Matrix pellets of the prolonged action


(57) Abstract:

The granules have a ball or lenticular shape with a single maximum diameter of 0.5 to 4 mm Granules consist of 0.1 to 87 wt.% at least one biologically active compounds, 5-50 wt.% at least one water-insoluble polymer, 5-45 wt.% at least one lipophilic component as specified plasticizer polymer, 3-40 wt.% natural or semi-synthetic polymer gel, 0-50 wt.% one or more standard excipients. Polymer gel is a water-soluble derivative of cellulose or water-soluble polysaccharide or a mixture thereof. Pellets obtained by extruding the molten mixture of the components at 50-200C and continuous molding. Matrix granules provide full controlled release of the active agent by an anemic profile. 7 C.p. f-crystals, 4 PL.

The invention relates preferably to a solid pharmaceutical form prolonged action (granules), in which the active principle vraboteni in a mixture of water-insoluble polymer, lipid and colloidal high-viscosity water-soluble, gel-forming or at least spoogie melt polymer and molding preferably by circumcision in the hot condition.

Suitable for melt extrusion process and slow release of the active agent matrix substances are plastificated under pressure and heat treatment of polymers and lipids. The authors Speiser, etc. in the source Pharm. Acta Helv. , 46, S. 31, 1971, describe the application of soluble in gastric juice epoxy amine resins and soluble in intestinal juice copolymers of vinyl acetate and crotonic acid dosage forms obtained by injection molding (see US patent N 3432592). The authors Huttenrauch and Schmeiss investigated the release of active model started from the resulting piston extrusion of the polyethylene matrix (see Pharmazie 30, S. 229, 536, 1975).

The authors mank Tuesday and other sources Pharmazie 44, S. 773, 1989, Pharmazie 45, S. 592, 1990 describe the release of the active beginning of the insoluble thermoplastic matrices. These methods do not allow to operate freely set by the slow release of the active agent, and, in particular, polyethylene matrix, the active principle is not fully released. Here added disadvantages of injection molding, such as a long time exposure at high temperature and high loss of material due to the presence of Gating channels, content to the public speed is extremely high.

Authors N. A. El Gindy, etc. in the source Acta Pharm. Technol. 33, 208-211 C., 1987, describe receiving tablets by melting mixtures with water-soluble active principles (glycols and block copolymers of polyoxyethylene and polyoxypropylene) and insoluble polymers and subsequent pressing. Depending on the selected polymers form data release of the active principle, more or less quickly. The method of obtaining periodical.

Authors N. Follonier, etc. in the source Capsule News 1, 1991, 2 and in the summary of the 6th International conference on pharmaceutical technology, held June 2-4, 1992 in Paris, describe obtaining pellets of the prolonged action by melt extrusion at adenocarcinom the extruder. The solidified extrudate pulverized in the knife granulator. As the matrix used water-insoluble polymers. Besides the size of the granules was investigated various additives to control the release of active principle. The polymer matrix comprised of a copolymer of ethylene and vinyl acetate. The release of the active principle of these forms along the kinetics zero order", however, failed.

In US patent N 3432592 described injection molding containing the active principle of polymer melts. According to patago polymer mainly describes non-standard in the pharmaceutical industry complex product of condensation aminodiol and epoxide. The slow release of the active principle is provided by the simultaneous use of sparingly soluble in the digestive juices of thermoplastics. Specified in the source combination of polymers unsuitable for slow release of water soluble active principles of the granules due to the unfavorable ratio of surface/volume. In General, the slow release of the active principle in this mode, poorly managed, with a strong deceleration portion of the active agent remains in the undissolved granules in the form (release of the active principle according to the t-law: see T. Higuchi, J. Pharm. Sci. 52, S. 1145-1149, 1963). The release of the active principle on the kinetics zero order" failed (see table 1).

Extrusion containing the active principle of the molten polymer, preferably copolymers of vinylpyrrolidone, known from applications EP N 240904 and 240906. Establishing a specific release profile of the active principle by using mixtures of polymers there is not described. In addition, it was found that the thus obtained products in many cases are metastability during storage, the slow effect decreases with time.

