CN101040855A - Compound including rimonabant and poloxamer, solid dispersion and the preparation and the application of the medicine - Google Patents

Compound including rimonabant and poloxamer, solid dispersion and the preparation and the application of the medicine Download PDF

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CN101040855A
CN101040855A CNA2007101014020A CN200710101402A CN101040855A CN 101040855 A CN101040855 A CN 101040855A CN A2007101014020 A CNA2007101014020 A CN A2007101014020A CN 200710101402 A CN200710101402 A CN 200710101402A CN 101040855 A CN101040855 A CN 101040855A
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rimonabant
sodium
poloxamer
limited
cellulose
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杨喜鸿
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Abstract

The invention relates to a compound and a solid disperser of limonaban and plasamu, for resolving the defects as humidity and solubility of limonaban, improving the dissolving degree of limonaban, and support the preparation and quality of agent. The invention also relates to relative preparation and drug application.

Description

Contain compositions, solid dispersion and preparation thereof and the medicinal application of Rimonabant and poloxamer
Technical field the invention belongs to the pharmaceutical technology field, relates to the compositions, the solid dispersion that contain Rimonabant (comprising its officinal salt) and poloxamer, and preparation method thereof with its application in medicine.
Background technology Rimonabant (Rimonabant), chemical name are N-piperidino-5-(4-chlorphenyl)-1-(2, the 4-Dichlorobenzene base)-4-methylpyrazole-3-Methanamide, and molecular structural formula is as follows:
Figure A20071010140200151
Molecular formula C 22H 21N 4OCl 3, molecular weight 463.79.
Rimonabant has the pharmacological action of the selective antagonist of cannabinoid CB 1 receptor, can be used for treatment and prevention article abuse or substance depilatory, comprise the effect that alcohol dependence and nicotine rely on and has fat-reducing, and to cardiovascular patient, metabolic syndrome patient, wine for giving off smoking patient and obese patient's cardiovascular danger situation is improved, and prevention and treatment type 2 diabetes mellitus, be used for prevention and treat unusual blood fat disease, prevention and treatment metabolic syndrome, prevention and treatment and fat and/or unusual lipidemia have the hepatic disease of class, prevention and treatment steatosis and/or non-alcoholic fatty liver disease inflammation, or the like.
European patent application EP 656354 and China Patent No. 94119030.7 disclose Rimonabant, its pharmaceutically acceptable acid addition salts and preparation method thereof and pharmaceutical composition; (it is at Chinese patent publication number CN1251524 for international publication WO98/43636, the patent No. 98803791.2) related to the compositions of Rimonabant or its officinal salt, said composition is improved its wettability and stripping at oral solid formulation with alkyl sodium sulfate after with the Rimonabant micronization, but the dosage form of said composition is single, especially oral hard capsule dosage form; International publication WO2003/040105 (it is at Chinese patent publication number CN1582278, number of patent application 02821968.6) discloses a kind of polymorphous Rimonabant and preparation method thereof.
Rimonabant or its officinal salt are fat-soluble compounds, be water insoluble or almost water-fast (notes: by 2005 editions " two note on the use explanations of Chinese pharmacopoeia, the 1g solute in the 10000ml solvent, can not dissolve fully be called insoluble or almost insoluble), and has a hydrophobicity of highly significant, be that not wettable (the biphase mutual immersional wetting of material can not take place not wettable being meant when contacting with water in water, Rimonabant or its officinal salt keep dry solid-state shape and not mixed with water), this character causes containing its active ingredient of ordinary preparation compositions not moistening and indiffusion in water of Rimonabant or its officinal salt, be easy in gastro-intestinal Fluid that crystallization or precipitation are separated out and can not stripping with the peroral dosage form of the pharmaceutical adjunct of routine and disperse system preparation, greatly influenced the absorption and the utilization of medicine.
Rimonabant or its officinal salt are as the active ingredient of medicine, when it is made as medicinal preparation for oral administration, having only Rimonabant or its officinal salt to be dissolved in or to be scattered in the water could absorb in gastrointestinal well, if can not be dissolved in or be scattered in the water, even can not give birth to infiltration with waterishlogging, then absorption and the biological utilisation for it can seem very difficult, therefore, the non-wettability and the dissolubility of improvement Rimonabant or its officinal salt are very important and significant.
Summary of the invention is because Rimonabant or its officinal salt have very strong hydrophobicity and non-wettability, therefore under the prerequisite of the chemical compound pharmacological properties that does not change it, improves the intermiscibility and the dissolution of it and water, is vital.
The inventor is by studying and putting into practice pleasantly surprisedly and find: Rimonabant is fat-soluble very strong chemical compound, and when poloxamer exists, can improve wettability and the dissolubility of Rimonabant in water well, for example Rimonabant and poloxamer are mixed with the different quality proportioning and when forming mixture, the wettability of Rimonabant is significantly improved, and significant dissolving and stripping can further take place.And within the specific limits, along with the amount increase of poloxamer, the wettability of Rimonabant and dissolubility also can further improve.
Based on above research and practice, the invention provides the technology contents of following aspect:
First aspect provides the pharmaceutical composition that contains Rimonabant and poloxamer, and its preparation method, application;
Second aspect, provide Rimonabant and poloxamer solid dispersion, and preparation method thereof, compositions is used and preparation;
The third aspect provides the solid dispersion of a kind of Rimonabant and poloxamer and other pharmaceutical carrier, and its preparation method, application.
The technology contents of above-mentioned three aspects below is described with level clearly respectively.
At first, should be noted that following definition is applicable to whole description of the present invention and claims:
(1) should be clear and definite, " Rimonabant " of the present invention comprising: the compound form of Rimonabant and solvate thereof, hydrate, various crystal formation, monocrystalline type, polymorphic, mixed crystal type, armorphous, crystal formation I (for example European patent EP 656345 provides), crystal form II (for example international patent publications WO2003/040105 provides); The officinal salt that also comprises Rimonabant, the biological effectiveness of finger reservation parent compound and characteristic, have with the pharmacological action of Rimonabant equivalence, pharmaceutically acceptable medicinal acid addition salt, for example include but not limited to the hydrochlorate of Rimonabant, mesylate, disulfate, phosphate, sulfate, hydrobromate, acetate, oxalates, acetate, lactate, gluconate, tartrate, citrate, fumarate, succinate, malate, maleate, benzoate, hydrobromate, the 2-naphthalene sulfonate, glycuronate, isethionate, right-toluene fulfonate, amino acid salts (as aspartate), and the solvate of above-mentioned salt, hydrate, various crystal formations, monocrystalline type, polymorphic, mixed crystal type, armorphous Rimonabant derivant salt material, or the like.Described above these all are the existence form of Rimonabant as active ingredient.
(2) poloxamer, English name Poloxamer is α-hydrogen-ω-hydroxyl poly-(oxygen second is rare) a-poly-(oxypropylene) b-poly-(oxygen second is rare) cBlock copolymer is the novel macromolecule non-ionic surface active agent of a class.According to its molecular weight difference, different models is arranged, as 188,407,124,128,108,237,338, or the like, " poloxamer " of the present invention comprises the mixture of its all models and any different model, the preferred model 188,407 of using has Pluronic F68 as 188 model trade names commonly used.
(3) " pharmaceutical composition " of the present invention is meant the semi-finished product that contain medicament active composition and pharmaceutic adjuvant composition, preparation, preparation compositions etc.
(4) " pharmaceutical carrier " of the present invention is meant in pharmaceutical preparation (or in compositions), except that the principal agent composition, can be used for diluting, the pharmaceutic adjuvant or the excipient of filling, bonding, disintegrate, lubricated, painted, seasoning, moistening etc.
(5) " solid dispersion " of the present invention is meant a kind of disperse system that exists with solid form that the medicine high degree of dispersion is formed in solid carrier, and perhaps high degree of dispersion is in liquid-carrier and make the disperse system of solid preparation, the latter such as soft capsule.
First aspect contains the medicine of Rimonabant and poloxamer
Compositions, and preparation method thereof, use
The invention provides a kind of pharmaceutical composition that contains Rimonabant and poloxamer, wherein the quality ratio range of Rimonabant and poloxamer is 1: (1～200), and promptly the poloxamer of the Rimonabant of per 1 gram and 5 to 200 grams carries out proportioning in pharmaceutical composition;
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2～190);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～180);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (4～150);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (5～120);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (6～100);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (7～90);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (8～80);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (9～70);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (10～60);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (11～50);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (12～40);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2.5～30);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～20).
For example, the quality proportioning of Rimonabant and poloxamer is 1: 1,1: 2,1: 3,1: 4,1: 5,1: 5.5,1: 6,1: 6.5,1: 7,1: 7.5,1: 8,1: 8.5,1: 9,1: 9.5,1: 10,1: 11,1: 12,1: 13,1: 14,1: 15,1: 16,1: 17,1: 18,1: 19,1: 20,1: 25,1: 30,1: 35,1: 40,1: 45,1: 50,1: 55,1: 60,1: 65,1: 70,1: 75,1: 80,1: 90,1: 100,1: 110,1: 120,1: 130,1: 140,1: 170,1: 195, or the like.The present invention defines the quality ratio range of Rimonabant and poloxamer, be based on the consideration of the factors such as medicinal application of improving Rimonabant wettability and deliquescent percentage contribution and said composition, if the consumption of poloxamer is very few, for example the mass ratio of poloxamer and Rimonabant was less than 1 o'clock, and its compositions is remarkable inadequately to wettability and the dissolubility of improving Rimonabant; If the poloxamer consumption is too much, the content of dispersion of Rimonabant in combination is low and improve its wettability and deliquescent percentage contribution is inconsiderable yet, even can prevent the stripping of Rimonabant, also is unfavorable for the application and the cost accounting of composite preparation.
The above-mentioned pharmaceutical composition that contains Rimonabant and poloxamer, it can be any pharmaceutical dosage form of acceptable on the pharmaceutics, be preferably tablet and (comprise dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), hard capsule (comprises gastric solubleness, enteric, slow releasing capsule), soft capsule (comprises gastric solubleness, enteric soft capsules), drop pill, pellet (is annotated: " be called piller in the Chinese pharmacopoeia two-shift system agent general rule, down together), granule, dry suspension, powder, oral fluid agent (comprises solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc., more than these pharmaceutical dosage forms " all on the books and describe in the Chinese pharmacopoeia.
According to the difference of pharmaceutical dosage form, optionally can also optionally contain other suitable pharmaceutical carrier, such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.Described " optionally containing " is meant and can selects wherein one or more, also can not select.
Used suitable filler or diluent comprise lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, or the like; Described disintegrating agent comprises sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, or the like; Described surfactant comprises sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (common name: tween, comprise its various models), the smooth (common name: span of fatty acid Pyrusussuriensis, comprise its various models), or the like; Described binding agent comprises polyvinylpyrrolidone, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like; Described suspending agent includes but not limited to hydroxypropyl emthylcellulose, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, or the like; Described lubricant comprises magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate, or the like.In addition, also can comprise pH value regulator or buffer agent, for example phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, or the like; Also can comprise antiseptic, for example sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, or the like; Also can comprise stabilizing agent and antioxidant, for example calcium disodium edetate, sodium sulfite, vitamin C, vitamin E, or the like; Also can comprise the taste regulator, for example maltose alcohol, aspartame, steviosin, fructose, sucrose, saccharin sodium, essence such as flavoring orange essence, strawberry essence, or the like.
Certainly, pharmaceutical carrier is not limited to the above, according to the difference of pharmaceutical dosage form, optionally also can comprise additive other routine, appropriate or pharmaceutic adjuvant, as wetting agent, can be selected from water, ethanol, water-ethanol solution etc.
Further, the present invention also provides the above-mentioned preparation of drug combination method that contains Rimonabant and poloxamer, it comprises Rimonabant, poloxamer and suitable pharmaceutical carrier fully are mixed and made into any pharmaceutical dosage form of acceptable on the pharmaceutics, and preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), hard capsule (comprises gastric solubleness, enteric, slow releasing capsule), soft capsule (comprises gastric solubleness, enteric soft capsules), drop pill, pellet, granule, dry suspension, powder, oral fluid agent (comprises solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc.
Particularly, by with Rimonabant, obtain granule or dry suspension after adopting wet granulation or dry granulation behind poloxamer and the suitable pharmaceutical carrier mix homogeneously, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: polyvinylpyrrolidone (polyvidone) as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By with Rimonabant, obtain dry suspension or powder behind poloxamer and the suitable pharmaceutical carrier mix homogeneously, optionally can further will obtain hard capsule in dry suspension or the powder fill Capsules shell, or mix homogeneously gets granule behind wet granulation or the dry granulation, to obtain hard capsule in the granule fill Capsules shell, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
Because poloxamer also can be as the good substrate of preparation drop pill, by with Rimonabant and poloxamer melting mixing evenly after, splash in the not miscible condensed fluid, shrink condensation and make drop pill, optionally drop pill can contain but be not limited to following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, can contain but be not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with Rimonabant, after poloxamer and the pharmaceutical carrier melting mixing that suits are even, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, Polyethylene Glycol 8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, polyoxyethylene stearate (40) ester, glyceryl monostearate, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with Rimonabant, drip to make to seal with soft capsule material compacting of gelatin or capsule material glue behind poloxamer and the suitable pharmaceutical carrier mix homogeneously and obtain soft capsule, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: Liquid Macrogol, PEG400, Macrogol 600, soybean oil, Semen Maydis oil, other vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described " soft capsule material compacting or the capsule material glue system of dripping are sealed " is meant and adopts pressing or dropping preparation method to prepare soft capsule, pressing is meant that the liquid or soft plastic state content that adopts press will contain Rimonabant and poloxamer wraps up formation preparation of soft capsule method with the compacting of capsule material film, can be pressed into different shapes and content content with different moulds, usually seal the capsule preparation with rotating the continuously automatic soft capsule production machine of rolling capsule machine or punching type automatically, dropping preparation method is meant the method that is equipped with soft capsule by a making mechanism, at a certain temperature, generally remain on more than 45 ℃, it is biphase utilizing capsule material glue and liquid content, after making a certain amount of capsule material glue with quantitative liquid content parcel, splash into that (condensed fluid can be a liquid paraffin in the another kind of not miscible condensed fluid, methyl-silicone oil, vegetable oil, in the kerosene any one), behind the capsule material glue condensation by contact liquid, owing to surface tension effects makes it to solidify the spherical soft capsule of formation; Or
By with Rimonabant, behind poloxamer and the suitable pharmaceutical carrier mix homogeneously, make the solid preparation of spherical or near-spherical, perhaps with Rimonabant, dissolving or molten being dispersed in the liquid medium behind poloxamer and the suitable pharmaceutical carrier mix homogeneously, and its deposition is coated on the surface of celphere and forms micropill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains pellet capsule in the capsulae vacuus of optionally can further micropill being packed into; Or
By Rimonabant, poloxamer and suitable pharmaceutical carrier and water or aqueous liquid mixing are evenly formed oral administration solution or suspension; Or
By with Rimonabant, poloxamer and suitable pharmaceutical carrier mix homogeneously, can obtain injection by the injection preparation method, wherein pharmaceutical carrier includes but not limited to the following material as filler or excipient: water, mannitol, sorbitol, lactose, xylitol, fructose, dextran, glucose, sodium chloride includes but not limited to the following material as surfactant: sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth).
