WO2008086733A1 - Nouvelle composition pharmaceutique - Google Patents

Nouvelle composition pharmaceutique Download PDF

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Publication number
WO2008086733A1
WO2008086733A1 PCT/CN2008/000048 CN2008000048W WO2008086733A1 WO 2008086733 A1 WO2008086733 A1 WO 2008086733A1 CN 2008000048 W CN2008000048 W CN 2008000048W WO 2008086733 A1 WO2008086733 A1 WO 2008086733A1
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WO
WIPO (PCT)
Prior art keywords
drug
sodium
preparation
pharmaceutical composition
cellulose
Prior art date
Application number
PCT/CN2008/000048
Other languages
English (en)
French (fr)
Inventor
Yaoru Lu
Jianhui Guo
Original Assignee
Shanghai Allist Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Allist Pharmaceuticals, Inc. filed Critical Shanghai Allist Pharmaceuticals, Inc.
Priority to EP08700608.6A priority Critical patent/EP2116242B1/en
Priority to JP2009544355A priority patent/JP5295123B2/ja
Priority to CN2008800016680A priority patent/CN101616668B/zh
Publication of WO2008086733A1 publication Critical patent/WO2008086733A1/zh
Priority to US12/497,282 priority patent/US8138214B2/en

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and in particular to a novel pharmaceutical composition having a pharmacologically active compound, and a preparation method of the composition and use thereof for preparing a cardiovascular drug .
  • Angiotensin II is a major vasoconstrictor of the renin angiotensin-aldosterone system (RAAS), which plays an important role in the pathophysiology of a variety of chronic diseases.
  • RAAS renin angiotensin-aldosterone system
  • Angiotensinogen can be converted to decapeptide angiotensin I (Angl) by renin, and Angl has only weak contractile blood vessels, which can be further Angiotensin II (Angll), which is an octapeptide, which is the final physiologically active substance of RAAS, which binds to a specific angiotensin II receptor to produce vasoconstriction, elevated blood pressure, etc.
  • Angl angiotensin II
  • EP0253310 discloses a series of imidazole derivatives.
  • the DuPont Company of the United States has developed a high blood pressure lowering effect of the compound DUP753. It was approved in the market in 1994 and became the first non-peptide Angll receptor antagonist. , that is, losartan potassium, which inhibits vasoconstriction by selectively blocking the action of angiotensin II of vascular smooth muscle on its type I receptor, thereby achieving relaxation of blood vessels and lowering blood pressure.
  • U.S. Patent No. 5,1964,446 discloses a series of benzimidazole derivatives and processes for their preparation. Such derivatives have angiotensin II antagonistic activity and antihypertensive activity and are useful as therapeutic hypertension.
  • candesartan ester was developed and marketed by Takeda, Japan in 1997. It removes ester groups in the body, hydrolyzes into active metabolites, and exerts blood pressure lowering effects.
  • No. 5,616,599 discloses a series of 1-biphenylmethylimidazole derivatives similar in structure to losartan.
  • the largest structural change is the conversion of the chlorine atom at the 4-position of the losartanidazole ring to 1-hydroxy-1-methyl.
  • Ethyl, 5 positions were modified into carboxyl, hydroxyl and prodrug structure esters or amides, which proved to have a good blood pressure lowering effect, and the Japanese Sankyo Company developed and marketed olmesartan. Summary of the invention
  • the pharmaceutical composition of the anti-drug may be in the form of a powder, a granule, a pellet, a dropping pill, a capsule, a tablet, a lozenge and other suitable solid preparations, or may be dispersed in a liquid before being taken, and then swallowed. solid preparations.
  • This new pharmaceutical composition can be used in the treatment of cardiovascular diseases.
  • Another object of the present invention is to provide a solubilizing composition of the drug, which is highly dispersed in a carrier material, especially a water-soluble carrier material, thereby improving the dissolution rate of the drug, increasing the absorption efficiency, and increasing bioavailability.
  • Another object of the present invention is to provide a solid preparation which can be used for oral administration, which is prepared from such a solubilizing composition containing the drug, and can be in the form of a powder, a granule, a dropping tablet, a capsule, a tablet, a lozenge. And other suitable solid forms may also be dispersed in a liquid prior to administration and then swallowed.
  • the invention also provides methods of preparing these formulations.
  • Another object of the present invention is to provide a novel pharmaceutical composition useful for cardiovascular diseases.
  • Another object of the present invention is to provide a method of treating cardiovascular diseases in humans, particularly hypertension.
  • Other objects of the invention include providing a formulation technique that increases the extent of absorption of a drug through the gastrointestinal tract.
  • the Applicant describes a series of imidazole-5-carboxylic acid derivatives in the PCT application (PCT/CN2006/001914) which are structurally characterized in that the 5-position on the imidazole ring is a sebacate structure, such compounds are in animals.
  • the body shows good blood pressure lowering activity.
  • the imidazole-5-carboxylic acid derivative has advantages of lower toxicity than other Angll receptor antagonists, and in particular, the following compounds are disclosed:
  • the active ingredient can be administered to a patient as a general oral preparation.
  • the solubility of a drug is closely related to the human bioavailability of the drug.
  • a method of improving the solubility such as a mechanical powder, may be employed. Techniques such as crushing and micronizing can reduce the particles, increase the surface area of dissolution, and improve the dissolution; structural modification of the compound, such as salt or ester; or formulation means, such as cyclodextrin inclusion technology, solid Dispersion technology, addition of solubilized substances, etc.
  • the present invention is a compound containing the formula I 2-butyl-4-chlorosucci [2'-(1 H-tetrazol-5-yl) fluorene, hydrazine-biphenyl-methyl]imidazol-5-carboxylic acid, 1 - [(Isopropoxy)carbonyloxy]methyl ester has been extensively and intensively studied as a pharmacologically active ingredient in a pharmaceutical composition for clinical use in a rational formulation.
  • the "drug” or “pharmacologically active ingredient” means a compound of the formula I 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl) fluorene, ⁇ - Biphenyl-methyl]imidazol-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester.
  • the present invention first provides 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl) 1,1'-biphenyl-methyl]imidazol-5-carboxyl
  • a solid composition of an acid, 1-[(isopropoxy)carbonyloxy]methyl ester, is achieved by the addition of a pharmaceutically acceptable carrier material (or excipient).
  • compositions include carrier materials including fillers, disintegrants, wetting agents, binders, surfactants, lubricants, glidants, flavoring agents, odorants, colorants, and other types of solids. Excipients for the formulation.
  • the composition may be in the form of a powder, granule, pellet, capsule, tablet or lozenge, but this does not constitute a limitation on the form of preparation thereof, as is known to those of ordinary skill in the art, in a tablet.
  • composition can be prepared as a plain tablet, a film-coated tablet, a sugar-coated tablet, a two-layer tablet or a multilayer tablet, an effervescent tablet, a dispersible tablet, an orally disintegrating tablet, and a sustained-release tablet.
  • the composition is suitable for oral administration, but is also suitable for administration in other ways, such as sublingual administration, for example, dispersion in a liquid prior to use and then swallowing in liquid form.
  • the filler may be selected from one or a combination of the following: calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sucrose, lactose, fructose, Xylitol, mannitol, starch or its derivatives, dextrin, microcrystalline cellulose.
  • the disintegrant may be selected from one or a combination of the following: starch, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, crosslinked polyvinylpyrrolidone, Low substituted hydroxypropyl methylcellulose, microcrystalline cellulose, methyl cellulose.
  • the surfactant may be selected from one or a combination of the following: sodium lauryl sulfate, poloxamer, tween, cetyltrimethylammonium bromide, sodium lauryl sulfate, stearyl sulfonate Sodium, polyoxyethylene higher fatty alcohol, sucrose ester, sorbitol fatty ester, soybean phospholipid, and the like.
  • the wetting agent may be selected from one or a combination of the following: distilled water, ethanol, starch slurry.
  • the binder may be selected from one or a combination of the following: gum arabic, gelatin, tragacanth, dextrin, polyvinylpyrrolidone, starch and its derivatives, sodium alginate, sorbitol, syrup, hydroxypropyl Methylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, glucose, polymethacrylate.
  • the lubricant may be selected from one or a combination of the following: calcium stearate, glyceryl monostearate, glyceryl palmitate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride , sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, zinc stearate, polyethylene glycol.
  • the glidant may be selected from one or a combination of the following: colloidal silica, powdered cellulose, magnesium trisilicate, silica, and talc.
  • the flavoring agent may be selected from the group consisting of aspartame, stevioside, fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizin, glycophyllin and various flavors,
  • the scenting agent can be selected from aromatic oils, and the coloring agent can be selected from artificial or synthetic pigments.
  • the technical solution of the above carrier material is that the drug accounts for 1% to 50% by weight of the composition, and can be prepared into powders, granules, pellets, tablets, troches, capsules. In the preparation, it is preferred to micronize the drug to increase the dispersion of the drug, increase the dissolution surface area of the drug, and improve the dissolution performance.
  • the percentages being by weight.
  • the disintegrant is selected from starch and cellulose derivatives, preferably sodium carboxymethyl starch, 4% ⁇ 8%, the balance is filler, selected from starch, microcrystalline fiber
  • the saccharin, lactose or sucrose, and the appropriate amount of binder are selected from the group consisting of starch syrup or povidone.
  • the balance is lactose
  • the drug is mixed with lactose, preferably the same amount of addition method, mixing and pulverizing, passing through 80-100 mesh sieve, adding sodium carboxymethyl starch, and also preferably mixing by equal amount, uniformly, adding adhesion Agent, soft material, prepare 12 ⁇ 14 mesh particles with swinging machine, dry at 50 ⁇ 90°C, control the moisture of the particles within 3%, mix evenly, and put into capsule No.0 to No.2.
  • the lubricant is selected from magnesium stearate
  • the binder is selected from a suitable concentration of PVPK30 in ethanol.
  • lactose as a filler can be replaced by starch
  • sodium carboxymethyl starch as a disintegrating agent can be replaced by crospovidone in an amount of 5% to 15%.
  • a micropellet technique can also be employed, for example, coating the drug on the surface of the blank pellet core to form pellets, or mixing the drug with a suitable carrier to prepare The pellet core is then coated with a barrier layer.
  • the drug-containing pellets obtained in any of the above manners may be coated with an intumescent layer, a barrier layer, a controlled release layer or the like to achieve an ideal control of the drug release rate.
  • Carrier materials commonly used as pellet cores or coatings for pellets are: sucrose, starch, dextrin, beeswax, fatty acids, shellac, povidone, methylcellulose, cellulose acetate, polyacrylic resin, cellulose acetate Acid ester, hydroxypropyl cellulose, polyethylene glycol or a mixture thereof.
  • the pellets may be administered in divided doses directly in the form of a bed, or may be further added with a suitable excipient, and may be formulated into capsules or compressed into tablets according to a conventional preparation method.
  • the compressed tablet may be subjected to a film coating or a sugar coating or an enteric coating.
