BG60754B2 - Delayed action matrix - Google Patents

Abstract

The matrix composition consists of an active agent and a hydrophilic and intestinal polymer. The intestinal polymer is impervious to gastric fluids, slows release of the drug to sites of low pH, and enables the use of small amounts of hydrophilic polymer that dissolves at pH values of the intestinal fluid and thus increases the penetration of the drug dose. Thus, the release of many active agents, whose solubility decreases with the increase in pH, is typical of low alkaline drugs. Because they respond to the change in physiological pH, these dosage-retarding formulations are acceptable regardless of the varying time for the drug to pass through the gastrointestinal tract.

Description

Delayed action matrix

Reference to such descriptions

This description is a continuation of description No. No. 07/136628, registered December 22, 1987, which is a continuation in part of description No. No. 07 / 019,915, registered February 27, 1987, now abandoned.

Background of the Invention

Ideally, the sustained release formulation should deliver the drug at a constant rate through the gastrointestinal tract. With many of the delivery systems currently in place, this expectation may not be fulfilled, since many drugs that are slightly acidic or alkaline have a solubility that varies with pH. Decreasing solubility according to different pH values of 6 different parts of the body can lead to a decrease in the rate of release of

the drug if the formulation does not appropriately alter its permeability characteristics.

Hydrophilic matrices are known to provide sustained release of the drug. Christenson et al. in US Pat. No. No. 3 065 143 describes the use of certain hydrophilic resins, including hydroxypropyl methylcelluloses, in the preparation of sustained release tablets. Hill in US Pat. No. 3 458 622 describes the preparation of sustained release tablets using a combination of povidone and carbopol. Weiss et al. In US Pat. No. No. 4,252,786 describe a core-release controlled release tablet identical to the tablet described by Hill containing the active ingredient, povidone and carbopol. A coating consisting of a hydrophobic and hydrophilic polymer is also used to prevent the initial rapid release of the drug present in the above tablet. Schor et al. in US Pat. No. 4 389 393 describe a sustained release therapeutic composition of a high molecular weight hydroxypropyl methylcellulose drug. Guley et al. in US Pat. No. No. 4,309,405 describes a sustained release pharmaceutical composition comprising a pressed core, an insulating sheath, and a sugar coating surrounding the isolated, enveloped core, wherein a) the core consists of an active ingredient, at least one pharmaceutically acceptable water-soluble polymer selected from the hydroxypropyl methylcellulose group, hydroxypropyl cellulose, xanthan and kagawa resins and at least one pharmaceutically acceptable water-insoluble polymer mixture selected from the group consisting of ethylcellulose and at least one component of carboxypolymethylene, hydroxypropylmethylcellulose phthalate and hydroxypropyl cellulose, said polymers being in an amount of about 30% to 72% by weight relative to the core,

B) the insulating jacket consists of a film coating selected from the group consisting of enteric and non-enteric materials and mixtures thereof; (c) the sugar coating includes sugar and an initial dose of said drug contained in the core. Dunn in US Pat. No. 4 522 804, 4 521 402 and 4 521 401 describe a solid oral formulation with uniform release. of the active ingredient drug from about 0.5 to about 6.0% acid retardant (acid suppressant) or hydrophobic cellulose derivative from about 2.5 to 35%

J hydrogenated vegetable oil, about 1 to 20% carbopol, about 0.5 to 4.0% vapor silica, and about 0.4 to 3.0% lubricant.

Conventional hydrogels, such as those based on highly viscous hydroxypropyl methylcelluloses, have been reported to deliver drugs at a constant rate, regardless of the pH relationship with hydration, gel viscosity, and relative permeability of the dosage form. However, this does not provide assurance that a drug whose solubility is 6 strongly pH dependent will be delivered at a constant rate at all pH of the gastrointestinal tract. With these conventional hydrogel formulations, the velocity of

............— ί * drug release is closely related to the solubility of the drug. If the drug has a higher solubility in gastric fluids than intestinal fluids, which is characteristic of many slightly alkaline active components, it would be expected that the rate of drug release from the matrix would be higher in gastric fluids than when the formulation passes through the small intestine, where pH values are considered to be higher. In these formulations, if the dosage form is not retained for the required period of time in the stomach, a decrease in the rate of drug release 6 to the intestine may lead to incomplete bioavailability and greater differences in individual patients.

Film coatings are known to have the ability to change the way a drug is released when applied to pharmaceuticals. A type of film coating known as intestinal (intestinal) ^{has been} used to prevent the drug from being released into or to protect the drug from the effects of the gastric environment. Intestinal coatings are used to delay the release of medicines that are deactivated by the gastric contents or that cause gastric irritation.

The matrix compositions of the present invention differ from existing formulations ^P0 that the present compositions are designed to respond to the increase in pH with a corresponding increase in .propusklivostta them. This allows the dosage form to release the active ingredient at an appropriate rate through the gastrointestinal tract.

SUMMARY OF THE INVENTION

This invention provides a matrix composition consisting of an active agent, a hydrophilic polymer and an intestinal (intestinal) polymer, which results in a dosage form sensitive to changes in physiological pH. In particular, the present invention relates to a matrix composition providing a sustained release drug, in the form of a tablet, comprising from about 0.1% by weight to about 90% by weight of the active agent, from about 5% by weight to about 29% by weight of the hydrophilic polymer and from about 0.5% by weight to about 25% by weight of the intestinal polymer,

-. _____ provided that the total weight of the hydrophilic and intestinal polymer is less than 30% by weight of the formulation. This formulation responds to an increase in pH with a corresponding increase in its permeability and decay rate. This results in an improved mechanism for delaying the delivery of many compounds, in particular those whose solubility decreases with increasing pH.