Optionally, can also add other suitable pharmaceutic adjuvant in the above-mentioned preparation method.
Second aspect, the solid dispersion of Rimonabant and poloxamer reaches
Its preparation method, compositions are used and preparation
Further, consider that its dispersion of mixture that carries out physics mode mixing formation is relatively poor, so study further on this basis and put into practice, the inventor adopts Rimonabant and poloxamer is made solid dispersion, and pleasantly surprised the discovery, because the dispersion of Rimonabant in poloxamer improves greatly, the solid dispersion of formation makes the wettability of Rimonabant and dissolubility obtain improving very significantly, and its dissolution also significantly improves.And find that within the specific limits, the wettability of Rimonabant and dissolubility improve with the amount increase of poloxamer in the solid dispersion.
The solid dispersion that the purpose of this invention is to provide a kind of Rimonabant, and preparation method thereof with this application of class solid dispersion in medicine, it solved well Rimonabant hydrophobicity and can not wettability, make it be easy to stripping and diffusion, can solve the technical barrier of Rimonabant aspect above-mentioned well.
The invention provides a kind of Rimonabant solid dispersion, contain Rimonabant and poloxamer, wherein the quality ratio range of Rimonabant and poloxamer is 1: proportioning is carried out and the solid dispersion that forms in (0.5～200), the poloxamer that the Rimonabant of promptly per 1 gram and 0.5 to 200 restrains;
The quality ratio range of preferred Rimonabant and poloxamer is 1: (1～190);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2～180);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～170);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (4～160);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (5～150);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (6～140);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (7～120);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (8～100);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (9～80);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (10～60);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (0.5～60);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (0.5～35);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (1～30);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2～25);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～20).
For example, the quality proportioning of Rimonabant and poloxamer is 1: 0.6,1: 0.8,1: 0.9,1: 1,1: 1.2,1: 1.3,1: 1.4,1: 1.5,1: 1.6,1: 1.7,1: 1.8,1: 1.9,1: 2,1: 2.2,1: 2.5,1: 2.8,1: 3,1: 3.5,1: 4,1: 4.5,1: 5,1: 5.5,1: 6,1: 6.5,1: 7,1: 7.5,1: 8,1: 8.5,1: 9,1: 9.5,1: 10,1: 11,1: 12,1: 13,1: 14,1: 15,1: 16,1: 17,1: 18,1: 19,1: 20,1: 25,1: 30,1: 35,1: 40,1: 45,1: 50,1: 55,1: 60,1: 65,1: 70,1: 75,1: 80,1: 90,1: 100,1: 110,1: 120,1: 130,1: 150,1: 180,1: 190, or the like.The present invention defines the quality ratio range of Rimonabant and poloxamer, be based on the consideration of the factors such as medicinal application of improving Rimonabant wettability and deliquescent percentage contribution and solid dispersion, if the consumption of poloxamer is very few, the dispersion of Rimonabant in solid dispersion can not exclusively and improve its wettability and dissolubility is not remarkable; If the poloxamer consumption is too much, the content of dispersion of Rimonabant in dispersion is low and improve its wettability and deliquescent percentage contribution is inconsiderable yet, also is unfavorable for application and the cost accounting of postorder when producing preparation compositions.
The present invention also provides two kinds of preparation methoies of the solid dispersion of Rimonabant and poloxamer:
Method one. this method comprises: after poloxamer is heated to complete fusion, add Rimonabant, mix, cooling is pulverized, and promptly obtains solid dispersion.
Method two. this method comprises: be dissolved or dispersed in Rimonabant and poloxamer in the solvent simultaneously, from this mixture, remove behind the mix homogeneously and desolvate, and dry and pulverize and obtain solid dispersion, wherein said solvent is selected from one or more in methanol, ethanol, isopropyl alcohol, acetone, chloroform, the water.In above-mentioned preparation, remove and to desolvate and exsiccant method can be taked to remove under reduced pressure, in the drying under reduced pressure, vacuum drying, lyophilization, spray drying, fluidized bed granulation drying, heating, drying one or more.
Particularly, the preparation method of the solid dispersion of Rimonabant provided by the invention and poloxamer, this method comprises:
(1) poloxamer is added Rimonabant in 50～80 ℃ after being heated to complete fusion, mix, after cooling is solidified it, pulverize, promptly obtain solid dispersion, wherein said chilling temperature is below 25 ℃, preferred below 0 ℃ (as-5 ℃ ,-10 ℃ ,-15 ℃ ,-18 ℃ ,-20 ℃ ,-25 ℃ ,-30 ℃ or the like), optionally can further solid dispersion drying under reduced pressure (comprising vacuum drying) be beneficial to pulverize and preserve; Or
(2) with Rimonabant with poloxamer is dissolved in methanol or/and ethanol, stir the back except that desolvating and drying, pulverize, promptly get the solid dispersion of Rimonabant and poloxamer, wherein said remove desolvate and drying can adopt remove under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, fluidized bed granulation drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
(3) Rimonabant is dissolved in methanol or/and in the ethanol, add poloxamer in 50～80 ℃ molten state liquid, fully stir and make methanol or/and the ethanol evaporation Ex-all, after cooling is solidified it, pulverize, promptly obtain solid dispersion, wherein said chilling temperature is below 25 ℃, preferred below 0 ℃ (as-5 ℃ ,-10 ℃ ,-15 ℃ ,-18 ℃ ,-20 ℃ ,-25 ℃ ,-30 ℃ or the like), optionally can further solid dispersion drying under reduced pressure (comprising vacuum drying) be beneficial to pulverize and preserve;
(4) Rimonabant and poloxamer are made pastel with suitable liquid, pastel is ground, further remove and desolvate and drying, pulverize, promptly get the solid dispersion of Rimonabant and poloxamer, wherein said liquid is selected from methanol, ethanol, isopropyl alcohol, acetone, chloroform, in the water one or more, wherein said remove desolvated and drying can adopt and removes under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, the fluidized bed granulation drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
(5) will fully grind behind the Rimonabant of the above granularity of 80 orders and the poloxamer mix homogeneously, promptly get the solid dispersion of Rimonabant and poloxamer, the preferred size size is more than 100 orders, and most preferably granule size is more than 200 orders.
In the above-mentioned preparation, the mode of described grinding can be carried out in such as grinder, extruder, homogenizer or blade blender.
The Rimonabant that the present invention is above-mentioned and the solid dispersion of poloxamer, it is the pressed powder of high degree of dispersion, the Rimonabant high degree of dispersion is in poloxamer, and poloxamer has changed the gathering or the crystalline form of Rimonabant molecule, can make the wettability and the dissolubility of Rimonabant significantly improve, the solid dispersion of Rimonabant and poloxamer can be seen a kind of composition with pharmacologically active as, come useful in preparing drug formulations to seem very easy and be easy to guarantee the quality of pharmaceutical preparation with this solid dispersion, therefore, the solid dispersion that the present invention also provides Rimonabant and poloxamer contains application in the pharmaceutical preparation of Rimonabant in preparation, the application in the medicine of preparation treatment and cannabinoid CB 1 receptor diseases associated.
Can pass through the administration Rimonabant of the present invention of any appropriate and the solid dispersion of poloxamer, but usually by oral or parenteral route.Use in order to carry out this class, the solid dispersion of Rimonabant and poloxamer can be prepared as acceptable any pharmaceutical dosage form on the pharmaceutics by adding suitable pharmaceutical carrier, and but, the definite form of said composition depends on form of medication naturally.
When the above-mentioned Rimonabant and the solid dispersion of poloxamer are used for the treatment of as active ingredient, can directly give the patient simple Rimonabant and the solid dispersion of poloxamer, for example with solid dispersion with the form of powder or directly the fill capsulae vacuus to give the patient oral, but sign in the assurance of the multiformity and the medicament quality of pharmaceutical dosage form, usually all be form appearance with the pharmaceutical composition that contains pharmaceutically suitable carrier, therefore, the present invention also provides a kind of pharmaceutical composition, solid dispersion and pharmaceutically suitable carrier of containing Rimonabant and poloxamer, wherein in unit formulation, the content of the Rimonabant that solid dispersion provided of Rimonabant and poloxamer is 1mg～100mg;
The content of preferred Rimonabant is 2.5mg～60mg;
The content of preferred Rimonabant is 5mg～40mg;
The content of preferred Rimonabant is 10mg～35mg;
The content of preferred Rimonabant is 20mg.Below for example 1mg, 2mg, 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, or the like.Above-described compositions, " unit formulation " is meant the medicament of every one preparation compositions or individual packaging, for example each tablet (comprises dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets etc.), each hard capsule (comprises gastric solubleness, enteric, the slow release hard capsule), each soft capsule (comprises gastric solubleness, enteric soft capsules), per 1 to 1000 pill (comprises drop pill, micropill, because of its volume little, so a number of any integer word is decided to be a unit in will per 1 to 1000), each bag granule, each bag dry suspension, each bag powder, each bottleneck clothes liquid agent, each bottle (or bag) injection, each bottle powder ampoule agent for injection, or the like.
Should be understood that, on the one hand, the solid dispersion of Rimonabant of the present invention and poloxamer, wherein poloxamer also can be regarded the pharmaceutical carrier of Rimonabant as, be this carrier be not the simple pharmaceutical carrier that mixes with Rimonabant on the meaning, but by the blend of unconventional technology with Rimonabant and poloxamer formation high degree of dispersion; On the other hand, will be clear that, pharmaceutically suitable carrier of the present invention is meant in pharmaceutical preparation (or in compositions), except that the principal agent composition, can be used for diluting, the pharmaceutic adjuvant or the excipient of filling, bonding, disintegrate, promotion dissolving or stripping, lubricated, painted, seasoning, moistening etc.
But be suitable for oral, non-intestinal or topical and can be tablet, hard capsule, soft capsule, pill, granule, dry suspension, powder, oral fluid agent, injectable or infusion solution or suspension, suppository, lozenge and transcutaneous device like this by being mixed with compositions and they.The Orally administered composition compositions of preferred oral administration, particularly molding or solid is because they are more convenient for generally using.
According to the difference of pharmaceutical dosage form, optionally can also optionally contain other suitable pharmaceutical carrier, such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.Described " optionally containing " is meant and can selects wherein one or more, also can not select.
There is and contains excipient commonly used in oral administration with unit dose usually with tablet (ordinary tablet, dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), capsule (hard capsule, soft capsule, enteric coated capsule etc.), granule, dry suspension, powder, pill (micropill, drop pill) and oral liquid (solution, suspension, emulsion agent), such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.
Used suitable filler or diluent comprise lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, or the like; Described disintegrating agent comprises sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, or the like; Described surfactant comprises sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), or the like; Described suspending agent includes but not limited to hydroxypropyl emthylcellulose, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, or the like; Described binding agent comprises polyvidone, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like; Described lubricant comprises magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate, or the like.In addition, also can comprise pH value regulator or buffer agent, for example phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, or the like; Also can comprise antiseptic, for example sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, or the like; Also can comprise stabilizing agent and antioxidant, for example calcium disodium edetate, sodium sulfite, vitamin C, vitamin E, or the like; Also can comprise the taste regulator, for example maltose alcohol, steviosin, aspartame, fructose, sucrose, saccharin sodium, flavoring orange essence, strawberry essence, or the like; Also can comprise additive other routine, appropriate in addition.
Further, the present invention also provides the preparation of drug combination method of the solid dispersion that contains Rimonabant and poloxamer, this method comprises the solid dispersion of Rimonabant and poloxamer and pharmaceutically acceptable, suitable pharmaceutical carrier fully is mixed and made into acceptable any pharmaceutical dosage form on the pharmaceutics, and preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), hard capsule (comprises gastric solubleness, enteric, slow releasing capsule), soft capsule (comprises gastric solubleness, enteric soft capsules), drop pill, pellet, granule, dry suspension, powder, oral fluid agent (comprises solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc.Can by Rimonabant is mixed with solid dispersion and pharmaceutically suitable carrier of poloxamer/common methods such as fusion/fusion/dissolution, granulation, filling, tabletting/fill gelatine capsule, compacting soft capsule prepare solid oral composition.Can use the operation of fusion repeatedly to be distributed in the pharmaceutical carrier so that make the abundant mixing of active ingredient; When preparation hard gelatin capsule and tablet, can adopt fill gelatine capsule or tabletting after the wet granulation drying, also can adopt dry granulation fill gelatine capsule or tabletting, also can be with direct fill gelatine capsule of the solid dispersion of Rimonabant and poloxamer or tabletting; When the preparation soft capsule, the Polyethylene Glycol that the solid dispersion dissolving or the dispersion of Rimonabant and poloxamer can be liquid state at normal temperatures is (as PEG300, PEG400, PEG600 etc.) or after forming liquid or soft plastic state mixture in the vegetable oil (as soybean oil, the corn wet goods) obtain soft capsule with the soft capsule material of gelatin environmental sealing; When preparation during drop pill, can with room temperature down for solid-state Polyethylene Glycol (as PEG3000, PEG4000, PEG6000, PEG8000 etc.) behind the heating and melting, make solid dispersion dissolving or be dispersed in the Polyethylene Glycol, form behind the liquefied mixture with drip the system machine system of dripping and cool off after obtain drop pill.Certainly, in the above-mentioned preparation, optionally also can add other pharmaceutic adjuvant, as disintegrating agent, surfactant, lubricant etc.