  • a film coating material which has a barrier effect on moisture; or may be coated with a sugar coating layer for the purpose of obtaining a better mouthfeel.
  • Another technical solution of the present invention is to provide a solid preparation which can be dispersed before administration, that is, a dispersible tablet, an orally disintegrating tablet, an effervescent tablet or the like as described in the formulation, which is for a patient having a swallowing disorder. It is very helpful.
  • a formulation in addition to one or more of the foregoing carrier materials, provides an improvement in disintegration or dispersion properties as described in the following technical scheme: (i) Dispersible tablet: A sufficient amount of disintegrant having excellent disintegration performance is added to the tablet to rapidly disperse the tablet in the liquid.
  • Preferred disintegrants are crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch in an amount sufficient to allow the tablet to disperse rapidly upon contact with water.
  • the choice of filler should take into account its compressibility, flowability and disintegration properties, such as microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose and Low-substituted hydroxypropylcellulose can be used as a filler with excellent properties.
  • Orally disintegrating tablets A sufficient amount of disintegrant having excellent disintegration performance is added to the tablet to cause rapid disintegration of the tablet.
  • Preferred disintegrants are crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch in an amount sufficient to allow the tablet to disperse rapidly upon contact with water.
  • the choice of filler should take into account its compressibility, flowability and disintegration properties, such as microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose and Low-substituted hydroxypropylcellulose can be used as a filler with excellent properties.
  • Effervescent tablets A substance that produces carbon dioxide gas in the form of water, that is, an effervescent agent, is added to the tablet.
  • the effervescent agent contained in the composition of the present invention may be selected from the group consisting of organic acids such as tartaric acid or a combination of malic acid and sodium hydrogencarbonate, or a combination of phosphates, or an organic acid anhydride such as succinic anhydride or phthalic anhydride.
  • an effervescent tablet For the purpose of rapidly disintegrating, the resulting tablet is called an effervescent tablet.
  • Such tablets can be taken directly or dissolved in water prior to administration, and are very beneficial for patients who are not accustomed to taking solid preparations such as capsules, tablets, and lozenges.
  • a specific technical solution is: drug, microcrystalline cellulose, croscarmellose sodium, povidone, sucrose fine powder, sodium saccharin, malic acid, sodium hydrogencarbonate, anhydrous sodium carbonate, dodecyl Sodium sulfate, flavor.
  • the particle size of the microparticles after disintegration is controlled to be 400 nm or less; in the preparation process, granulation is not an essential step, and direct compression is a preferred method.
  • the particle diameter of the drug-containing pellets prepared as described above is as small as that without causing a sand sensation, such as an average particle diameter of 400 nm or less, it can also be used for the preparation of such a dispersion which is dispersed before use. Flavoring agents, odorants or other excipients may also be added to these formulations for the purpose of obtaining a good mouthfeel.
  • composition comprising a solubilizing carrier
  • a pharmaceutical composition comprising the pharmacologically active ingredient and a solubilizing carrier, that is, first dispersing the drug in a pharmaceutically acceptable appropriate carrier to increase dissolution of the drug, in the present invention
  • a solubilizing carrier This part of the carrier is referred to as a solubilizing carrier.
  • the solubilized carrier materials of the present invention preferably use the following types: polyethylene glycols, povidones, Polyoxyethylene-containing surfactants, water-soluble cellulose derivatives, organic acids and sugars, and alcohols. These types of carriers can be used singly or in combination.
  • solubilizing carrier is specifically illustrated for the purpose of exemplification, but do not constitute a limitation of the present invention.
  • carrier Materials and methods of preparation can be substituted and are therefore included in the present invention.
  • Polyethylene glycol (PEG) has good water solubility and is also soluble in a variety of organic solvents.
  • the drug can be highly dispersed therein, and during the preparation process, the viscosity is increased due to evaporation of the solvent, and the drug aggregation is inhibited, and the molecular weight of the PEG used for the solid dispersion is generally 1000 to 20000.
  • a combination of one or more, polyoxyethylene (40) monostearate, stearic acid, or poloxamer surfactants Often used in combination with PEG to regulate drug dispersion and release.
  • the drug is dispersed in such a carrier, it is usually prepared by a dropping method, for example, a dropping pill machine can be used to prepare a drug-containing dropping pill having PEG as a main carrier.
  • a technical solution using PEG as a solubilizing carrier is as follows: The drug and the carrier are weighed according to the following weight ratio: drug; 1% to 8%, PEG4000 10% to 20%, PEG6000 60% to 70%, Polo ⁇ 188 3% ⁇ 5%, the drug powder. Broken through the 80 mesh sieve, added to the remaining matrix heated in a water bath at 80 ⁇ 90 ° C, stirred to make the mixture evenly, the drug powder completely disappeared, will melt the content The drug liquid is placed in the incubator of the dropping machine, and the drip rate is adjusted to be dropped into the condensing agent at a rate of 20 to 30 particles per minute : The condensing agent is selected from dimethicone or liquid paraffin, and the condensation temperature is 4 to 10 °C.
  • the obtained dropping pills were collected, and the surface condensate was wiped off with a blotting paper, and placed in a refrigerator at 4 ° C for 24 hours to obtain a dropping pill. This drop can be taken directly.
  • the dissolution test proves that the prepared dropping pills can be rapidly dispersed, and is particularly suitable for sublingual administration for quick action.
  • Another technical solution is: mixing the drug with PEG 6000 in a 1:1 ratio, adding a conventional prescription amount of a filler, a disintegrant, a lubricant, and pressing into a tablet.
  • Povidone is a 1-vinyl-2-pyrrolidone homopolymer (Polyvinylpyrrolidone; Povidone? Plasdone; Kollidone; hereinafter referred to as PVP), and its specifications are PVPkl2, PVPkl5, PVPkl7, PVPk25 PVPk30, PVPk29/32, PVPk60, PVPk90 , PVPkl20, etc.
  • PVPP cross-linked povidone
  • PVPP is a synthetic cross-linked N-vinyl-2-pyrrolidone homopolymer, the specifications are PVPPXL, PVPPXL-10 and so on.
  • solubilizing carrier material of the present invention may be used alone or in combination in the solubilizing carrier material of the present invention, and the preparation method may be a solvent method, a solvent deposition method, a spray drying method or a freeze drying method. Wait.
  • the technical solutions used in combination are listed below for example purposes:
  • PVPk29/32 and PVPPXL are used as carriers, and the weight ratio thereof is 1:1 to 3:7, and the ratio of the drug to the carrier material is 1:2 to 1:10.
  • Preparation method The drug and PVP29/32 are dissolved in a mixed solution of ethanol and acetone, sprayed on PVPPXL by fluidized bed method, or sprayed directly by solution.
  • Another preparation scheme is: taking the above-mentioned prescribed amount of the drug and the carrier material, dispersing in a suitable solvent system, and obtaining a dry powder by a freeze-drying process.
  • PVPk29/32 and PVPPXL are used as carriers, and the weight ratio is 1:2 ⁇ 1:3, and the ratio of drug to carrier material is 1:1 ⁇ 1:2.
  • Preparation method The drug and PVP29/32 were dissolved in a mixed solution of ethanol, acetone and water (4:4:1), and sprayed on PVPPXL by a fluidized bed method to obtain a dried solubilizing composition. After sieving, a suitable excipient is added to prepare a powder, granule, capsule or tablet.
  • Another preparation scheme is: taking the above-mentioned prescribed amount of the drug and the carrier material, dispersing in a suitable solvent system, and obtaining a dry powder by a freeze-drying process.
  • Cellulose derivatives are also useful as solubilizing carriers.
  • One embodiment is to use hydroxypropyl methylcellulose (HPMC) and polyoxyethylene polyoxypropylene glycol as carrier materials, and the weight ratio of drug, HPMC, polyoxyethylene polyoxypropylene diol is 1:3 ⁇ 5 : 0.2 ⁇ 0.5, HPMC and polyoxyethylene polyoxypropylene diol are dissolved in a mixture of ethanol/acetone/water, the drug is added thereto, uniformly mixed, and the prepared solution is sprayed onto the blank core of the fluidized bed. Thus, particles of the solid dispersion composition were obtained.
  • the solvent used is selected from one or a mixture of the following: methanol, ethanol, isopropanol, acetone, dichloromethane, water, and mixtures thereof.
  • sugars and alcohols which can be used as solubilizing carriers are: dextrose, galactose, sucrose, mannitol, sorbitol, xylitol, and the like. These substances have a plurality of hydroxyl groups in the molecule and can be hydrogen bonded to the drug.
  • mannitol is preferred as the main carrier.
  • the type of material from which the solubilizing support is prepared is not limited to the various types of materials mentioned above, and others such as hydrolyzed gelatin and surfactants are also suitable for use in the present invention. Even if a poorly soluble carrier material or a lipid material such as ethyl cellulose, acrylic resin E, RL, RS type, cholesterol, carnauba wax or the like is used, non-instant release can be prepared by adding a water-soluble carrier material such as PEG, PVP. Types of solubilizing compositions, as demonstrated by existing pharmaceutical research, are useful for maintaining long-term drug release.
  • solubilizing compositions can be directly administered, such as dropping pills, or as an intermediate of the preparation, and adding a pharmaceutically acceptable carrier to prepare other solid preparations such as powders, granules, pellets, tablets, capsules. Agents, tablets, etc.
  • These pharmaceutically acceptable carriers include the aforementioned excipients such as starches and derivatives thereof as fillers, cellulose derivatives, sucrose, mannitol, silicic acid and calcium hydrogen phosphate; MC, HPC, gelatin, PVP, disintegrant may be selected from cross-linked CMC-Na, PVPP, L-HPC, the lubricant may be selected from magnesium stearate and talc; the flavoring agent may be selected from the group consisting of rebaudioside, Aspartame and other flavors, but not limited to this. In the preparation of tablets, a direct compression process is preferred.
  • the excipients selected include fillers, disintegrants, lubricants and other excipients, such as glidants, flavoring agents, etc., which are suitable for direct tableting of powders, and microcrystalline cellulose for fillers. And / or lactose, which is used in the prescription of 20% to 90%.
  • the disintegrating agent may be selected from the group consisting of croscarmellose sodium, crosslinked polyvinylpyrrolidone, and low-substituted hypromellose, and the dosage is 1% to 6% in the prescription.
  • the tablets may be given a film coating, or a sugar coating film, if necessary.
  • One embodiment is: further preparing the solubilized composition into a capsule, the filler added is selected from the group consisting of MCC, starch, CMS-Na, PVPP, and the amount of the formulation is 60% to 95%, the added glidant and The lubricant is selected from the group consisting of talc, magnesium stearate, micronized silica or a mixture thereof in an amount of from 0 to 3% of the total prescription amount, and the amount of the drug-containing solubilizing carrier prepared according to the above scheme is 5% of the prescription amount. ⁇ 40%, crushed through a 60 mesh sieve, uniformly mixed with excipients, and filled into a hard capsule made of No. 1 or No. 2 gelatin shell.