DETAILED DESCRIPTION OF THE INVENTION

Quantities and percentages are described herein by weight, unless otherwise stated.

The present formulation, with its components, is in the form of a matrix. The term matrix, as defined herein, means a well-mixed composition of components fixed in tablet form. This intimate mixture of components provides a delayed release of the active agent contained therein as the pH of the medium changes in accordance with the administration to a patient in need of such sustained release.

The percentage of components required for the formulation according to the invention, i. the active ingredient, the hydrophilicT polymer and the intestinal polymer, are calculated on a dry weight basis without taking into account any water or other available components. Thus, when calculating the individual percentages, these three components together form 100% of the formulation. Then, if other ingredients are present, the sum of all the components except the film coating make up 100% of the formulation.

The active ingredient is any compound that is suitable for oral administration, although this invention in particular is intended for slightly alkaline agents. The active agent is present in the composition of the invention at concentrations ranging from about 0.1% by weight to about 90% by weight, preferably at concentrations ranging from about 45% by weight to about 85% by weight. Typical drugs that can benefit from this type of delivery system are, but are not limited to, the following groups of agents: betblockers such as propranolol, metoprolol, atenolol, labstolol, timolol and pindolol; antimicrobial agents such as cephalexin, cefachlor, cefadroxil, cefuroxime, cefuroxime axetil, erythromycin, penicillin, 7- [D (aminophenylacetyl) amino] -3-chloro-8-oxo-1azabicyclo [4.2.0] oct-2-en- 2-carboxylic acid, also known as loracarbif, 7 - [[amino [3 - [(methylsulfonyl-) amino] phenyl] acetyl] amino] -3-chloro-8-oxo-1-azabicyclo [4.2.0] oct -2-en-

2-carboxylic acid, and 7- [D-pino-N- ((ethylsulfonyl) amino] phenyl] acetyl] amino-3-chloro-8-oxo-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; anti-hypertensive agents such as clonidine, methyldopa and nifedipine; antihistamines such as chlorophenylamine dc and bromophenylamine; ataractics (neuroplegic drugs such as diazepam, inaM, chlordiazepoxide and oxazepam; anticonvulsants; nausea; muscle relaxants; anti-inflammatory substances; psychotropic agents; antimaniacal agents; stimulants;

decongestants; medicines for angina; vasodilators; anti-arrhythmias; counterfactuals; migraine remedies; vomiting agents; diuretics; antispasmodics; anti-asthmatics; antiparkinsonian agents; nutritional means. cough suppressants; mucolytics; vitamins; mineral and nutritional supplements.

This invention is particularly suitable for the agents cephalexin and cefaclor. Both compounds are amphoteric, having both an acidic and an alkaline functional group. Both have greater solubility at low pH values of gastric fluids (pH 1-3) than at normal intestinal fluid values (pH 5-7). When these compounds are placed in conventional hydrogel, the rate of drug release when the formulation is in simulated gastric fluids is higher than when it is in simulated intestinal fluids.

The compositions of the present invention also contain a hydrophilic polymer. Hydrophilic polymers are present in the compositions of the invention at concentrations ranging from about 5% by weight to about 29% by weight, preferably from about 5% by weight to about 20% by weight. Hydrophilic polymers suitable for use in the present invention are either water-soluble or water-swellable and include one or more natural or partially or wholly synthetic anionic or non-ionic hydrophilic resins, modified cellulosic substances or protein substances such as acacia, tragacanth resin, horn tar , §Iag * resin / kagawa ^ resin, agar, pectin, carrageen, soluble and insoluble alginates, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, sodium carboxymethyl cellulose, carboxypolymethylene, gelatin, casein, bentonite, magnesium-aluminum silicate and others. similar. Other hydrophilic polymers that may be used are polysaccharides and modified starch derivatives, such as Amazio 721A (American Maize Products) and Pullulan (Hayashibara Biochemical Laboratories, Inc.).

Preferred hydrophilic polymers are hydroxypropyl methylcelluloses manufactured by Dow Chemical and known as Methocel ethers. Preferred Methocel ethers are Methocel E Series resins (E5, E15, E50, E4M, E10M and others). The hydration rate of Methocel resins of Series E is generally lower than the rate of hydration of Methocel resins of Series K. When producing hydrogel tablets,

using Methocel E Series resins, thinner gel layers are obtained. As a consequence, when these tablets are placed in a medium with a higher pH, the tablets react faster than when polymers with thick, viscous, gel layers are placed in the same medium. Another preferred polymer is Pullulan, a water-soluble polysaccharide derived from starch. Pullulan is similar to the E Series Methocel resins in that hydrogel tablets containing Pullulan typically form thin gel layers. When used in conventional hydrogel tablets, Pullulan has a medium capacity to delay drug release.

The formulations of the invention also contain an intestinal polymer. These polymers are present in the compositions of the invention at concentrations in the range of about 0.5% by weight to about 25% by weight, preferably at concentrations in the range of about 1.5% by weight to about 15% by weight. The pH at which these polymers begin to dissolve is in the range of about 5.0 to about 7.4. The polymers are insoluble at pH below 5.0. Because these polymers are insoluble at the low pH values characteristic of gastric fluids, they help delay drug release at these sites. When exposed to the high pH liquids characteristic of the small intestine, these polymers dissolve, thus increasing the permeability and disintegration rate of the tablets of the present invention. Examples of suitable polymers are acrylic resins such as Eudragit L, Eudragit 8, Eudragit L-100-55-Rohm Pharma, acrylic latex dispersions, for example Eudragit L30D-Rohm Pharma, and also other polymers such as cellulose acetate phthalate , polyvinyl acetate phthalate and hydroxypropyl methylcellulose phthalate. A preferred intestinal polymer is Eudragit L-100-55. This resin has a fine powder form as well as the Eudragit L30D Water Dispersion form. It begins to dissolve at pH above about 5.5 and therefore helps to improve drug release in much of the small intestine. The total concentration of the hydrophilic and intestinal polymer is less than 30% of the total weight of the formulation.