It is also understood that when pharmaceutical dosage form is tablet or capsule, can be the film coating.Can give tablet coating (enteric coating or gastric solubleness film-coat) according to method well-known in the art, the material that is used for the film coating, comprise suitable coating materials, for example Opadry, hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, or the like; Also can comprise plasticizer, for example Polyethylene Glycol, triethyl citrate, or the like.The coating membrane color can be various, as orange colour, white, blueness or the like.
Preferred pharmaceutical dosage form is tablet (comprising dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets etc.), hard capsule (comprising gastric solubleness, enteric, slow releasing capsule), soft capsule (comprising gastric solubleness, enteric soft capsules), drop pill, pellet, granule, powder, oral fluid agent (comprising solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc.
Particularly, by adopting wet granulation or dry granulation to obtain granule or dry suspension behind the solid dispersion of Rimonabant and poloxamer and the pharmaceutical carrier mix homogeneously, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By obtaining dry suspension or powder behind the solid dispersion of Rimonabant and poloxamer and the pharmaceutical carrier mix homogeneously, optionally can further dry suspension or powder fill Capsules shell be obtained hard capsule, perhaps mix homogeneously obtains granule behind wet granulation or the dry granulation, to obtain hard capsule in the granule fill Capsules shell, wherein the solid medicinal carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By obtaining soft capsule with dripping to make to seal with soft capsule material compacting of gelatin or capsule material glue behind the solid dispersion of Rimonabant and poloxamer and the suitable pharmaceutical carrier mix homogeneously, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: Liquid Macrogol, PEG400, Macrogol 600, soybean oil, Semen Maydis oil, other vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described " soft capsule material compacting or the capsule material glue system of dripping are sealed " is meant and adopts pressing or dropping preparation method to prepare soft capsule, pressing is meant that the liquid or soft plastic state content that adopts press will contain solid dispersion wraps up formation preparation of soft capsule method with the compacting of capsule material film, can be pressed into different shapes and content content with different moulds, usually seal the capsule preparation with rotating the continuously automatic soft capsule production machine of rolling capsule machine or punching type automatically, dropping preparation method is meant the method that is equipped with soft capsule by a making mechanism, at a certain temperature, generally remain on more than 45 ℃, it is biphase utilizing capsule material glue and liquid content, after making a certain amount of capsule material glue with quantitative liquid content parcel, splash into that (condensed fluid can be a liquid paraffin in the another kind of not miscible condensed fluid, methyl-silicone oil, vegetable oil, in the kerosene any one), behind the capsule material glue condensation by contact liquid, owing to surface tension effects makes it to solidify the spherical soft capsule of formation; Or
Because poloxamer also can be as the good substrate of preparation drop pill, by with the solid dispersion melting mixing of Rimonabant and poloxamer evenly after, or with the mixture melting mixing of Rimonabant and poloxamer evenly after, splash in the not miscible condensed fluid, shrink condensation and make drop pill, optionally drop pill can contain but be not limited to following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, can contain but be not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with the solid dispersion of Rimonabant and poloxamer and suitable pharmaceutical carrier melting mixing evenly after, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, Polyethylene Glycol 8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, polyoxyethylene stearate (40) ester, glyceryl monostearate, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with behind the solid dispersion of Rimonabant and poloxamer and the suitable pharmaceutical carrier mix homogeneously, make the solid preparation of spherical or near-spherical, perhaps with the solid dispersion of Rimonabant and poloxamer and suitable pharmaceutical carrier dissolving or molten being dispersed in the liquid medium, and its deposition is coated on the surface of celphere and forms micropill, wherein the solid medicinal carrier includes but not limited to the following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains the drop pill capsule in the capsulae vacuus of optionally can further micropill being packed into; Or
Solid dispersion by Rimonabant and poloxamer and water or aqueous liquid mixing evenly form oral administration solution or suspension; Or
By with Rimonabant and poloxamer and the injection pharmaceutical carrier mix homogeneously that is fit to, can obtain injection by the injection preparation method, wherein pharmaceutical carrier includes but not limited to the following material as filler or excipient: water, mannitol, sorbitol, lactose, xylitol, fructose, dextran, glucose, sodium chloride.
Optionally, difference and the needs of guaranteeing the medicament quality according to pharmaceutical dosage form can also add other suitable pharmaceutic adjuvant in the above-mentioned preparation method.
The third aspect, the solid of Rimonabant and poloxamer and other pharmaceutical carrier
Dispersion, and preparation method thereof, use
On the other hand, the present invention also provides a kind of solid dispersions technique that disperses Rimonabant with binary vector or polynary carrier, wherein contain Rimonabant, poloxamer and other pharmaceutical carrier, the quality ratio range of Rimonabant and poloxamer is 1: proportioning is carried out and the solid dispersion that forms in (0.5～200), the poloxamer that the Rimonabant of promptly per 1 gram and 0.5 to 200 restrains;
The quality ratio range of preferred Rimonabant and poloxamer is 1: (1～180);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2～150);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～130);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (4～120);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (5～100);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (6～80);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (7～60);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (8～50);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (9～40);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (10～30);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (11～20);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (12～15);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (1～20).
For example, the quality proportioning of Rimonabant and poloxamer is 1: 0.6,1: 0.8,1: 0.9,1: 1,1: 1.2,1: 1.3,1: 1.4,1: 1.5,1: 1.6,1: 1.7,1: 1.8,1: 1.9,1: 2,1: 2.2,1: 2.5,1: 2.8,1: 3,1: 3.5,1: 4,1: 4.5,1: 5,1: 5.5,1: 6,1: 6.5,1: 7,1: 7.5,1: 8,1: 8.5,1: 9,1: 9.5,1: 10,1: 11,1: 12,1: 13,1: 14,1: 15,1: 16,1: 17,1: 18,1: 19,1: 20,1: 25,1: 30,1: 35,1: 40,1: 45,1: 50,1: 55,1: 60,1: 65,1: 70,1: 75,1: 80,1: 90,1: 100,1: 110,1: 120,1: 130,1: 150,1: 180,1: 190, or the like.
Described other pharmaceutical carrier is such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.
According to the difference of pharmaceutical dosage form, optionally can optionally contain other suitable pharmaceutical carrier, such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.Described " optionally containing " is meant and can selects wherein one or more, also can not select.
Described suitable filler or diluent include but not limited to lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, or the like; Described disintegrating agent includes but not limited to sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, or the like; Described surfactant comprises but is not limited to sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), or the like; Described suspending agent includes but not limited to hydroxypropyl emthylcellulose, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, or the like; Described binding agent includes but not limited to methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like; Described lubricant includes but not limited to magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate, or the like.In addition, also can comprise pH value regulator or buffer agent, for example phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, or the like; Also can comprise antiseptic, for example sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, or the like; Also can comprise stabilizing agent and antioxidant, such as but not limited to calcium disodium edetate, sodium sulfite, vitamin C, vitamin E, or the like; Also can comprise the taste regulator, for example maltose alcohol, steviosin, aspartame, fructose, sucrose, saccharin sodium, flavoring orange essence, strawberry essence, or the like.
Technical solution of the present invention has come down to provide with poloxamer and other suitable pharmaceutical carrier and has formed binary vector or polynary carrier, forms the solid dispersion system of disperseing Rimonabant to reach.
Certainly,, optionally can also use additive other routine, appropriate or pharmaceutic adjuvant,, can be selected from water, ethanol, water-ethanol solution etc. as wetting agent according to the difference of pharmaceutical dosage form.
Further, the present invention also provides the above-mentioned Rimonabant that contains, the preparation method of the solid dispersion of poloxamer and other pharmaceutical carrier, it comprises Rimonabant, poloxamer and other pharmaceutical carrier fully are mixed and made into any pharmaceutical dosage form of acceptable on the pharmaceutics, and preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), hard capsule (comprises gastric solubleness, enteric, slow releasing capsule), soft capsule (comprises gastric solubleness, enteric soft capsules), drop pill, pellet, granule, dry suspension, powder, oral fluid agent (comprises solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc.
Pharmaceutical dosage form is relevant with the preparation method of selected pharmaceutical carrier and postorder.
Particularly, by with Rimonabant, poloxamer is dissolved or dispersed in alcohol, in the alcohol-water solution, with this liquid mixture as wetting agent to the pharmaceutical carrier wet granulation, remove and desolvate and drying, make the granule or the dry suspension of dispersion, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein other pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, described alcohol, alcohol-water solution comprises ethanol, methanol, ethanol-water solution, methanol-water solution, described remove desolvated and drying can adopt and removes under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, the fluidized bed granulation drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
By with Rimonabant, poloxamer and other pharmaceutical carrier are dissolved or dispersed in alcohol, in the alcohol-water solution, stir or fully grind the back and remove and desolvate and dry, with solid drying and the pulverizing that obtains, promptly obtain the dry suspension or the powder of dispersion, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein other pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, described alcohol, alcohol-water solution comprises ethanol, methanol, ethanol-water solution, methanol-water solution, wherein said remove desolvated and drying can adopt and removes under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, the fluidized bed granulation drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
By with Rimonabant, poloxamer and other pharmaceutical carrier are dissolved or dispersed in Polyethylene Glycol or the vegetable oil, seal or the capsule material glue system of dripping is sealed and obtained soft capsule with the compacting of the soft capsule material of gelatin, other pharmaceutical carrier includes but not limited to the following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), wherein Polyethylene Glycol includes but not limited to Liquid Macrogol, PEG400, Macrogol 600, vegetable oil includes but not limited to soybean oil, Semen Maydis oil; Or
By with Rimonabant, after poloxamer and other pharmaceutical carrier melting mixing are even, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, PEG8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, polyoxyethylene stearate (40) ester, glyceryl monostearate, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or,
By with Rimonabant, behind poloxamer and other pharmaceutical carrier mix homogeneously, be dissolved or dispersed in alcohol, in the alcohol-water solution, make the solid preparation of spherical or near-spherical and make micropill, perhaps with Rimonabant, poloxamer is with other pharmaceutical carrier dissolving or be dispersed in alcohol, in the alcohol-water solution medium, and its deposition is coated on the surface of celphere and makes micropill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains pellet capsule in the capsulae vacuus of optionally can further micropill being packed into.
Above-mentioned preparation contains in the preparation method of solid dispersion of Rimonabant, poloxamer and other pharmaceutical carrier, and described " being scattered in alcohol, alcohol-water solution " is meant that material forms with homodisperse states such as suspension, suspension, emulsion, colloids in liquid medium.Should be appreciated that substance dissolves is the dispersity of topnotch in liquid medium, and dispersive states such as the suspension that forms, suspension, emulsion, colloid also are good dispersities in liquid is situated between.The inventor is by repeatedly experiment discovery, less and not simultaneously when the consumption of liquid medium, material is easy to form dispersion states such as suspension, suspension, emulsion, colloid, and the prepared solid dispersion that contains Rimonabant, poloxamer and other pharmaceutical carrier accordingly and the difference of formulations prepared from solutions are little.
Optionally, can also add other suitable pharmaceutic adjuvant in the above-mentioned preparation method.
Though the invention describes the concrete related content of compositions, solid dispersion and three aspects such as their preparation and medicinal application of Rimonabant and poloxamer, also should be included within the scope of the invention to conspicuous some modification of experienced technical staff in the art or the situation that is equal to.
Also should be noted that; the invention provides the technology contents of Rimonabant three aspects relevant with poloxamer; and define the dose-effect scope of Rimonabant and poloxamer pointedly; poloxamer can be regarded the dispersant of Rimonabant and chaotropic agent, solubilizing agent as in pharmaceutical composition (or preparation); but no matter which kind of purpose poloxamer is with and bears which kind of task; as long as existing within the dose-effect scope that the present invention limits of it all should be included within protection scope of the present invention.
Need to prove, in the preparation of tablet, especially in the preparation of dispersible tablet, the selection of disintegrating agent and use are very important, the key of dispersible tablet is its disintegration rate in water, so the selection of the disintegrating agent system in the tablet is extremely important, dispersible tablet provided by the present invention, at least a carboxymethyl starch sodium (CMS-Na) that is selected from of the disintegrating agent of choosing, low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl cellulose (CMC-Na), crospolyvinylpyrrolidone (PVPP), cross-linking sodium carboxymethyl cellulose (cCMC-Na), crosslinked carboxymethyl fecula sodium (cCMS-Na), microcrystalline Cellulose (MCC), carboxymethylcellulose calcium (CMC-Ca); In preparation process, disintegrating agent is made granule with the prescription powder, is referred to as addition in the disintegrating agent; Disintegrating agent mixes the back tabletting and is referred to as the outer addition of disintegrating agent with dried granules.Add in the disintegrating agent and add the speed that all can influence the dispersible tablet disintegrate, can adopt interior addition, also can adopt outer addition, can also in add, add common use; interiorly add, when adding common use, disintegrating agent can be identical, also can be different.This kind tablet, easy disintegrating disperses, and helps the stripping and the diffusion of Rimonabant.
