CN101085853A

CN101085853A - New film coating

Info

Publication number: CN101085853A
Application number: CN 200710139165
Authority: CN
Inventors: L·J·P·德亚特斯塔姆; J·－E·洛夫罗斯; S·尚茨; A·维林
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2001-12-19
Filing date: 2002-12-18
Publication date: 2007-12-12
Also published as: SE0104327D0; ZA200306168B; UA80940C2

Abstract

A film coating composition suitable for use in coating pharmaceutical formulations to provide modified release comprising a dispersion which includes: a) an acrylic polymer, b) a vinyl acetate polymer, and c) a water-containing liquid. The film coat is useful for the achievement of modified release from pharmaceutical formulations such as tablets, pellets, etc.

Description

New film clothing

The application be that December 18, application number in 2002 are 02808468.3 the applying date, denomination of invention divides an application for the application for a patent for invention of " new film clothing ".

Invention field

The present invention relates to new film clothing.More particularly, the present invention relates to be used to obtain pharmaceutical preparation, as the new film clothing that the improvement of tablet, pill etc. discharges, wherein the film clothing can be applicable to the environment of basic water-based.In addition, the invention provides the preparation method of this class film clothing.

Background of invention

Oral pharmaceutical are the most convenient for the patient.Suitable preparation also must meet safety and simple requirement.According to the character and the treatment requirement of medicine, must adopt diverse ways during the preparation, to obtain required drug release characteristics.Therefore the microsolubility medicine that is administered once every day requires to be different from the preparation of taking soluble drug type for several times every day.This proposition has been carried out discussing widely in document and the summary, for example Langer and Wise (editor) " Medicalapplication of controlled release " roll up I and II, CRC Press Inc, Boca Raton, 1984; Robinson and Lee (editor) " Controlled drugdelivery-fundamentals and applications ", Marcel Dekker, NY1987; Bogentoft and Sj  gren, and " Towards better safety of drugsand pharmaceutical products " (editor: Braimer), Elsevier, 1980; Sandberg " Extended-release metoprolol ", Thesis, UppsalaUniversity, 1994.

Different preparations has the mechanism of different controlled release active substances.In the paper of Sandberg 1994, summarized long-acting release (ER) preparation of different types of drugs.Its conclusion that draws is to have two types ER formulation in principle: its Chinese traditional medicine and framework material (normally polymkeric substance or wax) blended skeleton system; Wherein medicine is formulated into the drug-reservoir system that is aggregated in the membrane-enclosed nuclear of thing (sheet or piller).Film then is a barrier by decision controlled release speed such as for example its perviousness, solubility of substances.

Based on flexible viewpoint, medicine is formulated as the attention that the independent junior unit with film clothing has won many people.This class preparation demonstrates several interesting characteristics, as the snappiness of preparation and the regulating effect of release characteristics, can develop different formulations, can make dosage size be fit to the fixed Combined Preparation, tablet is made alienable etc.Many studies show that for medicine metoprolol and salt thereof, utilizes this principle can realize safety, treatment simply and easily (people such as Ragnarsson, Drug Develop Ind Pharmacy 13,1495 (1987); People such as Sanderg, Eur.J Clin Pharmacol 33, S3 (1988) and S9 (1988); People such as Ragnarsson, Int J Pharmaceutics 79,223 (1992); People such as Sanderg, ibid 68,167 (1991); People such as Sandberg, Pharmacuticl Res10,28 (1993); People such as Sandberg, Drug Invest 6,320 (1993); Sandberg, Thesis Uppsala University, 1994).But piller must have excellent mechanical intensity.These pillers and the mixed with excipients that forms tablet people such as (, Drug Dev Ind Pharmacy 13,1495 (1987)) Ragnarsson and compacting in flakes.Therefore, in the tablet manufacturing processed, the film clothing of piller will contact with external force.If the physical strength of film clothing is too low, in pressing process, can cause nuclear substance to break.Break can cause drug release fast with undesirable increase.

According to above-mentioned document, the film clothing that uses ethyl cellulose and the solution of HPMC in organic solvent to spray is made piller with metoprolol.But because environment needs to use the water-based film-forming system that this medicine and other medicines are mixed with the piller system in the near future.In addition, for the same reason, tablet coating with an organic solvent also must be replaced by the water-based film-forming material usually.Therefore, must strive to find the suitable aqueous based systems that is used for drug delivery system film clothing.

People know as the latex particle in the water of dispersion medium has almost had half a century.These particles are 10-1000nm aggregation colloid particles and for example are being used as membrane-forming agent in pigment, Floor paint, printing-ink, the tackiness agent etc.When water evaporated, if particulate polymers has enough low glass transition temp (Tg), then particle can condense the formation film.

From early eighties when commercial dispersion appears on the market comparatively at large, just known the water-based film-forming polymer latex that is used for pharmaceutical industries (as Aquacoat , FMC Corp.; Eudragit  NE30D, R  hm Pharma; Kollicoat  EMM30D, BASF AG.).Further several other products are prepared in exploitation, these products have been carried out test and have been reported in multiple publication (Petereit and Weisbrod, Eur J Pharmaceutics andBiopharm 47,15 (1999); People such as Petereit, ibid, and 41,219 (1995); Amighi and Moes, STP Pharma Sci 7,141 (1997); Bodmeier and Paeratukul, Pharm Res 11,882 (1994); People such as Ozturk, J ControlledReleas 14,203 (1990), people such as Goodhart, Pharmaceutical Tech April, 64 (1984); Bodmeier and Paeratakul, Int J Phafmceutics 152,17 (1997); Bodmeier and Paeratakul, Drug Develop Ind Pharmacy 20,1517 (1994)).

Can draw such conclusion from these and other research, promptly because the low Tg of latex polymer, making us one of comparatively interested dispersion is Eudragit  NE30D, and it comprises the EUDRAGIT NE 30 D particle of 28.5%w/w and as the nonionogenic tenside Nonoxynol 100 (the ethylating nonylphenol of polyoxy) of about 1.5%w/w of stablizer.With the similar a kind of dispersion of Eudragit  NE30D be Kollicoat  EMM30D (BASF AG, Ludwigshafen, Germany).But,, antisticking agent must be added in this class dispersion for obtaining best spray condition and being surrounded by the technology outward appearance of the piller of film clothing according to the report of Petereit and Weisbrod nineteen ninety-five.One of this class antisticking agent is glyceryl monostearate (GMS).Utilized the several pieces of patents or the patent application of these principles to be: people such as Wolff, WO00/13687; People such as Wolff, WO00/13686; People such as Nagy, WO99/42087; People such as Lee, WO99/30685; People such as Eichel, US 5529790; Eiche1, US 5478573; Chen, US 5260068; People such as Petereit, EP 403959; They disclose the purposes that (control) that Eudragits is used for different types of drugs discharges.In the time must using antisticking agent, modal is the combination of surface active molecules and talcum or stearate.But for our purpose, these methods are not attractive because may produce some problems, the reason of problem be Incompatible Substance for example combination, a large amount of additional dispersion body additives, during manufacturing processed, do not have reproducibility etc.

