CN1052397C - Pharmaceutical compositions in form of beadlets and method - Google Patents

Abstract

The present invention provides a multi-element medical composition in a small bead shape, which is suitable for filling medical hard-shell capsules or tablets. Small beads are composed of medicines (such as the ACE inhibitors of saptoril, etc.,), a beta-retarder (such as nadolol, propranolol or atenolol hydrochloride), a calcium channel retarder (such as diltiazem or nifedipine or other medicines, including the conjugate of the diltiazem or the nifedipine, an adhesive agent (such as cellulose microcrystalline), and at least 5 weight percentages of an auxiliary agent of acid treatment (such as citric acid). The acid is used for enabling wet blocks to obtain effective plasticity for squeezing and spheroidizing requirements. The present invention also provides a method for producing the small beads, which comprises the steps of squeezing the composition and spheroidizing the extruded products, and using the auxiliary agent of acid treatment (such as the citric acid) in operation in order to improve the operating process and form improved small beads.

Description

The preparation method that contains the globule of medicament

The present invention relates to a kind of method for preparing globule shape new pharmaceutical composition, prepared this globule shape pharmaceutical composition contains the organic acid (as citric acid) of one or more medicines (as a kind of ACE inhibitor, beta-Blocking agent, calcium channel blocker or its conjugate) and at least 5% weight.

People such as Ondetti are at United States Patent (USP) 4,105, and they are angiotensin converting enzyme (ACE) inhibitor to disclose proline derivative in 776, have following general formula.

Comprising captopril

Petrillo is at United States Patent (USP) 4,168, discloses the phosphinyl alkanoyl proline with following structural formula in 267

R in the formula ₁Be low alkyl group, phenyl or phenyl lower alkyl;

R ₂Be hydrogen, phenyl lower alkyl or metal ion;

R ₃Be hydrogen or low alkyl group;

R ₄Be hydrogen, low alkyl group, phenyl lower alkyl or metal ion; And

N is o or 1.

Petrillo is at United States Patent (USP) 4,337, discloses proline or its salt that phosphinyl alkanoyl with following structural formula replaces in 201,

Comprising fosinopril

People such as Karanewsky are at United States Patent (USP) 4,432, disclose aminoacid or imino acid (they are angiotensin converting enzyme inhibitor) and its salt of the aminating replacement of phosphono in 971, and they have following structural formula:

Comprising 1-[N-[hydroxyl (4-phenyl butyl) phosphinyl]-the L-alanyl]-L-proline dilithium salt

With 1-[N-[hydroxyl (4-phenyl butyl) phosphinyl]-the L-lysyl] L-proline dilithium salt.

People such as Patchett are at United States Patent (USP) 4,374, disclose the carboxyalkyl dipeptidase derivant in 829, it is said that they are angiotensin converting enzyme inhibitor, and have following structural formula:

Comprising enalapril

That is, N-(1-carbethoxyl group-3-phenyl propyl)-L-alanyl-L-proline.

People such as Karanewsky are at United States Patent (USP) 4,452, the phosphonic acids esterification is disclosed in 790 aminoacid or imino acid and its salt of replacement, they have following structural formula:

Comprising SQ29,852

That is, (S)-and 1-[6-amino-2-[[hydroxyl (4-phenyl butyl)-phosphinyl] the oxygen base]-the 1-oxo-hexyl]-the L-proline.

People such as Sawayame are at United States Patent (USP) 4,248, disclose 1-(3-sulfydryl-2-methylpropionyl)-prolyl amino acid derivant and the salt thereof with following structural formula in 883: Wherein R represents the phenyl lower alkyl of hydrogen atom, low alkyl group, phenyl lower alkyl or a replacement; R ₁The expression hydrogen atom, R ₄CO-, R ₅S-or

R ₂Expression hydrogen atom or low alkyl group;