The present formulations may comprise a pharmaceutically acceptable binder at concentrations ranging from about 2.0% by weight to about 10.0% by weight, preferably from about 2.0% by weight to about 6.0% by weight. Pharmaceutically acceptable binders suitable for use in the present compositions are selected from those commonly used by chemist-pharmacists and include sucrose, lactose, gelatin, starch paste, acacia, tragacanth and other resins; cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and ethylcellulose; microcrystalline cellulose; povidone; polyethylene glycols; corn syrup, and other binders known in the art. Preferred binders are Pullulan and hydroxypropyl cellulose.

The present compositions may. also contain a pharmaceutically acceptable excipient of from about 2.0% to about 25.0% by weight, preferably from about 5% to about 20% by weight. These fillers can be water-soluble and must be chemically inert to the other components. Preferred fillers are lactose and mannitol. You can also use a variety of other known excipients, such as glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, and other pharmaceutically acceptable monosaccharides and disaccharides. Other suitable excipients are inorganic compounds such as chloride, sulphate and phosphate salts of potassium, sodium and magnesium, as well as calcium and succinate salts of citrate, phosphate, lactate and gluconate.

The present formulations may also contain tablet lubricants. The concentration of the lubricant in the composition ranges from about 0.5% to about 4.0% by weight, preferably from 1.0% to about 2.5% by weight. Preferred lubricants are stearic acid in powder form as well as magnesium stearate. Other suitable tablet lubricants are calcium or zinc stearate, hydrogenated vegetable oils, talc, polyethylene glycols, mineral oils, or other pharmaceutically acceptable matrix lubricants.

If desired, conventional tablet ingredients such as preservative, stabilizing, gliding, pharmaceutically acceptable surfactants and FD&C coloring agents may be included in the present formulations. The total weight of these ingredients is generally in the range of about 0.1% to about 2.0% by weight of the composition. Suitable glidants are colloidal silicon dioxide and talc. Acceptable surfactants are sodium lauryl sulfate, dioctilob sodium sulfoxine (DSS), triethanolamine, polyoxyethylene sorbitan, and poloxalcohol derivatives, quaternary ammonium salts, or other pharmaceutically acceptable agents. In addition, lubricants and surfactants can be mixed and incorporated into the composition as one component.

If necessary, the resulting tablets can be coated with one of the many coatings available. The wrapping of the tablets serves to mask the taste of the drug, make the tablet easier to swallow and in some cases improve the appearance of the dosage form. The tablets may be sugar coated according to procedures well known in the art or any of the many polymeric film-forming agents commonly used by pharmaceutical chemists. Examples of such film-forming agents are hydroxypropyl methyl cellulose, carboxymethyl cellulose, hidrokdipropiloVa cellulose, methylcellulose, ethylcellulose, acrylic resins, povidone, polyvinyl diethylaminoacetate, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate, acrylic latex emulsions, ethylcellulose latex emulsions or other Commercially preparations such as Pharmacoat manufactured by Shin-Etsu Chemical Co., Ltd. u Opadry, manufactured by Colorcon, Inc.

The present formulations can be prepared by procedures well known to pharmacist chemists. The manufacturing method may affect the release characteristics of the tablets obtained. The intestinal polymer used in the present formulations can be applied 6 formulations in various ways. The polymer may be added to the active agent in the form of a fine powder together with all or part of the hydrophilic polymer. These components are thoroughly mixed and granulated with water or an aqueous solution of the hydrophilic polymer or other binder. The granules are dried and sized. The resulting granulate can be mixed with additional hydrophilic polymer and tablets; Lubricants and then compressed into tablets. This particular production method requires a greater percentage of intestinal polymer to obtain the desired balance of appropriate drug release in simulated gastric fluids and simulated intestinal fluids, but eliminates the need for organic solvents during tablet production.

Alternatively, the intestinal polymer may be added as a fine powder to the active agent, and optionally all or part of the hydrophilic polymer. These components are completely mixed. Subsequently, instead of using aqueous solutions of the constituents in the granulation step, organic solvents such as isopropyl alcohol, ethanol, and the like, water-free condensers may be used. If necessary, a suitable hydrophilic polymer may be dissolved in the solvent. Using this type of granulating fluid, the finely divided intestinal polymer can be activated or partially dissolved during granulation. In this case, the release of the drug at low pH may be more effectively delayed. The granulation is then continued as described above. This method of component incorporation can lead to low requirements for the intestinal and hydrophilic polymer, which can be a significant advantage when the active agent is very soluble or intended for use at high doses.

A secondary variant of the above method is to dissolve the intestinal (intestinal) polymer in a suitable solvent system such as isopropyl alcohol, ethanol and the like. similar with or without Water. The resulting intestinal polymer solution is then used to granulate the active agent, which may optionally contain part of the hydrophilic polymer. This method of incorporation allows the intestinal polymer to delay the drug release more effectively at low pH. The granulate obtained is then treated as described above. This treatment method can also lead to reduced requirements for both the intestinal polymer and the hydrophilic polymer.

A third method of incorporating the intestinal polymer into a composition of the invention involves the use of an aqueous latex dispersion of the polymer as a granulating liquid. At this point, the active agent and all or part of the hydrophilic polymer are completely mixed. The intestinal polymer dispersion is then added to complete the granulation. The tablets produced have many of the properties of the solvent-granulated tablets described above, but this method does not require the use of these solvents. However, the aqueous dispersion may not be very sticky and the hydrophilic polymer, which is required to produce a suitable granulate by this method, may lead to tablets that do not have the required drug release properties at high and low pH, which can is achieved through other manufacturing procedures.