Another dispersion known in the art is new latex polymer dispersion-Kollicoat  SR30D of BASF.Kollicoat  SR30D a kind ofly comprises about 27%w/w polyvinyl acetate and as the dispersion of the about 2.7%w/w polyvinylpyrrolidone and the 0.3%w/w SDS (Sodium Lauryl Sulphate BP/USP) of stablizer.But be used for dressing and film forming, this polymeric dispersions needs softening agent, as triethyl citrate (TEC) (Kolter, people such as K, Proc.Int.Symp.Controlled Release Bioact.Mater., 27,425 (2000)).Use the stability that softening agent can influence film in the film clothing, this may be because micromolecular migration causes, and this effect causes the film clothing to show the variation of aspect of performance in time.

Therefore, when as coating material, there are two subject matters in available latex polymer: (a) because low Tg can make that piller is clamminess, this just needs extra antisticking agent, (b) because high Tg, film may not have suppresses the intensity of force that contracts during being enough to bear tablet manufacturing, and this just needs to add extra softening agent.

US 4871546 discloses tablet coating, and this dressing comprises polymethylmethacrylate, diethyl phthalate, polyoxyethylene glycol and polyvinyl acetate, and they come out as deposition in the solution of methyl alcohol or methylene dichloride from organic liquid.Polyoxyethylene glycol is as softening agent.The document does not have the dressing of public use aqueous conditions.

EP 431877 discloses the enteric coating that comprises polymeric blends that is used for Cimitidine Type A/AB.Enteric coating is insoluble under low (gastric juice) pH, but under high (intestinal juice) pH the dissolved dressing.It all is application of water-insoluble polymkeric substance that this application is not disclosed under gastric juice and the intestinal juice pH.

US 4975283 discloses the acetylsalicylic acid of enteric coating dressing.It is water-insoluble that the document is not disclosed under the low pH, but the application of dissolved polymers under high pH.

US 4800087 disclose the Eudragit  L30D of combination and Eudragit  NE30D as dressing so that the tablet that discharges immediately to be provided, this tablet has the characteristic of taste masking and is masticable.The document does not disclose the preparation that improvement of the present invention discharges.

Goal of the invention

The purpose of this invention is to provide a kind of new film clothing system, this system does not have the problems referred to above.The improvement performance of the film clothing system that this is new comprises, for example inviscid, high mechanical strength during the processing and reproducibility, and in dispersion, add extra additive before the film process minimumly.Another aspect of the present invention provides and utilizes this new film clothing system to make coated preparation, for example method of piller or tablet.

Summary of the invention

We have unexpectedly found a kind of new film clothing composition now, and said composition provides the latex dispersion that is suitable for coated pharmaceutical preparation, and wherein the film of Chan Shenging is as making preparation produce the barrier that approaches constant release (zero level).

The invention provides and be applicable to that coated pharmaceutical preparation improves the film clothing composition that discharges to produce, said composition comprises dispersion, and this dispersion comprises:

A) acrylate copolymer,

B) vinyl acetate polymer,

C) liquid, aqueous and

D) stablizer.

Detailed Description Of The Invention

On the one hand, the invention provides a kind of film clothing that covers drug core, wherein core comprises pharmacological component and randomly comprises one or more pharmaceutically acceptable vehicle.The film clothing comprises dispersion, and this dispersion comprises:

A) acrylate copolymer,

B) vinyl acetate polymer,

C) liquid, aqueous and

D) stablizer,

Wherein the film clothing deposits the improvement release of coming out and pharmacological component being provided from liquid, aqueous.

This film clothing can comprise one or more stablizers.Stablizer can comprise one or more small molecules stablizers (molecular weight is less than 15KD) and/or one or more macromole stablizers (molecular weight is greater than 15KD).In another embodiment, dressing comprises the 0.5%w/w at least that 4%w/w at least that molecular weight is acrylate copolymer less than stablizer and its total amount of 15KD and/or its total amount are vinyl acetate polymer.

The physicals of film clothing does not produce processing problems, and as particle aggregation, so this film clothing shows high-mechanical property.And this film clothing can repeat to make.

In addition, find unexpectedly also that if reduce the amount or the removal stablizer wherein of stablizer in the film clothing, then the film clothing improves its physicals with the passing of time.For example, if the molecular weight of stablizer less than 15KD and its total amount less than the 4%w/w of acrylate copolymer and/or its total amount 0.5%w/w less than vinyl acetate polymer.

In another embodiment, the invention provides and be applicable to coated pharmaceutical preparation so that the film clothing composition of improved release to be provided, said composition comprises dispersion, and this dispersion comprises:

A) acrylate copolymer,

B) vinyl acetate polymer and

C) liquid, aqueous.

For the latex particle in the dispersion, the existence of stablizer produces and the softening agent or other the additive similar problem as stablizer that add, because stablizer can move in film, causes the film clothing to show changes of properties with the passing of time.Top embodiment has the advantage that reduces or eliminates this migration.

On the other hand, the invention provides the film clothing that covers drug core, core wherein comprises pharmacological component and randomly comprises one or more pharmaceutically acceptable vehicle that film clothing wherein provides the release of improved pharmacological component.The film clothing comprises dispersion, and this dispersion comprises:

A) acrylate copolymer,

B) vinyl acetate polymer and

It is c) liquid, aqueous,

Film clothing wherein deposits from liquid, aqueous.The thickness of the film clothing that is fit to is the 1-100 micron, preferred 5-50 micron, more preferably 10-30 micron.In one embodiment, the film clothing comprises one or more stablizers.Stablizer can comprise one or more small molecules stablizers (molecular weight is less than 15KD) and/or one or more macromole stablizers (molecular weight is greater than 15KD).In another embodiment, dressing comprises molecular weight and is lower than the stablizer of 15KD and its total amount less than the 4%w/w of acrylate copolymer (0.5-4% for example, 1-3% particularly) and/or its total amount less than the 0.5%w/w (for example 0.05-0.5%, particularly 0.1-0.3%) of vinyl acetate polymer.