R ₃Expression hydrogen atom, phenyl, low alkyl group, or the low alkyl group (substituent group wherein is hydroxyl, phenyl lower alkoxy, amino, guanidine radicals, N-nitro guanidine radicals, carboxyl, lower alkoxycarbonyl, phenyl lower alkoxycarbonyl, carbamyl, sulfydryl, lower alkylthio, phenyl, hydroxyphenyl, indyl or imidazole radicals) that replaces; Perhaps, R ₂And R ₃Form a heterocycle with nitrogen that links to each other with them respectively and carbon atom; R ₄The phenyl lower alkoxy of the phenyl lower alkyl of the phenyl of expression low alkyl group, lower alkoxy, phenyl, replacement, phenyl lower alkyl, replacement, phenyl lower alkoxy, replacement, phenoxy group or the phenoxy group that replaces; R ₅The phenyl lower alkyl of the phenyl of expression low alkyl group, phenyl, replacement, phenyl lower alkyl, replacement,

Or amino (carboxyl) low alkyl group; R ₆Expression hydrogen atom or low alkyl group; R ₇The phenyl of expression low alkyl group, phenyl or replacement; X represents oxygen or sulfur; And the substituent group in the substituted-phenyl is halogen atom, low alkyl group or lower alkoxy.

People such as Ondetti are at United States Patent (USP) 4,316, disclose ether shown in the following structural formula and thioether sulfydryl acyl group proline in 906:

Comprising zofenopril

Japanese Laid-Open Patent Application communique 61-36217 discloses the prescription of slow release ACE inhibitor, wherein ACE inhibitor is suspended in and is mixed with one or more following substances in lipophilic (oil or fat) substrate in this substrate: ascorbic acid, sodium ascorbate, arabo-ascorbic acid, sodium erythorbate, sodium sulfite, sodium sulfite and metabisulfite, and be mixed with thickening agent (as hydroxypropyl emthylcellulose or methylcellulose).The weight ratio of lipophilic matrices and ACE inhibitor is about 3: 1 to about 12: 1.

People such as Butler are at United States Patent (USP) 3,365, disclose in 365 and can be used in the globule shape pharmaceutical composition of filling hard-shell capsule.In one embodiment, globule shape medicine contain with provide two kinds of branches other with different drug doses, this point is partly to finish by the enteric coating that contains zein and Colophonium acid type resin.In another embodiment, globule shape medicine contains a kind of active medicine, and can make it to continue to discharge, and this finishes by multilamellar system row, and multilamellar system row comprise the Arabic glue-line of viscosity, are dispersed with active component in the glue-line; The permeable membrane that also comprises a lac and Macrogol 4000-20000, topped on the coating layer.

European patent application 0122077 (Elan) discloses the theophylline multilayer particle or the pill of long-acting release, and they are that adventitia forms by theophylline (3.59 gram) organic acid (as citric acid 875 grams) and polymer soluble and to have a slightly solubility polymer.

European patent 123470A discloses the propranolol of slow release, it is by propranolol, organic acid and mainly for the crossover layer of water miscible polymer with have that less dissolubility adventitia forms, comprise a propranolol (1000 gram) or its acceptable salt and a kind of organic acid for oral granule, as the nuclear of citric acid (500 gram), plant in the polymeric material that the multilamellar with adventitia is arranged.

The invention provides a kind of preparation with the method for medicine globule form as the new pharmaceutical composition of controlled delivery formulations.Contained medicine is ACE inhibitor (as captopril, zofenopril or fosinopril), beta-Blocking agent (as nadolol, propranolol or atenolol), calcium channel blocker (as sulfur nitrogen ketone or nifedipine) or various medicines hereinafter described or its conjugate for example, and it can be used for filling medicine hard-shell capsule or tabletting.New pharmaceutical composition of the present invention for keeping 12 hours drug release in stomach and/or upper intestines, is a fabulous sustained release mechanism, and this it seems that at least the tablet with present available isoplassont is bioequivalent.

Form among the present invention the sustained release preparation the medicine globule each all form by a kind of medicine, a kind of non-lipotropy binding agent-excipient and a kind of organic carboxyl acid (as citric acid), its organic acid consumption accounts for about 5% or about better 10% of total formulation weight amount at least, the medicine globule also can randomly comprise one or more auxiliary binders, one or more filleies or excipient, one or more lubricants, water and/or other conventional additives.Yet, no matter the composition of other existence, owing to will state that hereinafter the medicine globule must contain the organic acid of top described minute weight.