The method of incorporation of the hydrophilic polymer also affects the rate of drug release from the tablets obtained. These effects are well known to those familiar with hydrogel technology. It should be noted that when highly viscous hydrophilic polymers are added to the formulation prior to wet granulate with aqueous solutions, the resulting tablets may have compromising drug release characteristics when there are 6 media with a pH high enough to dissolve the intestinal polymer.

As mentioned above, examples of agents for which this invention is particularly suitable are cephalexin and cefaclor. When these compounds are incorporated into a conventional hydrogel composition, the drug release rate is higher in simulated gastric fluids than when the formulation is in simulated intestinal fluids. This feature is illustrated by the following example:

EXAMPLE A

The following example is a cephalexin monohydrate delayed-release tablet obtained using conventional hydrogel technology:

Composition of one tablet Weight (mg) cephalexin 1074.5 mg povidone-90 24.0 mg Methocel E4M Premium 161.3 mg powdered stearic acid 15.1 mg magnesium stearate 15.1 mg

The release characteristics of these tablets are evaluated using two solvent procedures. One procedure is called the gastric method '' and the other is a simulated GI method. According to the gastric method, the tablets are tested in 0.1N hydrochloric acid, which is simulated stomach fluids. The simulated gastrointestinal (G1) method is intended to simulate passage through the gastrointestinal tract. According to the simulated G1 method, the tablets were placed for one hour in 750 ml of 0.1N hydrochloric acid, during which time the pH in the dissolution vessel was increased to pH 6.8 by the addition of 250 ml of 0.2M tri-basic sodium phosphate. The results of the reconstitution of these tablets are shown below:

Dissolved cephalexin (cumulative percentage)

Time (min) Gastric method Simulated GI method

30 17 17 60 28 28 90 38 33 120 48 34 180 65 39 240 79 44 300 90 49 360 98 55 420 105 59

The tablets were placed in a 10 mesh basket and rotated in the upper medium at 100 rpm.

The dissolution data indicate a potential problem with the use of conventional hydrogel technology with a compound whose solubility decreases with increasing pH. When the tablets of the above composition were administered 6 high pH media and using the simulated GI method, the rate of release of cephalexin from the formulation decreased dramatically. When used clinically, this composition may not develop as required if the drug dose is not retained in the stomach. Premature disintegration of the tablet into the small intestine and an increase in pH as a result may result in a reduced rate of cephalexin release and poor bioavailability. These conditions lead to potential problems if they occur repeatedly, as with the unsuccessful therapeutic treatment of certain types of infections.

The following examples illustrate compositions of the invention and methods for their preparation. In no case will the examples be intended to limit the scope of the invention and should not be construed as such.

(EXAMPLE 1

A Hobart mixer is filled with 2149 g of cephalexin monohydrate. The resulting mixture was granulated with 1000 ml of a 15% solution]! (weight / volume) of Eudragit L-100-55 in a mixture of isopropyl

V alcohol: water (9: 1, v: v). The total granulation time is between five and seven minutes. The wet granulate is placed on a No. 4 sieve. 4 and falls on paper trays and dried at 35 ° C for 5.5 hours. Drying was continued at room temperature overnight. Place the dried granulate on a No. 4 sieve. 14 mesh and falls into a suitable container.

The ς V-mixer is filled with 575 g of this granulate and 62.5 g of hydroxypropyl methylcellulose E-50 to prepare 500 tablets. This mixture was stirred for about 30 minutes. To the mixture was added powdered stearic acid (7.5 g) and through a No. 4 sieve. Magnesium stearate (3.25 g) was added to 30 mesh. This material is mixed for five minutes and placed in a suitable container. The resulting mixture was compressed on Stokes F-npeca to obtain tablets using conventional means.

Composition of one tablet

Weight (mg) Weight (percent)

cephalexin monohydrate 1074.5 82.91 Eudragit L-1OO-55 75.0 5.79 hydroxypropyl methylcellulose E-50 125.0 9.65 powdered stearic acid 15.0 1.15 magnesium stearate 6.5 0.50

The dissolution of these tablets was evaluated by the methods described above with the following results;

Dissolved cephalexin (^ U ^m U ^la ™ veins hytsent)

Time (min) Gastritis method Simulated GI method 30 22 20 60 35 32 90 45 40 120 53 50 180 66 69 240 77 84 300 85 92 360 94 93 420 100 93

EXAMPLE 2

A Hobart mixer is filled with 1612 g of cephalexin monohydrate, 300 g of Eudragit L-100-55 and 225 g of hydroxypropyl methylcellulose E-5 through a suitable sieve. The mixture was thoroughly mixed and granulated with 750 ml of 8% (w / v) hydroxypropyl methylcellulose E5 solution in a mixture of isopropyl alcohol: water (3: 7, v: v). The total granulation load is between five and ten minutes. The wet granulate is placed on a No. 4 sieve. 4 and falls on paper trays and dried at 45 ° C for half an hour. Drying was continued at room temperature for 48 hours. Place the dried granulate on a No. 4 sieve. 14 mesh and falls into a suitable container.

The V-mixer is filled with 372 g of this granulate and 11 g of powdered stearic acid and 7.77 g of magnesium stearate are added through a No. 30 mesh sieve. This material is mixed on foot and placed in a suitable container. The resulting mixture was compressed on Stokes F-npeca to obtain tablets using conventional means.

The resulting tablets were coated with a solvent-based film-forming mixture ₅ consisting of hydroxypropyl methylcellulose E-50 (1.581 percent by weight) and glycerol (0.552 percent by weight) in a conventional tray. The tablets were then dried on paper-coated boards to obtain approximately 1000 tablets.