Pharmacological component can be the form of a plurality of globules, and this globule randomly comprises one or more pharmaceutically acceptable vehicle, the film clothing coating as defined above of each globule wherein.This class film dressing globule can be packed dosage form or be mixed with capsule, and for example hard gelatin capsule perhaps adopts currently known methods to be pressed into tablet with optional other pharmaceutically acceptable additive that adds.The globule of dressing by the known routine techniques compacting of this area professional and technical personnel in flakes.In this course of processing, also can add other suitable material.For example, during the film-making step, can use suitable weighting agent, as Microcrystalline Cellulose, talcum, stearyl-sodium fumarate etc., so that preparation has acceptable compression property, as the hardness of tablet.

Globule can randomly comprise insoluble nuclear, for example has the activeconstituents by sprayed deposit on the nuclear.The material that is applicable to inert core is silicon-dioxide, glass or plastic resin particle.The plastic material that is fit to type is pharmaceutically acceptable plastics, as polypropylene or polyethylene, optimization polypropylene.The particle diameter of the insoluble nuclear of this class is 0.01-2mm, preferred 0.05-0.5mm, more preferably 0.1-0.3mm.

In one embodiment, the ductility of film can be 500-20000kJ/m ³In another embodiment, ductility is 2500-20000kJ/m ³In another embodiment, ductility is 10000-20000kJ/m ³

On the other hand, the invention provides and improve the pharmaceutical preparation that discharges, said preparation comprises

A) comprise pharmacological component and optional one or more pharmaceutically acceptable vehicle drug core and

B) film clothing, this film clothing comprises:

I) acrylate copolymer,

Ii) vinyl acetate polymer and

Iii) stablizer,

Film clothing wherein deposits from liquid, aqueous.In one embodiment, the film clothing comprises one or more stablizers.Stablizer can comprise one or more small molecules stablizers (molecular weight is less than 15KD) and/or one or more macromole stablizers (molecular weight is greater than 15KD).In another embodiment, dressing comprises molecular weight and is lower than the 0.5%w/w at least that the stablizer of 15KD and 4%w/w at least that its total amount is acrylate copolymer and/or its total amount are vinyl acetate polymer.

One preferred aspect, the invention provides the pharmaceutical preparation that improve to discharge, said preparation comprises

B) film clothing, this film clothing comprises

I) acrylate copolymer and

Ii) vinyl acetate polymer,

Wherein the film clothing deposits from liquid, aqueous.

Pharmacological component can be the form of a plurality of globules, and this globule randomly comprises one or more pharmaceutically acceptable vehicle, the film clothing coating as defined above of each globule wherein.This class film dressing globule can be packed dosage form or be mixed with capsule, and for example hard gelatin capsule perhaps adopts currently known methods to be pressed into tablet with optional other pharmaceutically acceptable additive that adds.The globule of dressing by the known routine techniques compacting of this area professional and technical personnel in flakes.In this course of processing, also can add other suitable material.For example, during the film-making step, can use suitable weighting agent, as Microcrystalline Cellulose, talcum, stearyl-sodium fumarate etc., so that preparation has acceptable compression property, as the hardness of tablet.The diameter of suitable globule is 0.01-2mm, preferred 0.05-1.0mm, more preferably 0.1-0.7mm.

One preferred aspect in, the invention provides the preparation that improve to discharge, wherein compare with the tablet that discharges immediately, pharmacological component discharges the long time, for example is longer than 3 hours.Pharmacological component in the preparation preferably discharges 10-24 hour, for example 18-22 hour.

Pharmacological component preferably has the activity of treatment cardiovascular disorder.Particularly, pharmacological component is a beta-adrenergic blocking agent.Beta-adrenergic blocking agent alleged among the application comprises, but be not limited to be selected from following compound: acebutolol, alprenolol, amosulalol, Arottnolol, atenolol USP 23, befunolol, betaxolol, bevantolol, bisoprolol, Bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butofilolol, Carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, Sch-19927, epanolol, indenolol, Trate, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivolol, nipradolol, oxprenolol, perbutolol, pindolol, practolol, Pronethalol, Proprasylyte, sotalol, Sulfinalol, talinolol, Tertatolol, tilisolol, timolol, toliprolol and xibenolol, with and steric isomer and its pharmacologically acceptable salt or solvate, the perhaps solvate of this class salt.Preferred beta-adrenergic blocking agent is metoprolol or its pharmacologically acceptable salt.

On the other hand, the invention provides and improve the metoprolol preparation that discharges, said preparation comprises:

A) comprise metoprolol or its pharmacologically acceptable salt and optional one or more pharmaceutically acceptable vehicle the metoprolol core and

B) film clothing as defined above.

One preferred aspect, the core that comprises metoprolol or its pharmacologically acceptable salt comprises a plurality of globules, this globule comprises metoprolol or its pharmacologically acceptable salt and one or more optional pharmaceutically acceptable vehicle, wherein each globule is coated with film clothing as defined above.Globule preferably has foregoing inert core.

The suitable pharmacologically acceptable salt of metoprolol comprises tartrate, succinate, fumarate or benzoate, especially succinate.Also can use metoprolol or its salt, particularly benzoate or the sorbate of S-enantiomorph.

Film clothing of the present invention comprises the mixture of acrylate copolymer, vinyl acetate polymer and optional one or more stablizers.Preferred film clothing of the present invention comprises acrylate copolymer, as Tg less than the acrylic copolymer of room temperature and Tg mixture greater than the vinyl acetate polymer of room temperature.

In one embodiment, the weight ratio of acrylate copolymer (AP) and vinyl acetate polymer (VP) is 0.1/99.9-99.9/0.1 in the film clothing.The weight ratio of AP and VP is preferably 5/95-95/5 in the film clothing.The weight ratio of AP and VP 20/80-80/20 more preferably in the film clothing.The weight ratio of AP and VP most preferably is 30/70-70/30 in the film clothing.

Term acrylate copolymer used herein is meant water-insoluble copolymer (being both to be insoluble to the multipolymer that gastric juice also is insoluble to intestinal juice pH) or comprises two or more following monomeric blends: its acrylate or methacrylic ester, especially methyl esters, ethyl ester, propyl ester and butyl ester, and the water-insoluble derivative of acrylic or methacrylic acid.Also comprise water-insoluble hydroxylation acrylate and methacrylic ester.

The one group of preferred acrylate copolymer that is used for this application comprises ethyl propenoate/methylmethacrylate copolymer, for example dispersion Eudragit  NE30D and/or Kollicoat  EMM30D.In this was preferably organized, the weight ratio of ethyl propenoate/methyl methacrylate was about 2/1.