The medicine globule of the present invention that mentioned component forms not coating maybe can be a nuclear with a kind of pharmaceutically useful coating material package clothing, this pharmaceutically useful coating material may comprise one or more film former of about 60%～about 95% weight, one or more plasticizers of about 5%～about 40% weight, one or more solvents and/or other conventional ingredient, above said film former and plasticizer weight percent be based on the gross weight of coating material.

In addition, according to a kind of method (as described above) for preparing the medicine globule provided by the invention, this method is included in water or the organic solvent certain medicine, as ACE inhibitor, mix wet piece of formation with binding agent-excipient and organic acid, the wet piece of extruding makes its shaping, and nodularization shaping thing forms steps such as globule.Then, globule can be dried and resemble above-mentioned coating randomly.

Cold is very found, the existing of a large amount of organic carboxyl acids (as citric acid) (as account at least last globule weight about 5% or about better 10%) wet piece is had effectively and extrude plasticity with the required necessity of nodularization in high quality, can reduce institute's water requirement, processing time can be shortened, thereby make operation easier, also help to form stone globule, the hardness of globule is to be that a kind of survey tool of more sensitive pure machinery is used at large by this meter that a kind of Strong-Cobb of being called hardness measurement meter is determined.During measurement the tested person thing is put between two intermediate plates of this meter, by a little hydraulic pump two intermediate plates are pressed, on the graduated tile that indicates with Strong-Cobb unit's (being called for short SCU), indicate 1 SCU=0.714kP (kP=kip) by a pointer when tested person thing is crushed.The hardness of according to said method measuring globule of the present invention is about 2～5 Strong-Cobb units, and shines in pairs less than 1 Strong-Cobb unit form with the hardness of the non-Pareil globule that can compare size.The fragility of the pearl that is produced is low-down, and promptly less than 0.03%, the fragility of nonpareil pearl is 6～7% by contrast.In addition, because organic acid exists,, be about the narrow particle size distribution of 0.8-2 millimeter so can obtain necessary diameter so in the nodularization step, globule can not pulverized.

Globule shape pharmaceutical composition among the present invention contains the medicine of about 3～60% weight, and the medicine of preferably about 6～50% weight.Used here medicine preferably is angiotensin converting enzyme inhibitor or calcium channel blocker or its conjugate.

Available herein angiotensin converting enzyme inhibitor comprises the proline derivative of replacement, people such as Ondetti is at United States Patent (USP) 4,105 as above mentioned, in 776 disclosed any, be preferably captopril, be 1-(2S)-3-mercapto-2-methyl propionyl]-the L-proline, carboxyalkyl dipeptidase derivant, european patent application 0 as mentioned above, 012, in 401 disclosed any, be preferably N-(1-carbethoxyl group-3-phenyl propyl)-L-alanyl-L-proline, i.e. enalapril.

Be applicable to that other example that the inhibition angiotensin converting enzyme among the present invention suppresses comprises United States Patent (USP) 4; 452; the aminoacid of disclosed any phosphonate substituted or imino acid or its salt in 790; be preferably (S)-1-[6-amino-2-[[hydroxyl-(4-phenyl butyl) phosphinyl] the oxygen base]-the 1-oxo-hexyl]-the L-proline; United States Patent (USP) above-mentioned; 4; 168; disclosed phosphinyl alkanoyl proline in 267; be preferably fosinopril, the mercapto acyl derivative of substituted prolines is preferably zofenopril; United States Patent (USP) 4 discussed above; the proline that disclosed any phosphinyl alkanoyl replaces in 337,201, and United States Patent (USP) discussed above 4; disclosed phosphono aminate in 432,971.

