricant is blended in advance with the tablet raw material. In order to maintain the shape of the tablet, the pressing process must use a pressure not lower than the minimum pressure limit, and at the same time, in order to obtain a satisfactory porosity, a lower pressure is required, and the tableting pressure is usually 10 - 700 kg / ⁇ , satisfactory It is 30_400kg/ ⁇ , and more satisfactory is 50_250kg/ ⁇ .
  • the forming step in the method for producing a solid preparation according to the present invention preferably employs a non-pressing process.
  • the preparation raw material the above diluent, additive, active ingredient, molten binder, mechanical property enhancer, etc. are mixed or dissolved and/or suspended in a pharmaceutically acceptable solvent, and then directly dispensed.
  • a pharmaceutically acceptable solvent e.g., ethanol, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, etc.
  • the above-mentioned preparation raw materials are charged into a heatable word hopper or other suitable container, and the preparation material is heated and melted, and the melt is introduced into a calender having two reverse molding rolls to form a tablet.
  • the surfaces of the two reverse molding rolls have mutually opposite depressions to receive and mold the tablet composition.
  • the molded article obtained by the step (2) can be melted by melting the binder and the mechanical property enhancer used in the present invention as long as it is heated. No substance is degraded upon heating (except for degrading porogen) or volatilization of active ingredient, more preferably, the above-mentioned water-soluble crystalline granular or powdery diluent and the above active ingredient are not melted. There is no particular limitation on the method.
  • Such a "heating" process can be carried out, for example, in a ventilating oven, an oven, or an incubator.
  • the temperature conditions are appropriately determined according to the type of the diluent, the active ingredient, the melt binder, and the mechanical property enhancer used in the present invention, as long as the melt binder and the mechanical property enhancer used in the present invention are all dissolved, no substance.
  • the degradation is carried out upon heating (except for the degradation of the porogen) or the volatilization of the active ingredient, and the above-mentioned water-soluble crystalline particulate or powdery diluent and the above-mentioned active ingredient are not melted, and are not particularly limited.
  • the temperature used in the present invention is usually higher than the melting point of the above mechanical property enhancer, and the temperature used is usually from about 45 to about 130 ° C, preferably from about 60 to about 110 ° C, more preferably from about 70 to about 90 ° C. 5 ⁇ 120 ⁇ , compared with the diluent, the active ingredient, the type of the melt binder and the mechanical property enhancer, the desired strength of the solid preparation, the disintegration performance of the solid preparation, etc., usually 0.5 to 120 minutes. The best is 1 to 60 minutes, more preferably 2 to 30 minutes.
  • the "heating" process of the present invention may also be heated on the surface of the molded article or adjacent to the surface thereof to melt the surface of the molten adhesive and the mechanical property enhancer at a depth of 0.1 to 2 mm, and the internal molten adhesive.
  • the mechanical performance enhancer is maintained as it is, so that a solid formulation which disintegrates more rapidly can be obtained.
  • the "cooling" of the present invention is carried out by a known method, and the method of curing (solidifying) the molten binder and the mechanical property enhancer used in the present invention after melting is not particularly limited. Such "cooling” can be carried out, for example, by storage at a room temperature and in a low temperature environment such as a refrigerator.
  • the tablet may also contain volatile components and/or components that degrade into harmless gases to obtain tablets of greater porosity.
  • the volatile component and/or the component degradable into a harmless gas are blended and mixed into the tablet raw material to form a tablet, and the volatile component is removed from the tablet by heating under normal pressure or reduced pressure.
  • the volatilization is removed to form a porous tablet.
  • the volatile components are preferably removed by evaporation during the melting stage.
  • the tablets are heated to 45 to 110 ° C, preferably 50 to 80 ° C under continuous nitrogen purge until the volatile components are all sublimed and volatilized. The use of nitrogen purge helps to protect the unstable active ingredient from degradation under these conditions.
  • Suitable volatile components and components which degrade into harmless gases include sublimable materials and at or below binder and/or mechanical property enhancers a substance capable of decomposing at a melting point, which can be used in the examples of the present invention such as benzoic acid (mpl 21.5 to 123.5 ° C, 100 ° C to start sublimation (latm)), benzoic acid esters and benzoate compounds (such as benzoic acid B) Fat, phenyl benzoate, propyl benzoate, benzyl benzoate, methyl benzoate, benzoate such as sodium salt), vanillin (mp 81 ⁇ 83 ° C), ethyl vanillin ( ⁇ 76 ⁇ 8 ⁇ ) , pure mp77 ⁇ 78°C), natural or synthetic camphor (natural camphor mpl76 ⁇ 181°C, synthetic camphor mpl74 ⁇ 179°C), right-handed
  • Tablets prepared according to the various methods described above are "porous" and typically have a porosity of from about 10 to about 95%, desirably from about 20 to about 90%, more desirably from about 40 to about 80%.