In the application EP N 204596 described obtaining granules by incorporating the active agent in Matera two lipids, one of which is dissolving the polymer(s) property or capable of gelation of the polymer, and the other properties of a lubricant or a lipid that combines both of these properties, and if necessary one or more additives selected from the group of fillers and anti-static tools. A significant drawback is the fact that in the case of large quantities (more than about 20%) "negidrirovannogo polymer" release the active agent for the preparation of the prolonged action is too fast, and in the case of smaller quantities of the mode of release varies sharply after storage, and the release is incomplete.

The objective of the invention is to obtain granules preferably for pharmaceutical purposes, of which the active principle is released to be installed to the profile of the slow release of the active principle, i.e. with any slowdown, but completely. This task should be solved matrix granules, that is, without printed on the core granules slow film coverings.

In addition to managing the release of the active agent due to the composition of the matrix (matrix granules prolonged action) should be designed simply and not the ez previous mixing or pre-granulation of the components and without the final spheronization or similar molding/rounded granules after receipt.

It was found that by extruding a melt containing certain active principle of polymer matrix and subsequent continuous molding simple provide granules of the extended action with a high concentration of the active agent, including excellent water-soluble active principles, with only one change in the composition of the polymer matrix without controlling the diffusion of the polymer coatings are achieved mounted on a broad range of release profiles of the active agent with high stability during storage.

The polymer matrix according to the invention is essentially a plasticized suitable lipophilic substances matrix consisting of not soluble in water and gastrointestinal fluids polymer. In contrast to the above mentioned prior art solution provides a freely installable on a wide range of the release profile of the active principle, if in a matrix of insoluble polymer and a lipophilic component additionally gets used gelling, i.e. vysokokachestvenny in water (hydrocolloid) or at least nabuhay polymer. In the case above in origimage polymer, however, when too a small amount of polymer, there is a danger of disintegration of the drug, and when there is too much polymer release of the active agent may be incomplete, part of the active principle is fully enclosed and inaccessible. Due to the proposed addition of gelling is achieved by "divide matrix by swelling of this polymer, and the active principle can be fully released (see tab. I).

The proposed polymer matrix for the matrix granules prolonged action represents a new combination of inert lipophilic and hydrophilic matrices, which can be thermoplastic processing.

Therefore, an object of the invention is a solid pharmaceutical form prolonged action (matrix granules), we obtain the one-stage method in the melt extrusion in an extruder, preferably in dvuhserijnom extruder or adenocarcinom extruder with a mixing section at 50-200oC, and a continuous molding process (preferably by circumcision in the hot condition) mixture of the following composition:

a) at least one biologically active compound ("active principle", preferably medical or veterinary particular 45-75 wt.%,

b) at least one non-soluble in water and gastrointestinal fluids natural, semisynthetic or synthetic polymer in the amount of 5-50, preferably 10-40 wt.%,

C) 5 to 45, preferably 10-35 wt.%, at least one water-insoluble lipophilic component with the properties of the plasticizer relative to polymer b) and the properties of the lubricant or lubricants

g) 3-40, preferably 5-25 wt.%, at least one colloidal soluble in water or gastrointestinal fluids, forming highly viscous solutions or gels, or at least nabukelevu natural or semi-synthetic hydrophilic polymer (hereinafter used conditional reduction "gelling"), and

d) 0-50, preferably 0-40 wt.%, one or more standard excipients.

Interest instructions apply to the total weight of the granules.

Solid pharmaceutical forms of the extended steps according to the invention are, for example, granules, preferably granules delayed release of the active principle. The obtained molded product can then be milled to obtain a powder and used in this form (for example, in the solid is x coatings (such as, for example, polyacrylates, esters of cellulose, as phthalates of hydroxypropylmethylcellulose, and ethers of cellulose, such as, for example, ethylcellulose, hypromellose or hydroxypropylcellulose) is not excluded, but, as a rule, is not required.