Other example that can ACE inhibitor used in this invention comprises disclosed Beecham ' s BRL in European patent 80822 and 60668,36,378; Disclosed Chugai ' s MC-838 among CA.102:72588V and the Jap.J.Pharmacol.40:373 (1986); Disclosed Ciba-Geigy ' s CGS14824 in the British patent 2103614 (3-([1-carbethoxyl group-3-phenyl-(1S)-propyl group]-amino)-2,3,4,5-tetrahydrochysene-2-oxo-1-(3S)-benzo-aza -1-acetic acid hydrochloride) disclosed CGS16 and in the United States Patent (USP) 4,473,575,617 (3 (S)-[[1S)-5-amino-1-carboxylic amyl group] amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-benzo-aza -1-acetic acid); Disclosed cetapril in Eur.Therap.Res.39:671 (1986) and 40:543 (1986) (alacep-ril, Dainippon); Disclosed ramipril (Heochst) among European patent 79-022 and the Curr.Ther.Res.40:74 (1986); Disclosed Ru44570 (Hoechst) in Arzneimittelforschung 35:1254 (1985); Disclosed Cilazpril (Hoffman-LaRoche) in J.Cardiovasc.Pharmacol.9:39 (1987); Disclosed Ro 31-2201Hoffman-LaRoche in FEBS Lett.165:201 (1984); Disclosed Lisinopril (Merck) in Curr.Therap.RES.37:342 (1985) and european patent application 12-401; United States Patent (USP) 4,385, disclosed indalapril (delapril) in 051; Disclosed rentiapril in Clin.Exp.Pharmacol.Physiol.10:131 (1983) (fentiapril santen); At J.Cardiovasc.Pharmacoi.5:643, disclosed indolapril (Schering) in 655 (1983); At Acta.Pharmacol.Toxicol.59 (Supp.5): disclosed spirapril (Schering) in 173 (1986); Disclosed Perindopril (Servier) in Eur.J.Clin.Pharmacol.31:519 (1987); United States Patent (USP) 4,344, disclosed guinapril (War-ner-Lambert) and at Pharmacologist 26:243 in 949, disclosed CI 925 (Warner-Lambert) in 266 (1984) ([3S-[2[R ( ^*) R ( ^*)]] 3R ( ^*)]-the 2-[2-[[1-carbethoxyl group)-the 3-phenylpropyl] amino [1-oxopropyl]-1,2,3,4-tetrahydrochysene-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochlorate); Disclosed WY-44221 (Wyeth) in J.Med.Chem.26:394 (1983).

The beta-Blocking agent that can be used for the present invention comprises nadolol, propranolol, atenolol, timolol, metoprolol tartrate, and acebutolol hydrochlorate, carvisken, or the like.

Be applicable to that calcium channel blocker of the present invention or antagonist comprise sulfur nitrogen ketone, and United States Patent (USP) 3,562, in 257 other calcium antagonist, verapamil, the 4-phenyl-1 of dimeditiapramine (tiapamil) as hereinafter being limited disclosed, 4-dihydropyridines (comprising nifedipine), or the like.

Can calcium antagonist 4-phenyl-1 used in this invention, the 4-dihydropyridine has following structural formula:

R wherein ₁And R ₂Can be identical or different, and be C _1-4Low alkyl group or C _1-4Lower alkoxy (C _1-4Low alkyl group).

Disclose above-claimed cpd in the United States Patent (USP) 3,644,627,3,485,8473,3,488,359,3,574,843,3,799,934,3,932,645 and 4,154,839 that is hereby incorporated by and be total to preparation method.

Be used in globule of the present invention calcium antagonist dihydropyridine compound in the compositions is preferably nifedipine, one is R ₁Be methyl, R ₂For methyl and nitro are connected in 2 formula A chemical compound, promptly This chemical compound is disclosed in United States Patent (USP) 3,644, in 627 and 3,485,847.

Be applicable to other 4-phenyl-1 preferably of the present invention, the 4-dihydropyridine type calcium antagonists comprises Niludipine (niludipine), i.e. R ₁, R ₂Be-(CH ₂) ₂OC ₃H ₇Be connected in 3 formula A chemical compound (be disclosed in United States Patent (USP) 3,488,359 and 3,574,843 in) with nitro; Nimodipine (nimodipine), i.e. R ₁Be-(CH ₂) ₂OCH ₃, R ₂Be CH (CH ₃) ₂Be connected in 3 formula A chemical compound (be disclosed in United States Patent (USP) 3,799,934 and 3,932,645 in) with nitro; Nitrendipine (nitrendipine), i.e. R ₁Be ethyl, R ₂Be connected in 3 formula A chemical compound (be disclosed in United States Patent (USP) 3,799,934 and 3,932,645 in) for methyl and nitro; And nitre pyrrole fourth methyl ester (nisoldipine), i.e. R ₁Be methyl, R ₂For-CH ₂CH (CH ₃) ₂Be connected in 2 formula A chemical compound (be disclosed in United States Patent (USP) 3,799,934,3,932,645 and 4,154,839 in) with nitro;

Available other calcium channel blocker in the present invention comprises and is disclosed in United States Patent (USP) 4,654,335 and 4, benzothiozepine derivant in 584,131, be disclosed in United States Patent (USP) 4,650, benzodiazepine derivant in 797 and 4,647,561 and as be disclosed in United States Patent (USP) 4,684,656,4,689,414 and 4, pyrimidine derivatives class in 684,655.