  • Tablets prepared by any of the above methods may be coated with a thin layer of coating material to improve the surface integrity of the tablet.
  • Suitable coating materials include, but are not limited to, disaccharides such as sucrose, polysaccharides such as maltodextrin and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose, however, any coating It should be sufficiently thin and water soluble so as not to interfere with the rapid disintegration ability of the tablet in the mouth.
  • the tablet according to the invention has the following advantages over the tablet prepared by the meltable component in the tablet alone: one has stronger mechanical properties, maintains the integrity of the tablet, prevents the tablet from being produced, transported, etc. Fine or large cracks, abrasion, and breakage during the process to prevent unstable materials from being re-exposed to adverse environments;
  • the ratio is 1:1), abbreviated as dilute 2), the amount of molten binder (1 is polyoxyethylene (40) stearate, referred to as sticky 1; 2 is polyethylene glycol (60) Sesame oil, abbreviated as 2) and mechanical performance enhancer (1 is glyceryl monostearate, abbreviated as 1; 2 is hydrogenated castor oil, abbreviated as 2).
  • the ratio is 1:1), abbreviated as dilute 2), the amount of molten binder (1 is polyoxyethylene (40) stearate, referred to as sticky 1; 2 is polyethylene glycol (60) Sesame oil, abbreviated as 2) and mechanical performance enhancer (1 is glyceryl monostearate, abbreviated as 1; 2 is hydrogenated castor oil, abbreviated as 2).
  • Example 1 The following non-selective examples further describe preferred embodiments within the scope of the invention. Many variations of these embodiments are possible within the scope of the invention. Example 1
  • the composition is as follows:
  • the components D-mannitol, sucrose, hydroxypropyl cellulose are ground and made into wet granules with ethanol, dried, and ground; the obtained dry granules are sequentially combined with dipyridamole, polyoxyethylene (40) stearate And glyceryl monostearate, croscarmellose sodium, silica, sodium stearyl fumarate are mixed and mixed; finally, magnesium stearate is mixed with the obtained mixture.
  • the final mixture was compressed to a tablet having a diameter of 9 mm under a pressure of about 50 kg/min. The tablets were heated at a temperature of 75 ° C for 60 minutes and then allowed to cool naturally at room temperature.
  • Example 5 The amount of polyoxyethylene (40) stearate in the formulation of Example 3 was changed from 28.125 mg / tablet to 35. 438 mg / tablet, glyceryl monostearate was changed from 28. 125 mg
  • Example 6 The amount of polyoxyethylene (40) stearate in the formulation of Example 3 was changed from 28.125 mg/tablet to 22.5 mg/tablet, and glyceryl monostearate was changed from 28.125 mg/tablet to 33.
  • Example 6 was prepared as described above.
  • Example 7 Example 7
  • Example 7 was prepared as described above.
  • Example 11 Example 11
  • Example 12
  • Example 3 The glyceryl monostearate in the formulation of Example 3 was replaced with the equivalent weight of polyoxyethylene (40) stearate, and the others were unchanged.
  • Reference material 1 was prepared as described above.
  • the polyoxyethylene (40) stearate in the formulation of Example 3 was changed to an equivalent weight of glyceryl monostearate, and the others were unchanged.
  • Reference product 2 was prepared as described above.
  • the amount of polyoxyethylene (40) stearate in the formulation of Example 3 was changed from 28.125 mg/tablet to 50.625 mg/tablet, and glyceryl monostearate was changed from 28.125 mg/tablet to 5.625 mg.
  • Reference product 5 was prepared as described above.
  • Reference product 6 was prepared as described above.
  • the amount of the hydrogenated castor oil was changed from 47.5 mg/tablet to the amount of the ethylene glycol (60) hydrogenated castor oil.
  • the real reference 13 was prepared as described above.
  • the other unchanged Reference material 16 was prepared as described above.
  • Example 8 The isomalt and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 148.75 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 52. 5 mg/tablet of polysorbate 61, hydrogenated castor oil was removed, and cholesterol stearate was not added, and the others were unchanged.
  • Reference product 17 was prepared as described above.
  • Example 8 The isomalt and erythritol in the formulation of Example 8 were replaced by 122.5 mg/tablet to 148.75 mg/tablet, polyethylene glycol (60) hydrogenated castor oil was removed, and no polysorbate 61 was added. 5mg/ ⁇ 57. 75mg / piece of hydrogenated castor oil was replaced by 52.5 mg / piece Cholesterol stearate, other unchanged, reference product 18 was prepared as described above.
  • the hardness, mash, and intraoral disintegration time of the samples and reference samples of the examples were measured.
  • the sample samples and the reference materials were slowly heated, and the temperature at which the tablets began to soften was observed and recorded; the porosity was calculated (above Determined 9 times and averaged).
  • the intraoral disintegration time was determined by the following tests:
  • the tablet of the present invention is contained in an oral cavity which is healthy in the mouth of a man, i.e., which does not contain water in the mouth, and the time during which the tablet is completely disintegrated by saliva until dissolution is measured.
  • Porosity where V: the volume of the tablet The weight of the tablet component, ⁇ : The specific gravity of the tablet component.