Composition of aeon tablet Weight (mg) Weight (percent) cephalexin monohydrate 537.23 71.54 Eudragit L-100-55 100.00 13.32 hydroxypropyl methylcellulose E-5 95.00 ' 12.65 powdered stearic acid 11.00 1.46 magnesium stearate 7.77 1.03 pure film coating (theoretical) 15.88

The dissolution of these tablets is evaluated by the methods described above with the following results:

Dissolved cephalexin (cumulative percentage) It's time for me (min) Hashrishna method Simulated GI method 30 28 27 60 48 46 90 65 60 120 82 73 180 100 93 240 100 99

(

EXAMPLE 3

Fill a small mixer with 3224 g of cephalexin monohydrate, 300 g of Eudragit L-100-55 and 93 g of hydroxypropyl cellulose L.F. through a suitable sieve. The mixture was mixed thoroughly and granulated with 1200 ml of a 6% (w / v) aqueous solution of hydroxypropyl cellulose L.F. Purified water is added in an amount sufficient to obtain a satisfactory granulate. The total granulation time is between 5 and 10 minutes. 4 and falls on G-padded paper trays and dried at 35 ° C for 20.5 hours. Place the dried granulate in a suitable container through sieve No. 2. 12 mesh.

To obtain 1000 tablets, the v-mixer was filled with 1230 g of this granulate and 100 g Methocel E4M type CR was added through a No.30 mesh sieve. This mixture was stirred for about 20 minutes and then 15 g of powdered stearic acid and 10.5 g of magnesium stearate were added through a No. 30 mesh _C sieve. This material was mixed for 5 minutes and placed in a suitable container. The resulting mixture was compressed on Stokes F-npeca. for the preparation of tablets using conventional means.

The resulting tablets are coated with a solvent-based film-forming mixture consisting of hydroxypropyl methylcellulose E-50 (1.581 percent by weight) and glycerol (0.552 percent by weight) in a conventional tray. The tablets are then dried on paper-coated boards.

Composition of one tablet Weight (mg) Weight (percent) cephalexin monohydrate 1 - 1074.50 79.30 ' Eudranite L-100-55 100.00 7.38 hydroxypropyl methylcellulose L.F. 55.00 4.06 Methocel E4M type CR 100.00 7.38 powdered stearic acid 15.00 1.11 magnesium stearate 10.50 0.77 pure film coating (theoretical) 50.54

The dissolution of these tablets is evaluated by the methods described above with the following results: Dissolved cephalexin (cumulative percentage) Time (min) Gastric method Simulated GI method 30 12 12 60 31 30 90 47 37 120 60 41 180 80 58 240 93 72 300 99 82 360 103 89 420 105 93

EXAMPLE 4

A Hobart mixer is filled with 1612 g cfalexin monohydrate and 45 g hydroxypropyl cellulose L.F. through a suitable sieve. This mixture was thoroughly mixed and granulated with 500 ml of water dispersion of Eudragit L30D (equivalent to 150 g of Eudragit L-100-55). Purified water is added in an amount sufficient to obtain a satisfactory granulate. The total granulation time is between 5 and 10 minutes. The wet granulate is placed on sieve No. 2. 4 and the paper trays were dried at 35 ° C for 20 hours. Place the dried granulate in a suitable container through sieve No. 2. 14 mesh.

To obtain 500 tablets, the v-mixer was filled with 602 g of this granulate and 50 g of Methocel E4M type CR was added through a No. 30 mesh sieve. This mixture was stirred for about 20 minutes and then 7.5 g of powdered stearic acid and 5.25 g of magnesium stearate were added through a No. 30 mesh sieve. This material is mixed for 5 minutes and placed in a suitable container. The resulting mixture was compressed on Stokes F-npeca to obtain tablets using conventional means.

Composition of one tablet Weight (mg) Weight (percent) cephalexia monohydrate 1074.50 80.79 Eudragit L30D (Hard) 100.00 7.52 hydroxypropyl methylcellulose L.F. 30.00 2.26 Methocel E4M type CR .100.00 7.52 powdered stearic acid 15.00 1.13 magnesium stearate 10.50 0.78

The dissolution of these tablets is evaluated by the methods described above and the following results are obtained:

Dissolved cephalexin Accumulation percentage)

Time (min) _________ Gastric method Simulated GI method

30 22 21 60 33 32 90 42 37 120 50 39 180 63 49 240 75 67 300 85 '79 360 93 85 420 97 88

EXAMPLE 5

A Hobart mixer is filled with 2149 g of cephalexin MOHOXUgpam. ^This material was granulated with 1000 ml of a 10% (w / v) solution of Eudragit L-100-55 in a mixture of isopropyl alcohol and water (9: 1, v: v). The total granulation time is about 7 minutes. The wet granule is placed on a No. 4 sieve. 4 and fall on paper trays and dry at 35 ° C for 2 hours. Drying was continued at room temperature overnight. Place the dried granules in a suitable container through sieve No. 2. 14 mesh.

To obtain 300 tablets, the v-mixer was filled with 337 g of granule and 45 g of hydroxypropyl methylcellulose E-50. This mixture was stirred for about 30 minutes. Powder stearic acid (4.5 g) and magnesium stearate (1.95 g) were added through a No. 30 mesh sieve. This material is mixed for about 5 minutes and placed in a suitable container. The resulting mixture was triturated on Stokes F-npeca to obtain tablets using conventional means.