Tableting of pellets by extrusion is possible in many cases. Pressing recommended, inter alia, in cases where the dose of the active agent is high and, thus, would be undesirable large dosage forms. In the control conditions tabletting (in particular, the pressure) of the individual pellets can fall apart, so that the release of the active principle may not significantly differ from those pellets loaded in capsules in non-compacted form. Pelleting reduces the volume of the dosage form, which may be predominant in some cases. By adding agents from osmotic action (e.g., inorganic salts) can then be obtained granules that can be used as an osmotically active layer swelling (see international application WO N 92/04011) to ensure release of the active principle, for example, tablets (PEFC what about the invention shall be interpreted to mean any substances with a pharmaceutical effect and as fewer side effects, because they do not disintegrate in the processing conditions. The amount of active agent per dose, and the concentration can verheiratet within wide limits depending on the activity and the desired rate of release. The only condition is sufficient to achieve the desired effect. Thus the concentration of the active agent may be 0.1-87, preferably 1-80, in particular between 45 and 75 wt.%. The active principles according to the invention are also, as already mentioned, other biologically active compounds. The preferred compounds are betamethason, thioctic acid, sotalol, salbutamol, norfenefrine, silymarin, digidroergotamin, buflomedil, etofibrate, indomethacin, oxazepam, beta-acetyldigoxin, piroxicam, haloperidol, ISMN, amitriptyline, diclofenac, nifedipine, verapamil, pyritinol, nitrendipin, doxycycline, Bromhexine, methylprednisolone, clonidine, fenofibrate, allopurinol, pirenzepine, levothyroxine, tamoxifen, metildigoxin, o-(beta-hydroxyethyl)rutozid, propicillin, acyclovir-Mononitrate, paracetamol, naftidrofuryl, pentoxifylline, propafenone, acebutolol, L-thyroxine, tramadol, parlodel, loperamide, ketotifen, fenoterol, Ca-DubaiSat, propranolol, minocycline xanthineolytica, digitoxin, flunitrazepan, benzilan, dexapanthenol, pindolol, lorazepam, diltiazem, piracetam, dentists, furosemide, bromazepam, flunarizin, erythromycin, metoclopramide, acemetacin, ranitidine, biperiden, metamizol, doxepin, Dikili-chlorazepate, tetrazepam, estramustine, terbutaline, captopril, maprotiline, prazosin, atenolol, glibenclamide, cefaclor, etilefrine, cimetidine, theophylline, hydromorphone, ibuprofen, primidone, clobazam, oxaceprol, medroxyprogesterone, flecainide, Mg-pyridoxal-5-postinpatient, gamename, autofilelinkedfile, vincamine, Cinnarizine, diazepam, Ketoprofen, flupentixol, molsidomin, glibornuride, dimetindene, melperone, socfinal, Dihydrocodeine, clomethiazole, clemastin, glisoxepide, kallidinogenase, oksifedrin, baclofen, carboxymethylcysteine, thioridazine, betahistine, L-tryptophan, myrtol, bromelain, prenilamin, salazosulfapiridin, astemizole, sulpirid, benserazide, dibenzepin, acetylsalicylic acid, miconazole, nystatin, ketoconazole, Na picosulfate, cholestyramine, gemfibrozil, rifampicin, fluorocortisone, meksiletin, amoxicillin, terfenadine, ester mucopolysaccharidoses acid, triazolam, mianserin, tiaprofenic acid, antinicotine, Na-valproat, mebeverine, Bisacodyl, 5-aminosalicylic acid, dihydralazine, magaldrate, phenprocoumon, amantadine, naproxen, carteolol, famotidine, hydrochlorothiazide methyldopa, auranofin, estriol, nadolol, levomepromazine, doxorubicin, medianext, azathioprine, flutamide, norfloxacin, fendilin, prikalivaetes, aeschin.

Particularly preferred are solid solutions of active principles, such as, for example, acetaminophen (paracetamol), acetohexamide, acetyldigoxin, acetylsalicylic acid, achromycin, anipamil, benzocaine, beta-carotene, chloramphenicol, chlordiazepoxide, chlormadinone, chlorthiazide, cinnarizin, clonazepam, codeine, dexamethasone, diazepam, difenacoum digitoxin, digoxin, digidroergotamin, drotaverine, flunitrazepam, furosemide, gramicidin, griseofluvin, hexobarbital, hydrochlorothiazide, hydrocortisone, hydroflumethiazide, indometacin, Ketoprofen, lonetal, medazepama, mefruside, methandrostenolone, methylprednisolone, metilsulfate (=solfataric), Kalinicheva acid, nifedipine, nitrazepam, nitrofurantoin, nystatin, estradiol, papaverine, phenacetin, phenobarbital, phenylbutazone, phenytoin, prednisone, reserpine, spironolactone, streptomycin, sulfadimidine (=sulfamethazine), sulfa is tolbutamide, trimethoprim, tyrothricin.

