HRP920377A2 - Process for the preparatin of a carrier base material for drug dosage forms with an extended release of active substance - Google Patents

Description

The field of technology

The invention is from the pharmaceutical industry. The designation of the invention according to the International Classification of Patents is A61K 9/22; A61K 9/26.

Technical problem

The invention solves the technical problem of the basic carrier material, which is combined with the active substance in dosage forms of drugs with extended release. Improved extraction characteristics compared to materials from prior art are the result of the presence of alkali metal carboxylates in the carrier material.

State of the art

Administering drugs that, in order to be effective, require a high dose can be done in the form of a single, potentially toxic dose or in the form of multiple doses. Another solution is to achieve continuous dosing with a single administration, by controlled and prolonged extraction of the drug from a solid single dose.

However, in order to place a sufficient amount of a medicinal substance in a single dose, the effective action of which requires a high dose, without at the same time significantly increasing the size of the individual dose, it is necessary to use a basic carrier material that effectively slows down the release of the drug in small concentrations.

Hydroxypropylmethylcelluloses are widely used as binding material, as matrices or as basic carriers in solid dosage forms for extended release of active substances. If necessary, lubricants and excipients are added to them. Commercially available hydroxypropylmethylcellulose actually represents a series of chemical compounds, each of which has a different chemical structure and composition, with the methoxyl content ranging from 16.5 to 30 wt.%, and the hydroxypropoxyl content ranging from 4 to 32 wt.%. All hydroxypropylmethylcelluloses are also available in multiple viscosity levels.

Commercial designations of various hydroxypropylmethylcelluloses are given based on the viscosity of a 2% aqueous solution at 20ºC. Viscosities range from 5 to 100,000 mPa.sec and correspond to average molecular weights from below 10,000 to over 150,000, calculated from data given in "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974).

Christenson and Dale (U.S. Patent 3,065,143) and Huber, Dale and Christenson (J.Pharm. Sci., 55, 974 (1966)) describe the preparation of an extended release tablet using high viscosity, i.e. high molecular weight, hydroxypropylmethylcellulose as a binder. weight and in the amount of at least one third of the total weight of the tablet. Binding agents include hydroxypropylmethylcellulose with a viscosity of 4,000 mPa-sec, known today as Methocel E4M, which has a methoxyl content of 28-30 wt.% and a hydroxypropoxyl content of 7.5-12 wt.% and an average molecular weight of 93,000. Also described are hydroxypropylmethylcelluloses with a viscosity of 4,000 or 15,000 mPa-sec, known today as Methocel K4M or K15M, which have a methoxyl content of 19-24 wt.%, a hydroxypropoxyl content of 4-12 wt.% and an average molecular weight of 89,000 or 124,000, respectively.

Christenson and his colleagues hypothesized that water is rapidly absorbed and forms a gel barrier on the surface of the tablet. The control of drug release is achieved by its diffusion through the gel barrier, as well as by the slight disintegration of this barrier.

Christenson and Huber (U.S. Patent 3,590,117) reported that neither low-viscosity hydroxypropylmethylcellulose nor high-viscosity hydroxypropylmethylcellulose made long-lasting pastilles.

Lapidus (Dissertation, Rutgers State University, 1967) and Lapidus and Lordi (J. Pharm. Sci., 55, 840 (1966); 57, 1292 (1968)) report the use of hydroxypropylmethylcelluloses with viscosities of 25 and 15,000 mPa-sec, respectively. which have a methoxyl content of 19-24 wt.% and a hydroxypropoxyl content of 4-12 wt.%, i.e. Methocel K25 and K15M, in compressed pharmaceutical tablets.

Salomon, Doelker and Buri (Pharm. Acta Helv., 54 (3), 82 (1979)) described the need for the presence of more than 30 wt.% hydroxypropylmethylcellulose with a viscosity of 15,000 mPa-sec, with a methoxyl content of 19-24 wt. % and hydroxypropoxyl content of 4-12 wt.% (Methocel K15M) in tablets containing potassium chloride, in order to prolong the release of the drug for more than a few hours.