  • a preparation method comprises the following steps: preparing a solution of povidone K29/32 and PVPPXL in a mixed amount of acetone and ethanol (volume ratio of 1:1), and spraying the prepared solution into a fluidized bed by means of a top spray method. Granules, dry, mix the dry material with the rest of the material and directly compress it.
  • Another embodiment is: the drug and povidone K29/32, PVPPXL are made into a solubilizing composition, the drug accounts for 8% to 30% in the composition, and the mass ratio of povidone K29/32 to PVPPXL is 1: 2 ⁇ 1:3, prepared as a solubilizing composition according to the above method, pulverized, sieved, adding filler such as microcrystalline cellulose, accounting for 40% ⁇ 60% of the total weight of the preparation, disintegrating agent such as PVPP, accounting for total preparation The weight is from 1% to 6%, and the rest is an excipient such as a lubricant.
  • a preparation method is as follows: a drug is sprayed into a fluidized bed by a top spray method in a mixed solution of povidone K29/32 and PVPPXL in an appropriate amount of acetone, ethanol and water (volume ratio 4:4:1). Granules, dry, mix the dry material with the rest of the material and directly compress it. The solubilizing composition is further formulated into tablets. The solubilizing composition accounts for 35 to 65% of the total weight of the tablet.
  • Another embodiment is: the drug is combined with povidone K29/32, PVPPXL to form a solubilizing composition, the mass ratio of povidone 29/32 to PVPPXL is 1:2 to 1:3, and the drug accounts for in the composition. 30 ⁇ 40%.
  • the solubilizing composition is further prepared Into a tablet. Fillers such as microcrystalline cellulose, accounting for 25 to 35%, disintegrants such as PVPP, accounting for 1 to 5%, and the rest are excipients such as lubricants.
  • a preparation method is as follows: a drug is sprayed into a fluidized bed by a top spray method in a mixed solution of povidone K29/32 and PVPPXL in an appropriate amount of acetone, ethanol and water (volume ratio 4:4:1). Granules, dry, mix the dry material with the rest of the material and directly compress it.
  • the content of the pharmacologically active ingredient may be 5 mg to 180 mg, preferably one third or one half of the daily dose of the human body, or a multiple of the daily dose, such as a universal animal effective dose and human use.
  • the method of converting the dose may be 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, based on the results of the animal test.
  • compositions of the invention or their formulations can be used in the preparation of anti-cardiovascular drugs, especially anti-hypertensive drugs.
  • the drug can be administered directly to a human, and the route of administration can be oral or sublingual administration.
  • the solid preparation form of the pharmaceutical composition of the present invention mentioned above is in accordance with the second method of the dissolution test method of Appendix XC of the Chinese Pharmacopoeia 2005, the dissolution medium is 900 ml of phosphate buffer solution of pH 6.8, constant temperature 37 ° C, rotation speed 50 Rpm/min, sampling at 45 minutes The content of the drug was determined by ultraviolet spectrophotometry, and the dissolution was calculated.
  • the solid preparation containing the pharmaceutical composition of the present invention has a good dissolution degree, and in particular, the solid preparation containing the solubilizing carrier has an excellent dissolution degree.
  • the preparation form of the pharmaceutical composition prepared by the present invention is subjected to a beagle dog absorption test by a conventional pharmacological experiment method, and the results show that: the drug preparation form is better in the body than the suspension of the drug substance, in particular, Solid preparations containing solubilizing carriers have better absorption in animals.
  • the pharmacologically active ingredient of the present invention can also be administered by other means than oral or sublingual administration, such as injection, transdermal or inhalation. These modes of administration have particular needs in the clinic. These preparations may be formulated and prepared by conventional injection, transdermal or inhalation preparations, and thus preparation forms other than orally containing the pharmacologically active ingredients of the present invention are also included in the scope of the present invention.
  • compositions of the present invention are useful for treating cardiovascular diseases in humans, particularly hypertension, by administering a pharmaceutical composition comprising an effective amount of the active ingredient, preferably once a day. It can also be used in combination with other antihypertensive drugs, including diuretics such as hydrochlorothiazide, angiotensin converting enzyme inhibitors, calcium ion antagonists, and the like. It is preferably used in combination with antihypertensive drugs of different antihypertensive mechanisms.
  • Preparation separately pulverize the drug through 120 mesh sieve, lactose through 80 mesh sieve, gradually add the prescription amount of lactose according to the equal amount of addition method, until the mixture is hooked, and the powder is obtained by dispensing.
  • an appropriate amount of a flavoring agent, a flavoring agent, and a preservative may also be added as needed.
  • the starch sodium is uniformly mixed, and a suitable amount of starch slurry is added to make a soft material, and the granules are sieved by a 14-mesh sieve, dried under a condition of 60 ⁇ , and sieved into a 12-mesh sieve to obtain a granule of the drug.
  • an appropriate amount of a flavoring agent, a flavoring agent, and a preservative may also be added as needed.
  • Preparation The drug is mixed with lactose and crushed through a 80-100 mesh sieve, and a pre-pulverized 80 mesh sieve microcrystalline cellulose, sodium carboxymethyl starch, and a 5% to 20% PVPK30 ethanol solution are added to prepare a soft material.
  • the granules of 12 ⁇ 14 mesh were prepared by swinging machine, dried at 50 ⁇ 90 °C, the moisture of the granules was controlled within 3%, and the mixture was evenly mixed, and the capsule No. 1 was obtained. The dissolution was determined to be 76.6% at 45 minutes.
  • main drug 5g lactose 29g, hydroxypropylmethylcellulose 15g, sodium carboxymethyl starch 4g, magnesium stearate lg
  • the drug is dried with each excipient at 60 , and the drug is mixed with the prescribed amount of lactose. Fully smashed, passed through 80 mesh sieve, add the prescribed amount of hydroxypropylmethylcellulose and sodium carboxymethyl starch, mix well, add appropriate amount of steamed water to make soft material, granulate with 24 mesh sieve, wet granule at 60 ⁇ It is dried by hot air. After drying, it is sifted with a 14-mesh sieve, and the prescribed amount of magnesium stearate is added, and the mixture is uniformly hooked, and the tablet is obtained. The dissolution rate was determined to be 75.5% at 45 minutes.
  • main drug 4g starch 15g, hydroxypropylmethylcellulose 12g, PVPPXL 4g, magnesium stearate 0.5g 7% concentration of starch slurry
  • Preparation The drug and each excipient are dried at 60 ° C, the drug is mixed with the prescribed amount of starch, fully pulverized, passed through a 100 mesh sieve, and the prescribed amount of hydroxypropylmethylcellulose and PVPPXL are added, and the mixture is uniformly mixed, and the amount is 7
  • the concentration of starch slurry is made into soft material, 14 mesh sieve granules, wet granules are dried at 60 ⁇ hot air, and the prescribed amount of magnesium stearate is added, uniformly mixed, and the whole granules are filled into hard capsule No. 1, which is obtained.
  • the dissolution rate was determined to be 74.8% at 45 minutes.
  • Pill core prescription drug 5g, microcrystalline cellulose 20g, low substituted hydroxypropyl cellulose 10g, magnesium stearate lg, sodium dodecyl sulfonate lg
  • Formulation coating solution hydroxypropyl methylcellulose (Pharmacoat 606) 13g, polyethylene glycol 400 2.6g, talc 6.5g, water
  • the drug is pulverized through an 80 mesh sieve, and the other excipients are separately pulverized through a 60 mesh sieve.
  • the sodium dodecyl sulfate is dissolved in an appropriate amount of water to remove the drug, microcrystalline cellulose, low substituted hydroxypropyl cellulose and stearic acid.
  • the magnesium acid is uniformly mixed, the soft material is prepared by using sodium dodecyl sulfonate solution, and the pellets are prepared by using an extrusion spheronization apparatus, and the pellets are dried at 60 ° C, sieved, and 18 to 24 mesh pellets are placed in fluidized.
  • the bed is covered with an insulation layer.
  • the pellets of the separator layer are 40 ⁇ dried for 30 minutes to obtain pellets.
  • the dissolution rate was determined to be 84.5% at 45 minutes.
  • Preparation Dissolve a prescribed amount of hypromellose 603 in water, pulverize the drug through a 80 mesh sieve, and low-substituted hydroxypropyl
  • the cellulose is dispersed in an aqueous solution of hypromellose 603, and 60 g of the blank pellet core is put into a fluidized bed, and the pellet is sprayed by a bottom spray process, and the obtained pellets are filled in a gelatin hard capsule.
  • the dissolution rate was determined to be 74.5% at 45 minutes.
  • Preparation The drug is mixed with mannitol and crushed through an 80 mesh sieve. The other components are pulverized through a 60 mesh sieve, uniformly mixed, and directly compressed. The tablet was disintegrated in 5 ml of distilled water for 3 minutes. The dissolution was measured as described above, and the dissolution at 64 minutes was 64.5%.
  • the drug, tartaric acid, carboxymethyl cellulose, microcrystalline cellulose drug is mixed through a 16 mesh sieve, granulated in a solution of 7% povidone isopropanol, dried, sieved through a 30 mesh sieve; sodium hydrogencarbonate pulverized After passing through a 30 mesh sieve, mix with the prepared granules, add talc powder, magnesium stearate, and mix and knead.
  • the tablet is an effervescent tablet. According to the aforementioned dissolution measurement method, the tablet had a dissolution rate of 64.5% at 45 minutes.
  • the condensing agent is selected from dimethyl silicone oil or liquid paraffin, and the condensation temperature is 4 ⁇ 10 °C.
  • the obtained dropping pills were collected, and the surface condensate was wiped off with a blotting paper, and placed in a refrigerator at 4 ° C for 24 hours to obtain a dropping pill.
  • the dissolution test proved that the prepared pellets were able to dissolve within 15 minutes.
  • the drop pellet is suitable for sublingual administration for quick action.
  • the drug is pulverized through an 80 mesh sieve, added to the remaining matrix heated in a water bath at 80-90 ° C, stirred to make the mixture hook, the drug powder completely disappears, and the molten drug-containing liquid is placed in the dropping machine.
  • the condensing agent is selected from dimethicone or liquid paraffin, and the condensation temperature is 4 to 10 °C.
  • the dissolution test proved that the prepared pellets were able to dissolve in 5 minutes.
  • the drop pill is particularly suitable for sublingual administration for quick action.
  • Drug 5g PVPK29/32 36g Microcrystalline Cellulose 20g Lactose 20g PVPPXL 4g Magnesium Stearate 4g
  • Preparation Dissolve the drug in an appropriate amount of acetone, add PVPPXL (A) and mix well. Dry the sample under reduced pressure, mix the dried material with the rest of the material, and compress it. The dissolution rate is 96.8% at 45 minutes.
  • Preparation Dissolve the drug and PVPK29/32 in a suitable amount of acetone and ethanol mixed solution (1:1 by volume), add PVPPXL (A) to the fluidized bed, and spray the prepared solution into the fluidized solution by spray gun.