Composition of one tablet Weight (mg) Weight (percent) cephalexin monohydrate 1074.5 82.91 Eudragit L-100-55 50.0 3.86 hydroxypropyl methylcellulose E-50 ¹ 150.0 11.57 powdered stearic acid 15.0 1.16 magnesium stearate 6.5 0.50

The dissolution of these tablets is evaluated by the methods described above and the following results are obtained:

Dissolved cephalexin (cumulative percentage)

Time (min) Gastric method Simulated GI method 30 24 24 ⁶⁰ 38 37 90 47 46 120 54 55 180 73 76 240 94 ⁸⁹ 300 99 94

EXAMPLE 6

The Hobart mixer 11a is filled with 500 g of cefaclor monohydrate, 65 g of lactose and 100 g of hydroxypropyl methylcellulose E-5 through a suitable sieve. The mixture was completely mixed and granulated with 350 ml 5% (w / v) solution of Eudragit L-100-55 8 mixture of isopropyl alcohol and water (19: 1, v: v). The total granulation time is between 5 and 10 minutes. 4 and fall on paper trays and dry at 50 ° C for 1 hour. Drying was continued at room temperature for 48 hours. Place the dried granulate in a suitable container through sieve No. 2. 16 mesh.

To obtain 500 tablets, the v-mixer was filled with 268 g of the granule and 3.75 g of powdered stearic acid and 2.5 g of magnesium stearate were added through a No.30 sieve. The resulting mixture was stirred for 5 min and placed in a suitable container. The resulting mixture was pressed onto a Stokes E-tablet for tabletting using conventional means.

Composition of eana tablet Weight (mg) Weight (percent) cefaclor monohydrate 392.30 71.60 lactose 50.98 9.30 Eudragit L-100-55 13.71 2.50 hydroxypropyl methylcellulose E-5 78.45 14.32 powdered stearic acid 7.50 1.37 magnesium stearate 5.00 0.91

The dissolution of these tablets was evaluated by the methods described above and the following results were obtained:

Dissolved cefaclor (cumulative percentage).

Time (min) Gastric method Simulated GI method

90 41 54 120 47 97 180 61 112 240 75 300 85 360 92 420 97

EXAMPLE 7

The Hobart mixer is filled with 500 µf cefaclor monohydrate, 40 g Eudragit L-100-55, 50 g lactose and 75 g Pullulan PI-20 through a suitable sieve. The mixture was thoroughly mixed and granulated with 200 ml of a 5% (w / v) solution of hydroxypropyl cellulose L.F. in a mixture of isopropyl alcohol and water (19: 1, v: v). The total granulation time is between 5 and 10 minutes. 4 and fall on paper trays and dry at 50 ° C for 2 hours. Drying was continued at room temperature for 24 hours. Place the dried granulate in a suitable container through sieve No. 2. 14 mesh.

Fill the V-mixer with 266 g of the granule and then, through a No.30 mesh sieve, 3.75 g of powdered stearic acid and 2.5 g of magnesium stearate are added. Stir this material for 5 minutes and place in a suitable container. The resulting mixture was compressed on Stokes F-npeca for tabletting using co-conventional means to obtain 500 tablets.

Composition of one tablet

Weight (mg) Weight (percent) of cefaclor lactose monohydrate

392.30

39.23

73.43

7.34

Eudragit L-100-55 31.36 5.87 Pullulan PI-20 58.85 11.02 powdered stearic acid 7.50 1.40 magnesium stearate 5.00 0.94

The dissolution of these tablets is evaluated by the methods described above and the following results are obtained: Dissolved cefaclor (cumulative percentage) ₍ Time (min) Gastric method 30 18 60 24 90 30 120 34 180 44 240 50 300 56 360 61 420 66

EXAMPLE 8

The Hobart mixer is filled with 1177 g of cefaclor monohydrate, 212 g of mannitol and 176 g of hydroxypropyl methylcellulose E-5 through a suitable sieve. The mixture was thoroughly mixed and granulated with 720 ml of a 5% (w / v) solution of Eudraglt L-100-55 in a mixture of isopropyl alcohol and water (9: 1, v: v). The total granulation time is 5 minutes. The wet granulate is placed on a No. 4 sieve. 4 and falls on paper trays and dried at 40 ° C for 3 hours. Drying was continued at room temperature overnight. Place the dried granulate in a suitable container through sieve No. 2. 16 mesh.

To obtain 1500 tablets, the v-mixer was filled with 800 µm of this granulate and through a No. 4 sieve. Powdered stearic acid (11.25 g) and magnesium stearate (7.5 g) were added to 30 mesh. The resulting material was stirred for 5 min and placed in a suitable container. The resulting mixture was compressed on a Stokes F tablet press using conventional means.

Composition of aeon tablet % w / w mg / tablet cefaclor monohydrate 392.30 71.83 mannitol 70.70 12.95 hydroxypropyl methylcellulose E-5 58.50 10.71 Eudragit L-100-55 12.00 2.20 powdered stearic acid 7.50 1.37 magnesium stearate 5.00 0.94

p

The dissolution of these tablets was evaluated by the methods described above and obtained the following results:

Dissolved cefaclor (cumulative percentage) _t

Time (min) Gastric method Simulated GI method 30 20 21 60 31 30 90 38 61 120 46 W 180 63

240 79 300 91 360 98 420 103

EXAMPLE 9

A Hobart mixer is filled with 1177 grams of cefaclor monohydrate, 212 grams of mannitol and 176 grams of hydroxypropyl methylcellulose E-5 through a suitable sieve. The mixture was thoroughly mixed and granulated with 720 ml of a 5% (w / v) solution of Eudragit L-100-55 in a mixture of isopropyl alcohol and water (9: 1, v: v). The total granulation time is about 5 minutes. The wet granulate is placed on sieve No. 2. 4 and falls on paper trays and dried at 40 ° C for 3 hours. Drying was continued at room temperature overnight. Place the dried granulate in a suitable container through sieve No. 2. 16 mesh.