The term vinyl acetate polymer can comprise multipolymer or its adulterant with polyethylene, poly-nitric acid vinyl acetate, polyvinyl chloride, polyvinyl alcohol, polyvinylpyrrolidone or poly(vinylidene fluoride).Vinyl acetate polymer also can comprise the multipolymer with dialkyl maleate, stearic acid vinyl ester and fumaric acid alkyl ester.Preferred vinyl acetate polymer is dispersion Kollicoat  SR30D (BASF AG, Ludwigshafen, Germany).

In a preferred embodiment of the invention, acrylate copolymer and vinyl acetate polymer are by Eudragit  NE30D and/or Kollicoat  EMM30D in film clothing or the preparation compositions as defined above, and Kollicoat  SR30D.Stablizer is Nonoxynol100 and/or Sodium Lauryl Sulphate BP/USP (SDS) and polyvinylpyrrolidone.

The term stablizer comprises any molecule that can guarantee and keep the latex dispersion characteristic.Molecular weight is lower than the total concn of small molecules stablizer of 15KD less than the 4%w/w of acrylate copolymer and/or less than the 0.5%w/w of vinyl acetate polymer, and molecular weight be higher than the concentration of the stablizer of 15KD can suitably be selected from arbitrarily 0%w/w to more than.

The example of the stablizer that is fit to includes, but are not limited to:

Nonionogenic tenside is as Arlacels (Span series); Polysorbate class (Tween series); Polyoxy ethylization glycol monoether (as Brij series); Polyoxyethylated alkylphenol class (as Triton series or Igepal series, as Nonoxynol); Alkyl glucoside class (as the lauryl maltoside); Sucrose fatty ester (as the lauric acid sucrose ester); The Saponaria officinalis glycoside; Or its mixture;

Amphoterics is as betaines;

Anion surfactant is as sulphated fatty alcohol, as Sodium Lauryl Sulphate BP/USP SDS; Sulfated polyoxy ethylizes pure; Other class is as dioctylsulfosuccinat; Biliary salts (for example dihydroxyl biliary salts such as Sodium desoxycholate, trihydroxy-biliary salts such as Sodium glycocholate etc.); Fusidate (as the dihydro fucidin) etc.;

Cats product is as the ammonium compound class;

Soap class, fatty acid and lipoid and salt thereof are as the phosphatide (as dialkyl group phosphatidylcholine, dialkyl group phosphatidylserine etc.) of paraffinic acid (as sad, oleic acid), monoglyceride (as XU 61518.10), neutral, positively charged or negative charge; Monoglyceride; Phosphatide; Derivatived cellulose; Polysaccharide; Other natural polymer; Synthetic polymer (as polyvinylpyrrolidone); Other material is as shellac; Wax; Nylon; Stearate; Lipoid; Paraffin etc.

Also can be with these combinations of materials.

Adopt technology known in the art to reduce the concentration or the removal stablizer wherein of the stablizer that exists in the dispersion.These examples comprise (people such as M C Wilkinson, Adcances inColloid and Interface Science 81,77 (1999)), but be not limited to dialysis, microfiltration, slurries exchange, ultrafiltration, saturating filter, cross-flow microfiltration, centrifugal-decant, ion-exchange, resins exchange, active carbon cloth, stripping, gel-filtration and particular polymeric technology.Reducing stabilizer concentration can followingly carry out: every kind of dispersion before mixing is used cleaning procedure separately, perhaps before the spray film blended dispersion is used cleaning procedure.

The term softening agent that the present invention uses is meant that one or more following materials, phenylformic acid benzyl ester, chlorobutanol, Uniflex DBS, diethyl phthalate, glycerine, mineral oil and Wool wax alcohol, Vaseline and Wool wax alcohol, polyoxyethylene glycol, propylene glycol, sorbyl alcohol, triacetin, triethyl citrate (select from Handbook of PharmaceuticalExcipients, the 2nd edition, A.Wade and P.J.Weller edit, ThePharmaceutical Press, London 1994).It is particularly advantageous making plasticizer dosage keep minimum or fully it be removed for the present invention, because use softening agent may influence the stability of film clothing in the film clothing, this may be caused by micromolecular migration, and this effect makes the film clothing show variation on the performance with the passing of time.On the other hand, the present invention includes film clothing composition, film clothing or the preparation described in any one embodiment as the front, be characterised in that wherein not contain softening agent as defined above, perhaps have very low amount, as 0.005-0.5%, the softening agent of 0.01-0.1% weight especially.

Suitable liquid, aqueous water and the organic liquid miscible with water of comprising, low-level chain triacontanol for example is as ethanol, propyl alcohol and Virahol.Based on the viewpoint of safety, preferably the ratio of organic liquid should remain on minimumly, but can tolerate as the amount of 0-20% volume on a small quantity.Preferred liquid is water.

Film clothing composition is particularly suitable for using as aqueous film clothing composition, wherein makes water as liquid application film clothing.When liquid is water, latex is EUDRAGIT NE 30 D and vinyl acetate polymer preferably, for example be respectively Eudragit  NE30D (R  hm Pharma) and/or Kollicoat  EMM30D (BASF), and Kollicoat  RS30D (BASF).Present method is useful especially, so it does not need the unacceptable organic solvent of environment for use, and some such organic solvent is also because there is processing problems in their combustibility, and this method has also been eliminated many problems that above-mentioned aqueous coatings runs into.

On the other hand, the invention provides preparation film clothing method for compositions.Therefore, a kind of preparation film clothing method for compositions that provides is included in 0-100 ℃, for example mix acrylic acid polymer dispersion and vinyl acetate polymer dispersion in 20-100 ℃ the temperature range simply, before or after mixing, reduce the concentration that may be present in the stablizer in the dispersion.

In another embodiment of this method, at room temperature acrylate copolymer and vinyl acetate polymer dispersion are mixed, before or after mixing, reduce the concentration that may be present in stablizer in the dispersion.

In another embodiment of this method, under temperature as defined above, acrylate copolymer, vinyl acetate polymer, described liquid and one or more stablizers are mixed together, before or after mixing, reduce the concentration that may be present in the stablizer in the dispersion.

Suitable mixing can realize by the method as stirring or jolting, but also can use other homogenizing method well known by persons skilled in the art.

On the other hand, the invention provides the method for coated drugs core, wherein film clothing composition is applied to core as defined above.Film clothing composition is preferably by for example using top-spray or bottom spray technology spray application in fluidized-bed.Other coating method that uses is that (Lachman edits as " Theoryand Practice in Industrial Pharmacy ", Lea andFeabiger published in 1986, the 3rd edition) described in, the dressing that uses pot with holes, Accela-cota, immersion ditch seam (swords), Glatt or immersion pipe in the standard coating pan, to carry out.