  • the granules were granulated in the bed, dried, and the dried materials were uniformly mixed with the rest of the materials.
  • the tablets were tableted and the dissolution rate was determined to be 96.7% at 45 minutes.
  • Preparation Dissolve the drug and PVPK29/32 in a suitable amount of acetone and ethanol mixed solution (1:1 by volume), add PVPPXL (A) to the fluidized bed, and spray the prepared solution into the fluidized solution by spray gun.
  • the granules in the bed were dried, and the dry materials were uniformly mixed with the rest of the materials.
  • the tablets were tableted and the dissolution rate was determined to be 98.5% at 45 minutes.
  • Preparation Dissolve the drug and PVP 29/32 in an appropriate amount of acetone and ethanol mixed solution (1:1 by volume), add PVPPXL (A) to the fluidized bed, and spray the prepared solution into the flow by spray gun. Granulation in a chemical bed, drying, The dried material was uniformly mixed with the rest of the materials, and the tablets were tableted at a rate of 97.8% at 45 minutes.
  • Preparation Dissolve the drug and PVPK29/32 in a suitable amount of acetone and ethanol mixed solution (1:1 by volume), add PVPPXL (A) to the fluidized bed, and spray the prepared solution into the fluidized solution by spray gun.
  • the granules were granulated in the bed, dried, and the dry materials were uniformly mixed with the rest of the materials, and the tablets were tableted, and the dissolution rate was determined to be 98.3% at 45 minutes.
  • Preparation The drug was mixed with microcrystalline cellulose (A) for 20 minutes, mixed well with the rest of the material, and the dissolution was determined to be 86.7% when pressed for 45 minutes.
  • the beagle dogs were used as test animals, and each group of six, the preparations of the drug substance suspension, the preparations prepared in Examples A1 and D3 were administered by a single dose of 9.0 mg/kg, respectively, at each set time.
  • the blood sample was collected, and the blood plasma was separated and prepared.
  • the concentration of the metabolite EXP3174 in the plasma was determined by liquid chromatography-tandem mass spectrometry.
  • the pharmacokinetic parameters of the metabolite EXP3174 were calculated according to the drug concentration-time curve. The results are shown in Table 1. .
  • the same dose of the drug is administered by the beagle dog, and the drug preparation form is superior to the suspension of the drug substance in the body, and the preparation containing the solubilizing carrier absorbs more in the body than the ordinary preparation.

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Description

新的药用组合物 技术领域 本发明属于药物制剂领域， 具体说， 涉及一种新的具有药理活性的化合物的药用组 合物， 以及该组合物的制备方法和用于制备心血管药物的用途。 技术背景 血管紧张素 II是肾素血管紧张素 -醛固酮系统 (RAAS)的主要血管收缩激素，它在多种 慢性疾病的病理生理学中起着重要的作用。 它存在于多种组织中，其生成的途径主要为: 血管紧张素原经肾素作用可转化为十肽的血管紧张素 I(Angl), Angl仅有微弱的收缩血管 的作用，可进一步在血管紧张素转化酶的作用下转化为八肽的血管紧张素 II (Angll ), 它 是 RAAS 的最终生理活性物质，可与特异性的血管紧张素 II受体结合而产生血管紧缩, 血压升高等生理作用。
EP0253310公开了一系列咪唑衍生物， 美国杜邦公司经研究发现代号为 DUP753的 化合物有很好的降血压作用，并于 1994年获得上市批准， 成为了第一个非肽类的 Angll 受体拮抗剂， 即氯沙坦钾， 它通过选择性地阻断血管平滑肌的血管紧张素 II对其 I型受 体的作用而抑制血管收缩， 从而达到舒张血管、 降低血压的作用。
随着氯沙坦钾的开发上市， 各类医药研发机构和公司陆续开展了 Angll受体拮抗剂 的结构学研究。 US5196444公开了一系列苯并咪唑衍生物以及它们的制备方法， 这类衍 生物具有血管紧张素 II拮抗活性和抗高血压活性， 从而可用作治疗高血压。 其中的坎地 沙坦酯由日本武田公司于 1997年开发上市， 它在体内脱除酯基， 水解为其活性代谢物， 发挥降血压作用。
US5616599公开了与氯沙坦结构类似的一系列 1-联苯甲基咪唑衍生物， 结构上的最 大变化就是将氯沙坦咪唑环上 4位的氯原子改造为 1-羟基 -1-甲基乙基， 5位改造为羧基、 羟基以及前药结构酯或酰胺， 证明具有良好的降血压作用， 由此日本三共公司开发上市 了奥美沙坦。 发明内容
本发明的目的是提供一种包含新的药理活性成分， 具体说是一种新的 Angll受体拮 抗剂的药用组合物， 其形式可以是散剂、 颗粒剂、 微丸、 滴丸、 胶囊、 片剂、 锭剂及其 他适宜的固体制剂， 也可以是服用之前以液体分散， 然后吞服的固体制剂。 这种新的药 用组合物可用于心血管疾病的治疗。
本发明的另一目的是提供所述药物的增溶组合物， 将药物高度分散于载体材料中， 尤其是一种水溶性的载体材料中， 从而提高药物的溶出度， 提高吸收利用率， 增加生物 利用度。
本发明的另一目的是提供由这种包含所述药物的增溶组合物制成的可用于口服的固 体制剂， 其形式可以是散剂、 颗粒剂、 滴丸、 胶囊剂、 片剂、 锭剂及其他适宜的固体形 式， 也可以是服用之前以液体分散， 然后吞服。 本发明还提供了这些制剂的制备方法。
本发明的另一目的是提供一种新颖的可用于心血管疾病的药用组合物。
本发明的另一目的是提供一种人类心血管疾病， 尤其是高血压的治疗方法。
本发明的其他目的包括提供一种可以提高药物经胃肠道吸收程度的制剂技术。
本申请人在 PCT申请（PCT/CN2006/001914)中描述了一系列咪唑 -5-羧酸类衍生物， 结构上的特点在于咪唑环上 5位为偕二酸酯结构， 这类化合物在动物体内表现出良好的 降血压活性。 与其他 Angll受体拮抗剂相比， 该咪唑 -5-羧酸类衍生物具有毒性更低的优 点， 尤其公开了以下化合物：
2-丁基 -4-氯 -1-[2'-(1 H -四唑 -5-基) 1,1'-联苯基-甲基]咪唑 -5-羧酸， 1- [(异丙氧基)羰氧 基]甲基酯， 结构式如式 I所示。
Figure imgf000003_0001
式 I
该活性成分可作为普通的口服制剂供患者服用。 在口服制剂中， 药物的溶解性能与 人体对药物的生物利用度紧密相关。 改善溶解度的方法， 可采用粉碎的方法， 如机械粉 碎、 微粉化等技术， 使颗粒减小， 增加溶出表面积， 提高溶出度； 也可对化合物进行结 构改造， 如成盐或酯； 也可采用制剂手段， 如采用环糊精包合技术、 固体分散技术、 添 加增溶物质等。