Also need to prove, in the preparation of micropill, celphere is meant the prefabricated profiled microspheroidal ball that does not contain the medicine active ingredient, it is a kind of intermediate pharmaceutic adjuvant, usually outward appearance is spherical shape, the adjuvant that is used for celphere mainly contains filler and binding agent, optionally also can add a certain amount of disintegrating agent, porogen, lubricant and surfactant etc., can not only improve its dissolving, disintegrate, the outward appearance rounding property, also can improve its further machinability, as coating, be easy to performances such as drying, celphere can be buied celphere from the market with the product of pharmaceutic adjuvant, as sucrose-starch celphere (35 to 40 order), microcrystalline Cellulose celphere, sucrose celphere.This kind pellet or drop pill, specific surface area is big, easily disperses and contacts with water, helps the stripping and the diffusion of Rimonabant.Same, granule provided by the invention, dry suspension, powder because the medicine high degree of dispersion is easy to contact with water, help the stripping and the diffusion of Rimonabant.Soft capsule because content is liquid or soft plastic state, has been the pre-wetted state, be easier to aqueous dispersion with contact with water, stripping.
Pharmaceutical dosage form of the present invention, (comprise dispersible tablet as tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), hard capsule (comprises gastric solubleness, enteric, slow releasing capsule), soft capsule (comprises gastric solubleness, enteric soft capsules), pellet, granule (comprises effervescent granule, enteric coated particles etc.), dry suspension, powder, oral fluid agent (comprises solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc., more than these pharmaceutical dosage forms " all on the books and describe in the Chinese pharmacopoeia at 2005 editions.
The implication of nouns such as diluent of the present invention, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent belongs to the pharmaceutics category, be that those skilled in the art are familiar with maybe should being familiar with, should be able to understand the intention of the inventor for these nouns.For example: flavoring agent can be understood that to cover the pharmaceutic adjuvant (or additive) of bitter taste of drug or improvement taste perception very easily, purposes such as accent is sweet such as reaching, acid adjustment, perfumery, good mouthfeel can allow the patient be easy to accept pharmaceutical preparation, as effervescent tablet, oral cavity disintegration tablet, chewable tablet, granule, dry suspension, powder, oral fluid agent.
In addition, " including but not limited to " of the present invention is meant and comprises in the concrete material that is outlined one or more, but also can be outline outside, those skilled in the art can predict and to obtain, play the material of effect same and effect, for example " vegetable oil includes but not limited to soybean oil; Semen Maydis oil " refers to comprise soybean oil and/or Semen Maydis oil, but also comprise in addition vegetable oil or the oils and fats of its extraction, as Oleum Arachidis hypogaeae semen, olive oil, Fructus Maydis oil, soybean salad oil, rape salad oil, the corn salad oil, Petiolus Trachycarpi oil, olive oil, Oleum Gossypii semen, Oleum sesami, Oleum Helianthi, chilli oil, Oleum Ricini, Oleum Brassicae campestris, oleic acid, ethyl oleate, hydrogenated vegetable oil, lecithin, fabaceous lecithin, plant embryo oil, Oleum Camelliae or the like.
The solid dispersion of Rimonabant provided by the invention and poloxamer is white in color or off-white powder, and is mobile good, stable in properties.Adopt differential scanning calorimetric analysis (DSC), X-ray diffraction analysis that the solid dispersion of prepared different quality proportioning is investigated.DSC result shows that the DSC absworption peak of Rimonabant concentrates on 154+2 ℃, and does not observe the fusing point peak of Rimonabant in the solid dispersion; X-ray diffraction analysis is the result show, in the solid dispersion of Rimonabant and poloxamer, Rimonabant mainly is scattered in wherein with microcrystalline form or unformed state, has formed eutectic mixture.
The compositions of Rimonabant of the present invention and poloxamer, solid dispersion are used to prepare the pharmaceutical composition for the treatment of with the cannabinoid CB 1 receptor diseases associated.Further, the compositions of Rimonabant of the present invention and poloxamer, solid dispersion and preparation thereof, application in the following areas:
(1) application in the medicine of preparation treatment article abuse or substance depilatory disease;
(2) application in the medicine of preparation treatment alcohol dependence or nicotine dependence disease;
(3) application in the medicine of preparation treatment appetite disorder or obesity;
(4) improve application in cardiovascular patient, metabolic syndrome patient, wine for giving off smoking patient and obese patient's the medicine of cardiovascular status in preparation;
(5) application in the medicine of preparation treatment or prevention type 2 diabetes mellitus;
(6) in preparation prevention with treat application in the medicine of unusual blood fat disease;
(7) application in the medicine of preparation prevention and treatment metabolic syndrome;
(8) preparation prevention and treatment with fat and/or unusually lipidemia application in the medicine of hepatic disease of class is arranged;
(9) application in the medicine of preparation prevention and treatment steatosis and/or non-alcoholic fatty liver disease inflammation;
(10) application in the medicine of preparation treatment memory and awareness obstacle.
The compositions, solid dispersion of further verifying Rimonabant of the present invention and poloxamer with following test improved the wettability of Rimonabant, improved the significant advantage of aspects such as hydrophilic, dissolution.
One. the wettability test is relatively
Illustrate that with following experiment the technology of the present invention is at the remarkable result that improves aspect the Rimonabant non-wettability.
Under 35 ± 1 ℃, in the phosphate buffered solution of the pH=3.5 that is similar to the gastric juice medium, observe the dissolved dynamic variation of Rimonabant:
1. get the Rimonabant powder that 10mg crosses 80 mesh sieves respectively, join in the phosphate buffered solution of 100ml pH=3.5, observing the Rimonabant powder floats on the liquid level, put the bilobate motor stirrer in 400 rev/mins of high-speed stirred after 20 minutes, range estimation finds that the Rimonabant powder still floats on the liquid level, and powder is particle shape and flocks together, and moistening does not take place, more do not observe dissolved generation, Rimonabant shows significant non-wettability and difficult dissolubility.
2. (physical property was simply mixed by 1: 0.8,1: 1,1: 4,1: 10,1: 15,1: 20,1: 30,1: 50,1: 80,1: 100,1: 155,1: 180 mix powder to get the Rimonabant of about 100mg and poloxamer respectively, cross 80 mesh sieves), number consecutively is 1A～13A, join in the phosphate buffered solution of 100mlpH=3.5, putting the bilobate motor stirrer stirs in 75 rev/mins, observe and the complete time required when moistening of record mix powder, write down as follows:
Table 1 (error amount ± 2)
Numbering 1A 2A 3A 4A 5A 6A 7A 8A 9A 10A 11A 12A
Time (second) Greater than 350 98 62 60 55 48 42 37 33 30 26 25
As can be seen from Table 1, in the mixed-powder, the existence of poloxamer improves the wettability of Rimonabant, and wettability obtains very significant improvement, and increases with the poloxamer ratio, and hydrophilic obviously improves, and complete wettable required time shortens.
3. get the Rimonabant of about 100mg and poloxamer respectively by 1: 0.7,1: 2,1: 5,1: 10,1: 15,1: 20,1: 30,1: 50,1: 80,1: 100,1: 150,1: 170,1: 180 solid dispersion, number consecutively is 1B～13B, join in the phosphate buffered solution of 100mlpH=3.5, putting the bilobate motor stirrer stirs in 75 rev/mins, observe and the complete time required when moistening of record mix powder, write down as follows:
Table 2 (error amount ± 2)
Numbering 1B 2B 3B 4B 5B 6B 7B 8B 9B 10B 11B 12B 13B
Time (second) 90 65 35 27 25 21 20 18 14 13 11 10 8
As can be seen from Table 2, in the solid dispersion, the existence of poloxamer significantly improves the wettability of Rimonabant, and increases with the poloxamer ratio, and hydrophilic obviously improves, and complete wettable required time shortens, and is better than the wettable time of mixed-powder in the table 1.
Two. water-soluble is relatively
Under the normal temperature and pressure, record the dissolubility of Rimonabant in water less than 0.02mg/ml;
The dissolubility of Rimonabant and poloxamer physical mixture (1: 6) is greater than 5mg/ml, and the dissolubility that is equivalent to Rimonabant wherein is greater than 0.7mg/ml;
The dissolubility of the solid dispersion of Rimonabant and poloxamer (1: 6) is greater than 15mg/ml, and the dissolubility that is equivalent to Rimonabant wherein is greater than 2mg/ml;
As seen, the solid dispersion of Rimonabant of the present invention and poloxamer physical mixture, Rimonabant and poloxamer all has very significant effect to the dissolubility raising of Rimonabant, and solid dispersion is better than physical mixture to deliquescent raising.
Three. the dissolution test is relatively
Illustrate that with following experiment the technology of the present invention is at the remarkable result that improves aspect the Rimonabant dissolution.
Specimen is divided into three groups, wherein the I group: Rimonabant powder and Rimonabant hydrochlorate powder; II group: Rimonabant and the mix powder (physical property simply mix, cross 80 mesh sieves) of poloxamer by 1: 1,1: 4,1: 10,1: 30,1: 80,1: 150; The III group: Rimonabant and poloxamer are pressed 1: 4,1: 10,1: 30,1: 80,1: 150 solid dispersion.
Dissolution content assaying method: according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol is mobile phase; Flow velocity 1.0ml/min; The detection wavelength is 226nm.Theoretical cam curve is pressed the Rimonabant peak and is calculated, and should be not less than 2500.
Get the about 20mg of testing sample (in Rimonabant), the accurate title, decide, test according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C three therapeutic methods of traditional Chinese medicine), 250ml is a dissolution medium with phosphate buffer (pH6.8), rotating speed is 75 rev/mins, and operation in accordance with the law is when 30 minutes and 60 minutes, get solution 10ml and filter, get subsequent filtrate as need testing solution; Other gets the about 20mg of Rimonabant reference substance, accurate claims surely, puts that to add methanol in the 100ml measuring bottle an amount of, ultrasonic dissolution, add the stripping medium again to scale, shake up, precision is measured 1ml, put and add the stripping medium in the 100ml measuring bottle, shake up, in contrast product solution to scale.Precision is measured each 20 μ l of above-mentioned two kinds of solution and is injected chromatograph of liquid, and the record chromatogram is pressed the stripping quantity that external standard method is calculated, and calculates the dissolution of various specimen.Result such as following table 3.
Table 3
Figure A20071010140200341
II organizes (mixture) 1∶4 62.09 76.73
1∶10 73.66 82.39
1∶30 82.46 89.68
1∶80 89.90 93.54
1∶150 92.30 96.27
III organizes (solid dispersion) 1∶1 81.25 90.10
1∶4 85.53 92.51
1∶10 90.57 97.65
1∶30 94.61 98.93
1∶80 96.98 101.22
1∶150 99.02 100.98
As can be seen from Table 3, in mixed-powder and the solid dispersion, the existence of poloxamer all makes the dissolution of Rimonabant significantly improve, and increases with the poloxamer ratio, dissolution rate is accelerated, and solid dispersion is being better than mixed-powder aspect dissolution and the dissolution rate.
Three. the test of preparation dissolution
Modelling: get Rimonabant, Rimonabant and mixtures of poloxamers (1: 5), Rimonabant and poloxamer solid dispersion (1: 5), make basic adjuvant glue wafer, test respectively, relatively its dissolution with starch.
Sample preparation: respectively with Rimonabant, Rimonabant and mixtures of poloxamers (1: 5), Rimonabant and poloxamer solid dispersion (1: 5) are principal agent, by every capsules is 10mg with the Rimonabant, with the carboxymethyl starch sodium is disintegrating agent (every capsules contains 10mg), make surfactant and chaotropic agent (every capsules contains 5mg) with Tween-80, with the magnesium stearate is lubricant (every capsules contains 3.5mg), with an amount of 50% ethanol is wetting agent, all the other are the filler adjuvant with starch, make the heavy 350mg of every capsules, wet granulation, the granule filling capsule, keep preparation technology identical, each prepares three batches, makes Rimonabant respectively, Rimonabant and mixtures of poloxamers (1: 5), the capsule of Rimonabant and poloxamer solid dispersion (1: 5).
Stripping content assaying method: according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol is mobile phase; Flow velocity 1.0ml/min; The detection wavelength is 226nm.Theoretical cam curve is pressed the Rimonabant peak and is calculated, and should be not less than 2500.
Get the capsule of above-mentioned preparation, test according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C three therapeutic methods of traditional Chinese medicine), 250ml is a dissolution medium with phosphate buffer (pH6.8), rotating speed is that per minute 75 changes, operation in accordance with the law, in the time of 45 minutes, get solution 10ml and filter, get subsequent filtrate as need testing solution; Other gets Rimonabant or the about 20mg of its officinal salt reference substance, accurate claims surely, puts that to add methanol in the 100ml measuring bottle an amount of, ultrasonic dissolution, add the stripping medium again to scale, shake up, precision is measured 1ml, put and add the stripping medium in the 100ml measuring bottle, shake up, in contrast product solution to scale.Precision is measured each 20 μ l of above-mentioned two kinds of solution and is injected chromatograph of liquid, and the record chromatogram is by the stripping quantity of every of external standard method calculating.
The dissolution determination result (meansigma methods) and the relative standard deviation (RSD) of three kinds of capsule samples see the following form.
Dissolution determination result (n=8) table 4
Figure A20071010140200361
Above table 4 measurement result explanation, in mixture capsule and the solid dispersion body capsule, poloxamer all makes the dissolution of Rimonabant from preparation significantly improve (P＜0.001), and the capsular dissolution of solid dispersion is better than the mixture capsule.
The specific embodiment in implementation process of the present invention, various embodiments that those skilled in the art produce on the basis that does not depart from the scope of the present invention with spirit and modify conspicuous and be to carry out easily.Come the present invention done further specifying by the following examples, but do not represent the embodiment limitation of the present invention.