On the other hand, the invention provides and prepare the method for film clothing as defined above, this method comprises from removing liquid the film clothing composition as defined above.Suitable is with liquid by evaporation, as by for example in fluidized-bed spraying drying remove.

On the other hand, the invention provides and prepare the method for preparation as defined above, this method comprises with film clothing composition as defined above and applies drug core as defined above.

On the other hand, the invention provides the method for preparing preparation, wherein pharmacological component is a plurality of forms of globule as defined above, and this method comprises with film clothing composition as defined above and applies described a plurality of globule.

Embodiment

The following example is nonrestrictive and only provides in illustrational mode.This area professional and technical personnel should be clear, and it is guide that embodiment should be considered as, and the invention is not restricted to the composition that exemplified.The composition of wide scope can make the film clothing that the required characteristic of various concrete application is arranged.

Embodiment 1: by Eudragit  NE30D and Kollicoat  SR30D system film

By also stirring the film clothing that prepared Eudragit  NE30D and Kollicoat  SR30D in 2 hours gently in two kinds of dispersions of mixed at room temperature.The weight ratio of Eudragit  NE30D is in the different solutions: solution A: 20%, and solution B: 30%, solution C: 50% and solution D: 70%.Be poured over the free film (10 * 10cm that obtains dispersion in the Teflon mould by every kind of dispersion with about 10ml ²).Then this mould was placed the dry and film forming of the control phytotron of 25 ℃/60% relative humidity 19 hours.

Comparative Examples 1: by GMS/PS80/Eudragit  NE30D system film

Three kinds of mixtures of preparation GMS, PS80 and Eudragit  NE30D.Use different mixing condition mixing GMS and PS80 to detect the influence of stir speed (S.S.).According to following E, F or G, at first mix GMS and PS80.Then this an amount of dispersion is added to the composition that obtains expecting among the Eudragit  NE30D.Use GMS, PS80 and the Eudragit  NE30D of same amount to prepare solution E, F and G, i.e. 0.225g GMS, 0.090g PS80 and 15.0gNE30D, they provide the dispersion (the GMS/ particle is than=5%) that contains 1.5%w/w GMS.This composition is taken from the scientific paper of Petereit and Weisbrod nineteen ninety-five.

E:1 hour; With the 6000rpm homogenize; 65 ℃

F:20 minute; With the 3000rpm homogenize; 65 ℃

G:4 hour; Magnetic agitation; 65 ℃

Be poured over the free film (10 * 10cm that obtains three kinds of dispersions in the Teflon mould by every kind of dispersion with about 10ml ²), make this mould dry and film forming 18 hours under 25 ℃, 60% relative humidity.

Embodiment 2: mechanical property

For estimating mechanical property, on the material testing machine Hounsfield H5K-S that 250N load chamber is installed, carry out ductility test.Prepare several pieces films B, C and G and they are placed between two anchor clamps according to embodiment 1 (B and C) and Comparative Examples 1 (G).Sample length is 40mm, and width is 10mm, and when measuring with micrometer, typical thickness is 250 μ m.Stretching experiment is the 4mm/ branch, and all experiments are all carried out under the relative humidity of 23-23 ℃ and 28-30%.Every kind of film is carried out the replicate(determination) more than three times or three times and writes down ductility.

The result:

Table 1 has shown the ductility result of study.

Film	B	C	G
Film	B	C	G	Ductility (kJ/m ³) SD(％)	10693 27.6	20335 10.2	6550 28.6

The ductility of table 1. free film

The result shows, by mixing the film that two kinds of dispersions have obtained high ductility.

Embodiment 3: free membrane permeability

Several pieces film A-G according to embodiment 1 (film A, B, C and D) and Comparative Examples 1 (film E, F and G) preparation are placed in the diffuser casing, this diffuser casing is made up of two chambers and tested diaphragm is separated (Hj  rtstam, Thesis, Chalmers University ofTechnology, G  teborg 1998).A small amount of tritium is added to for taking out a spot of water and analyze scintillometer from receiving chamber in the chamber and with particular time interval for water.The slope of the data of time is calculated the water permeate of film by the amount of the mark water of transporting.

The result:

Table 2 has shown the water permeate result of study.

Film	A	B	C	D	E	F	G
Film	A	B	C	D	E	F	G	Perviousness (10 ^-12m ²/s)	22.3	19.6	5.4	2.3	30.1	40.5	51.0

Membrane permeability is executed in table 2. trip

This result demonstrates, and the amount increase of NE30D (A → D), perviousness reduces, and the perviousness of more deep mixing reduction Comparative Examples (G → E).

Embodiment 4: the preparation of dressing metroprolol succinate piller

Metroprolol succinate globule (size distribution is 0.40-0.63mm) is carried out dressing with film dispersion A, B, C and D.Dispersion is sprayed on the globule in laboratory scale fluidized-bed Wurster device.Coating conditions is as follows:

The heavy 200g of bed

Dressing solution～170g

Spray rate 4.6g/ branch

Atomization air pressure 2.5 crust

Fluidization air flow velocity 35m ³/ h

30 ℃ of inlet air temperatures

20 ℃ of outlet air temperatures

Make coated pellets then in fluidized-bed, in 40 ℃ of dryings (about 20 minutes).During this step, the fluidized bed air flow velocity is maintained at about 20m ³/ hour and atomization air pressure be 1 the crust.

Result: do not encounter problems during the processing, be clamminess as piller.

Embodiment 5: the metoprolol of coated pellets discharges

In USP dissolving device No.2 (revolving rotary propeller type), discharge with the metoprolol of the piller of the speed evaluation 100mg embodiment 4 of 100rpm.Test(ing) medium be 500ml pH be 6.8 and ionic strength equal the phosphate buffered saline buffer of 0.1M.Bath temperature fixes on 37 ℃.(light absorption ratio of measuring metoprolol in the 1cm pond at 274nm) analyzed in sampling.By measure based on release experiment in the light absorption ratio of standard metoprolol solution of the same media used determine the amount of the metoprolol that discharges.