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Abstract

La présente invention concerne un comprimé dont les performances globales sont améliorées et son procédé de préparation. Le comprimé comprend un principe actif, un diluant cristallin hydrosoluble sous forme de particules ou sous forme de poudre, un agent de liaison pouvant fondre et un agent améliorant les performances mécaniques, pouvant fondre et/ou ne comprend pas d'additif pharmaceutiquement acceptable, ledit diluant et/ou ledit principe actif étant liés et reliés par le mélange fondu solidifié de l'agent de liaison et de l'agent améliorant les performances mécaniques, le rapport de l'agent améliorant les performances mécaniques /(l'agent de liaison + l'agent améliorant les performances mécaniques) étant compris entre 0,25 et 0,70, le rapport du diluant/(l'agent de liaison + l'agent améliorant les performances mécaniques + le diluant) étant compris entre 0,40 et 0,93, la teneur en poids du diluant dans le comprimé n'étant pas inférieure à 25 %, la teneur en poids de l'agent de liaison et de l'agent améliorant les performances mécaniques n'étant pas inférieure à 5 %. Ainsi, les performances mécaniques, la résistance à l'usure, l'hydrophilicité, la porosité et le délitement du comprimé sont améliorés.
PCT/CN2011/077211 2010-07-16 2011-07-15 Comprimé dont les performances globales sont améliorées et son procédé de préparation WO2012006965A1 (fr)

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CN103462914B (zh) * 2013-09-04 2015-12-09 南京正宽医药科技有限公司 一种头孢克肟片剂及其制备方法
CN103432091A (zh) * 2013-09-13 2013-12-11 钟术光 一种性能改善的片剂及其制备方法
CN103860502B (zh) * 2014-04-15 2015-12-30 张绪伟 一种含有盐酸莫索尼定的片剂及其制备方法
CN104920360B (zh) * 2015-06-18 2017-04-12 青岛农业大学 丁苯羟酸在制备用于防治由植物病原菌引起的植物病害的杀菌剂中的用途
CN105434381A (zh) * 2015-12-17 2016-03-30 远大医药（中国）有限公司 氯霉素片的制备方法、其产品及其应用
CN107412176A (zh) * 2017-05-21 2017-12-01 天津双硕医药科技有限公司 一种含有奥利司他的减肥片剂
CN111481568B (zh) * 2020-04-22 2021-04-02 一力制药(罗定)有限公司 一种铝碳酸镁片及其制备工艺

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CN101001613A (zh) * 2004-06-28 2007-07-18 生命周期药物公司 作为液体制剂载体的多孔片剂
CN101365428A (zh) * 2006-01-05 2009-02-11 生命周期药物公司 可负载崩解片剂
CN101530399A (zh) * 2009-04-15 2009-09-16 江苏中兴药业有限公司 一种水飞蓟宾固体自乳化片及其制备方法
CN101711762A (zh) * 2008-10-08 2010-05-26 鲁南制药集团股份有限公司 一种治疗高血压的药物组合物

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CN101001613A (zh) * 2004-06-28 2007-07-18 生命周期药物公司 作为液体制剂载体的多孔片剂
CN101365428A (zh) * 2006-01-05 2009-02-11 生命周期药物公司 可负载崩解片剂
CN101711762A (zh) * 2008-10-08 2010-05-26 鲁南制药集团股份有限公司 一种治疗高血压的药物组合物
CN101530399A (zh) * 2009-04-15 2009-09-16 江苏中兴药业有限公司 一种水飞蓟宾固体自乳化片及其制备方法

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