To obtain 1100 tablets, the v-mixer was filled with 587 g of this granulate and 26.4 g of mannitol. This mixture was stirred for about 30 min and through sieve No. 2. Powdered stearic acid (8.25 g) and magnesium stearate (5.5 g) were added to 30 mesh. This material was stirred for 5 min and placed in a suitable container. The resulting mixture was compressed on Stokes F-npeca for tabletting using conventional means. The resulting tablets were coated with a solvent-based film-forming mixture consisting of hydroxypropyl methylcellulose E50 (1.55 weight percent), glycerol (0.54 weight percent) and Opaspray Blue (solid 0.75 weight percent) in a conventional tray. The tablets are then dried on paper-coated boards.

Composition of a pill weight (percent) weight (mg) cefaclor monohydrate 392.30 68.82 mannitol 94.70 16.61 hydroxypropyl methylcellulose E-5 58.50 10.26 Eudragit L-100-55 12.00 2.11 powdered stearic acid 7.50 1.32 magnesium stearate 5.00 0.88 color film coating (theoretical) 13.01

The dissolution of these tablets is evaluated by the methods described above and the following results are obtained:

Dissolved cefaclor (cumulative n%)

Time (min) Gastric method Simulated GI method 30 18 18 60 28 28 90 36 53 120 46 95 180 66 240 83 300 93 360 97

EXAMPLE 10

The Hobart mixer 11a is filled with 1569 g of cefaclor monohydrate, 201 g of mannitol and 264 g of hydroxypropyl methylcellulose E-5 through a suitable sieve. The mixture was thoroughly mixed and granulated with 960 ml of a 5% (w / v) solution of Eudragit L-100-55 in a mixture of isopropyl alcohol and water (9: 1, v: v). The total granulation time is about 6 minutes. The wet granulate is placed on sieve No. 2. 4 and falls on paper trays and dried at 28 ° (6 hours. Drying is continued at room temperature overnight. The dried granulate is placed in a suitable container through a No. 16 mesh sieve.

1500 tablets were obtained for the eja, the v-mixer was filled with 781 g of the granule, 11.25 g of powdered stearic acid and 7.5 g (···· of magnesium stearate. Oils were added through a No. 30 mesh sieve. This material was mixed 5 The resulting mixture was then compressed _{onto a} Stokes F tablet press using conventional means The resulting tablets were coated with a solvent-based film-forming mixture consisting of hydroxypropyl methylcellulose E-50 (1.55 weight percent), glycerol (0.54 weight percent) and O paspray Blue (solid 0.75% by weight) in a conventional tray, then the tablets were dried on a paper-coated tablet.

with _________________________________________.

Composition of eana tablet weight (mg) weight (percent) cefaclor monohydrate 392.30 73.60 mannitol 50.20 9.42 hydroxypropyl methylcellulose E-5 66.00 12.38 Eudragit L-100-55 12.00 2.25 powdered stearic acid 7.50 1.41 magnesium stearate 5.00 0.94 color film coating (theoretical) 12.87

The dissolution of these tablets is evaluated but the methods described above and the following results are obtained:

Dissolved cefaclor (cumulative percentage) µ

Time (min) Gastric method Simulated GI method

30 17 17 60 26 26 90 33 45 120 38 42 180 49 240 58 300 67 360 76 420 83

EXAMPLE 11

The Hobart mixer is filled with 1046 g of cefaclor monohydrate, g of mannitol and 70 g of hydroxypropyl methylcellulose E-5 through a suitable sieve. The mixture was thoroughly mixed and granulated with 500 ml of a 3% (w / v) solution of Eudragit L-100-55 and 2. 6% (w / v) of a solution of hydroxypropyl cellulose EF in a mixture of isopropyl alcohol and water (isopropyl alcohol 90 parts: 10 parts water). The total granulation time is between 3 and 4 minutes. The wet granulate is placed on a No. 4 sieve. 4 and comes up with paper trays and boards. dried at 40 ° C for 5 hours. Drying was continued at room temperature for 24 hours. The dried granulate is sieved through a No. 4 sieve. 16 mesh and return to paper-coated boards and dry at 40 ° C for 2.5 hours to remove residual solvent.

To obtain 900 tablets, the v-mixer is filled with 550.8 g of this granulate. To this, 61.2 g of hydroxypropyl methylcellulose E-50 was added through a No. 30 mesh sieve. The mixture was stirred for 20 min in a v-mixer. To this mixture, through sieve No. 30 mesh, the oil was added with powdered stearic acid (6.3 g) and magnesium stearate (2.7 g). This material was stirred for 5 minutes and placed in a suitable container. The resulting mixture was then compressed onto Stokes F-peca for tabletting, using conventional means.

The tablets were coated with a solvent-based film-forming mixture consisting of hydroxypropyl methylcellulose E50 (1.581 percent by weight), glycerol (0.552 percent by weight) and Opaspray Blue (1.961 percent by weight) in a conventional tray. The tablets were then air-dried on paper-coated boards.

Composition of one tablet weight (mg) weight (percent) 'cefaclor monohydrate 523.00 75.80 'mannitol 40.20 5.80 hydroxypropyl methylcellulose E-5 35.00 5.07 Eudragit L-100-55 7.50 1.09 hydroxypropyl cellulose EF 6.50 0.94 hydroxypropyl methylcellulose E-50 68.00 9.86 powdered stearic acid 7.00 1.01 magnesium stearate 3.00 0.43 blue film coating (theoretical) 12.50

The dissolution of these tablets was evaluated by the methods described above and the following results were obtained:

Dissolved cefaclor / cumulative percentage)

Time (min) Gastric method Simulated GI method 30 16 17 60 30 34 90 44 56 120 57 71 180 81 88 240 101 100