The term "solid solutions are known to the expert (see Chiou and Riegelman, J. Pharm. Sci. 60, S. 1281-1302, 1971). In solid solutions of active principles in polymers, the active principle present in the matrix in the molecular-disperse distribution.

Not soluble in water and gastrointestinal fluids natural, semisynthetic or synthetic polymer (b) can represent, for example, a simple cellulose ether as ethylcellulose or ester of cellulose as cellulose diacetate, cellulose triacetate, propionate, cellulose acetate and butyrate cellulose acetate. In addition, you can apply insoluble polysaccharides such as chitin and chitin derivatives and microcrystalline cellulose. Examples of suitable synthetic polymers are esters of poly(meth)acrylic acid, Homo - and copolymers of vinyl acetate, etc., Preferred are ethyl cellulose.

Water-insoluble lipophilic component) to the properties of the plasticizer relative to polymer b) and the properties of the grease or lubricant may represent, for example, fatty alcohol series, as cetyl alcohol or stearyl alcohol, fatty acid like stearic acid or wax, for example afiring series fatty acids and vegetable oils, hydrogenated vegetable oils, mono-, di - and triglycerides, as well as the lecithins. In addition, you can apply complex polyglycidylether fatty acids, saturated polyoxethylene glycerides, polyethylene oxides, polypropyleneoxide or their block copolymers, esters of phthalic acid, acetylated monoglycerides. Preferred are mono-, di - or triglycerides or mixtures thereof and complicated polyglycidylether fatty acids. Preferred lipophilic components), the value of the hydrophilic-lipophilic balance which is 1-9, in particular 2-5.

As geleobrazovanie g), i.e., forming in water viscous colloidal solutions or gels, or at least swellable in water of the polymers are suitable, in particular, water-soluble derivatives of cellulose, as alkylsilanes, hydroxyethylcellulose, hydroxyalkyl-alkylaryl, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylmethylcellulose, hypromellose, further karboksimetsiltsellyulozy, carboxyethyl-alkylaryl, esters of karboksimetsiltsellyulozy, such as carboxylate is, as, for example, alginic acid and their salts (alginates), carragenan, guar gum, xanthan gum, agar-agar, gum Arabic and related rubber, pectins, galactomannans, tragant, further water-soluble derivative of chitin, as chitosan. Preferred are water-soluble alkylaryl, hydroxyethylcellulose or hydroxyalkyl-alkylsalicylate that as a 2% solution in water at 20oC have a viscosity equal to more than 1000 SP, preferably 3500-120000 SP. Especially preferred hydroxypropylmethylcellulose with a degree of methylation of 1.36-1,81 and degree of hydroxypropylamino of 0.12 to 0.23, and hydroxypropylcellulose.

A synergistic increase in viscosity due to mixtures of polymers, such as hydroxypropylcellulose with anionic polymers, such as, for example, carboximetilzellulozu or sodium alginate, are particularly advantageous.

"Water-soluble" means that 100 g of water with a temperature of 20oC at least 0.5, and preferably at least 2 g of polymer colloidal dissolved.

As the polymer component g) is suitable and is not soluble in water or gastrointestinal fluids, but hydrophilic nabukenya polymers, as with the first acid, sodium salt croscarmellose, low substituted hydroxypropylcellulose and low substituted crosslinked carboxymethylcellulose sodium.

The decisive criterion for the suitability of the polymer as component d) is that the polymer, on the one hand, is hydrophilic, and on the other hand, not too quickly dissolves in the digestive tract. On the one hand, it should be released as a result of diffusion of the active agent of the granule, and on the other hand, this process should be slow. Therefore, the polymer must form together with water gel or viscous solution. The choice of this component and its amount has a decisive influence on the effect of the prolonged action. It has been unexpectedly found that the above-mentioned natural or semi-synthetic hydrophilic, gel-forming polymers in contrast to the fully synthetic polymers, such as, for example, polyvinylpyrrolidone or copolymer of vinylpyrrolidone and vinyl acetate, to ensure high storage stability (constancy effect extended to the storage).