Embodiment 1. contains the tablet (dispersible tablet) and the preparation of Rimonabant and poloxamer
Rimonabant 20g
Poloxamer (188) 100g
Lactose 55g
Carboxymethyl starch sodium 13g (in disintegrating agent)
Crospolyvinylpyrrolidone 7g (adding disintegrating agent)
Sodium lauryl sulphate 1.5g
50% alcoholic solution is an amount of
Magnesium stearate 2g
Preparation method: by above prescription, preceding four kinds of pressed powder mixings are also crossed 80 mesh sieves, be dissolved in the liquid wet granulation of 50% alcoholic solution with sodium lauryl sulphate, the system soft material, 20 mesh sieve granulate, in 44～48 ℃ of dryings, the back adds crospolyvinylpyrrolidone and magnesium stearate mix homogeneously, 20 mesh sieve granulate, tabletting (2.5～3.0kg/cm 2) be made as 1000, every contains active ingredient and counts 20mg with Rimonabant, for orally using.The accumulative total dissolution is 81.78% during its 45min.
In addition, also can adopt conventional packaging technique that the tablet of above-mentioned preparation is carried out Cotton seeds, can obtain the coating diaphragm, for example can adopt the coating solution that contains hydroxypropyl methylcellulose, titanium dioxide, Polyethylene Glycol, Tween-80, iron oxide yellow, iron oxide red, citric acid diethylester and water to carry out Cotton seeds, obtain the coating diaphragm.
Embodiment 2. contains the hard capsule and the preparation of Rimonabant and poloxamer
Rimonabant (hydrochlorate) 10.8g
Poloxamer (407) 58g
Mannitol 55g
Sodium carboxymethyl cellulose 7g
Tween-80 1.5g
3% polyvidone aqueous solution is an amount of
Magnesium stearate 1.2g
Preparation method: by above prescription, preceding four kinds of pressed powder mixings are also crossed 80 mesh sieves, Tween-80 is dissolved in 3% polyvidone aqueous solution wet granulation, the system soft material, granulate is in 50 ℃ of dryings, add the magnesium stearate mix homogeneously, after be filled in 1000 Capsuleses promptly.Every contains active ingredient and counts 10.8mg with the Rimonabant hydrochlorate, for orally using.The accumulative total dissolution is 82.09% during its 45min.
Embodiment 3. contains the hard capsule and the preparation of Rimonabant and poloxamer
Rimonabant 20g
Poloxamer 200g
Stearic acid 2.5g
Preparation method: by above prescription, will preceding two kinds of pressed powders be mixed in fully grind 60min in the mortar after, add stearic acid and mix the back and continue grinding 20min, pulverized 80 mesh sieves, be filled in 1000 Capsuleses (gastric solubleness or enteric) promptly.Every contains active ingredient and counts 20mg with Rimonabant, for orally using.The accumulative total dissolution is 82.70% during its 45min.
Embodiment 4. contains the soft capsule and the preparation of Rimonabant and poloxamer
Rimonabant 10g
Poloxamer 65g
PEG400 (or soybean oil) 300ml
Sodium carboxymethyl cellulose 2.5g
Preparation method 1 (pressing): by above prescription, loose in PEG400 (or soybean oil) above-mentioned all solids powder is molten, fully stirring and evenly mixing (or with homogenizer homogenize processing) makes into heavy-gravity liquid state, with this liquefied mixture is content, be pressed into 1000 soft capsules with ' Yanming ' capsules for clearing material film, every contains active ingredient and counts 10mg with Rimonabant, for orally using.The accumulative total dissolution is 85.32% (PEG400) during its 45min, 82.73% (soybean oil).
(attached: the preparation of capsule material film: get gelatin 550g, add 600～900ml distilled water, under room temperature, stir to quicken to make gelatin expansion post-heating to 55～60 ℃, make its fusion and filter, in filtrate, add 70g PEG400,220g glycerol, 10g glycine, mix homogeneously, decompression outgases to transparent glue solution does not have bubble, and repaste makes thickness even on smooth steel plate, heating makes surface moisture evaporation, is an elasticity, capsule material film that toughness is suitable.)
Preparation method 2 (dropping preparation method): by above prescription, loose in PEG400 (or soybean oil) above-mentioned all solids powder is molten, fully stirring and evenly mixing (or with homogenizer homogenize processing) makes into heavy-gravity liquid state, with this liquefied mixture is the content of making soft capsule, adopts dropping preparation method to be embedded in the ' Yanming ' capsules for clearing material.
Adjust the temperature control system of drop pill machine, make the water dropper temperature heating of drop pill machine and remain on 55～65 ℃, adjust the content of head size with the control soft capsule content, with 10 ℃ liquid paraffin is condensed fluid, adopt dropping preparation method the content embedding to be made with ' Yanming ' capsules for clearing material glue, clean, promptly get spherical soft capsule.
(attached: the preparation of capsule material glue, get gelatin 100g, glycerol 30g, water 130g, get gelatin adding suitable quantity of water it is expanded, the water of glycerol and remainder is put be heated to 70～80 ℃ of mix homogeneously in the glue pot in addition, add expansible gelatin and stir, fusing, be incubated 1～2 hour, leave standstill, remove the foam of come-up, filter heat preservation for standby use with medicinal clean calico.)
Embodiment 5. contains the drop pill and the preparation of Rimonabant and poloxamer
Rimonabant 10g
Poloxamer 280g
Sodium carboxymethyl cellulose 10g
Make 10000 altogether.
Preparation method: by above prescription, poloxamer heating in water bath to 62 ± 2 of getting recipe quantity ℃ are in a liquid state complete fusion, adding recipe quantity Rimonabant and sodium carboxymethyl cellulose and abundant stirring make it molten and loose in fused liquid state, mix liquid, this fused solution is poured in the Materials hopper that drop pill drips the system machine, 62 ± 2 ℃ of insulations, the water dropper of the suitable bore of selection drips makes 10000, splash in 4 ℃ the dimethicone, to be formed after, isolate drop pill, wiped clean, that is, every heavily about 30mg contains the about 1mg of Rimonabant.This drop pill can oral or sublingual administration use.The accumulative total dissolution is 82.27% during its 45min.
Embodiment 6. contains the drop pill and the preparation of Rimonabant and poloxamer
Rimonabant 10g
Poloxamer 75g
Polyethylene glycol 6000 210g
Carboxymethyl starch sodium 15g
Make 10000 altogether.
Preparation method: by above prescription, polyethylene glycol 6000 heating in water bath to 74 ± 1 of getting recipe quantity ℃ makes complete fusion be clear and bright liquid state, adding recipe quantity Rimonabant and poloxamer and abundant stirring make it molten and loose in the polyethylene glycol 6000 of molten state, mix liquid, the carboxymethyl starch sodium that adds recipe quantity again stirs, this fused solution is poured in the Materials hopper that drop pill drips the system machine, 75 ± 3 ℃ of insulations, the water dropper that select to be fit to bore drips makes 10000, splashes in 4 ℃ the dimethicone, after to be formed, isolate drop pill, wiped clean, promptly, every heavily about 31mg contains the about 1mg of Rimonabant.This drop pill can oral or sublingual administration use.The accumulative total dissolution is 81.90% during its 45min.
Embodiment 7. contains the drop pill capsule and the preparation of Rimonabant and poloxamer
Get embodiment 5 or execute 10000 of the drop pill that example 6 makes, divide in 1000 Capsuleses (gastric solubleness or enteric) of packing into promptly, every capsules contains 10 drop pill, promptly get the drop pill capsule that contains Rimonabant and poloxamer, every drop pill capsule contains active ingredient and counts 10mg with Rimonabant, for orally using.
Embodiment 8. contains the pellet and the preparation of Rimonabant and poloxamer
Rimonabant 20g
Poloxamer 150g
Lactose 130g
Pregelatinized Starch 100g
Microcrystalline Cellulose 65g
Carboxymethyl starch sodium 25g
Sodium lauryl sulphate 10g
80% ethanol water is an amount of
Preparation method: sodium lauryl sulphate is dissolved in an amount of 80% ethanol water, does wetting agent, will make soft material behind Rimonabant, poloxamer, lactose, pregelatinized Starch, microcrystalline Cellulose, the carboxymethyl starch sodium pressed powder mixing with this liquid.By extruding-rolling circle equipment system micropill, granulate makes micropill be straight spherical shape through about 0.6mm, promptly obtains containing the pellet of Rimonabant and poloxamer.The accumulative total dissolution is 85.44% during its 45min.
Further, can adopt the hydroxypropyl methylcellulose water slurry to above-mentioned micropill coating, and constantly add Pulvis Talci removing the static that produces when subsequent drying, granulate finally obtains the pellet that contains Rimonabant and poloxamer of isolation coat.
Embodiment 9. contains the pellet and the preparation of Rimonabant and poloxamer
Celphere: sucrose-starch micropill (commercial, 40 orders) 530g
Medicine layer: Rimonabant 20g
Poloxamer 80g
Hydroxypropyl methylcellulose 10g
Tween-80 1g
Smooth-60 1g of fatty acid Pyrusussuriensis
Carboxymethyl starch sodium 8g
Preparation method: with medicine layer recipe quantity with distilled water modulation into about 20% suspension, and fully grinding homogenizes to reduce the suspension particle diameter, at fluidized bed dryer, the suspension that ground is sprayed on the celphere of sucrose-starch micropill, after having applied the medicine layer coating solution of aequum, make it bone dry in fluidized bed dryer, drying can make composition depositions such as Rimonabant and poloxamer be coated on the celphere surface, obtains containing the pellet of Rimonabant and poloxamer.The accumulative total dissolution is 83.48% during its 45min.
Embodiment 10. contains the pellet capsule and the preparation of Rimonabant and poloxamer
(1). get the micropill that embodiment 8 makes, divide in 2000 Capsuleses (gastric solubleness or enteric) of packing into, promptly get the pellet capsule that contains Rimonabant and poloxamer, every pellet capsule contains active ingredient and counts 10mg with Rimonabant, for orally using.
(2). get the micropill that embodiment 9 makes, divide in 1000 Capsuleses (gastric solubleness or enteric) of packing into, promptly get the pellet capsule that contains Rimonabant and poloxamer, every pellet capsule contains active ingredient and counts 20mg with Rimonabant, for orally using.
Embodiment 11. contains the granule and the preparation of Rimonabant and poloxamer
Rimonabant 2g
Poloxamer 15g
Lactose 200g
Icing Sugar 60g
Sodium carboxymethyl cellulose 20g
Sodium lauryl sulphate 3g
Aspartame is an amount of
Water is an amount of
Make 100 bags altogether.
Preparation method: pulverized 80 mesh sieves after the first five of getting recipe quantity planted the abundant mix homogeneously of pressed powder, mixing, sodium lauryl sulphate and aspartame are dissolved in the suitable quantity of water, to above-mentioned mixed-powder system soft material, 16 mesh sieves are granulated, aeration-drying with this solution, 14 mesh sieve granulate, be distributed into 100 bags of aluminum plastic film bag packings, promptly get the granule that contains Rimonabant and poloxamer, every bag contains Rimonabant 20mg (the taste band is sweet).The accumulative total dissolution is 83.66% during its 45min.
Embodiment 12. contains the dry suspension and the preparation of Rimonabant and poloxamer
Rimonabant 2g
Poloxamer 10g
Hydroxypropyl emthylcellulose 4g (suspending agent)
Lactose 20g
Mannitol 40
Icing Sugar 100g
Sodium stearyl sulfate 2g
Flavoring orange essence is an amount of
Make 100 bags altogether.
Preparation method: the above-mentioned pressed powder of getting recipe quantity is dry respectively, to reduce the water content in the solid powder, put the mixer moderate and increase progressively mix homogeneously, cross 200 mesh sieves, with 18 mesh sieve dry granulations, put 45 ℃ of baking oven drying under reduced pressure, spray wine flavoring orange essence, behind granulate, be distributed into 100 bags of aluminum plastic film bag packings, promptly get every bag of dry suspension (sweet Fructus Citri tangerinae taste) that contains Rimonabant 20mg.The accumulative total dissolution is 88.99% during its 45min.
Embodiment 13. contains the oral fluid agent and the preparation of Rimonabant and poloxamer
Rimonabant 0.2g
Poloxamer 4.5g
Hydroxypropyl cellulose 2.8g
Sodium lauryl sulphate 1g
Citric acid/sodium citrate an amount of (pH buffer agent)
Steviosin is an amount of
Water adds to 100ml
Preparation method: loose in 90ml water above-mentioned recipe quantity material is molten, homogenizer homogenizing 2 times is transferred pH=6, after add water to 100ml, promptly get the oral fluid agent that contains Rimonabant and poloxamer, sour-sweet taste, containing the Rimonabant amount is 2mg/ml.The accumulative total dissolution is 95.67% during its 45min.
The solid dispersion (1: 5) of embodiment 14. Rimonabants and poloxamer and preparation
Getting 5g poloxamer (407) heating in water bath makes it be fused liquid state for 65 ℃, add the 1g Rimonabant, make mix homogeneously in 62～66 ℃ of abundant stirrings, put refrigerator and make curing in-5 ℃, pulverize, and put 35 ℃ of dry 24h in the vacuum desiccator, and pulverized 80 mesh sieves, promptly get the solid dispersion (1: 5) of Rimonabant and poloxamer.The accumulative total dissolution is 87.56% during its 45min.
The solid dispersion (1: 3) of embodiment 15. Rimonabants and poloxamer and preparation
Getting 1g Rimonabant and 3g poloxamer is dissolved in 68ml, 40 ℃ the methanol of heating in water bath, reduction vaporization reclaims methanol on Rotary Evaporators, collects solids, vacuum drying 12h, room temperature is pulverized (crossing 100 mesh sieves), promptly gets the solid dispersion (1: 3) of Rimonabant and poloxamer.The accumulative total dissolution is 82.98% during its 45min.