EXAMPLE 12

To obtain 40 tablets, the following components were loaded through a No. 1 sieve. 30 mesh and mixed together in a mortar with nec.uk: 8.44 g 7- [0- (amipo-phenylethyl) amino] -3-chloro-8-oxo-1-azabicyclo [4.2.0] oct-2-ene-2- carboxylic acid monohydrate, 0.84 g Eudragit L-100-55 and 2.56 g hydroxypropyl methylcellulose E-50. 0.104 g of magnesium stearate and 0.216 g of talc are added to this mixture and mixed thoroughly. The resulting mixture was then pressed with a Stokes-F press for 0 tableting using conventional means ._____

Composition of one tablet weight (mg) weight (percent)

7- [B- (amino-phenylacetyl) amino] -3-chloro

8- oxo-1-azabicyclo [4.2.0] oct-2-en-2-

carboxylic acid monohydrate 211.00 69.41 Eudragit L-100-55 21.00 6.91 hydroxypropyl methylcellulose E-50 64.00 21.05 magnesium stearate 2.60 0.86 talc 5.40 1.78

The dissolution of these tablets was evaluated by the methods described above and obtained with the following results:

Dissolved active agent (cumulative percentage)

Time (min) Gastric method Simulated GI method 30 23 24 60 43 44 90 65 59 120 80 68 150 92 79 180 100 87 240 105 ⁹⁹ 300 104 105

EXAMPLE 13

To obtain 40 tablets, the following components were sieved through a No. 1 sieve. 30 mesh and mixed together In pestle mortar: 8.0 g 7 - [[amino [3 [(methylsulfonyl) amino] phenyl] acetyl] amino] -3-chloro-8-oxo-1-azabicyclo [4.2.0] oct-2 -en-2-carboxylic acid, 0.8 g

Eudragit L-100-55, 1.6 g hydroxypropyl methylcellulose E-50 and 0.96 g Methocel E4M spike CR. 0.120 g of magnesium stearate and 0.200 g of talc are added to this mixture and mixed thoroughly. The resulting mixture was then compressed on a Stokes-F tablet press using conventional means.

The composition of the is qua tablet weight (mg) weight (percent) 7 - [[amino | 3 - ((methylsulfonyl) amino] phenyl] acetyl] amino | -3-chloro-8-oxo-1- gabicycle | 4.2.0] oxp-2-en-2- carboxylic acid 200.00 68.4 9 It is also a drag it L-100-55 8 pm 6.85 hydroxypropyl methylcellulose E-50 40.00 13.70 Methocel E4M type CR 24.00 8.22 magnesium stearate 3.00 1.03 talc 5.00 1.71

The dissolution of these tablets is evaluated by the methods described above and the following results are obtained:

Dissolved active agent. (cumulative percentage) Time (min) Gastric method Simulated GI method 30 19 18 60 29 28 90 40 36 120 50 40 150 58 43 180 65 48 240 78 58 300 89 69 360 97 78 420 100 84

EXAMPLE 14

To obtain 40 tablets, the following components were sieved through a No. 1 sieve. 30 mesh and mixed together in a pestle mortar: 8.0 g 7- [D- [amino [3-] (ethyl-) sulfonyl) amino] phenyl] acetyl] amino] -3-> loro-8-oxo-1a> 'abicyclo (4.2.0] oct-2-ene-2 <carboxylic acid, 0.8 g

Eudragit L-100-55, 1.6 g hydroxypropyl methylcellulose E-50 and 1.0 g Methocel E4M tin CR. 0.20 g of magnesium stearate and 0.200 g of talc are added to this mixture and mixed thoroughly. The resulting mixture was then compressed, using a Stokes-F tabletting press, using conventional means.

Composition of one tablet weight (mg) weight (percent)

7- [N- [amino [3 - {(ethylsulfoyl) amino] phenyl] acetyl] amino] -3-chloro-8-oxo-1-azabicyclo [4.2.0] oct-2-en-2-

carboxylic acid 200.00 67.80 Eudragit L-100-55 8 pm 6.78 hydroxypropyl methylcellulose E-50 40.00 13.56 Methocel E4M type CR 25.00 8.47 magnesium stearate 5.00 1.69 talc 5.00 1.69

The dissolution of these tablets is evaluated by the methods described above and the following results are obtained:

3Ί

3 a 3 m Boiling acup iuBen agent (cumulative percentage)

Time (min) l'acmpumeii method Simulated GI method

30 18 17 60 27 28 90 34 35 120 43 39 150 50 42 180 56 47 240 67 56 300 76 65 360 86 75 420 92 84

Claims (5)

Patent Claims A sustained-release matrix composition, in the form of a tablet, characterized in that it consists of about 0.1% by weight. up to about 90% by weight cefaclor, of about 5% by weight. up to about 29% by weight hydrophilic polymer and of about 0.5% by weight. up to about 25% by weight an acrylic polymer that dissolves at a pH in the range of about 5.0 to about 7.4, provided that the total weight of the hydrophilic and acrylic polymer is less than 30% by weight of the composition. Composition according to claim 1, characterized in that cefaclor is in concentrations in the range of about 45% by weight. up to about 85% by weight. Composition according to claim 1, characterized in that the hydrophilic polymer is in concentrations in the range of about 5% by weight. up to about 20% by weight Composition according to claim 1, characterized in that the acrylic polymer is in concentrations in the range of about 1.5% by weight. up to about 15% by weight. Composition according to claim 1, characterized in that it contains predominantly the following components, in weight percent: Component Weight (percent) Cefaclor 75.80 The floor 5.80 Hydroxypropyl methylcellulose 14.93 Methacrylic acid copolymer 1.09 Hydroxypropyl cellulose 0.94 Powdered stearic acid 1.01 Magnesium stearate 0.43 Publication of the Patent Office of the Republic of Bulgaria Sofia - 1113, 52-B GM Dimitrov Blvd.