Component d) may consist of one or more standard auxiliary substances, such as, for example, fillers, with the tools and their mixtures. Examples of fillers are inorganic fillers, as the oxides of magnesium, aluminum, silicon, titanium, etc., and also microcrystalline cellulose and powdered cellulose, various starches and their decomposition products (maltodextrins), lactose, mannitol, calcium diphosphate at a concentration of 0.02 to 50, preferably 0.20 to 20% of the total weight of the granules.

As examples of lubricants can be called the stearates of aluminum and calcium, as well as talc and silicone at a concentration of 0.1-5, preferably 0.1 to 3% of the total weight of the granules.

Examples of plasticizers are low molecular weight poly(alkalinity) as poly(etilenglikoli), poly(propylenglycol), poly(ethylene-propylenglycol); organic plasticizers with low molecular weight, as glycerine, pentaerythritol, monoacetate, diacetate or triacetate of glycerol, propylene glycol, sorbitol, diethylsulfoxide sodium added in concentrations of from 0.5 to 15, preferably from 0.5 to 5% of the total weight of the granules.

As examples of dyes can be called well-known azo dyes, organic or inorganic pigments or dyes of natural origin. Preferred inorganic pigments in concentrations from 0.001 to 10, predpochtitel also include substances to obtain a solid solution with the pharmaceutical active early. These excipients include, for example, sugars and polyhydric alcohols, give the oxidation of monosaccharides, such as mannitol, sorbitol, xylitol, further urea, pentaerythritol and leads to compounds, which pentaerythritol, polymers such as polyethylene oxides or polypropyleneoxide and their block copolymers (poloxamer), phosphatides, as lecithin, Homo - and copolymers of vinylpyrrolidone, surface-active substances, such as polyoxyethylene-40-stearate and citric acid, succinic acid, bile acids, sterols and other specified, for example, in the source J. L. Ford, Pharm. Acta Helv. 61, S. 69-88, 1986

Pharmaceutical auxiliary substances is also considered a base or acid to control the solubility of the active principle (see, for example, K. Thoma and others, Pharm. Ind. 51, 98-101 C., 1989).

Mixing the active agent or active principles with a polymeric binder and, if necessary, additional standard galenovye additives can occur before or after melting the polymer binder according to standard methods. Prefer mixing in the extruder, preferably dvuhserijnom extruder or adenocarcinom extruder with a mixing section.

After mixing all components is preferably 50-180oC, in particular 60-150oC, so that the mass had been filed.

The melt is free from solvents. This means that you do not add any water or an organic solvent.

Molding is carried out by melt extrusion at a temperature of 50-200oC, preferably 50-180oC, in particular 60-150oC, and subsequent continuous molding is still plastic harness, for example, molding into tablets, for example according to the patent application EP N 240906 by passing the harness between the two rotating in the opposite direction the rollers located opposite each other recesses in the surface of the rolls, the performance of which determines the form of tablets. It is also possible circumcision in a cold state.

Prefer the so-called circumcision in the hot condition. While the wiring directly after the exit of the nozzle unit of the extruder is subjected to crushing, such as rotating knives or other suitable device, it is advisable to obtaining pieces, the length of which is approximately equal to the diameter of the harness. Cropped particles in air or gas stream cools so that the surface prior to contact with other particles or wall with for example connected with the wall of the cyclone, take a spherical shape. So a simple way get in the ball or lenticular particles with a diameter, comprising 0.5 to 4, preferably 0.8 to 2 mm is Preferred smaller particles primarily suitable for loading into capsules.

The present invention is simple and environmentally friendly way (without the use of solvent) allows to obtain the matrix granules extended actions regarding the release of the active agent are controlled within wide limits. The slow release of the active principle possible without causing the control film coating consisting of organic solvents or aqueous dispersions and requiring subsequent stage of drying. The release of the active agent is carried out as a result of erosion and diffusion. The invention provides the possibility of achieving independent from the pH value of the release of the active principle. The proposed form suitable for active started with very different dissolution properties. The desired effect of slowing can be installed also in the case of smaller forms of the prolonged action. The method allows to obtain solid solutions of active principles in the polymeric matrix due to technology is Oh accessibility. This method is very economical, as it is continuous. Thus, it is superior to standard methods of granulation. Offered granules may have a high proportion of the active agent. Scattering release of the active principle with good homogeneity of the mass is low and perfectly reproducible. The kinetics of release of the active principle even in extreme climatic conditions storage (storage for at least a month at a temperature of 50oC or 30oC and 75% relative humidity) remains unexpectedly stable (deviation from the mode of release of the active principle Max. 20% absolutely, see table. II).