The result:

Time/hour	1	2	4	6	8	10	12	16	20
Time/hour	1	2	4	6	8	10	12	16	20	(A) discharge % SD (%)	2.2 0	4.4 0	12.2 0	29.4 0	55.8 0	75.1 0	85.9 0	--- ---	99.9 0
(B) discharge % SD (%)	20.0 2.4	24.0 2.4	33.7 1.8	52.0 2.0	72.3 2.1	86.0 1.0	93.0 1.0	96.3 0.58	99.3 0.73	(A) discharge % SD (%)	2.2 0	4.4 0	12.2 0	29.4 0	55.8 0	75.1 0	85.9 0	--- ---	99.9 0
(B) discharge % SD (%)	20.0 2.4	24.0 2.4	33.7 1.8	52.0 2.0	72.3 2.1	86.0 1.0	93.0 1.0	96.3 0.58	99.3 0.73	(C) discharge % SD (%)	2.0 0	4.0 0	16.0 0	41.0 0	66.0 0	83.0 0	91.0 0	97.0 0	99.0 0
(D) discharge % SD (%)	13.0 1.0	19.3 0.58	31.3 0.58	48.0 0	63.3 0.58	76.3 0.58	85.0 1.0	90.3 0.58	95.3 0.58	(C) discharge % SD (%)	2.0 0	4.0 0	16.0 0	41.0 0	66.0 0	83.0 0	91.0 0	97.0 0	99.0 0

The ratio that table 3. piller discharges

Result's demonstration of table 3 can obtain near the constant release conditions, and improved release was 20 hours.

Embodiment 6: prepare tablet by dressing metoprolol piller

With in Turbula mixing tank T2C (Willy A.Bachofen, Switzerland), mixing about 4 minutes of embodiment 4 with the piller of film dispersion C dressing and the Microcrystalline Cellulose Avicel PH102 of equivalent.After adding 0.15% sodium stearyl fumarate, with this powder mass remix 2 minutes.After mix finishing, use the pressure of about 8kN, eccentric press (KilianSP300, Germany) go up this material is suppressed in blocks.Sheet heavily is about 200mg.

Result: do not encounter problems during the processing.

Embodiment 7: the release of the metoprolol of the sheet of coated pellets

Use USP dissolving device No.2 (revolving rotary propeller type),, discharge at 37 ℃ of metoprolols of studying the sheet of pressing embodiment 6 preparations down with the stir speed (S.S.) of 100rpm.Release medium is that 0.1M and pH are that 6.8 phosphate buffered saline buffer is formed by ionic strength.(light absorption ratio of measuring metoprolol in the 1cm pond at 274nm) analyzed in sampling.By measure based on release experiment in the light absorption ratio of standard metoprolol solution of the same media used determine the amount of the metoprolol that discharges.

The result:

The results are shown in table 4.When the piller of this result and table 3 being discharged result that (solution C) obtain and compares, has good consistence between these two groups of release characteristics as can be seen, therefore can draw such conclusion, can the piller compacting is in blocks, and can not lose improved release characteristics.

Time/hour	1	2	4	6	8	10	12	16	20
Time/hour	1	2	4	6	8	10	12	16	20	Discharge %	0	18	31	47	66	79	88	95	98

Table 4. tablet discharges ratio

Embodiment 8: adopt dialysis cleaning blended dispersion

Use in water (ELGA quality), the dialyse mixture of dispersion Eudragit  NE30D (R  hm Pharma) and Kollicoat  SR30D (BASF) (wherein containing 30%w/w Eudragit  NE30D and 70%w/w Kollicoat  SR30D) of Spectra/Por  dialysis membrane.When utilizing different molecular weight to hold back, because in different experiments, the size difference of film, so the volume of the amount of the hybrid dispersions of dialysis time, dialysis and water is also slightly different.Provided underlying condition among the following result.By the dialysis dispersion mixture of dry known quantity and the solid total content of weighing and determining mixture.Concentration by NF100 in the UV spectrometry NE30D dispersion of 276nm.(sulphur=11.1%w/w of SDS wherein, the nitrogen of PVP=12.6%w/w) and/or LC-MS (liquid chromatography-mass spectrography) measure the concentration of SDS and PVP in the Kollicoat dispersion by ultimate analysis.

The result:

Table I: the analysis of the dispersion of dialysis

The dialysis number of times	D1-4，7 ^a)	D2-4，4 ^a)
The dialysis number of times	D1-4，7 ^a)	D2-4，4 ^a)	Molecular retention	14 000D	100 000D
Total content	21.2％w/w ^b)(29.8％w/w) ^c)	17.3％w/w ^b)(29.8％w/w) ^c)	Molecular retention	14 000D	100 000D
Total content	21.2％w/w ^b)(29.8％w/w) ^c)	17.3％w/w ^b)(29.8％w/w) ^c)	NF 100 concentration	0.24％w/w ^d)(0.45％w/w) ^c)	0.28％w/w ^d)(0.45％w/w) ^c)
SDS concentration	0.04％w/w ^d)(0.14％w/w) ^c)	0.007％w/w ^d)(0.14％w/w) ^c)	NF 100 concentration	0.24％w/w ^d)(0.45％w/w) ^c)	0.28％w/w ^d)(0.45％w/w) ^c)
SDS concentration	0.04％w/w ^d)(0.14％w/w) ^c)	0.007％w/w ^d)(0.14％w/w) ^c)	PVP concentration	2.0％w/w ^d) (2.2％w/w) ^c)	1.3％w/w ^d)(2.2％w/w) ^c)

A) number of times represents to change the number of times of water and the fate of dialysis

B) the solid total concn after the dialysis

C) desired value of the non-dialysis mixture of two component prose style free from parallelisms of Shi Yonging

D) result of ultimate analysis or UV or LC-MS; Proofread and correct to 21.2% and 17.3% by 29.8% respectively for diluting effect.

As can be seen, reduced the amount of the stablizer that exists among commercially available dispersion Eudragit  NE30D and the Kollicoat  SR30D by the final dispersion of dialysis.

Embodiment 9: the dispersion by dialysis prepares free film

Be poured over the dispersion D1 of acquisition embodiment 8 in the Teflon mould and free film (10 * 10cm of D2 by every kind of dispersion with about 10ml ²).Then this mould is placed on and makes its dry and film forming 19 hours in the control phytotron of 25 ℃/60% relative humidity.Dispersion (D0) with not dialysis prepares free film to be used for comparison.Calculate forming of the film F0, the F1 that make by dispersion D0, D1 and D2 and F2 respectively by the concentration known of the stablizer of the dispersion shown in the last Table I and solid total content.The results are shown in Table II.The results of elemental analyses that has also comprised relevant SDS of free film and PVP in the Table II.