The solid dispersion and the preparation of embodiment 16. Rimonabants and poloxamer
Similarly, press the foregoing description 14 preparation methoies, the mass ratio that can make Rimonabant and poloxamer is 1: 12,1: 15,1: 20,1: 25,1: 100,1: 180 a solid dispersion, the white powder solid.
Similarly, press the foregoing description 15 preparation methoies, the mass ratio that dissolves Rimonabant and poloxamer in an amount of ethanol respectively is 1: 0.5,1: 0.8,1: 1,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10 a solids, 45 ℃ of heating in water bath reduction vaporizations reclaim ethanol on Rotary Evaporators, collect solids, vacuum drying is to constant weight, room temperature is pulverized (crossing 80～100 mesh sieves), promptly get the Rimonabant of various different proportionings and the solid dispersion of poloxamer, the white powder solid.
The solid dispersion (1: 20) of embodiment 17. Rimonabants and poloxamer and preparation
Get the 1g Rimonabant be dissolved in methanol-ethanol (V: V=1: 1) 50ml in the solution, add the 20g poloxamer in 60 ℃ molten state liquid, fully stir, decompression makes methanol-ethanol evaporation Ex-all, after-10 ℃ of coolings are solidified it, pulverizes, and promptly obtains solid dispersion.The accumulative total dissolution is 93.38% during its 45min.
The solid dispersion (1: 10) of embodiment 18. Rimonabants and poloxamer and preparation
Get 1g Rimonabant and 10g poloxamer, put in the mortar, mixed liquor (the V: V=1: 1), make pastel, grind 30mim that adds 15 methanol and acetone, drying under reduced pressure is removed liquid, collect solids, oven for drying is pulverized to constant weight, promptly get the solid dispersion (1: 10) of Rimonabant and poloxamer, powder solid is white in color.The accumulative total dissolution is 89.17% during its 45min.
The solid dispersion (1: 6) of embodiment 19. Rimonabants and poloxamer and preparation
Get 10g Rimonabant and 60g poloxamer, behind dissolve with methanol, spray drying is removed methanol, gets powder of solid particles, pulverizes, promptly.
The solid dispersion (1: 4) of embodiment 20. Rimonabant mesylates and poloxamer and preparation
Get 10g Rimonabant mesylate and 40g poloxamer, behind dissolve with ethanol, the fluidized bed granulation drying gets solid particle, pulverizes, promptly.
The solid dispersion (1: 30) of embodiment 21. Rimonabants and poloxamer and preparation
Get 10g Rimonabant and 300g poloxamer, pulverize separately is crossed 200 mesh sieves, grinds 40min behind the mixing in mortar, scrapes the material of getting after the grinding, and vacuum drying 48h pulverizes, and crosses 200 mesh sieves, promptly.The accumulative total dissolution is 94.80% during its 45min.
Embodiment 22. contains the tablet and the preparation of Rimonabant and poloxamer solid dispersion
Rimonabant/poloxamer solid dispersion (1: 4) 100g
Mannitol 60g
Microcrystalline Cellulose 45g
Carboxymethyl starch sodium 13g (in disintegrating agent)
Sodium lauryl sulphate 2g
80% alcoholic solution is an amount of
Pregelatinized Starch 10g (adding disintegrating agent)
Magnesium stearate 2g
Preparation method: by above prescription, preceding four kinds of pressed powder mixings are also crossed 80 mesh sieves, be dissolved in the liquid wet granulation of 80% alcoholic solution with sodium lauryl sulphate, the system soft material, 20 mesh sieve granulate, in 40 ℃ of dryings, the back adds pregelatinized Starch and magnesium stearate mix homogeneously, 20 mesh sieve granulate, tabletting (3.0kg/cm 2) be made as 1000, every contains active ingredient and counts 20mg with Rimonabant, for orally using.The accumulative total dissolution is 90.33% during its 45min.
In addition, also can adopt conventional packaging technique that the tablet of above-mentioned preparation is carried out coating (gastric solubleness film-coat or enteric coating) and handle, can obtain the coating diaphragm.
Embodiment 23. contains the capsule and the preparation of Rimonabant and poloxamer solid dispersion (1: 6)
Rimonabant mesylate/poloxamer solid dispersion (1: 6) 140g
Magnesium stearate 1.5g
By above prescription, two kinds of solids are put in the mixer, to be filled into behind the equivalent incremental manner mix homogeneously in 1000 Capsuleses (gastric solubleness or enteric) promptly.Every contains active ingredient and counts 20mg with the Rimonabant mesylate, for orally using.
Embodiment 24. contains the soft capsule and the preparation of Rimonabant and poloxamer solid dispersion (1: 2)
Rimonabant/poloxamer solid dispersion (1: 2) 30g
PEG400 210g
Glycerol 5g
Carboxymethyl starch sodium 5g
Make 1000 altogether.
Preparation method: get Rimonabant/poloxamer solid dispersion (1: 2), PEG400 and the propylene glycol heating in water bath to 42 ℃ of recipe quantity and stir and make dissolving fully, obtain adding carboxymethyl starch sodium behind the clear and bright solution, dissolving stirs, stand-by, this clear and bright solution will be added to as the content of soft capsule in the continuously automatic soft capsule production machine of punching type, select appropriate mould model, adopt pressing to be embedded in the ' Yanming ' capsules for clearing material film, 1000 soft capsules are made in mold pressing, every contains Rimonabant 10mg, for orally using.The accumulative total dissolution is 94.23% during its 45min.(also can adopt the dropping preparation method preparation)
(attached: the preparation of capsule material film, get gelatin 500g, arabic gum 80g, add 600～900ml distilled water, under room temperature, stir to quicken to make gelatin expansion post-heating to 55～60 ℃, make its fusion and filter, in filtrate, add 75g PEG400,370g glycerol, 10g glycine, mix homogeneously, decompression outgases to transparent glue solution does not have bubble, and repaste makes thickness even on smooth steel plate, heating makes surface moisture evaporation, is an elasticity, capsule material film that toughness is suitable.)
Embodiment 25. contains the drop pill and the preparation of Rimonabant and poloxamer solid dispersion (1: 30)
Rimonabant/poloxamer solid dispersion (1: 25) 260g
Sodium lauryl sulphate 2g
Make 10000 altogether.
Preparation method: get Rimonabant/poloxamer solid dispersion (1: the 30) heating in water bath to 58 of recipe quantity～62 ℃ complete fusion is in a liquid state, add the recipe quantity sodium lauryl sulphate and fully stir and make molten loosing in fused solution, stir, this fused solution is poured in the Materials hopper that drop pill drips the system machine, 62 ℃ of insulations, the water dropper of the suitable bore of selection drips makes 10000, splash in 4 ℃ the dimethicone, after to be formed, isolate drop pill, wiped clean, promptly, every heavily about 26mg contains the about 1mg of Rimonabant.This drop pill can oral or sublingual administration use.The accumulative total dissolution is 88.91% during its 45min.
Embodiment 26. contains the drop pill and the preparation of Rimonabant and poloxamer solid dispersion (1: 3)
Rimonabant/poloxamer solid dispersion (1: 3) 20g
Polyethylene glycol 6000 220g
Cetomacrogol 1000 0 50g
Sodium carboxymethyl cellulose 10g
Make 10000 altogether.
Preparation method: get the polyethylene glycol 6000 of recipe quantity and cetomacrogol 1000 0 heating in water bath to 73 and ℃ make complete fusion be clear and bright liquid state, add recipe quantity Rimonabant/poloxamer solid dispersion (1: 3) and fully stir and make molten loosing in the mixture of liquid state, be half clear and bright mixed liquor, the sodium carboxymethyl cellulose that adds recipe quantity again, stir, this fused solution is poured in the Materials hopper that drop pill drips the system machine, 75 ± 3 ℃ of insulations, the water dropper that select to be fit to bore drips makes 10000, splashes in 4 ℃ the dimethicone, after to be formed, isolate drop pill, wiped clean, promptly, every heavily about 30mg contains the about 0.5mg of Rimonabant.This drop pill can oral or sublingual administration use.The accumulative total dissolution is 92.44% during its 45min.
Embodiment 27. contains the drop pill capsule and the preparation of Rimonabant and poloxamer solid dispersion
Get 10000 of the drop pill that embodiment 25 or embodiment 26 make, divide in 500 Capsuleses (gastric solubleness or enteric) of packing into promptly, every capsules contains 20 drop pill, promptly get the drop pill capsule of Rimonabant and poloxamer solid dispersion, every drop pill capsule contains active ingredient and counts 20mg or 10mg with Rimonabant, for orally using.
Embodiment 28. contains the micropill and the preparation of Rimonabant and poloxamer solid dispersion (1: 2)
Rimonabant/poloxamer solid dispersion (1: 2) 60g
Lactose 250g
Cane sugar powder 70g
Hydroxypropyl emthylcellulose 10g (binding agent)
Cross-linking sodium carboxymethyl cellulose 10g
80% ethanol water is an amount of
Preparation method: by above prescription, the first five is planted the pressed powder mixing and crosses 80 mesh sieves, with 80% alcoholic solution wet granulation, the system soft material, by extruding-rolling circle equipment system micropill, granulate makes micropill be straight spherical shape through about 0.6mm, promptly obtains containing the micropill of Rimonabant and poloxamer solid dispersion (1: 2).The accumulative total dissolution is 84.80% during its 45min.
Further, can adopt the hydroxypropyl methylcellulose water slurry to above-mentioned micropill coating, and constantly add Pulvis Talci removing the static that produces when subsequent drying, granulate finally obtains the pellet of isolation coat.
Embodiment 29. contains the pellet capsule and the preparation of Rimonabant and poloxamer solid dispersion (1: 2)
Get the micropill that embodiment 28 makes, divide in 1000 Capsuleses (gastric solubleness or enteric) of packing into, promptly get the pellet capsule that contains Rimonabant and poloxamer solid dispersion (1: 2), every pellet capsule contains active ingredient and counts 20mg with Rimonabant, for orally using.
Embodiment 30. contains the granule and the preparation of Rimonabant and poloxamer solid dispersion (1: 20)
Rimonabant/poloxamer solid dispersion (1: 20) 42g
Mannitol 80g
Icing Sugar 30g
Carboxymethyl starch sodium-starch (2: 8) 48g
Sodium lauryl sulphate 2.5g
Steviosin is an amount of
Flavoring orange essence is an amount of
30% alcoholic solution is an amount of
Make 100 bags altogether.
Preparation method 1: the first five of getting recipe quantity planted and to be pulverized 80 mesh sieves after pressed powder equivalent increases progressively mix homogeneously, mixing, steviosin and flavoring orange essence are dissolved in an amount of 30% alcoholic solution, to above-mentioned mixed-powder system soft material, 16 mesh sieves are granulated, aeration-drying with this solution, 14 mesh sieve granulate, be distributed into 100 bags of aluminum plastic film bag packings, promptly contain the granule of Rimonabant and poloxamer solid dispersion (1: 20), every bag contains Rimonabant 20mg (sweet Fructus Citri tangerinae taste).The accumulative total dissolution is 95.11% during its 45min.
Preparation method 2: the first five of getting recipe quantity planted and to be pulverized 80 mesh sieves after pressed powder equivalent increases progressively mix homogeneously, mixing, steviosin and flavoring orange essence are dissolved in the wetting agent of making wet granulation in an amount of 30% alcoholic solution, with boiling granulating fluidized bed granulation (operational factor: 35～44 ℃ of temperature of charge, spray pressure 〉=3.8bar, spray fast 0.5kg/min, 60 ℃ of inlet temperature, leaving air temp≤35 ℃.), granulate is distributed into 100 bags of aluminum plastic film bag packings, promptly contains the granule of Rimonabant and poloxamer solid dispersion (1: 19), and every bag contains Rimonabant 20mg (sweet Fructus Citri tangerinae taste).
Embodiment 31. contains the dry suspension and the preparation of Rimonabant and poloxamer solid dispersion (1: 4)
Rimonabant/poloxamer solid dispersion (1: 4) 10g
Lactose 20g
Mannitol 35g
Icing Sugar 60g
Hydroxypropyl emthylcellulose 5g (suspending agent)
Flavoring orange essence is an amount of
Dehydrated alcohol is an amount of
Make 100 bags altogether.
Preparation method 1: it is dry respectively that the first five of side's amount planted pressed powder, to reduce the water content in the solid powder, get Rimonabant/poloxamer solid dispersion, hydroxypropyl emthylcellulose is dissolved in an amount of dehydrated alcohol, add lactose, mannitol, Icing Sugar, cross 18 mesh sieves and granulate, put in 45 ℃ of baking ovens dry, spray wine flavoring orange essence, granulate is distributed into 100 bags of aluminum plastic film bag packings, promptly gets every bag of dry suspension (sweet Fructus Citri tangerinae taste) that contains Rimonabant 20mg.
Preparation method 2: the above-mentioned pressed powder of recipe quantity is dry respectively, to reduce the water content in the solid powder, put the mixer moderate and increase progressively mix homogeneously, cross 200 mesh sieves, with 18 mesh sieve dry granulations, put 45 ℃ of oven dryings, spray wine flavoring orange essence and alcoholic acid solution, behind granulate, be distributed into 100 bags of aluminum plastic film bag packings, promptly get every bag of dry suspension (sweet Fructus Citri tangerinae taste) that contains Rimonabant 20mg.The accumulative total dissolution is 95.10% during its 45min.
Embodiment 32. contains the oral fluid agent and the preparation of Rimonabant and poloxamer solid dispersion (1: 8)
Rimonabant/poloxamer solid dispersion (1: 8) 1.8g
Hydroxypropyl cellulose 2.8g
Fructose 10g
Sodium lauryl sulphate 1g
Sodium benzoate 0.4g
Potassium dihydrogen phosphate/sodium hydrogen phosphate an amount of (pH buffer agent)
Steviosin is an amount of
Water adds to 100ml
Preparation method: loose in 80ml water above-mentioned material is molten, stir, add water to 100ml, fully stir and homogenizing, promptly get the oral administration mixed suspension that contains Rimonabant and poloxamer solid dispersion (1: 3).The accumulative total dissolution is 97.18% during its 45min.