本发明对含有式 I化合物 2-丁基 -4-氯小 [2'-(1 H -四唑 -5-基) Ι,Γ-联苯基-甲基]咪唑 -5- 羧酸， 1- [(异丙氧基)羰氧基]甲基酯作为药理活性成分的药用组合物进行了广泛而深入的 研究， 使之能以合理的制剂形式供临床使用。
在本发明中， 所述 "药物"或 "药理活性成分"指式 I化合物 2-丁基 -4-氯 -1-[2'-(1 Η -四唑 -5-基) Ι,Γ-联苯基-甲基]咪唑 -5-羧酸， 1- [(异丙氧基)羰氧基]甲基酯。
固体口服组合物
本发明首先提供了包含有 2-丁基 -4-氯 -1-[2'-(1 Η -四唑 -5-基) 1,1'-联苯基-甲基]咪唑 -5- 羧酸， 1- [(异丙氧基)羰氧基]甲基酯的固体组合物，通过添加药学上可接受的载体材料（或 称赋形剂）达到这个目的。
本发明的一种技术方案是提供直接口服的固体制剂。 这种组合物包括的载体材料包 括填充剂、 崩解剂、 润湿剂、 粘合剂、 表面活性剂、 润滑剂、 助流剂、 矫味剂、 矫嗅剂、 着色剂以及其他种类的固体制剂的赋形剂。 该组合物可以是散剂、 颗粒剂、微丸、 胶囊、 片剂或锭剂的制剂形式， 但这并不构成对其制剂形式的限制， 如本领域一般技术人员所 知的， 在片剂中， 可任选地制备为普通素片、 薄膜衣片、 糖衣片、 双层片或多层片、 泡 腾片、 分散片、 口崩片、 缓释片。 通常该组合物适合于口服， 但也适合于其他方式的给 药， 例如舌下给药， 例如使用前以液体分散， 然后以液体形式吞服。
填充剂可选自以下物质一种或几种的组合： 碳酸钙、 碳酸镁、 磷酸钙、 硫酸钙、 氧 化镁、 羧甲基纤维素钙、 羧甲基纤维素钠、 蔗糖、 乳糖、 果糖、 木糖醇、 甘露醇、 淀粉 或其衍生物、 糊精、 微晶纤维素。
崩解剂可选自以下物质一种或几种的组合： 淀粉、 藻酸、 羧甲基纤维素钙、 羧甲基 纤维素钠、 交联羧甲基纤维素钠、 交联聚乙烯吡咯烷酮、 低取代羟丙基甲基纤维素、 微 晶纤维素、 甲基纤维素。
表面活性剂可选自以下物质之一种或几种的组合： 十二烷基硫酸钠、 泊洛沙姆、 吐 温类、 溴化十六烷三甲胺、 月桂醇硫酸钠、 硬脂醇磺酸钠、 聚氧乙烯高级脂肪醇、 蔗糖 酯、 山梨醇脂肪酯、 大豆磷脂等。
润湿剂可选自以下物质一种或几种的组合： 蒸馏水、 乙醇、 淀粉浆。 粘合剂可选自以下物质一种或几种的组合： 阿拉伯胶、 明胶、 黄蓍胶、 糊精、 聚乙 烯吡咯烷酮、 淀粉及其衍生物、 藻酸钠、 山梨醇、 糖浆、 羟丙基甲基纤维素、 甲基纤维 素、 羟丙基纤维素、 羟乙基纤维素、 乙基纤维素、 羧甲基纤维素钠、 羧甲基纤维素钙、 葡萄糖、 聚甲基丙烯酸酯。
润滑剂可选自以下物质一种或几种的组合： 硬脂酸钙、 单硬脂酸甘油酯、 棕榈硬脂 酸甘油酯、 硬脂酸镁、 微晶纤维素、 苯甲酸钠、 氯化钠、 十二烷基硫酸钠、 硬脂酸镁、 硬脂基富马酸钠、 滑石粉、 硬脂酸锌、 聚乙二醇。
助流剂可选自以下物质一种或几种的组合： 胶体二氧化硅、粉状纤维素、三硅酸镁、 二氧化硅和滑石粉。
矫味剂可选自阿斯巴坦、 甜菊苷、 果糖、 葡萄糖、 糖浆、 蜂蜜、 木糖醇、 甘露醇、 乳糖、 山梨醇、 麦芽糖醇、 甘草甜素、 甘茶叶素及各种香精， 矫嗅剂可选用芳香油， 着 色剂可选用人工或合成的色素。
如本领域技术人员所容易理解的， 对固体口服制剂而言， 上述物质的列举并不构成 对技术方案的限制， 未列举的其他的固体制剂常规采用的赋形剂同样也可以适用于本方 案， 因而也包括在本方案中。
采用上述载体材料的技术方案为：药物占组合物的重量百分比为 1%至 50%,可制备 成散剂、 颗粒剂、 微丸、 片剂、 锭剂、 胶囊剂。 在制备中， 优选将药物微粉化， 以提高 药物的分散度， 增加药物的溶出表面积， 提高溶出性能。 下面对实现本发明的几个具体 的技术方案作为举例的目的给出， 所述百分比均为重量百分比。
(一）药物 1%~30%， 乳糖或葡萄糖 70%~99%。 制备： 分别粉碎药物和赋形剂过 80-120目筛， 按等量递加法逐渐加入所处方量的乳糖或葡 ^糖， 至混合均匀， 分装即得 该药物的散剂。 在该方案中， 还可视需要加入适量的矫味剂、 矫嗅剂以及防腐剂，
(二）药物 5%~50%， 崩解剂选自淀粉和纤维素类衍生物， 优选羧甲基淀粉钠， 占 4%~8%, 余量为填充剂， 选自淀粉、 微晶纤维素、 乳糖或蔗糖， 以及适量的粘合剂选自 淀粉浆或聚维酮。制备： 粉碎药物和赋形剂过 80~120目筛， 均匀混合， 加入用水或有机 溶剂溶解的粘合剂溶液进行混合， 制软材， 制粒， 干燥， 整粒， 进行或不进行包衣， 分 装即得该药物的颗粒剂。 在该方案中， 还可视需要加入适量的矫味剂、 矫嗅剂以及防腐 剂， 也可加入酸碱缓冲剂， 制成泡腾颗粒剂。
(三）药物 5%~15%， 羧甲基淀粉钠 5%~20%， 润滑剂 0.3%~3.0%， 以及适量的粘 合剂， 余量为乳糖， 将药物与乳糖混合， 优选等量递加法， 进行混合粉碎， 过 80~100目 筛， 加入羧甲基淀粉钠， 同样优选以等量递加法混合均匀， 加入粘合剂， 制软材， 以摇 摆式制料机制备 12~14目的颗粒， 50~90°C干燥， 颗粒水分控制在 3%以内， 混合均匀， 装入 0号至 2号胶囊，即得。在本方案中，优选采用 PH101或 PH103型号的微晶纤维素， 润滑剂选用硬脂酸镁， 粘合剂选用适宜浓度的 PVPK30的乙醇溶液。
(四）药物 5%~15%， 乳糖 25%~40%， 交联聚维酮 5%~15%， 硬脂酸镁 0~5%， 余 量为微晶纤维素， 将药物与微晶纤维素和乳糖进行混合粉碎， 过 80~100目筛， 加入预先 粉碎的 80~100目的交联聚维酮， 优选以等量递加法混合均匀， 以普通旋转式直接压片， 即得。
(五）药物 5%〜15% ， 羟丙甲基纤维素 20%〜40%， 羧甲基淀粉钠 5%~8%， 滑石粉 0-3%, 佘量为乳糖， 将药物与羟丙甲基纤维素和乳糖进行混合粉碎， 过 80~100 目筛， 加入预先粉碎的 80~100目的羧甲基淀粉钠，优选以等量递加法混合均匀， 加入蒸馏水或 淀粉漿， 制软材， 制备 20~50目的颗粒， 50~90°C干燥， 整粒， 加入适量的润滑剂， 以普 通旋转式压片， 或装入 1号至 2号胶囊， 即得。 在该方案中， 作为填充剂的乳糖可以淀 粉替换， 作为崩解剂的羧甲基淀粉钠可以交联聚维酮替换， 其用量为 5%~15%。
除釆用上述载体材料宣接制备组合物和制剂外， 还可采用微丸技术方案， 例如将药 物包覆于空白丸芯表面制成微丸， 或将药物与适当的载体混合在一起制备为丸芯再包覆 隔离层。 不论以上述哪种方式得到的含药微丸， 还可包覆膨胀层、 隔离层、 控释层等， 以达到对药物释放速度的理想控制。 常用作微丸的丸芯或包衣的载体材料有： 蔗糖、 淀 粉、 糊精、 蜂蜡、 脂肪酸、 虫胶、 聚维酮、 甲基纤维素、 醋酸纤维素、 聚丙烯酸树脂、 醋酸纤维素酞酸酯、 羟丙基纤维素、 聚乙二醇或它们的混合物。 微丸可直接分剂量供临 床服用， 或可进一步添加适宜的赋形剂， 按照常规的制备方法制成胶囊剂或压制为片剂。
在上述提到的技术方案中， 对压制成的片剂可以施以薄膜包衣或糖衣或肠溶衣。 例 如在所选用的填充剂或崩解剂对水分比较敏感时， 可选用对水分具有隔离作用的薄膜衣 材料进行包衣； 或出于获得更好的口感的需要， 可包覆糖衣层。
本发明的另一种技术方案是提供可在服用前分散的固体制剂， 即制剂学中所说的分 散片、 口崩片、 泡腾片等， 这种制剂形式对于有吞咽障碍的患者而言是非常有益的。 这 种制剂除包含前述的载体材料中的一种或多种之外， 对崩解或分散性能的改进由如下技 术方案述及： (一） 分散片： 在片剂中加入足量的崩解性能优良的崩解剂使片剂在液体中迅速分 散。 优选的崩解剂有交联聚乙烯吡咯烷酮、 交联羧甲基纤维素钠、 羧甲基淀粉钠， 其用 量足以使片剂遇水后迅速分散。 对于这种希望迅速分散的制剂而言， 填充剂的选择应考 虑其可压性、 流动性及崩解性能， 如微晶纤维素、 羧甲基纤维素钠、 羟丙基甲基纤维素 和低取代羟丙基纤维素均可作为性能优良的填充剂。
(二） 口崩片： 在片剂中加入足量的崩解性能优良的崩解剂， 可使片剂迅速崩解。 优选的崩解剂有交联聚乙烯吡咯烷酮、 交联羧甲基纤维素钠、 羧甲基淀粉钠， 其用量足 以使片剂遇水后迅速分散。 对于这种希望迅速分散的制剂而言， 填充剂的选择应考虑其 可压性、 流动性及崩解性能， 如微晶纤维素、 羧甲基纤维素钠、 羟丙基甲基纤维素和低 取代羟丙基纤维素均可作为性能优良的填充剂。
(三） 泡腾片： 在片剂中加入遇水能够产生二氧化碳气体的物质， 即泡腾剂。 本发 明组合物中含有的泡腾剂可选自有机酸如酒石酸或苹果酸与碳酸氢钠的组合， 或选用磷 酸盐的组合， 或选用琥珀酸酐， 枸橼酸酐等有机酸酐类， 也可达到使之迅速崩解的目的， 所制得的片剂称为泡腾片。 这种片剂可直接服用， 或在服用前先以水溶解， 对不习惯服 用胶囊、 片剂、 锭剂等固体制剂的患者而言是非常有益的。 一个具体的技术方案为： 药 物、 微晶纤维素、 交联羧甲基纤维素钠、 聚维酮、 蔗糖细粉、 糖精钠、 苹果酸、 碳酸氢 钠、 无水碳酸钠、 十二烷基硫酸钠、 香精。 制备： 先将碳酸氢钠过 30目筛备用， 将无水 碳酸钠、十二烷基硫酸钠、香精过 60目筛备用， 将药物与 MCC混合粉碎过 80目筛， 交 联羧甲基纤维素钠、 苹果酸、蔗糖粉碎过 30目筛， 与糖精钠混合， 混合物以聚维酮异丙 醇液制粒， 干燥， 过 30目筛整粒后与其余成分混合， 以普通压片机压片即得。
在上述分散片、 口崩片、泡腾片的处方中，控制崩解后的微粒的粒径在 400nm以下； 在其制备过程中， 制粒也不是必需的工序， 直接压片是优选的方式。 同样， 如果如前述 所制得的含药微丸的粒径小至不产生砂砬感， 如平均粒径在 400nm以下， 也可用于制备 这种使用前分散的制剂。 出于获得好的口感的需要， 也可以在这些制剂中加入矫味剂、 矫嗅剂或其他赋形剂。