Also can use with oral many other kind medicines of tablet form according to the form of the globule of the present invention's preparation.For example, these medicines comprise adrenergic agent such as ephedrine, dexoxyn, phyenlephrinium, epinephrine etc., cholinergic medicament such as physostigmine, neostigmine etc., anti-spasmodics are tropine how, Methantheline, papaverine etc., curare-like agent agent such as ecolid etc., neuroleptic agent and muscle relaxant such as fluphenazine, chlorpromazine, triflupromazine, mephensine, miltown etc., antidepressants such as amitriptyline, nortriptyline etc., anti-resistance amine medicine such as diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, chlorpheniramine, chlorphenamine, the maleic acid Brompheniramine, terfe-nadine etc., depressor such as Radix Rauvolfiae, reserpine, aldactone, methyldopa, the phenylhydrazine hydrochloride pyridazine, dichloranilino imidazolin, minipress, hydrochloric acid miaow pyrazine etc., cardioactive medicine such as bendroflumethiazide, flumethiazide, chlorothiazide, hydrochlorothiazide, chlortalidone, aminotrate phosphate and procainamide, Decongestant example hydrochloric acid cathine, isoephedrine etc., anti-inflammatory agent such as indometacin, Bu Luolao, naproxen, Piroxicam etc., renin inhibitor, bronchodilator such as theophylline, sterols such as tes PP, meticortelone etc., as if antimicrobial drug is sulfadiazine, sulfamerazine, sulfadimidine, the sulphonamides that gantrisin diethanolamine etc. are such, antimalarial such as chloroquine etc., antibiotics such as tetracycline, nystatin, streptomycin, hexamethylene enamine cephamycin and other cephamycin, penicillin, semisynthetic penicillin, griseofulvin etc., tranquilizer such as chloral hydrate, phenobarbital and other barbiturates, glutethimide, antitubercular agent such as isoniazid etc., analgesic such as aspirin, acetominopnen, the third oxygen sweet smell, pethidine etc., vitamin, or the like.These medicines usually or as free cpds or with the form of salt use, acid-addition salts for example, the basic salt that alkali metal salt is such etc.Other medicine with identical or different physiologically active also can be used for the interior pharmaceutical preparation of the scope of the invention.

The content of all above-mentioned U.S. Patent Publications is drawn at this and is reference.

Globule shape pharmaceutical composition of the present invention can contain a kind of in the said medicine, the perhaps conjugate of two kinds of multiple said medicine.Good especially is independent ACE inhibitor such as captopril; A kind of independent calcium channel blocker such as mercapto nitrogen ketone, nifedipine or verapamil; A kind of by the ACE inhibitor that combined to the weight ratio of about 10: 1 scopes in about 0.1: 1 and the conjugate of calcium channel blocker, the conjugate of captopril, enalapril, zofenopril, fosinopril or any other disclosed ACE inhibitor and mercapto nitrogen ketone for example, the conjugate of captopril or any other disclosed ACE inhibitor and nifedipine; A kind of bonded beta blocker of weight ratio and the conjugate of calcium channel blocker, for example conjugate of nadolol, propranolol, atenolol etc. and any calcium channel blocker disclosed herein by 0.1: 1 to 10: 1 scope of big medicine; A kind of weight ratio by about 0.1: 1 to 10: 1 proportion is bonded as ACE inhibitor and diuretic, as the conjugate of hydrochlorothiazide, bendroflumethiazide, chlortalidone etc.

People also will understand, and the globule that contains one or more medicines can physically mix with other globule that contains one or more different pharmaceuticals in a capsule or tabletting.