Embodiment 33. contains the powder ampoule agent for injection and the preparation of Rimonabant and poloxamer solid dispersion (1: 4)
Rimonabant/poloxamer (188) solid dispersion (1: 4) 5g
Mannitol 150g
Sodium lauryl sulphate 1g
Acid dihydride potassium/sodium hydrogen phosphate an amount of (pH buffer agent)
Preparation method: solid dispersion, mannitol and the sodium lauryl sulphate of getting above-mentioned recipe quantity, add the dissolving of injection water and be diluted to 1800 milliliters, regulate pH with phosphate buffer and add injection water to 2000 milliliter after 6.5, fine straining, divide in fill to the 1000 bottle cillin bottle, carry out lyophilization (pre-freeze, freezing, drying under reduced pressure, normal temperature drying, jump a queue, gland packing etc.) by lyophilized injectable powder preparation technology, can be prepared into 1000 bottles of freeze-dried powder injections, every bottle contains Rimonabant 1mg, uses for injection.
The solid dispersion and the preparation of embodiment 34. Rimonabants and poloxamer and carboxymethyl starch sodium
Rimonabant 2
Poloxamer 10g
Carboxymethyl starch sodium 2g
Preparation method: get Rimonabant and poloxamer and be dissolved in 80ml, 40 ℃ the ethanol of heating in water bath, add carboxymethyl starch sodium, behind the stirring and evenly mixing on Rotary Evaporators reduction vaporization reclaim ethanol, collect solids, vacuum drying 12h, pulverize (crossing 100 mesh sieves), promptly get the solid dispersion of Rimonabant and poloxamer and carboxymethyl starch sodium.The accumulative total dissolution is 92.88% during its 45min.
Solid dispersion and the preparation of embodiment 35. Rimonabants and poloxamer and PEG6000
Rimonabant 2
Poloxamer 10g
PEG6000 3g
Preparation method 1: three kinds of materials getting above-mentioned recipe quantity are dissolved in the 150ml dehydrated alcohol, remove under reduced pressure after stirring and reclaim ethanol and obtain semisolid, put semisolid 24h in the vacuum constant temperature drying baker, take out after the embrittlement and pulverize, cross 80 mesh sieves, promptly get the solid dispersion of Rimonabant and poloxamer and PEG6000.The accumulative total dissolution is 96.43% during its 45min.
Preparation method 2: get the poloxamer of above-mentioned recipe quantity and PEG6000 and mix back heating in water bath to 57 and ℃ make its complete fusion, stir, add the Rimonabant of recipe quantity again, make molten loosing in the mixture of liquid state, be half clear and bright mixed liquor, fully mix, reduce to room temperature, pulverize, 24h in the vacuum constant temperature drying baker, take out after the embrittlement and pulverize, cross 80 mesh sieves, promptly get the solid dispersion of Rimonabant and poloxamer and PEG6000.
The solid dispersion and the preparation of embodiment 36. Rimonabants and poloxamer and microcrystalline Cellulose
Rimonabant 2
Poloxamer 200g
Microcrystalline Cellulose 8g
Preparation method: get above-mentioned material mixing, add 50% methanol-water solution 950ml, grind 30min, 50 ℃ of pressure reducing and steaming solvents are collected solids, vacuum drying 12h, be cooled to 0 ℃ of pulverizing (crossing 100 mesh sieves), promptly get the solid dispersion of Rimonabant and poloxamer and microcrystalline Cellulose.The accumulative total dissolution is 91.29% during its 45min.
The solid dispersion and the preparation of embodiment 37. Rimonabants and poloxamer and mannitol
Rimonabant 2
Poloxamer 2g
Mannitol 46g
Preparation method: get above-mentioned three kinds of pressed powders and add in the 250ml methanol, fully stir and make its dissolving (optionally can heat or supersound process is dissolved fully to impel it), 47 ℃ remove and reclaim methanol under reduced pressure, collect solids, vacuum drying 12h, be cooled to-4 ℃, pulverize (crossing 80 mesh sieves), promptly get the solid dispersion of Rimonabant and poloxamer and mannitol.The accumulative total dissolution is 95.53% during its 45min.
Embodiment 38.
Get the prepared solid dispersion of embodiment 34, embodiment 35, embodiment 36, embodiment 37 respectively, as principal agent, select suitable pharmaceutic adjuvant for use, adopt appropriate preparation technology, mix with pharmaceutic adjuvant and be prepared into and disperse sheet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, hard capsule, soft capsule, micropill, granule, dry suspension, powder, for orally using.
Embodiment 39. contains the granule and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Rimonabant 2g
Poloxamer 78g
Mannitol 30g
Lactose 40g
Crospolyvinylpyrrolidone 5g (disintegrating agent)
Dehydrated alcohol is an amount of
Preparation method: recipe quantity Rimonabant and poloxamer are dissolved in dehydrated alcohol, with this solution as wetting agent, with the abundant mixing of the pressed powder of mannitol, lactose and crospolyvinylpyrrolidone, with alcoholic solution as wetting agent, the system soft material, 16 mesh sieve wet granulations, drying, 14 mesh sieve granulate, be distributed into 100 bags of aluminum plastic film bag packings, promptly get the granule of the solid dispersion that contains Rimonabant and poloxamer and other pharmaceutical carrier, every bag contains Rimonabant 20mg, for orally using.The accumulative total dissolution is 100.21% during its 45min.
Embodiment 40. contains the tablet and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Get the granule of embodiment 39 preparations, add the 1.5g stearic acid and make lubricant, even with above-mentioned mixing of materials, tabletting is made 200, promptly get the tablet of the solid dispersion that contains Rimonabant and poloxamer and other pharmaceutical carrier, every contains Rimonabant 10mg, for orally using.
Embodiment 41. contains the dry suspension and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Rimonabant 2g
Poloxamer 10g
Xylitol 55g
Sucrose 30g
Xanthan gum 5g (suspending agent)
Sodium hexadecyl sulfate 0.5g
50% ethanol is an amount of
Make 100 bags
Preparation method: the pressed powder of above-mentioned recipe quantity is scattered in 50% alcoholic solution, make into suspension, after homogenizing stirs 30min, with this suspension spray drying, obtain dried powder, pulverized 18 mesh sieves, promptly obtain containing the dry suspension of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier, be distributed into 100 bags of aluminum plastic film bag packings, promptly get the dry suspension of the solid dispersion that contains Rimonabant and poloxamer and other pharmaceutical carrier, every bag contains Rimonabant 20mg, for orally using.The accumulative total dissolution is 94.09% during its 45min.
Embodiment 42. contains the hard capsule and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Get the dry suspension of embodiment 41 preparations, add 1g magnesium stearate mix homogeneously, in fill to 100 empty gelatin capsule, promptly get the capsule of the solid dispersion that contains Rimonabant and poloxamer and other pharmaceutical carrier, every contains Rimonabant 20mg.
Embodiment 43. contains the soft capsule and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Prescription: Rimonabant 5g
Poloxamer 10g
Sodium carboxymethyl cellulose 5g
Tween-80 1.5ml
Soybean oil 300ml
Make 1000 altogether.
Preparation method: with molten the loosing of preceding four kinds of materials of above-mentioned recipe quantity in soybean oil, processing stirs and homogenizes, obtain heavy-gravity liquefied mixture, with the content of this liquefied mixture, as soft capsule material, produce machine with the continuously automatic soft capsule of punching type with the gelatin film as soft capsule, select appropriate mould model, 1000 soft capsules are made in mold pressing, and every contains Rimonabant 5mg, for orally using.The accumulative total dissolution is 89.58% during its 45min.
Embodiment 44. contains the drop pill and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Rimonabant (hydrochlorate) 12g
Poloxamer 50g
Carboxymethyl starch sodium 26g
Macrogol 4000 50g
Polyethylene glycol 6000 180g
Make 1000 altogether.
Preparation method: taking polyethylene glycol 4000, the polyethylene glycol 6000 recipe quantity, heating in water bath to 73 ℃ makes complete fusion be clear and bright liquid state, add the recipe quantity Rimonabant Hydrochloride, the mixed melting liquid state that poloxamer and carboxymethyl starch sodium and abundant stirring and evenly mixing are translucent, this fused solution is poured in the Materials hopper that drop pill drips the system machine, 73 ± 3 ℃ of insulations, the water dropper of the suitable bore of selection drips and is made as 10000, splash in-5 ℃ the dimethicone, after to be formed, isolate drop pill, wiped clean, the drop pill agent that promptly gets the solid dispersion that contains Rimonabant and poloxamer and other pharmaceutical carrier is for orally using.The accumulative total dissolution is 90.98% during its 45min.
Optionally the drop pill that makes can be packed into obtains the drop pill capsule in 1000 capsulae vacuuses, so that orally use.
Embodiment 45. contains the micropill and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Rimonabant maleate 20g
Poloxamer 85g
Low-substituted hydroxypropyl cellulose 5g
Microcrystalline Cellulose 60g
Pregelatinized Starch 90g
Tween-80 5g
Dehydrated alcohol is an amount of
Preparation method: with the first five of above-mentioned recipe quantity plant mixing of materials evenly after, loose in dehydrated alcohol with Polysorbate is molten, stir, remove the soft material that the appropriate amount solvent makes becomes modest viscosity, by extruding-rolling circle equipment system micropill granulate, dry, make micropill directly through about 0.5mm, promptly obtain containing the micropill of the solid dispersion of Rimonabant maleate and poloxamer and other pharmaceutical carrier, for orally using.The accumulative total dissolution is 95.33% during its 45min.
Embodiment 46. contains the micropill and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Medicine layer: Rimonabant 20g
Poloxamer 90g
Lactose 90g
Sodium lauryl sulphate 2g
Hydroxypropyl methylcellulose 5g (bonding agent)
Celphere: sucrose-starch micropill (commercial, 35 to 40 orders) 100g
Sealing coat: hydroxypropyl methylcellulose 10g
Sucrose 5g
(superfine talcum powder 10g)
Preparation method: with medicine layer recipe quantity with 50% ethanol modulation into about 30% suspension, and fully grinding homogenizes to reduce the suspension particle diameter, obtain medicine layer coating solution, at fluidized bed dryer, the suspension that ground is sprayed on the celphere of sucrose-starch micropill, after having applied the medicine layer coating solution of aequum, in fluidized bed dryer, make it bone dry, obtain containing the ball core of Rimonabant.
With the sealing coat recipe quantity with distilled water modulation into about 25% suspension, and after fully grinding homogenizes, at fluidized bed dryer, the sealing coat suspension is coated on the ball core that contains Rimonabant, after having applied the sealing coat suspension of aequum,, promptly obtain containing the micropill of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier with micropill bone dry in fluidized bed dryer, for orally using the about 0.8mm of above micropill particle diameter.The accumulative total dissolution is 94.87% during its 45min.(optionally, micropill can be added a small amount of Pulvis Talci during bone dry to reduce electrostatic charge in fluidized bed dryer, prevent that micropill from assembling agglomerating.)
Embodiment 47. contains the pellet capsule and the preparation of the solid dispersion of Rimonabant and poloxamer and other pharmaceutical carrier
Get the micropill that embodiment 46, embodiment 45 make respectively, divide in 1000 Capsuleses (gastric solubleness or enteric) of packing into, promptly get the pellet capsule (gastric solubleness or enteric) of the solid dispersion that contains Rimonabant (or its maleate) and poloxamer and other pharmaceutical carrier, every pellet capsule contains Rimonabant (or its maleate) 20mg, for orally using.

Claims (16)

1. pharmaceutical composition that contains Rimonabant and poloxamer, the quality ratio range that it is characterized in that Rimonabant and poloxamer is 1: (1～200), optionally can also optionally contain other suitable pharmaceutical carrier, and described pharmaceutical composition can be any pharmaceutical dosage form of acceptable on the pharmaceutics, is preferably tablet, hard capsule, soft capsule, drop pill, pellet, granule, dry suspension, powder, oral fluid agent, injection.
2. pharmaceutical composition according to claim 1, the quality ratio range of Mo Naban and poloxamer is 1: (2～190);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～180);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (4～150);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (5～120);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (6～100);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (7～90);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (8～80);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (9～70);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (10～60);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (11～50);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (12～40);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2.5～30);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～20).
3. the method for preparing claim 1 or 2 any described pharmaceutical compositions, it comprises Rimonabant, poloxamer and suitable pharmaceutical carrier fully is mixed and made into any pharmaceutical dosage form of acceptable on the pharmaceutics that preferred pharmaceutical dosage form is tablet, hard capsule, soft capsule, drop pill, pellet, granule, dry suspension, powder, oral fluid agent, injection.