包含增溶载体的药用组合物
本发明的另一方面是提供一种包含所述药理活性成分和增溶载体的药用组合物， 即 首先将药物分散于药学上可接受的适当的载体中， 增加药物的溶出， 在本发明中将这部 分载体称为增溶载体。本发明增溶载体材料优先选用以下几类： 聚乙二醇类、聚维酮类、 含有聚氧乙烯基的表面活性剂类、 水溶性纤维素衍生物、 有机酸类和糖类及醇类。 这几 类载体可单独或联合使用。
下面对增溶载体的几个方案以举例的目的进行具体说明， 但并不构成对本发明的限 制， 在本发明提供的技术方案的基础上， 进行简单的处方筛选和制备工艺的优化， 载体 材料和制备方法可以进行替换， 因而也包括在本发明之内。
(一）聚乙二醇 （PEG)作为增溶载体
聚乙二醇类 （PEG) 具有良好的水溶性， 亦能溶于多种有机溶剂。 当药物分散于其 中时， 可使药物高度分散于其中， 并且在制备过程中， 由于溶剂蒸发， 而粘度骤增， 可 阻药物聚集，用于固体分散体的 PEG的分子量一般在 1000~20000之间，常用有 PEG2000、 PEG4000、 PEG6000. PEG10000、 PEG 12000 ^ PEG20000中一种或几种之组合， 聚氧乙 烯（40)单硬脂酸酯、 硬脂酸、 或泊洛沙姆类表面活性剂常与 PEG类联合使用以调节药 物的分散和释放。 药物分散于该类载体时， 常以滴制法来制备， 如可采用滴丸机来制备 PEG为主要载体的含药滴丸。
以 PEG类作为增溶载体的一个技术方案如下： 按下述重量配比称量药物和载体： 药; 物 1%〜8%， PEG4000 10%~20%, PEG6000 60%~70%, 泊洛沙姆 188 3%~5%， 将药物粉. 碎过 80目筛， 加入到在 80~90°C水浴加热融熔的其余基质中， 搅拌使混合均匀， 药物粉 末完全消失， 将熔融的含药液体置于滴丸机的保温箱中， 调整滴速， 以每分钟 20〜30粒: 的速度滴至冷凝剂中。 冷凝剂选用二甲基硅油或液体石蜡， 冷凝温度 4〜10°C。 然后收集 制得的滴丸， 以吸水纸拭干表面冷凝液， 置于 4°C的冰箱中放置 24小时， 即得滴丸。 这 种滴丸可直接服用。 溶出试验证明制得的滴丸能够在迅速分散， 特别适用于舌下给药， 以起到速效作用。
另一个技术方案为： 将药物与 PEG6000以 1:1混合， 加入常规处方量的填充剂、 崩 解剂、 润滑剂， 压制为片剂。
(二）聚维酮和 /或交联聚维酮作为增溶载体
聚维酮为 1-乙烯基 -2-吡咯垸酮均聚物（ Polyvinylpyrrolidone; Povidone? Plasdone; Kollidone; 以下简称 PVP)， 其规格有 PVPkl2、 PVPkl5、 PVPkl7、 PVPk25 PVPk30、 PVPk29/32, PVPk60、 PVPk90、 PVPkl20等， 交联聚维酮 （PVPP) 为合成交联 N-乙烯 基 -2-吡咯烷酮均聚物， 规格有 PVPPXL、 PVPPXL-10等。 这两种物质可单独或联合用于 本发明的增溶载体材料， 制备方法可用溶剂法、 溶剂沉积法、 喷雾干燥法或冷冻干燥法 等。 联合使用的技术方案以举例目的列举如下：
PVPk29/32和 PVPPXL作为载体， 其重量比为 1 :1〜3:7， 药物与载体材料的比为 1 :2~1 :10。 制备方法： 药物和 PVP29/32溶解于乙醇和丙酮的混合溶液中， 采用流化床法 喷在 PVPPXL上， 或者将溶液直接喷雾干燥。 另一个制备方案为： 取上述处方量的药物 与载体材料， 分散于适宜的溶剂系统中， 采用冷冻干燥工艺得到干燥粉末。
PVPk29/32和 PVPPXL 作为载体， 其重量比为 1:2~1:3， 药物与载体材料的比为 1:1~1:2。制备方法： 药物和 PVP29/32溶解于乙醇、丙酮和水（4:4:1 )的混合溶液中， 釆 用流化床法喷在 PVPPXL上， 得到干燥的增溶组合物。 经过筛， 添加适当的赋形剂制备 为散剂、 颗粒剂、 胶囊或片剂。 另一个制备方案为： 取上述处方量的药物与载体材料， 分散于适宜的溶剂系统中， 釆用冷冻干燥工艺得到干燥粉末。
(三）纤维素类衍生物作为增溶载体
纤维素类衍生物也可作为增溶载体。 一个实施方案是将羟丙基甲基纤维素（HPMC) 和聚氧乙烯聚氧丙烯二醇用作载体材料， 药物、 HPMC、 聚氧乙烯聚氧丙烯二醇的重量 比为 1:3~5:0.2~0.5， HPMC和聚氧乙烯聚氧丙烯二醇溶解于乙醇 /丙酮 /水的混合物， 将药 物加入其中， 混合均匀， 将制得的溶液喷到流化床中的空白丸芯上， 从而制得固体分散 体组合物的颗粒。 在该方案中， 所用溶剂选择下列一种或几种的混合物： 甲醇、 乙醇、 异丙醇、 丙酮、 二氯甲垸、 水以及它们的混合物。
(四）糖类和 /或醇类物质作为增溶载体
可作为增溶载体的糖类与醇类有： 右旋糖、 半乳糖、 蔗糖、 甘露醇、 山梨醇、 木糖 醇等。 这些物质的分子中有多个羟基， 可以同药物以氢键结合。 针对本发明中的药物， 优选甘露醇作为主要载体。
(五）其他载体材料
如本领域技术人员所公知的， 制备所述增溶载体的材料种类不限于上述提及的各类 材料， 其他如水解明胶、 表面活性剂类也是适用于本发明方案的。 即使采用难溶性载体 材料或脂质材料， 如乙基纤维素、 丙烯酸树脂 E、 RL、 RS型、 胆固醇、 巴西棕榈蜡等， 通过加入水溶性载体材料如 PEG, PVP, 可制备出非速释型的增溶组合物， 正如现有药 学研究所表明的， 这种缓控释制剂对于维持长时间的药物释放是有益的。
上述的这些增溶组合物可直接给药， 如滴丸， 也可作为制剂的中间体， 添加药学上 可接受的载体制成其他固体制剂， 如散剂、 颗粒剂、 微丸剂、 片剂、 胶囊剂、 锭剂等。 这些药学上可接受的载体包括前面提及的赋形剂， 如可作为填充剂的淀粉及其衍生物、 纤维素类衍生物、 蔗糖、 甘露醇、 硅酸和磷酸氢钙； 作为粘合剂的 MC、 HPC、 明胶、 PVP， 崩解剂可选自交联 CMC-Na， PVPP, L-HPC, 润滑剂可选自硬脂酸镁和滑石粉； 矫味剂可选自甜叶菊甙、 阿司巴甜和其它香精， 但不限于此。 在制备为片剂时， 优选直 接压片工艺。 选用的赋形剂包括适合于粉末直接压片的填充剂、 崩解剂、 润滑剂及必要 时添加的其他赋形剂， 如助流剂， 矫味剂等， 填充剂可选用微晶纤维素和 /或乳糖， 其在 处方中的用量为 20%~90%。 崩解剂可选用交联羧甲基淀粉钠、 交联聚乙烯吡咯垸酮、 低 取代羟丙甲纤维素等， 在处方中用量为 1%~6%。在必要时可给予片剂以薄膜包衣， 或糖 衣膜包衣。
一个实施方案为： 将所得增溶组合物进一步制成胶囊剂， 加入的填充剂选自 MCC、 淀粉、 CMS-Na， PVPP,用量占处方量的 60%~95%，加入的助流剂和润滑剂选自滑石粉、 硬脂酸镁、微粉硅胶或它们的混合物， 用量为总处方量的 0~3%， 按前述方案制得的含有 药物的增溶载体的用量占处方量的 5%~40%， 粉碎过 60目筛， 与赋形剂均匀混合， 装入 1号或 2号明胶壳制成的硬胶囊即得。
另一个实施方案为： 药物与聚维酮 K29/32、 PVPPXL制成增溶组合物， 药物在该组 合物中占 8%~30%。 该增溶组合物进一步制成片剂。 增溶组合物占片剂总重 35%~65%， 填充剂如微晶纤维素， 占 10%~40%, 崩解剂如 PVPP, 占 5%~8%， 其佘为润滑剂等赋形 剂。一种制备方法为：将药物与聚维酮 K29/32、 PVPPXL在适量丙酮与乙醇混合溶液（体 积比 1 : 1 ) 中， 用喷枪将配制的溶液以顶喷方式喷入流化床中制粒， 干燥， 将干燥物料 与其余物料混合均匀， 直接压片即得。
另一个实施方案为： 药物与聚维酮 K29/32、 PVPPXL制成增溶组合物， 药物在该组 合物中占 8%~30%， 聚维酮 K29/32与 PVPPXL的质量比为 1:2~1 :3， 按前述方法制备为 增溶组合物， 粉碎， 过筛， 添加填充剂如微晶纤维素， 占制剂总重量的 40%~60%， 崩解 剂如 PVPP, 占制剂总重量的 1%~6%， 其余为润滑剂等赋形剂。 一种制备方法为： 将药 物与聚维酮 K29/32、 PVPPXL在适量丙酮、 乙醇和水的混合溶液中 （体积比 4:4:1 ) 中， 以顶喷方式喷入流化床中制粒， 干燥， 将干燥物料与其余物料混合均匀， 直接压片即得。 该增溶组合物进一步制成片剂。 增溶组合物占片剂总重 35~65%。
另一个实施方案为：药物与聚维酮 K29/32、 PVPPXL制成增溶组合物，聚维酮 29/32 与 PVPPXL的质量比为 1 :2~1:3， 药物在该组合物中占 30〜40%。 该增溶组合物进一步制 成片剂。 填充剂如微晶纤维素， 占 25~35%， 崩解剂如 PVPP, 占 1〜5%, 其余为润滑剂 等赋形剂。 一种制备方法为： 将药物与聚维酮 K29/32、 PVPPXL在适量丙酮、 乙醇和水 的混合溶液中 （体积比 4:4:1 ) 中， 以顶喷方式喷入流化床中制粒， 干燥， 将干燥物料与 其余物料混合均匀， 直接压片即得。
本发明药用组合物中， 药理活性成分的含量可以是 5mg~180mg， 优选人体日剂量的 三分之一或二分之一， 或日剂量的倍数， 如以通用的动物有效剂量与人用剂量的换算方 法， 根据动物试验结果推算， 可以为 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, lOOmg, 120mg, 140mg, 160mg,180mg。
本发明药用组合物或其制剂形式可用于制备抗心血管药物， 尤其是抗高血压药物。 这种药物可以直接给药于人， 给药途径可以是口服或舌下给药。
将上述提及的本发明药用组合物的固体制剂形式按照中国药典 2005版附录 XC溶出 度测定法第二法， 溶出介质为 900ml pH6.8的磷酸盐缓冲液， 恒温 37°C， 转速 50转 /分， 45分钟时取样以紫外分光光度法测定其中药物的含量， 计算溶出度。 结果表明， 含有本 发明药用组合物的固体制剂有较好的溶出度， 尤其是， 含有增溶载体的固体制剂具有优 越的溶出度。