Sheth and Tossounian (U.S. Patents 4,126,672; 4,140,755; and 4,167,558) have described solid dosage forms containing 20-75% hydrochloride, such as hydroxypropylmethylcellulose with a viscosity of 4000 mPa-sec, in combination with various additives including gas-forming compounds, e.g. calcium carbonate and inert fatty substances, which leads to a hydrodynamically balanced product whose density, in contact with gastric fluid, is less than one, so that it swims and separates the drug from its composition.

Schor, Nigalaye and Gaylord (U.S. Patent 4,389,393) describe solid extended-release single dosage forms in which the base carrier material constitutes less than one-third of the weight of the dosage form and consists of hydroxypropylmethylcellulose of a viscosity of at least 4,000 mPa-sec, an average molecular weight of at least 50,000 , with a methoxyl content of 16-24 wt.% and a hydroxypropoxyl content of 4-32 wt.%, i.e. from Methocel J and Methocel K.

The use of high-viscosity hydroxypropylmethylcelluloses - Methocel E, F and K - in solid dosage forms of drugs with extended release is also described in the technical bulletin "Formulating Sustained Release Pharmaceutical Products with Methocel" (The Dow Chemical Co., 1982).

The state of the art described so far describes that hydroxypropylmethylcelluloses of high viscosity and different chemical compositions are useful for obtaining solid dosage forms of drugs with extended release. In contrast, Schor, Nigalaye and Gaylord (U.S. Patent 4,369,172) describe that extended release therapeutic preparations can be obtained when low viscosity hydroxypropylmethylcellulose, with a hydroxypropyl content of 9-15% by weight and an average molecular weight of less than of 50,000.

Lowey and Stafford (U.S. Patent 3,870,790) and Schor (U.S. Patent 4,226,844) described that effective extended-release tablets can be obtained when a low viscosity modified hydroxypropylmethylcellulose with a hydroxypropoxyl content of less than 9 wt.% and an average molecular weight is used as the basic carrier material. from 23000, for example Mathocel E50. The modification was performed by exposing low-viscosity 1-hydroxypropylmethylcellulose to high air humidity and then drying it in air. This led to an increase in the carboxyl content in the polymer.

Davis and Gaylord (L.S. Patent 4,540,566) and Daly, Davis and Kennerley (International J. Pharmaceutics, 18, 201 (1984)) describe that the presence of an alkali metal sulfate or sulfonate prolongs the release form of tablets containing modified hydroxypropylmethylcellulose as the basic carrier material. viscosity.

Lowey (U.S. patent 4,259,314) describes the use of a mixture of dried hydroxypropylmethylcellulose with a viscosity in the range of 50 to 4,000 mPa-sec with hydroxypropylcellulose in the preparation of pharmaceutical preparations with controlled release of the medicinal substance.

The present invention relates to further improvements in the base carrier material containing high molecular weight hydroxypropylmethylcellulose, as well as to solid pharmaceutical extended release dosage forms containing such improved carrier material. The improvements are a result of the presence of alkali metal carboxylates in the base carrier material.

Description of the solution to the technical problem with implementation examples

The aim of the present invention is to provide a process for obtaining a basic carrier material containing hydroxypropylmethylcellulose and alkali metal carboxylates and which can be used in the production of therapeutically active solid dosage forms of drugs with extended release, which contain it in combination with a therapeutically active medication. Such preparations can be administered orally, buccally, sublingually, etc., in the form of lozenges and tablets, as well as in the form of suppositories and other solid single dosage forms.

Another object of the invention is to provide an improved basic carrier material for use in solid pharmaceutical unit dosage forms containing a high dose of active substance.

The present invention relates to a process for obtaining a basic carrier material that can be used in the production of therapeutically active solid dosage forms that, after administration, show a controlled and extended release of a drug containing a mixture of a medication and the specified material, wherein the basic carrier material consists of ( a) one or more water-soluble nonionic cellulose ethers, wherein at least one of these cellulose ethers is hydroxypropylmethylcellulose with an average molecular weight of at least 50,000, and (b) of an alkali metal carboxylate, wherein the carrier base constitutes less than 30 wt.% total mass of the dosage form.