The result:

Table II: the content of the film of perviousness experiment

Film	F0	F1	F2
Film	F0	F1	F2	NF100	1.5％w/w ^a)	0.80％w/w ^a)	0.94％w/w ^a)
SDS	0.47％w/w ^a)1.7％w/w ^b)	0.13％w/w ^a)＜0.45％w/w ^b)	0.02％w/w ^a)＜0.45％w/w ^b)	NF100	1.5％w/w ^a)	0.80％w/w ^a)	0.94％w/w ^a)
SDS	0.47％w/w ^a)1.7％w/w ^b)	0.13％w/w ^a)＜0.45％w/w ^b)	0.02％w/w ^a)＜0.45％w/w ^b)	PVP	8.1％w/w ^b)6.2％w/w ^b)	6.7％w/w ^a)5.8％w/w ^b)	4.4％w/w ^a)3.4％w/w ^b)

A) the analysis desired value (seeing Table I) of the dispersion of Shi Yonging

B) results of elemental analyses

As can be seen, compare small molecular weight stablizer NF100 (M with the film that the F0 film that is obtained by the hybrid dispersions with not dialysis is made _w～4000D) and SDS (M _w～300D) amount has obviously reduced.(very likely the existing of sulphur that exists with the initiator form of polymerization process disturbed the SDS ultimate analysis)

Embodiment 10: free membrane permeability

Film F0, F1 and F2 that several pieces embodiment 9 are made are placed in the diffuser casing, and this diffuser casing is made up of two chambers and tested diaphragm is separated (Hj  rtstam, Thesis, Chalmers University of Technology, G  teborg 1998).A small amount of tritium is added to for taking out a spot of water and analyze scintillometer from receiving chamber in the chamber and with particular time interval for water.The slope of the data of time is calculated the water permeate of film by the amount of the mark water of transporting.For the stability of evaluated for film, before measuring, diaphragm was kept for 2 weeks in the moisture eliminator under the RT/60%RH.

The result:

Table III: the water permeate of making instant and 2 all caudacorias

Film	F0	F1	F2
Film	F0	F1	F2	P(m ^-12m ²/ s): new film	19.6	9.8	2.6
P(m ^-12m ²/ s): after 2 weeks	10.4(-47％)	7.0(-29％)	2.4(-7％)	P(m ^-12m ²/ s): new film	19.6	9.8	2.6

As can be seen, more effective dialysis (dialysis membrane is held back bigger molecule) obtains the film than low-permeability.In addition, for the film of being made by the dispersion of dialysis, film perviousness in time reduces not obvious.

Embodiment 11: the preparation of dressing metroprolol succinate piller

Metroprolol succinate globule (size distribution is 0.40-0.63mm) is carried out dressing with film dispersion D2.Before Cotton seeds, water is diluted to total solids level with this dispersion and is about 14%w/w.Dispersion is sprayed on the globule in laboratory scale fluidized-bed Wurster device.Coating conditions is as follows:

The heavy 200g of bed

Dressing solution～340g

Spray rate 4.6g/ branch

Atomization air pressure 2.5 crust

Fluidization air flow velocity 35m ³/ h

50 ℃ of inlet air temperatures

28 ℃ of outlet air temperatures

Embodiment 12: the metoprolol of coated pellets discharges

In USP dissolving device No.2 (revolving rotary propeller type), the metoprolol release of the about 100mg piller that obtains with the speed evaluation embodiment 11 of 100rpm.Test(ing) medium be 500ml pH be 6.8 and ionic strength equal the phosphate buffered saline buffer of 0.1M.Bath temperature fixes on 37 ℃.(light absorption ratio of measuring metoprolol in the 1cm pond at 274nm) analyzed in sampling.By measure based on release experiment in the light absorption ratio of standard metoprolol solution of the same media used determine the amount of the metoprolol that discharges.Experimentize in the moisture eliminator of RT/60%RH, storing the piller in 2 weeks before fresh piller (0 week) and the releasing research.

The result:

Table IV: the metoprolol of coated pellets discharges

Time (hour)	1	2	4	6	8	10	12	16	20
Time (hour)	1	2	4	6	8	10	12	16	20	Discharge %-0 week	12	18	26	34	41	48	54	70	84
Discharge %-2 week	9	14	22	31	37	44	51	66	80	Discharge %-0 week	12	18	26	34	41	48	54	70	84

As can be seen, during studying (0-20 hour), the release of metoprolol is near constant.Only can detect a small amount of minimizing of burst size for the piller of instant research and the piller in preparation 2 weeks of back, consistent with the infiltrative a small amount of reduction of report among the embodiment 10.In addition, identical in " 0 week " rate of release during with " 2 week ".

Claims

1. one kind is applicable to coated pharmaceutical preparation to produce the film clothing composition of improved release, and said composition comprises the mixture of following material:

A) aqueous dispersion, it contains ethyl propenoate/methylmethacrylate copolymer particle of the 28.5%w/w that has an appointment,

B) vinyl acetate polymer aqueous dispersion, wherein contain the 27%w/w that has an appointment polyvinyl acetate and

C) liquid, aqueous.

2. the film clothing composition of claim 1 also comprises d) stablizer.

3. the film coated composition of claim 2, stablizer wherein is Nonoxynol 100 or sodium lauryl sulphate (SDS) and/or polyvinylpyrrolidone.

4. according to each film coated composition of aforementioned claim, wherein the weight ratio of ethyl propenoate/methylmethacrylate copolymer is about 2/1.

5. can require the film clothing that each composition removing liquid body obtains in 1,2,3 or 4 by Accessory Right.

6. one kind covers drug core to produce the film clothing of improved release, and wherein core comprises pharmacological component and randomly contains one or more pharmaceutically acceptable vehicle, and wherein the film clothing comprises:

A) ethyl propenoate/methylmethacrylate copolymer, wherein its weight ratio be about 2/1 and

B) vinyl acetate polymer,

Wherein the film clothing deposits from liquid, aqueous.

7. the film clothing of claim 6 also comprises c) stablizer.

8. the film clothing of claim 7, wherein stablizer is Nonoxynol 100 or sodium lauryl sulphate (SDS) and/or polyvinylpyrrolidone.

9. claim 7 or 8 film clothing or claim 2,3 or 4 coated composition, wherein the molecular weight of stablizer is lower than 15kD, and its total amount is less than the 4%w/w of acrylate copolymer and/or the total amount 0.5%w/w less than vinyl acetate polymer.

10. pharmaceutical preparation that improves release, said preparation comprises

A) comprise pharmacological component and randomly contain one or more pharmaceutically acceptable vehicle drug core and

B) comprise the film clothing of following material:

I) ethyl propenoate/methylmethacrylate copolymer, wherein its weight ratio be about 2/1 and

Ii) vinyl acetate polymer, wherein film clothing deposition from liquid, aqueous.