利用药理学常规实验方法， 将本发明制备的药用组合物的制剂形式进行比格犬吸收 试验， 结果表明： 药物各制剂形式在体内的吸收程度优于原料药的混悬液， 尤其是， 含 有增溶载体的固体制剂在动物体内具有较好的吸收。
以下通过具体的实施例对本发明作进一步详细的说明。 正如本领域技术人员所应知 道的， 本发明中所表述的实施方案和实施例仅以举例的目的提供， 并不构成对载体选择、 制备方法和用途的限制。
本发明药理活性成分也可采用除口服或舌下给药之外的其他给药方式， 如注射、 透 皮或吸入等方式。这些给药方式在临床上会有特别的需求。这些制剂可采用常规的注射、 透皮或吸入制剂的处方组成和制备方式， 因而包含本发明药理活性成分的除口服之外的 制剂形式也包括在本发明的范围之中。
本发明药用组合物可用于治疗人类心血管疾病， 尤其是高血压， 其方法包括施以含 有有效剂量活性成分的药用组合物， 优选每天服用一次。 也可与其他降压药物联合使用 以更好地控制血压， 所述的其他降压药物包括利尿剂如氢氯噻嗪、 血管紧张素转换酶抑 制剂、 钙离子拮抗剂等。 优选与不同降压机理的降压药物联合使用。 具体实施方式
式 I化合物 2-丁基 -4-氯小[2'-(1 H -四唑 -5-基) 1,1，-联苯基 -甲基 I咪唑 -5-羧酸， 1-【(异 丙氧基)羰氧基】 甲基酯的制备
于 100ml单口瓶中依次加入 2-丁基 -4-氯 -1-[2'-(1-三苯甲基 -四唑 -5-基) Ι,Γ-联苯基-甲 基]咪唑 -5-羧酸 0.523g， K2C03 0.124g, Ν,Ν-二甲基乙酰胺 5ml， 室温搅拌 20min,室温 下加入异丙氧基甲酸氯甲酯 0.562g，45~50°C反应 16h。反应结束后，过滤，滤液中加 30ml 水， 用乙酸乙酯 30ml萃取两次， 有机相干燥， 浓缩后得到油状物 1.724g,不用纯化， 直 接用于下面反应。
再加入二氧六环 10ml， 加入 4mol/L的盐酸溶液 5ml， 室温反应 16h.停止反应， 加入 碳酸氢钠水溶液调节反应液 pH 6~7， 有混浊出现， 乙酸乙酯萃取， 有机相用饱和盐水洗 漆， 再干燥， 浓缩， 得到式 I化合物 2-丁基 -4-氯 -1-[2'-(Γ Η -四唑 -5-基) Ι,Γ-联苯基-甲基] 咪唑 -5-羧酸， 1- [(异丙氧基)羰氧基] 甲基酯 0.436g。
本化合物的结构特征光谱数据如下：
lHNMR: (CDC13)
δ H(ppm): 0.89(t,3H,J=14.6),1.24(d,6H,J=6.3), 1.37(m,2H,J=22.1), 1.69(m,2H,
J=30.5),2.64(t,2H,J=15.5),4.81(m?lH,J=12.4),5.54(s,2H),5.86(s,2H),
6.95-7.64(8H),8.08(d, 1H,J=7.42)
ESI(+)m/z: 552.7
Mp: 134.5-136°C
药理作用以及相关的医药用途研究
(一）采用比格犬作为试验动物， 每组六只动物， 分别以 3.0 mg/kg, 9.0 mg/kg和 27 mg/kg将 2-丁基 -4-氯 -1-[2'-(1 H -四唑 -5-基：) 1,1'-联苯基-甲基]咪唑 -5-羧酸， 1-[(异丙氧 基)羰氧基]甲基酯混悬于生理盐水中单剂量灌胃给药， 各剂量组在设定的时间点采集血 样， 分离制备血浆， 采用液相色谱-串联质谱法测知药物在体内转变为其活性代谢物 EXP3174 (2-丁基斗氯小[2'-(1 H -四唑 -5-基) Ι,Γ-联苯基-甲基]咪唑 -5-羧酸）， 测定血浆中 该活性代谢产物 EXP3174的浓度， 根据药物浓度 -时间曲线计算代谢物 EXP3174的药动 学参数，对主要药动学参数 Cmax和 AUC0.t与剂量进行相关性考察，结果表明：在 3.0 mg/kg - 27 mg/kg剂量范围内， CMAX和
Figure imgf000012_0001
(二）采用大鼠自发性高血压模型（SHR)， 以 15mg/kg和 30mg/kg， 将 2-丁基 -4- 氯小 [2'-(1 H -四唑 -5-基) 1,1'-联苯基-甲基]咪唑 -5-羧酸， 1- [(异丙氧基)羰氧基]甲基酯混悬 于生理盐水中灌胃给药， 给药前后血压分别下降 10mm汞柱和 20mm汞柱， 结果表明： 将该化合物以大于或等于 15mg/kg的剂量经口服给药吸收后， 对大鼠具有明显的降压作 用。
含有 2-丁基 -4-氯 -1-〖2'-(1 H -四唑 -5-基) 1，1'-联苯基-甲基】咪唑 -5-羧酸， 1-〖(异丙氧基) 羰氧基】 甲基酯的组合物的制备
实施例 A1
处方： 药物 4g 乳糖 36g
制备： 分别粉碎药物过 120目筛， 乳糖过 80目筛， 按等量递加法逐渐加入处方量的 乳糖， 至混合均勾， 分装即得该药物的散剂。 在该方案中， 还可视需要加入适量的矫味 剂、 矫嗅剂以及防腐剂。
实施例 A2
处方： 药物 5g 淀粉 15g蔗糖 10g羧甲基淀粉钠 2g 浓度为 70%的淀粉浆适量 制备： 分别粉碎药物过 120目筛， 其他赋形剂过 80目筛， 将药物与淀粉、乳糖及羧 甲基淀粉钠均匀混合，加入适量淀粉浆制软材， 以 14目筛制粒，' 60Ό干燥， 12目筛整粒， 分装即得该药物的颗粒剂。 在该方案中， 还可视需要加入适量的矫味剂、 矫嗅剂以及防 腐剂。
实施例 A3
处方：药物 5g,微晶纤维素 20g，乳糖 20g，羧甲基淀粉钠 5g，硬脂酸镜 lg PVPK30 适量
制备： 将药物与乳糖混合粉碎过 80〜100目筛， 加入预先粉碎的 80目筛的微晶纤维 素， 羧甲基淀粉钠， 加入 5%~20%的 PVPK30的乙醇溶液， 制软材， 以摇摆式制料机制 备 12~14目的颗粒， 50~90°C干燥， 颗粒水分控制在 3%以内， 混合均匀， 装入 1号胶囊， 即得。 45分钟时测定溶出度为 76.6%。
实施例 A4
处方. · 药物 4g， 微晶纤维素 15g， 乳糖 15g， PVPPXL 5g， 硬脂酸镁 lg 制备： 将药物与各赋形剂充分粉碎过 80目筛， 混合均匀， 直接压片即得。 45分钟时 测定溶出度为 71.9%。 实施例 A5
处方： 主药 5g， 乳糖 29g， 羟丙甲基纤维素 15g， 羧甲基淀粉钠 4g， 硬脂酸镁 lg 制备： 将药物与各赋形剂在 60Ό干燥， 药物与处方量的乳糖混合， 充分粉碎， 过 80 目筛， 加入处方量的羟丙甲基纤维素和羧甲基淀粉钠， 混合均匀， 加入适量蒸镏水， 制 成软材， 以 24目筛制粒， 湿颗粒于 60Ό热风干燥， 干燥后以 14目筛整粒， 加入处方量 硬脂酸镁， 混合均勾， 压片即得。 45分钟时测定溶出度为 75.5%。
实施例 A6
处方： 主药 4g， 淀粉 15g， 羟丙甲基纤维素 12g， PVPPXL 4g, 硬脂酸镁 0.5g 7% 浓度的淀粉浆适量
制备：将药物与各赋形剂在 60°C干燥，药物与处方量的淀粉混合，充分粉碎，过 100 目筛， 加入处方量的羟丙甲基纤维素和 PVPPXL, 混合均匀， 以适量 7%浓度的淀粉浆制 成软材， 14目筛制粒，湿颗粒于 60Ό热风千燥， 加入处方量硬脂酸镁， 混合均匀，整粒， 装入 1号硬胶囊， 即得。 45分钟时测定溶出度为 74.8%。
实施例 A7 .
丸芯处方：药物 5g，微晶纤维素 20g，低取代羟丙基纤维素 10g，硬脂酸镁 lg, 十二烷基磺酸钠 lg
隔离层包衣液处方：羟丙基甲基纤维素（Pharmacoat 606) 13g,聚乙二醇 400 2.6g， 滑石粉 6.5g， 水 适量
制备： 将药物粉碎过 80目筛， 其余辅料分别粉碎过 60目筛， 将十二烷基磺酸钠溶 于适量水， 将药物、 微晶纤维素、 低取代羟丙基纤维素和硬脂酸镁混合均匀， 用十二垸 基磺酸钠溶液制备软材， 应用挤出滚圆设备制备微丸， 将微丸 60°C烘干， 筛分， 取 18〜 24目微丸置于流化床中包隔离层。 ,
将羟丙基甲基纤维素溶于水，加入聚乙二醇 400，将滑石粉分散在其中配制隔离层包 衣液， 将制备的微丸用流化床底喷包衣， 包衣增重为 4%。包隔离层微丸 40Ό干燥 30min 即得微丸。 45分钟时测定溶出度为 84.5%。
实施例 A8
处方：空白丸芯 60g，药物 10g，羟丙甲纤维素 603 10g，低取代羟丙基纤维素 3g， 水适量
制备： 将处方量的羟丙甲纤维素 603溶于水， 药物粉碎过 80目筛， 与低取代羟丙基 纤维素分散于羟丙甲纤维素 603的水溶液中， 将空白丸芯 60g投入流化床中， 以底喷工 艺上药， 制得的微丸填装于明胶硬胶囊即得。 45分钟时测定溶出度为 74.5%。
实施例 B1
处方：药物 5g甘露醇 10g微晶纤维素 10g PVPPXL 2.25g硬脂酸镁 0.25g柠檬香 精 0.12g阿斯巴甜 0.12g滑石粉 0.2g
制备： 将药物与甘露醇混合粉碎过 80目筛， 其余成分粉碎过 60目筛， 混合均匀， 直接压片即得。 该片剂在 5ml蒸馏水中， 3分钟内崩解。 按照前述方法测定溶出度， 45 分钟时溶出度为 64.5%。
实施例 B2
处方： 药物 20g酒石酸 50g碳酸氢钠 56g羧甲基纤维素 20g微晶纤维素 30g滑 石粉 6g硬脂酸镁 2g
制备： 将药物、 酒石酸、 羧甲基纤维素、 微晶纤维素药物混合过 16目筛， 以 7%聚 维酮异丙醇溶液制粒， 干燥， 过 30目筛制粒； 碳酸氢钠粉碎过 30目筛， 与制得的颗粒 相混合， 加入滑石粉， 硬脂酸镁， 混合均勾， 压片即得。 该片剂为泡腾片。 按前述的溶 出度测定方法， 该片剂在 45分钟时溶出度为 64.5%。
实施例 C1
处方: 药物 10g PEG4000 10g PEG6000 60g泊洛沙姆 188 5g硬脂酸 5g 制备： 将药物粉碎过 80目筛， 加入到在 80~90°C水浴加热融熔的其余基质中， 搅拌 使混合均匀， 至药物粉末完全消失， 将熔融的含药液体置于滴丸机的保温箱中， 调整滴 速， 以每分钟 20~30粒的速度滴至冷凝剂中。 冷凝剂选用二甲基硅油或液体石蜡， 冷凝 温度 4~10°C。 然后收集制得的滴丸， 以吸水纸拭干表面冷凝液， 置于 4°C的冰箱中放置 24小时， 即得滴丸。溶出试验证明制得的滴丸能够在 15分钟内溶散。该滴丸适用于舌下 给药， 以起到速效作用。