The basic carrier material obtained by the process of the invention can be used in the production of therapeutically active solid dosage forms that contain it in a mixture with a medication, wherein the mixture of essential ingredients contains (a) one or more water-soluble nonionic cellulose ethers, wherein at least one of cellulose ethers of hydroxypropylmethylcellulose having an average molecular weight of at least 50,000, and (b) an alkali metal carboxylate.

It is preferable that the ratio of cellulose ether to alkali metal carboxylate in the carrier base is in the range of 1/0.05 to 1/3. The content of hydroxypropylmethylcellulose in the preparation preferably makes up from 3 to 25 wt.% of the dosage form, and the therapeutically active medication will preferably make up at least 70 wt.% of the dosage form.

Hydroxypropylmethylcellulose materials that are particularly desirable for use in the carrier base are materials that (a) have a methoxyl content of 28-30 wt.% and a hydroxypropoxyl content of 7.5-12 wt.%, and (b) have a methoxyl content of 19-24 wt.% .% and hydroxypropoxyl content of 4-12 wt.%.

The alkali metal carboxylate used in the process will preferably be a salt of a carboxylic acid having 8-40 carbon atoms. It is most preferable to use sodium stearate or sodium laurate.

Base carrier materials and therapeutically active medicaments can be mixed homogeneously by any suitable mixing technique. To obtain solid unit dosage forms, suitable amounts of the ingredients are mixed, shaped and compressed under conditions suitable to obtain a solid unit dosage form of the desired size and the desired extended release characteristics.

In accordance with the present invention, it has now been found that, by mixing hydroxypropylmethylcellulose with an alkali metal carboxylate, significant advantages and improvements can be achieved over prior art products containing water-soluble nonionic cellulose ethers, especially high molecular weight hydroxypropylmethylcellulose, as basic carriers materials.

Hydroxypropylmethylcelluloses that are effective in the present invention include, but are not limited to, commercially available high viscosity, ie high molecular weight, hydroxypropylmethylcelluloses. Included are materials of various viscosities that have an average molecular weight of at least 50,000, regardless of chemical structure. Thus, if the viscosity is at least around 500 mPa.sec, hydroxypropylmethylcelluloses that have the following methoxyl and hydroxypropoxyl contents will be effective:

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The use of low concentrations of high viscosity hydroxypropylmethylcellulose as the base carrier material in solid unit dosage forms is described in U.S. Pat. patent 4,389,393. It has now been unexpectedly discovered that the presence of an alkali metal carboxylate leads to an even more delayed and prolonged release time than can be provided by using hydroxypropylmethylcellulose at the same concentrations in the dosage form, but in the absence of the alkali metal carboxylate. This allows individual dosage forms to be prepared with a higher concentration of the active medication while simultaneously maintaining the desired delayed and extended release characteristics.

Alkali metal carboxylates which are effective in the present invention include alkali metal salts of carboxylic acids having 8 to 40 carbon atoms. Acids may have a straight or branched hydrocarbon chain structure, may contain alicyclic and/or aromatic groups, and may be saturated or unsaturated. Examples of alkali metal carboxylates include sodium caprylate, sodium pelargonate, potassium palmitate, sodium stearate, sodium archidate, sodium behenate, potassium lignocerate, sodium oleate, potassium oleate, sodium ricinoleate, sodium linoleate and the like.

The mass ratio of hydroxypropylmethylcellulose to alkali metal carboxylate in solid dosage forms is preferably from 1/0.05 to 1/3, and their combined mass preferably does not make up more than 30 wt.% of the total mass of the solid dosage form. Solid dosage forms can preferably contain from 3 to 25 wt.% of hydroxypropylmethylcellulose. It is desirable that the therapeutically active drug constitutes at least 70 wt. % of the total weight of the dosage form.