11. the preparation of claim 10 wherein also contains iii) stablizer.

12. the preparation of claim 11, wherein stablizer is Nonoxynol 100 or sodium lauryl sulphate (SDS) and/or polyvinylpyrrolidone.

13. the preparation of claim 11 or 12, wherein the molecular weight of stablizer is lower than 15kD, and its total amount is less than the 4%w/w of acrylate copolymer and/or the total amount 0.5%w/w less than vinyl acetate polymer.

14. pharmaceutical preparation that improves release, said preparation comprises pharmacological component, this activeconstituents is a plurality of globules, and this globule randomly comprises one or more pharmaceutically acceptable vehicle, and wherein each globule is coated with the film clothing of each definition in the claim 5,6,7,8 or 9.

15. each preparation in the claim 10,11,12,13 or 14, wherein pharmacological component has the treating cardiovascular disease activity.

16. the preparation of claim 15, pharmacological component wherein is a beta-adrenergic blocking agent.

17. the preparation of claim 16, pharmacological component wherein are metoprolol or its pharmacologically acceptable salt.

18. the preparation of claim 17, wherein metoprolol salt is tartrate, succinate, fumarate or benzoate.

19. each composition in the claim 1,2,3 or 4, wherein liquid is water.

20. the composition of aforementioned any claim, film clothing or preparation, wherein ethyl propenoate/methylmethacrylate copolymer is by Eudragit ^NE30D and/or Kollicoat ^EMM30D provides.

21. the composition of aforementioned any claim, film clothing or preparation, vinyl acetate polymer wherein is with Kollicoat ^SR30D provides.

22. the composition of aforementioned any claim, film clothing or preparation, wherein the weight ratio of acrylate copolymer and vinyl acetate polymer is 20/80-80/20 in the film clothing.

23. one kind prepare claim 1,2,3 or 4 or claim 19,20,21 or 22 in each film clothing method for compositions, this method is included in 0-100 ℃ scope with acrylic acid polymer dispersion and vinyl acetate polymer dispersion with randomly mix liquid, aqueous.

24. one kind prepare claim 5,6,7,8 or 9 or claim 20,21 or 22 in each the method for film clothing, this method comprise Accessory Right requirement 1,2,34 or claim 19,20,21 or 22 in remove liquid in each the composition.

25. a method for preparing each preparation among claim 10-18 or claim 15-18 or the claim 20-22, this method comprise with claim 1,2,3 or 4 or claim 19,20,21 or 22 in each film clothing composition coating medicine core.

26. a method for preparing each preparation among claim 14-18 or the 20-22, this method comprise with claim 1,2,3 or 4 or claim 19,20,21 or 22 in each film clothing composition coat a plurality of globules.

27. a pharmaceutical preparation that improves release, said preparation comprises

A) pharmacological component, this activeconstituents is a plurality of globules, and this globule randomly comprises one or more pharmaceutically acceptable vehicle; With

B) dressing on each globule, wherein said dressing contains:

Ii) vinyl acetate polymer.

28. the pharmaceutical preparation that the improvement of claim 27 discharges, wherein the weight ratio of acrylate copolymer and vinyl acetate polymer is 20/80 to 80/20 in the film clothing.

29. the pharmaceutical preparation that the improvement of claim 27 or 28 discharges, wherein the film clothing deposits from liquid, aqueous.

30. the pharmaceutical preparation that each improvement discharges among the claim 27-29, wherein the film clothing also contains Nonoxynol 100.

31. the pharmaceutical preparation that each improvement discharges among the claim 27-30, wherein the film clothing also contains sodium lauryl sulphate (SDS) and/or polyvinylpyrrolidone.

32. the pharmaceutical preparation that each improvement discharges among the claim 27-31, pharmacological component wherein is metoprolol or its pharmacologically acceptable salt.

33. the pharmaceutical preparation that the improvement of claim 32 discharges, pharmacological component wherein is the metoprolol succinate.

34. a pharmaceutical preparation that improves release wherein contains:

A) metoprolol succinate, it is a plurality of globules, and this globule randomly comprises one or more pharmaceutically acceptable vehicle; With

B) dressing on each globule, wherein said dressing contains:

Ii) vinyl acetate polymer.

35. the pharmaceutical preparation that the improvement of claim 34 discharges, wherein the weight ratio of acrylate copolymer and vinyl acetate polymer is 20/80 to 80/20 in the film clothing.

36. the pharmaceutical preparation that the improvement of claim 34 or 35 discharges, wherein the film clothing deposits from liquid, aqueous.

37. the pharmaceutical preparation that each improvement discharges among the claim 34-36 wherein also contains Nonoxynol 100 in the film clothing.

38. the pharmaceutical preparation that each improvement discharges among the claim 34-37 wherein also contains sodium lauryl sulphate (SDS) and/or polyvinylpyrrolidone in the film clothing.

39. a pharmaceutical preparation that improves release wherein contains:

A) drug core, it contains the metoprolol succinate as pharmacological component, and randomly comprises one or more pharmaceutically acceptable vehicle; With

B) film clothing, it contains:

I) acrylate copolymer, wherein this acrylate copolymer is ethyl propenoate/methylmethacrylate copolymer, wherein its weight ratio be about 2/1 and

Ii) vinyl acetate polymer, wherein this polymkeric substance is a polyvinyl acetate, wherein the film clothing deposits from water.

40. the pharmaceutical preparation that the improvement of claim 39 discharges, wherein the weight ratio of acrylate copolymer and vinyl acetate polymer is 20/80 to 80/20 in the film clothing.

41. the pharmaceutical preparation that the improvement of claim 39 or 40 discharges wherein also contains Nonoxynol 100 in the film clothing.

42. the pharmaceutical preparation that each improvement discharges among the claim 38-41 wherein also contains sodium lauryl sulphate (SDS) and/or polyvinylpyrrolidone in the film clothing.

43. the pharmaceutical preparation that each improvement discharges among each or the claim 27-42 among the claim 10-18, wherein active constituents of medicine discharged from preparation in 10-24 hour.

44. the pharmaceutical preparation that the improvement of claim 43 discharges, wherein active constituents of medicine discharged from preparation in 18-22 hour.

45. a tablet wherein contains among the claim 27-38 each film dressing globule and randomly contains other the pharmaceutically acceptable additive that is pressed in the tablet.

46. the pharmaceutical preparation that the improvement of each tablet form discharges among the claim 39-42.