实施例 C2
处方： 药物 2g PEG12000 20g PEG6000 60g泊洛沙姆 188 6g
制备： 将药物粉碎过 80目筛， 加入到在 80~90°C水浴加热鹬熔的其余基质中， 搅拌 使混合均勾， 药物粉末完全消失， 将熔融的含药液体置于滴丸机的保温箱中， 调整滴速， 以每分钟 20〜30粒的速度滴至冷凝剂中。 冷凝剂选用二甲基硅油或液体石蜡， 冷凝温度 4~10°C。 然后收集制得的滴丸， 以吸水纸拭干表面冷凝液， 置于 4°C的冰箱中放置 24小 时， 即得滴丸。 溶出试验证明制得的滴丸能够在 5分钟溶散。 该滴丸特别适用于舌下给 药， 以起到速效作用。
实施例 D1
处方： 药物 5g PVPK29/32 36g 微晶纤维素 20g乳糖 20g PVPPXL 4g 硬脂 酸镁 4g
制备： 将药物和 PVPK29/32溶解在适量乙醇中， 喷雾干燥， 将喷雾干燥样品与其余 物料混合均匀， 压片， 45分钟时测定溶出度为 95.5%。
. 实施例 D2
处方： 药物 5g PVPPXL (A) 20g 微晶纤维素 20g 乳糖 20g PVPPXL (B) 4g 硬脂酸镁 4g
制备： 将药物溶解在适量丙酮中， 加入 PVPPXL (A) 混合均匀， 将样品减压干燥， 将干燥物料与其余物料混合均匀， 压片， 45分钟时测定溶出度为 96.8%。
实施例 D3
处方： 药物 5g PVPK29/32 10g PVPPXL(A) 26g 微晶纤维素 10g 乳糖 10g PVPPXL(B) 3g 硬脂酰富马酸钠 0.5g
制备： 将药物和 PVPK29/32溶解在适量丙酮与乙醇混合溶液 （体积比 1:1 ) 中， 将 PVPPXL (A)加入流化床中，用喷枪将配制的溶液以顶喷方式喷入流化床中制粒，干燥， 将干燥物料与其余物料混合均匀， 压片， 45分钟时测定溶出度为 96.7%。
实施例 D4
处方：药物 15g PVPK29/32 20g PVPP L (A) 20g 微晶纤维素 lOg乳糖 lOg PVPPXL(B) 2.5g 硬脂酰富马酸钠 0.4g
制备： 将药物和 PVPK29/32溶解在适量丙酮与乙醇混合溶液 （体积比 1:1 ) 中， 将 PVPPXL (A)加入流化床中，用喷枪将配制的溶液以顶喷方式喷入流化床中制粒，千燥， 将干燥物料与其余物料混合均匀， 压片， 45分钟时测定溶出度为 98.5%。
实施例 D5
处方： 药物 15g PVPK29/32 8g PVPPXL(A) 20g 微晶纤维素 10g乳糖 10g PVPPXL(B) 2.5g 硬脂酰富马酸钠 0.4g
制备： 将药物和 PVP 29/32溶解在适量丙酮与乙醇混合溶液（体积比 1:1 ) 中， 将 PVPPXL (A)加入流化床中，用喷枪将配制的溶液以顶喷方式喷入流化床中制粒，干燥， 将干燥物料与其余物料混合均匀， 压片， 45分钟时测定溶出度为 97.8%。
实施例 D6
处方： 药物 15g PVP 29/32 23g PVPPXL(A) 23g 微晶纤维素 10g乳糖 10g PVPPXL(B) 2.5g 硬脂酰富马酸钠 0.4g
制备： 将药物和 PVPK29/32溶解在适量丙酮与乙醇混合溶液 （体积比 1:1 ) 中， 将 PVPPXL (A)加入流化床中，用喷枪将配制的溶液以顶喷方式喷入流化床中制粒，干燥， 将干燥物料与其余物料混合均匀， 压片， 45分钟时测定溶出度为 98.3%。
实施例 E1
处方： 药物 10g 微晶纤维素（A) 20g微晶纤维素 （B) 10g乳糖 10g羧甲基淀 粉钠 2.5g 硬脂酸 0.4g
制备： 将药物与微晶纤维素（A)研磨混合 20分钟， 与其余物料混合均匀， 压片 45 分钟时测定溶出度为 86.7%。
实施例 F1
釆用比格犬作为试验动物， 每组六只， 以原料药混悬液、 实施例 A1和 D3制备的制 剂分别以 9.0 mg/kg单剂量灌胃给药， 各组在设定的时间点采集血样， 分离制备血桨， 釆 用液相色谱 -串联质谱法测定血浆中该活性成分的代谢产物 EXP3174的浓度， 根据药物 浓度-时间曲线计算代谢物 EXP3174的药动学参数，结果见表 1。 由结果可知， 比格犬口 服同等剂量的药物， 药物各制剂形式在体内的吸收程度优于原料药的混悬液， 含有增溶 载体的制剂其在体内的吸收程度大于普通制剂。
表 1 动物吸收试验结果
动物分组
药动学参数
原料药混悬液 A1制剂 D3制剂
AUC0-t(ng.h/ml) 651 ±230 890±258 1122 ±344
AUC0-»(ng.h/ml) 671 ±236 916±276 1174±390
Cmax(ng/ml) 208 ± 123 362 ± 169 574 ±278
Tmax(h) 2.60 ±0.89 2.0±0.80 1.50±0.77

Claims

权利要求
1、 一种药用组合物， 含有药理活性成分 2-丁基 -4-氯 -1-[2'-(1 H -四唑 -5-基) 1,1'-联苯 基-甲基]咪唑 -5-羧酸， 1- [(异丙氧基)羰氧基]甲基酯和药学上可接受的载体材料。
2、如权利要求 1所述的药用组合物， 其特征在于， 所述药理活性成分在组合物中的 重量百分比为 1%~50%。
3、 如权利要求 2所述的药用组合物， 其特征在于， 所述载体材料包括填充剂、 崩解 剂、 润湿剂、 粘合剂、 润滑剂、 表面活性剂、 助流剂、 矫味剂、 矫嗅剂和着色剂中一种 或几种。
4、如权利要求 3所述的药用组合物， 其特征在于， 所述填充剂选自以下物质一种或 几种的组合： 碳酸钙、 碳酸镁、 磷酸钙、 硫酸钙、 氧化镁、 羧甲基纤维素钙、 羧甲基纤 维素钠、 蔗糖、 乳糖、 果糖、 木糖醇、 甘露醇、 淀粉或其衍生物、 糊精和微晶纤维素； 崩解剂可选自以下物质一种或几种的组合： 淀粉、 藻酸、 羧甲基纤维素钙、 羧甲基纤维 素钠、 交联羧甲基纤维素钠、 交联聚乙烯吡咯烷酮、 低取代羟丙基甲基纤维素、 微晶纤 维素和甲基纤维素； 润湿剂可选自以下物质一种或几种的组合： 蒸馏水、 乙醇和淀粉浆； 粘合剂可选自以下物质一种或几种的组合： 阿拉伯胶、 明胶、 黄蓍胶、 糊精、 聚乙烯吡 咯烷酮、 淀粉及其衍生物、 藻酸钠、 山梨醇、 糖浆、 羟丙基甲基纤维素、 甲基纤维素、 羟丙基纤维素、 羟乙基纤维素、 乙基纤维素、 羧甲基纤维素钠、 羧甲基纤维素钙、 葡萄 糖和聚甲基丙烯酸酯； 润滑剂可选自以下物质一种或几种的组合： 硬脂酸钙、 单硬脂酸 甘油酯、 棕榈硬脂酸甘油酯、 硬脂酸镁、 微晶纤维素、 苯甲酸钠、 氯化钠、 十二烷基硫 酸钠、 硬脂酸镁、 硬脂基富马酸钠、 滑石粉、 硬脂酸锌和聚乙二醇； 表面活性剂可选自 以下物质一种或几种的组合： 十二烷基硫酸钠、 泊洛沙姆、 吐温类、 溴化十六垸三甲胺、 月桂醇硫酸钠、 硬脂醇磺酸钠、 聚氧乙烯高级脂肪醇、 蔗糖酯、 山梨醇脂肪酯和大豆磷 脂； 助流剂可选自以下物质一种或几种的组合： '胶体二氧化硅、粉状纤维素、三硅酸镁、 二氧化硅和滑石粉。
5、如权利要求 3所述的药用组合物，其特征在于，所述载体材料进一步包括泡腾剂， 所述泡腾剂选自碳酸氢钠、 磷酸盐、 有机酸类和有机酸酐类。
6、 如权利要求 1至 5任一所述的药用组合物， 其特征在于， 所述载体材料进一步包 含增溶载体， 药理活性成分分散在增溶载体中， 所述增溶载体选自聚乙二醇类、 聚维酮 类、 含有聚氧乙烯基的表面活性剂、 水溶性纤维素衍生物、 有机酸和糖类、 固醇类和脂 类物质中之一种或几种。
7、如权利要求 6所述的药用组合物， 其特征在于， 所述增溶载体材料选自聚乙二醇 类、 聚维酮类、 含有聚氧乙烯基的表面活性剂和水溶性纤维素衍生物中之一种或几种。
8、如权利要求 7所述的药用组合物， 其特征在于， 药理活性成分与增溶载体的重量 比例为 1:1 1:100。
9、包含如权利要求 1至 8任一所述的药用组合物的制剂， 含有药理活性成分的重量 为 5mg~180mg。
10、 如权利要求 9所述的制剂， 其特征在于， 所述制剂含有的药理活性成分选自如 下重量： 5mg， 10mg, 20mg, 30mg， 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, lOOmg, 120mg, 140mg, 160mg和 180mg。
11、 如权利要求 9所述的制剂， 其特征在于， 其形式为散剂、 颗粒剂、 微丸、 片剂、 胶囊剂、 滴丸剂或锭剂。
12、 如权利要求 1至 8任一所述的组合物用于制备心血管药物的用途。
13、 如权利要求 1至 8任一所述的组合物用于制备降血压药物的用途。
14、 一种治疗人类心血管疾病的方法， 包括给患者施以含有有效剂量 2-丁基 -4-氯 小 [2'-(1 H -四唑 -5-基) 1,1'-联苯基-甲基]咪唑 -5-羧酸， H (异丙氧基)羰氧基]甲基酯的如权 利要求 9至 11任一所述的制剂。
15、 一种治疗人类高血压疾病的方法， 包括给高血压患者施以含有有效剂量 2-丁基 -4-氯小 [2'-(1 H -四唑 -5-基) Ι,Γ-联苯基-甲基]咪唑 -5-羧酸， 1- [(异丙氧基)羰氧基]甲基酯的 如权利要求 9至 11任一所述的制剂。
16、如权利要求 15所述的治疗人类高血压疾病的方法， 包括给高血压患者施以含有 有效剂量 2-丁基 -4-氯 -1-[2'-(1 Η -四唑 -5-基) Ι,Γ-联苯基-甲基]咪唑 -5-羧酸， 1- [(异丙氧基) 羰氧基]甲基酯的如权利要求 9至 11任一所述的制剂， 和其他的降压药物， 其他降压药 物选自利尿剂、 血管紧张素转换酶抑制剂、 钙离子拮抗剂中之一种或多种。
PCT/CN2008/000048 2007-01-05 2008-01-07 Nouvelle composition pharmaceutique WO2008086733A1 (fr)

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