Although the exact nature of the interaction between the alkali metal carboxylate and hydroxypropylmethylcellulose is not known, nor do we wish to be bound by any theory, it is believed that the mixing of these two components leads to an ion-dipole interaction. When the solid single dosage form is placed in an aqueous environment, the hydrocarbon moiety in the bound alkali metal carboxylate promotes hydrophobic bonding between the hydroxypropylmethylcellulose chains, thereby retarding the release of the drug incorporated between them to an even greater degree than is the case with the swollen hydroxypropylmethylcellulose alone. .

The hydroxypropylmethylcellulose of the present invention may be used with or without prior wetting or similar treatment. Its mixture with alkali metal carboxylate and active medication has excellent compressibility. Tablets prepared from this mixture are rigid and have a high density, they are difficult to break and during long periods they ensure a controlled and extended extraction of the medicinal substance. The solid forms of the drug of the present invention are stable and their release rate does not change significantly (if at all) during long periods of storage.

Hydroxypropylmethylcellulose with an average molecular weight of at least 50,000 can be used in the basic carrier material, together with an alkali metal carboxylate, alone or in a mixture with other nonionic cellulose ethers. It is preferable that hydroxypropylmethylcellulose with an average molecular weight of at least 50,000 constitutes at least 3 wt. % of total mass of solid dosage form.

The active ingredient can be any type of medicine that acts locally in the oral cavity or systemically. A unit dosage form containing a systemic drug can be administered orally, in order to transport the active drug into the gastrointestinal tract and from it into the blood, body fluids and tissues, without excessive peak concentrations. Alternatively, the active medication can be any type of medication that acts through the buccal tissues of the oral cavity, in order to transfer the active ingredient directly into the blood, thus avoiding metabolization through the liver and contact with gastric and intestinal fluid that has an undesirable inactivating effect, or destroys many active ingredients unless they are specially protected against the action of these liquids (eg enterological coating or similar). The active drug may also belong to the type of drugs that can be transferred into the blood through the rectal tissues. Thus, the invention is applicable to sublingual lozenges, buccal tablets, suppositories and compresses. These latter are intended to be swallowed in the form of a single dose and provide, after introduction into the gastrointestinal tract in accordance with the prescribed regimen, a controlled and slow release of the active medication, while at the same time they are protected against inactivating gastric fluid.

Examples of active drugs include antacids, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, anti-infectives, psychotropic agents, antipsychotics, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, antidiarrheal agents, antianginal drugs, antiarrhythmics, antihypertensive drugs , vasoconstrictors and anti-migraine agents, anticoagulants and antithrombotic agents, analgesics, antipyretics, hypnotics, sedatives, antiemetics, anti-seasickness agents, anticonvulsants, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, minerals and nutritional supplements, antiobesity agents, anabolics, erythropoietic drugs, antiasthmatics, expectorants, cough suppressants, mucolytics, antiuricemic drugs, as well as other drugs and substances that act lok orally, such as local analgesics, local anesthetics, etc.

A mixture of alkali metal carboxylates and hydroxypropylmethylcellulose with an average molecular weight of at least 50,000 forms what may be termed a slow-dissolving, long-acting carrier. The carrier, by its very nature, has a protective, mitigating and buffering effect in the body and enables the active medication to show its optimal therapeutic effect, both immediately and over a longer period of time, which achieves the full therapeutic effect of the entire or almost entire amount of the given medication. This unexpectedly high degree of efficiency represents a special advantage achieved by the invention and reduces the side effects of the drug to a minimum.

In the preparation of tablets that contain an active component that can be administered orally and that can later be systemically absorbed, such as the medications listed in the previous text, hydroxypropylmethylcellulose and alkali metal carboxylate are completely mixed with the medication, which can be in the form of powder, granules or in solution, as well as with any additional ingredients conventional in the manufacture of tablets, such as magnesium stearate, lactose, starch, fumed silica, hydrogenated vegetable oil and, in general, binders, fillers, disintegrants and the like. Hydroxypropylmethylcellulose and alkali metal carboxylate can be mixed in water, alcohol, or other medium known in the art, then dried to form granules, and then mixed with the medicament or other ingredients. Alternatively, the medicament may be granulated together with hydroxypropylmethylcellulose and an alkali metal carboxylate prior to mixing with the other ingredients.