Organic carboxyl acid is essential for the globule that forms via the extrusion-spheronization route, and at this, it makes wet piece have plasticity, so just can form to have the hard pearl that desired diameter is about the granular size narrow range of 0.8-2 millimeter.The percentage by weight of organic acid in the globule preparation is about 5-50%, and is preferably 10-40%.

The example that is applicable to organic carboxyl acid of the present invention comprises (but not only being limited to these): citric acid, malic acid, tartaric acid, fumaric acid, maleic acid and succinic acid are preferably citric acid.

Non-lipophilic binding agent-excipient accounts for the 3-70% of globule weight, is preferably 5-60%.Better binding agent-the excipient that is used for globule of the present invention is a microcrystalline Cellulose, and in this case, binding agent also can be used as excipient.Yet other binding agent can use separately or use with known excipient.These binding agents can be hydrophilic polymers or the hydrocolloid that formed by water swellable polymer such as cellulosic polymer and natural gum.Used hydrocolloid preferably comprises one or more cellulosic polymers, they are cellulose ether such as methylcellulose, hydroxy alkyl cellulose such as hydroxypropyl emthylcellulose (low viscosity of 2-200cp), hydroxypropyl cellulose, hydroxy methocel or hydroxyethyl-cellulose, carboxyl alkyl cellulose such as carboxymethyl cellulose, and carboxyethyl cellulose, and the alkali metal salt of carboxyl alkyl cellulose such as sodium carboxymethyl cellulose and sodium hydroxyethlcellulose, or acrylate homopolymer or copolymer or its alkali metal salt.

Certainly, the hydrocolloid that oneself know other can be used for the present invention, for example, comprises gelatin, polyvinylpyrrolidone, pectin, Radix Acaciae senegalis, CAR, melon ear (tree) glue, gum tragacanth, xanthan gum, ammonium, alginic acid or sodium alginate or its mixture.The example of the hydrocolloid that other is suitable is seen

People's United States Patent (USP)s such as Sheth 4,140,755.

Can randomly be used to wrap the coated preparation that can be comprised any routine by the coatings of globule, and can comprise one or more film former or binding agent, as a kind of hydrophilic polymer, as hydroxypropyl emthylcellulose and a kind of hydrophobic polymer such as ethyl cellulose, cellulose acetate, polyvinyl alcohol-copolymer-maleic anhydride, acrylate copolymer, as acrylic acid-α-Jia Jibingxisuan ester copolymer, polyvinyl alcohol, beta-pinene polymer, wood gum glyceride etc., and one or more plasticizers, as triethyl citrate, tributyl citrate, diethyl phthalate, single-acetyl triglyceride, propylene glycol, glycerol, butyl phthalate, the Semen Ricini wet goods.Coating materials comprises a hydroxypropyl emthylcellulose seal coat with Polyethylene Glycol plasticising preferably, be subsequently one by the speed control barrier coat of the ethyl cellulose of single-acetyl triglyceride (Myvacet9-40) plasticising.

Use film former by a dicyandiamide solution that contains one or more solvents.These solvents comprise that water, alcohol are as methanol, ethanol or isopropyl alcohol, ketone such as acetone or ethyl methyl ketone, chlorohydrocarbon such as dichloromethane, dichloroethanes and 1.

When needs are painted, colorant can be used with film former plasticizer and solvent compositions.

According to the present invention, a kind of globule that improves release preferably comprises nuclear and coatings arbitrarily, the ACE inhibitor such as independent captopril or independent sulfur nitrogen ketone or the nifedipine of about 10-50% (weight) that contain the 5-40% that has an appointment (weight) in the nuclear, or the sulfur nitrogen ketone of captopril and above-mentioned consumption or the conjugate of nifedipine, the binding agent of about 15-60% (weight), be preferably the hydroxypropyl methylcellulose that microcrystalline Cellulose also randomly contains the 3-10% that has an appointment (weight), the organic acid of about 10-35% (weight) is preferably citric acid, contain one or more film former 20-75% (weight) hydroxypropyl emthylcellulose according to appointment in (all percentage ratios all are the basis with respect to nuclear weight) coatings, the ethyl cellulose of about 5-60% (weight), with one or more plasticizers, the single-acetyl triglyceride of the Polyethylene Glycol of 5-25% (weight) and about 5-40% (weight) according to appointment, (all percentage ratios all are for the coatings gross weight).