The advantage of this method of extrusion in comparison with other methods, such as, for example, granulation and tableting is a simple technique that avoid the use of solvents, minimizing the number and quantity of auxiliary substances, the possibility of obtaining solid solutions, avoidance capabilities of the bundle components, in other words - in a safe uniform composition of individual forms of the prolonged action during the whole production process. Here added advantages of continuous operation of the method the active principle, polymer, a lipophilic component, and other auxiliary substances or pre-mix, or through a separate metering device directly served in the boot area dvuhseriynogo extruder of type ZSK 30 firm Werner &Pfleiderer. Extrusion of the melt is carried out with a flow rate of the product is equal to approximately 3-4 kg/h Temperature of the individual zones ("injection") of the extruder are 30/150/100/100/100oC, and the temperature of the heated nozzle unit are listed separately. Nozzle node has seven holes with a diameter of 1 mm is Coming out of a heated nozzle unit harness granularit cooled by air pruning in hot condition with knife rolls.

The release of the active agent is determined according to USP XXI paddle apparatus according to the USP monograph. This test method "in vitro" is used to determine the rate of dissolution containing the active principle molded parts, for example tablets.

For testing 900 ml of phosphate-containing buffer with a pH of 6.8 in round-bottom vessel with a capacity of 1 liter was heated to 37oC. Dispense a suitable amount of pellets (about 300 mg) with a grain size of 1.25-1,60 mm Percentage release sports the 00 rpm, through 1, 2, 3, 4, 5, 6, 7 and 8 h, respectively.

In table. IV comparative tests on stability storage (according to application EP N 0024596).

1. Matrix granules extended to the ball or lenticular shape with a single maximum diameter constituting 0.5 to 4 mm, consisting of (a) 0.1 to 87 wt.% at least one biologically active compounds (a), (b) 5 to 50 wt.% at least one water-insoluble polymer) 5 to 45 wt.% at least one lipophilic component as a plasticizer of the polymer (b), g), 3 to 40 wt.% natural or semi-synthetic polymer gel, which represents a water-soluble derivative of cellulose or water-soluble polysaccharide or a mixture thereof, d) 0 to 50 wt.% one or more standard excipients.

2. Matrix pellets of the prolonged action on p. 1, wherein the following concentrations of components:

a) 1 to 75 wt.%

b) 10 to 40 wt.%,

C) 10 to 35 wt.%

d) 5 to 25 wt.%

d) - 0 - 40 wt.%

3. Matrix pellets of the prolonged action under item 1 or 2, characterized in that the maximum diameter is 0.8 - 2 mm

4. Matrix granules extended to the one of the PP.1 - 3, ex is duly extended to the one of the PP.1 - 4, wherein they are obtained by extruding the molten mixture of the components at 50 - 200oC and continuous molding.

6. Matrix pellets of the prolonged action on p. 5, characterized in that they are obtained by extrusion at 50 - 180oC.

7. Matrix pellets of the prolonged action on p. 5, characterized in that they are obtained by extrusion at 60 - 150oC.

8. Matrix granules extended to the one of the PP.5 to 7, characterized in that they are obtained by molding by cutting in a hot condition.


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15 cl, 10 tbl, 2 dwg, 4 ex

FIELD: pharmacy.

SUBSTANCE: invention relates to a granulated pharmaceutical composition comprising granulated material and erythritol. Granulated material comprises a medicinal substance of unpleasant taste and wax. Also, invention relates to a pharmaceutical product for oral using that comprises the indicated granulated composition. The composition masks unpleasant taste of a medicinal agent and provides good feeling in oral using. The granulated composition can be swallowed easily by elderly humans, children and patients suffering with dysphagia. Except for, the product is useful for administration by using a tube.

EFFECT: improved and valuable properties of composition.

15 cl, 5 tbl, 6 ex