The entire mixture is then, in an amount sufficient to obtain a uniform batch of tablets, e.g. 50,000, each of which will contain an effective amount of active ingredient, subjected to tableting in conventional tableting apparatus at a compression pressure of 135 x 105 to 1100 x 105 Pa . With regard to the use of a specific carrier material from the present invention in the production of tablets, a product is obtained that has the desired hardness, a low degree of friability and a predetermined controlled and prolonged action, as well as a regular delayed release of the medicinal substance during a period of 0.25-36 hours depending on the exact tablet size, hardness and specific carrier composition. In this way, it is possible to obtain tablets with a controlled and easy continuous release and in a relatively simple and economical way on an industrial scale, in contrast to the more complicated and complex materials and procedures used and proposed earlier.

The moisture content of the carrier used in the formulation of controlled release tablets may be in the range of 0.1-10%, with the lower end of this range being preferred when dealing with moisture sensitive medicaments. If the moisture content is outside this range, it can be adjusted using dry or moist air at room or elevated temperature. Suitable equipment is used, such as static or convex chambers, forced air chambers, vacuum chambers, and other equipment known to those skilled in the art. During tableting, the moisture content of the carrier has an influence on the compactness of tablets obtained under a given compression pressure. However, the moisture content has less influence on the characteristics of the controlled separation than the composition of the carrier and its concentration.

The form of extracting the active medication from the carrier according to the present invention can be controlled in accordance with the specific drug and its planned therapeutic effect. For sublingual lozenges or tablets, the extraction time can vary from 0.25 to 4 hours. For buccal tablets, the withdrawal time can be from 0.25 to 24 hours. For orally administered tablets, the withdrawal time can be 2-4 hours, 4-8 hours, 8-10 hours, 15-18 hours, 20-24 hours, etc., depending on the need. For vaginal and rectal suppositories, the withdrawal time ranges from 2 to 36 hours, although, if indicated, it can be shorter or longer. It is possible to provide controlled extraction with unusually reliable characteristics. The invention is very versatile and adaptable in nature, which enables a wide range of applications and ultimate needs.

Illustrative examples describing the present invention hereinafter should not be construed as limiting. Variations in its application will be readily apparent to those skilled in the art.

EXAMPLES 1-2

Controlled-release theophylline tablets are prepared from granular, anhydrous theophylline and from hydroxypropylmethylcellulose (HPMC) with a viscosity of 4,000 mPa.sec, a methoxyl content of 19-24 wt.%, a hydroxypropoxyl content of 4-12 wt.%, and an average molecular weight of 89,000. , which is commercially available under the name Methocel K4M. Tablets are manufactured with or without sodium stearate.

Theophylline tablets of 306 mg are obtained from the following ingredients:

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Ingredients 1 and 2 were mixed, ingredient 3 was added to the mixture and then, after mixing, ingredients 4 and 5. The mixture was mixed for 20 minutes and then compressed in a Parr tablet press with a 9.525 screen. Tablet hardness was determined on a Penwalt Stokes hardness tester.

Extraction rates were determined at pH 7.0 using a rotary basket solubilizer described in U.S. Pat. Pharmacopeia, Chapter XX, p. 959. The blade rotated at a speed of 100 revolutions per minute, and the temperature of the water medium was maintained at 37ºC. The results are given in the following table:

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The amounts recovered were also determined at pH 7.0 using a rotary vane solubilizer described in U.S. Pat. Pharmacopeia, vol. XX, p. 959. The blade rotated at a speed of 50 revolutions per minute, and the temperature of the water medium was maintained at 37°C. The results are given in the following table:

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EXAMPLES 3-4

Controlled-release theophylline tablets were prepared from anhydrous theophylline and hydroxypropylmethylcellulose (HPMC) with a viscosity of 4000 mPa.sec and a methoxyl content of 28-30 wt. %, with a hydroxypropoxyl content of 7.5-12 wt. % and with an average molecular weight of 93,000, which is commercially available under the name Methocel E4M. Tablets are prepared with and without sodium laurate.