4. prepare the method for claim 1 or 2 any described pharmaceutical compositions, it comprises:
By with Rimonabant, obtain granule or dry suspension after adopting wet granulation or dry granulation behind poloxamer and the suitable pharmaceutical carrier mix homogeneously, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By with Rimonabant, obtain dry suspension or powder behind poloxamer and the suitable pharmaceutical carrier mix homogeneously, optionally can further will obtain hard capsule in dry suspension or the powder fill Capsules shell, or mix homogeneously gets granule behind wet granulation or the dry granulation, to obtain hard capsule in the granule fill Capsules shell, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By with Rimonabant and poloxamer melting mixing evenly after, splash in the not miscible condensed fluid, shrink condensation and make drop pill, optionally drop pill can contain but be not limited to following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, can contain but be not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with Rimonabant, after poloxamer and the pharmaceutical carrier melting mixing that suits are even, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, Polyethylene Glycol 8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, polyoxyethylene stearate (40) ester, glyceryl monostearate, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with Rimonabant, drip to make to seal with soft capsule material compacting of gelatin or capsule material glue behind poloxamer and the suitable pharmaceutical carrier mix homogeneously and obtain soft capsule, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: Liquid Macrogol, PEG400, Macrogol 600, soybean oil, Semen Maydis oil, other vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described " soft capsule material compacting or the capsule material glue system of dripping are sealed " is meant and adopts pressing or dropping preparation method to prepare soft capsule, pressing is meant that the liquid or soft plastic state content that adopts press will contain Rimonabant and poloxamer wraps up formation preparation of soft capsule method with the compacting of capsule material film, can be pressed into different shapes and content content with different moulds, dropping preparation method is meant the method that is equipped with soft capsule by a making mechanism, more than 45 ℃, it is biphase utilizing capsule material glue and liquid content, after making a certain amount of capsule material glue with quantitative liquid content parcel, splash in the another kind of not miscible condensed fluid, behind the capsule material glue condensation by contact liquid, solidify the spherical soft capsule of formation in surface tension effects, described condensed fluid is selected from liquid paraffin, methyl-silicone oil, vegetable oil, in the kerosene any one; Or
By with Rimonabant, behind poloxamer and the suitable pharmaceutical carrier mix homogeneously, make the solid preparation of spherical or near-spherical, perhaps with Rimonabant, dissolving or molten being dispersed in the liquid medium behind poloxamer and the suitable pharmaceutical carrier mix homogeneously, and its deposition is coated on the surface of celphere and forms micropill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains pellet capsule in the capsulae vacuus of optionally can further micropill being packed into; Or
By Rimonabant, poloxamer and suitable pharmaceutical carrier and water or aqueous liquid mixing are evenly formed oral administration solution or suspension; Or
By with Rimonabant, poloxamer and suitable pharmaceutical carrier mix homogeneously, can obtain injection by the injection preparation method, wherein pharmaceutical carrier includes but not limited to the following material as filler or excipient: water, mannitol, sorbitol, lactose, xylitol, fructose, dextran, glucose, sodium chloride includes but not limited to the following material as surfactant: sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth).
Optionally, can also add other suitable pharmaceutic adjuvant in the above-mentioned preparation method.
5. a Rimonabant solid dispersion is characterized in that containing Rimonabant and poloxamer, and the quality ratio range of Rimonabant and poloxamer is 1: (0.5～200).
6. the described solid dispersion of claim 5, wherein the quality ratio range of Mo Naban and poloxamer is 1: (1～190);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2～180);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～170);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (4～160);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (5～150);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (6～140);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (7～120);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (8～100);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (9～80);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (10～60);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (0.5～60);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (0.5～35);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (1～30);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2～25);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～20).
7. prepare the method for claim 5 or 6 any described solid dispersion, it comprises:
After poloxamer is heated to complete fusion, add Rimonabant, mix, cooling is pulverized, and promptly obtains solid dispersion; Or
Rimonabant and poloxamer are dissolved or dispersed in the solvent, from this mixture, remove behind the mix homogeneously and desolvate, and dry and pulverize and obtain solid dispersion, wherein said solvent is selected from one or more in methanol, ethanol, isopropyl alcohol, acetone, chloroform, the water.In above-mentioned preparation, remove and to desolvate and exsiccant method can be taked to remove under reduced pressure, in the drying under reduced pressure, vacuum drying, lyophilization, spray drying, fluidized bed granulation drying, heating, drying one or more.
8. prepare the method for claim 5 or 6 any described solid dispersion, it comprises:
(1) poloxamer is added Rimonabant in 50～80 ℃ after being heated to complete fusion, mix, after cooling is solidified it, pulverize, promptly obtain solid dispersion, wherein said chilling temperature is below 25 ℃, preferred below 0 ℃ (as-5 ℃ ,-10 ℃ ,-15 ℃ ,-18 ℃ ,-20 ℃ ,-25 ℃ ,-30 ℃ or the like), optionally can further solid dispersion drying under reduced pressure (comprising vacuum drying) be beneficial to pulverize and preserve; Or
(2) with Rimonabant with poloxamer is dissolved in methanol or/and ethanol, stir the back except that desolvating and drying, pulverize, promptly get the solid dispersion of Rimonabant and poloxamer, wherein said remove desolvate and drying can adopt remove under reduced pressure, drying under reduced pressure, vacuum drying, spray drying, lyophilization, fluidized bed granulation drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
(3) Rimonabant is dissolved in methanol or/and in the ethanol, add poloxamer in 50～80 ℃ molten state liquid, fully stir and make methanol or/and the ethanol evaporation Ex-all, after cooling is solidified it, pulverize, promptly obtain solid dispersion, wherein said chilling temperature is below 25 ℃, preferred below 0 ℃ (as-5 ℃ ,-10 ℃ ,-15 ℃ ,-18 ℃ ,-20 ℃ ,-25 ℃ ,-30 ℃ or the like), optionally can further solid dispersion drying under reduced pressure (comprising vacuum drying) be beneficial to pulverize and preserve;
(4) Rimonabant and poloxamer are made pastel with suitable liquid, pastel is ground, further remove and desolvate and drying, pulverize, promptly get the solid dispersion of Rimonabant and poloxamer, wherein said liquid is selected from one or more in methanol, ethanol, isopropyl alcohol, acetone, chloroform, the water, wherein said remove desolvate and drying can adopt remove under reduced pressure, drying under reduced pressure, vacuum drying, spray drying, lyophilization, fluidized bed granulation drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
(5) will fully grind behind the Rimonabant of the above granularity of 80 orders and the poloxamer mix homogeneously, promptly get the solid dispersion of Rimonabant and poloxamer, the preferred size size is more than 100 orders, and most preferably granule size is more than 200 orders.
9. claim 5 or 6 any described solid dispersion contain application in the pharmaceutical preparation of Rimonabant in preparation, the application in the medicine of preparation treatment and cannabinoid CB 1 receptor diseases associated.
10. a pharmaceutical composition contains claim 5 or 6 any described solid dispersion and pharmaceutically suitable carrier, and wherein in unit formulation, the content of the Rimonabant that solid dispersion provided of Rimonabant and poloxamer is 1mg～100mg;
The content of preferred Rimonabant is 2.5mg～60mg;
The content of preferred Rimonabant is 5mg～40mg;
The content of preferred Rimonabant is 10mg～35mg;
The content of preferred Rimonabant is 20mg.
11. prepare the method for the described pharmaceutical composition of claim 10, it comprises the solid dispersion of Rimonabant and poloxamer and pharmaceutically acceptable, suitable pharmaceutical carrier fully is mixed and made into acceptable any pharmaceutical dosage form on the pharmaceutics that preferred pharmaceutical dosage form is tablet, hard capsule, soft capsule, drop pill, pellet, granule, dry suspension, powder, oral fluid agent, injection.
12. prepare the method for the described pharmaceutical composition of claim 10, it comprises:
By adopting wet granulation or dry granulation to obtain granule or dry suspension behind the solid dispersion of Rimonabant and poloxamer and the pharmaceutical carrier mix homogeneously, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By obtaining dry suspension or powder behind the solid dispersion of Rimonabant and poloxamer and the pharmaceutical carrier mix homogeneously, optionally can further dry suspension or powder fill Capsules shell be obtained hard capsule, perhaps mix homogeneously obtains granule behind wet granulation or the dry granulation, to obtain hard capsule in the granule fill Capsules shell, wherein the solid medicinal carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By obtaining soft capsule with dripping to make to seal with soft capsule material compacting of gelatin or capsule material glue behind the solid dispersion of Rimonabant and poloxamer and the suitable pharmaceutical carrier mix homogeneously, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: Liquid Macrogol, PEG400, Macrogol 600, soybean oil, Semen Maydis oil, other vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described " soft capsule material compacting or the capsule material glue system of dripping are sealed " is meant and adopts pressing or dropping preparation method to prepare soft capsule, pressing is meant that the liquid or soft plastic state content that adopts press will contain solid dispersion wraps up formation preparation of soft capsule method with the compacting of capsule material film, can be pressed into different shapes and content content with different moulds, usually seal the capsule preparation with rotating the continuously automatic soft capsule production machine of rolling capsule machine or punching type automatically, dropping preparation method is meant the method that is equipped with soft capsule by a making mechanism, more than 45 ℃, it is biphase utilizing capsule material glue and liquid content, after making a certain amount of capsule material glue with quantitative liquid content parcel, splash in the another kind of not miscible condensed fluid, behind the capsule material glue condensation by contact liquid, under surface tension effects and solidify and form spherical soft capsule, described condensed fluid is selected from liquid paraffin, methyl-silicone oil, vegetable oil, in the kerosene any one; Or
By with the solid dispersion melting mixing of Rimonabant and poloxamer evenly after, or with the mixture melting mixing of Rimonabant and poloxamer evenly after, splash in the not miscible condensed fluid, shrink condensation and make drop pill, optionally drop pill can contain but be not limited to following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, can contain but be not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with the solid dispersion of Rimonabant and poloxamer and suitable pharmaceutical carrier melting mixing evenly after, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, Polyethylene Glycol 8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, polyoxyethylene stearate (40) ester, glyceryl monostearate, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with behind the solid dispersion of Rimonabant and poloxamer and the suitable pharmaceutical carrier mix homogeneously, make the solid preparation of spherical or near-spherical, perhaps with the solid dispersion of Rimonabant and poloxamer and suitable pharmaceutical carrier dissolving or molten being dispersed in the liquid medium, and its deposition is coated on the surface of celphere and forms micropill, wherein the solid medicinal carrier includes but not limited to the following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains the drop pill capsule in the capsulae vacuus of optionally can further micropill being packed into; Or
Solid dispersion by Rimonabant and poloxamer and water or aqueous liquid mixing evenly form oral administration solution or suspension; Or
By with Rimonabant and poloxamer and the injection pharmaceutical carrier mix homogeneously that is fit to, can obtain injection by the injection preparation method, wherein pharmaceutical carrier includes but not limited to the following material as filler or excipient: water, mannitol, sorbitol, lactose, xylitol, fructose, dextran, glucose, sodium chloride.
Optionally, difference and the needs of guaranteeing the medicament quality according to pharmaceutical dosage form can also add other suitable pharmaceutic adjuvant in the above-mentioned preparation method.
13. Rimonabant solid dispersion, contain Rimonabant, poloxamer and other pharmaceutical carrier, wherein the quality ratio range of Rimonabant and poloxamer is 1: (0.5～200), and described other pharmaceutical carrier includes but not limited to the lactose as filler or diluent, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate; Include but not limited to sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium as disintegrating agent; Include but not limited to sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) as surfactant; Include but not limited to hydroxypropyl emthylcellulose, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose as suspending agent, or the like; Include but not limited to methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum as binding agent; Include but not limited to magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate as lubricant.
14. the described solid dispersion of claim 13, wherein the quality ratio range of Rimonabant and poloxamer is 1: (1～180);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (2～150);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (3～130);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (4～120);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (5～100);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (6～80);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (7～60);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (8～50);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (9～40);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (10～30);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (11～20);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (12～15);
The quality ratio range of preferred Rimonabant and poloxamer is 1: (1～20).
15. prepare the method for claim 13 or 14 any described solid dispersion, it comprises Rimonabant, poloxamer and other pharmaceutical carrier fully is mixed and made into any pharmaceutical dosage form of acceptable on the pharmaceutics that preferred pharmaceutical dosage form is tablet, hard capsule, soft capsule, drop pill, pellet, granule, dry suspension, powder, oral fluid agent, injection.
16. prepare the method for claim 13 or 14 any described solid dispersion, it comprises:
By with Rimonabant, poloxamer is dissolved or dispersed in alcohol, in the alcohol-water solution, with this liquid mixture as wetting agent to the pharmaceutical carrier wet granulation, remove and desolvate and drying, make the granule or the dry suspension of dispersion, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein other pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, described alcohol, alcohol-water solution comprises ethanol, methanol, ethanol-water solution, methanol-water solution, described remove desolvated and drying can adopt and removes under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, the fluidized bed granulation drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
By with Rimonabant, poloxamer and other pharmaceutical carrier are dissolved or dispersed in alcohol, in the alcohol-water solution, stir or fully grind the back and remove and desolvate and dry, with solid drying and the pulverizing that obtains, promptly obtain the dry suspension or the powder of dispersion, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein other pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, described alcohol, alcohol-water solution comprises ethanol, methanol, ethanol-water solution, methanol-water solution, wherein said remove desolvated and drying can adopt and removes under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, the fluidized bed granulation drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or pass through Rimonabant, poloxamer and other pharmaceutical carrier are dissolved or dispersed in Polyethylene Glycol or the vegetable oil, seal or the capsule material glue system of dripping is sealed and obtained soft capsule with the compacting of the soft capsule material of gelatin, other pharmaceutical carrier includes but not limited to the following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), wherein Polyethylene Glycol includes but not limited to Liquid Macrogol, PEG400, Macrogol 600, vegetable oil includes but not limited to soybean oil, Semen Maydis oil; Or
By with Rimonabant, after poloxamer and other pharmaceutical carrier melting mixing are even, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, PEG8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, polyoxyethylene stearate (40) ester, glyceryl monostearate, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or,
By with Rimonabant, behind poloxamer and other pharmaceutical carrier mix homogeneously, be dissolved or dispersed in alcohol, in the alcohol-water solution, make the solid preparation of spherical or near-spherical and make micropill, perhaps with Rimonabant, poloxamer is with other pharmaceutical carrier dissolving or be dispersed in alcohol, in the alcohol-water solution medium, and its deposition is coated on the surface of celphere and makes micropill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains pellet capsule in the capsulae vacuus of optionally can further micropill being packed into.
Optionally, can also add other suitable pharmaceutic adjuvant in the above-mentioned preparation method.
CNA2007101014020A 2007-04-12 2007-04-12 Compound including rimonabant and poloxamer, solid dispersion and the preparation and the application of the medicine Pending CN101040855A (en)

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