The inert filler that can randomly add comprises lactose, sucrose, mannose, xylitol etc.

Be appreciated that according to the present invention,, all will keep above-mentioned organic acid percent by weight (5-50%), to guarantee to form the very narrow hard globule of particle size distribution no matter whether there is the component that randomly adds.

When forming globule shape medicine according to method of the present invention, medicine or drug conjugates, organic carboxyl acid, as citric acid, and binding agent-excipient thoroughly mixes with water and knead (kneading machine of for example using a routine) to form wet piece.For example use a Nica then, the extruder of Luwa or other model pushes wet piece and forms extrudate, allows extrudate through the nodularization equipment such as Nica, Luwa or other type again, makes extrudate become the suitable globule of granular size scope.Globule is with plate rack drying furnace or fluidized bed dryer drying then.When needing, globule can coating, for example, carries out coating with the solution or the dispersion of film former and plasticizer by coating pan, coating fluid bed etc.

So the globule that forms can be inserted in the hard-shell capsule or tabletting, makes with single dose or divided dose to be about 2-200 milligram, the best preparation taken of about 5-150 milligram (every day 1～4 time).

Following example has illustrated the present invention's embodiment preferably preferably.Unless specialize, all temperature are all represented with Celsius temperature.

Example 1

A kind of can be in that to reach in 6 hours the globule formulation preparation that the improvement with following composition that slowly discharges the angiotensin converting enzyme inhibitor captopril discharges as follows:

The composition parts by weight

Captopril 27

Citric acid 30

Microcrystalline Cellulose ^*43

^*Consumption can change the chemical purity with the reflection captopril.

Above-mentioned each composition mixed and adds water in a planetary-type mixer knead, with form wet piece, wet piece forms extrudate (～1 mm dia) by a Nica E140 squeezer.Extrudate forms globule by a Nica nodularization device then.With globule at 40 ℃ with dry 12-18 hour of tray dryer or with fluidized bed dryer drying 2-4 hour.The formed globule of sub-fraction is inserted the duricrust medicament capsule, form a kind of preparation of the present invention.

Example 2

The coating globule formulation preparation that a kind of improvement with following composition discharges is as follows:

Composition milligram/agent

I) nuclear

Captopril 100

Microcrystalline Cellulose 159.1

Citric acid 37.

Lactose 74.1

Ii) seal coating

Hydroxypropyl methyl dimension fine plain about 8.3

Polyethylene Glycol about 2.8

The iii sealing coat

Ethyl cellulose

[as Aguacoat ^Solid) about 4.2

Single-acetyl triglyceride

(Myvacet ^9-40) about 1.3

As preparation globule nuclear as described in the example 1.After forming exsiccant globule, carry out coating through following two-stage process: the aqueous solution of preparation hydroxypropyl methylcellulose (7.5% weight) and Polyethylene Glycol (2.5% weight) is sprayed to formation sealing coating on the globule with it.Use commercially available and the blended ethyl cellulose of single-acetyl triglyceride (9.5% weight) (as Aguacoat then ^) aqueous dispersion of (30% weight) makes the globule bag by a sealing coat, in the duricrust medicament capsule of again globule being packed into.

Example 3

The coating globule that a kind of improvement with following composition discharges is prepared as follows:

Composition accounts for the percentage ratio of coating globule weight

Nuclear

Captopril 26.2

Citric acid 29.1

Microcrystalline Cellulose 41.8

The film coating

Ethyl cellulose about 2.6

Triethyl citrate about 0.3

Nuclear as preparation globule as described in the example 1.

Ethyl cellulose (9 parts) and triethyl citrate (1 part) are dissolved in the ethanol (90 parts), it are sprayed onto form the coating product on the globule then.With the formed globule duricrust medicament capsule of packing into.