Theophylline tablets of 306 mg were obtained from the following ingredients:

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The ingredients were mixed in the same manner as in Examples 1-2 and compressed in a pellet press using a 9,525 mm screen.

Extraction rates were determined at pH 37°C using the rotary basket method at 100 rpm. Theophylline tablets of 306 mg had the following properties:

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Extracted amounts were also determined at pH 7.0 at 37ºC using the rotary vane method at 50 rpm. The following results were obtained:

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EXAMPLE 5

Controlled release theophylline tablets were prepared from anhydrous theophylline and hydroxypropylmethylcellulose (HPMC) of viscosity 4,000 mPa.sec (Methocel E4M) used in Examples 3-4, in the presence of sodium stearate.

Theophylline tablets of 306 mg are obtained from the following ingredients:

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The ingredients were mixed as described in Example 4, and tablets were obtained using a 9,525 mm sieve. The hardness and release rates of the 306 mg theophylline tablets were determined as described in the previous examples to give the following results:

[image] EXAMPLES 6-7

Controlled-release theophylline tablets are obtained from anhydrous theophylline and HPMC viscosity 15,000 mPa.sec with a methoxyl content of 19-24 wt.%, a hydroxypropoxyl content of 4-12 wt.% and an average molecular weight of 124,000, obtained under the commercial name Methocel K15M. The tablets were prepared with and without sodium laurate.

Theophylline tablets of 306 mg are obtained from the following ingredients:

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The ingredients were mixed as described in Examples 1-2 and compressed in a pallet press using a 9,525 mm screen.

Extraction rates were determined at pH 1.5, at 37°C, using the basket method rotating at 100 revolutions per minute. Theophylline tablets of 306 mg had the following properties:

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EXAMPLES 8-9

Controlled release ibuprofen tablets were obtained from ibuprofen and HPMC viscosity 4000 mPa.sec (Methocel K4M) used in Examples 1-2. The tablets were prepared with and without sodium stearate.

Ibuprofen tablets of 700 mg are obtained from the following ingredients:

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The ingredients were mixed as described in Examples 1-2 and compressed in a pellet press using a 9,525 mm screen.

Extraction rates were determined at pH 7.2 at 37ºC using the rotating basket method at 100 rpm. Ibuprofen tablets of 700 mg had the following properties:

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EXAMPLES 10-11

Controlled-release aspirin tablets are prepared from the U.S.P. aspirin and HPMC viscosity 4,000 mPa.sec (Methocel K4M) used in Examples 1-2. Tablets are prepared with and without sodium stearate.

Aspirin tablets of 650 mg are prepared from the following ingredients:

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The ingredients were mixed as described in Examples 1-2. The mixture was compressed in a tableting machine with a 7.13×15.88 mm mold under a compression pressure of 27.45 mPa to obtain 1,000 capsule-shaped tablets scored over half on one side.

Extraction rates were determined at pH at 37ºC using the paddle method rotating at 100 rpm and the results were as follows:

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Claims (6)

1. Process for obtaining the basic carrier material for dosage forms of drugs with prolonged release of the active substance, indicated by the fact that a mixture is prepared which, as essential components, contains an alkali metal carboxylate and one or more water-soluble nonionic cellulose ethers, of which at least one is hydroxypropylmethylcellulose with an average molecular weight of at least 50,000. 2. The method according to claim 1, characterized in that the mixture contains hydroxypropylmethylcellulose and alkali metal carboxylate in a mass ratio of 1/0.05 to 1/3. 3. The method according to claim 1, characterized in that the alkali metal carboxylate is a salt of a carboxylic acid with 8 to 40 carbon atoms. 4. The method according to claim 1, characterized in that the alkali metal carboxylate is sodium stearate or sodium laurate. 5. The method according to claim 1, characterized in that hydroxypropylmethylcellulose has a methoxyl content of 28-30 wt.% and a hydroxypropoxyl content of 7.5-12 wt.%. %. 6. The method according to claim 1, characterized in that hydroxypropylmethylcellulose has a methoxyl content of 19-24 wt.% and a hydroxypropoxyl content of 4-12.