Example 4-8

With following ACE inhibitor, organic acid and binding agent-excipient, press the step of example 1-3, prepare following globule compositions: example number ACE inhibitor organic acid binding agent 4 N-(1-carbethoxyl group-3-citric acid microcrystalline Cellulose

Phenylpropyl)-L-proline 5 (S)-1-[6-amino-2-malic acid microcrystalline Cellulose

[[hydroxyl (phenyl butyl) and hydroxypropyl methyl

Phosphinyl]-the oxygen base]-1-oxygen cellulose

For hexyl]-L-proline 6 Lisinopril tartaric acid sodium carboxymethyl cellulose 7 zofenopril succinic acid gelatin, pectin and carboxylics

Sodium carboxymethylcellulose pyce 8 fosinopril maleic acid microcrystalline Cellulose

Example 9

Replace 27 parts of captoprils in the example 1 to prepare the globule preparation with 20 parts sulfur nitrogen ketone according to example 1 method.

Example 10

Prepare the captopril globule by example 2 methods, by example 2 methods (using 25 parts sulfur nitrogen ketone instead) preparations sulfur nitrogen ketone globule, with the above-mentioned globule of the equivalent hard gelatin capsule of packing into.

Example 11

Replace 27 parts of captoprils to prepare the globule preparation with 12 parts of captoprils and 10 parts of nifedipines or 10 parts of sulfur nitrogen ketone by example 2 methods.

Example 12

Replace 27 parts of captoprils in the example 1 to prepare the globule preparation with 27 parts of nadolols according to example 1 method.

Example 13

Replace 27 parts of captoprils in the example 1 to prepare the globule agent with 13.5 parts of nadolols and 13.5 parts of nitropyridines according to the method for example 1.

Be appreciated that the prepared globule preparation of the present invention of example 1-13 can be filled in the capsule or tablet forming with the pharmaceutical technology of routine.

Claims (17)

1. method for preparing the globule that contains medicament, this method may further comprise the steps: form a kind of conjugate that contains captopril or captopril and calcium channel blocker or beta-Blocking agent, can invest the required plastic a kind of organic carboxyl acid of this wet piece, and a kind of wet piece of binding agent, extruding should be wet piece to form extrudate, again this extrudate is made mean size and be distributed as the globule that diameter equals 0.8-2mm, and dry this globule, wherein the consumption of said organic carboxyl acid is 5% to 50% of a globule total formulation weight amount, it is 2 to 5 Strong-Cobb units that made globule has hardness, optionally with one or more film former of the 60%-95% weight that accounts for coating material gross weight, one or more plasticizers and one or more solvents that account for the 5%-40% weight of coating material gross weight apply made globule.

2. method according to claim 1, organic carboxyl acid wherein are citric acid, malic acid, tartaric acid, maleic acid, fumaric acid or succinic acid.

3. method according to claim 2, wherein contained organic carboxyl acid are citric acid.

4. method according to claim 1, wherein said blocker are calcium channel blocker.

5. method according to claim 1, its percentage by weight of the amount of wherein contained captopril is 3-60%.

6. method according to claim 1, wherein said binding agent are a kind of hydrocolloid.

7. method according to claim 6, wherein said hydrocolloid are a kind of cellulose ether.

8. method according to claim 7, wherein said cellulose ether are hydroxypropyl methylcellulose.

9. method according to claim 1, wherein said organic acid are that citric acid and described binding agent are microcrystalline Cellulose.

10. method according to claim 3, the percentage by weight of wherein contained captopril are 5-40%, and the percentage by weight of described citric acid is 10-35%.

11. method according to claim 1 is included in little bead surface and is surrounded by a film coating.

12. method according to claim 1, wherein said blocker are beta-Blocking agent.

13. method according to claim 1, wherein said beta-Blocking agent is nadolol, propranolol or atenolol, and described calcium channel blocker is sulfur nitrogen ketone, Nifedipine, verapamil or Tiapamie.

14. method according to claim 1, blocker wherein are sulfur nitrogen ketone, nifedipine or verapamil.

15. method according to claim 1, wherein said wet piece contain the conjugate of captopril and sulfur nitrogen ketone.

16. method according to claim 1, globule wherein is the mixture of globule, each globule contains the conjugate of captopril acid inhibitor and a kind of blocker, in the conjugate of the contained captopril acid inhibitor of this globule and a kind of blocker, its blocker can be identical or different.

17. method according to claim 1 is included in the capsule and contains multiple globule.