CZ699A3 - Granulate for preparing quick disintegrating and quick soluble compositions with high amount of a medicament - Google Patents

Abstract

A granulate, containing an active ingredient, having a solubility in water of 1:>10, in admixture with </=15 wt.% of a water dispersible cellulose, is provided for the preparation of fast-disintegrating and fast-dissolving compositions.

Description

Field of the invention:

The present invention relates to a granulate comprising an active ingredient having a water solubility of 1: 10, mixed with a water-dispersible cellulose, and rapidly disintegrating and rapidly dissolving compositions containing said granulate.

BACKGROUND OF THE INVENTION:

It is well known that for effective treatment of diseases, high amounts of drugs, especially antimicrobials, must sometimes be administered. In addition, there is a need to reduce the frequency of drug administration from 4 or 3 doses per day to 2 or 1 doses per day to increase patient compliance. Thus, the daily dose of drug may be divided into 1 or 2 doses instead of 3 or 4. This means, however, that the amount of drug in the dosage form must be increased. Some drugs, depending on their potency and pharmacokinetic properties, may be suitably incorporated into so-called modified release formulations. Other drugs, such as amoxicillin, exhibit the best bioavailability only when included in immediate release drug formulations (Scand. J. Gastroenterol. (1966) 31 (1), pages 49-53). It is not convenient for a patient, especially the elderly who normally take several medicines, to take two or more small formulations containing the same medicament at the same time instead of one large product. Therefore, there is a need for readily swallowable dosage forms that contain a maximum amount of drug and a minimum amount of carriers while maintaining the ability to rapidly disintegrate and dissolve. Since the 1970s, many attempts have been made to formulate such dosage forms. However, as it turned out, the developed formulations and production methods were applicable only to some selected drugs.

I.M. Jalal et al. in J.Pharm. Sci (1972) 6f: 9, pages 1466-1467, described tablets containing 80% of a drug which is magnesium hydroxide, sulfadiazine or acetaminophen and 20% a binder which is Avicel® RC581 (microcrystalline cellulose and sodium carboxymethylcellulose). Tablets were prepared by mixing the drug and said binder, granulating the mixture with water, drying the granules and compressing them into tablets. The opening times aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa aaa 3.5 minutes (sulfadiazine). It is clear from the experience of the present inventor that the results greatly depend on the properties of the drug: for example when using the above method to prepare tablets containing 80 wt% amoxicillin trihydrate, a disintegration time of 12.5 minutes was observed. Tablets containing ibuprofen disintegrated in more than 5 minutes and tablets containing sulfamethoxazole required 35 minutes to disintegrate in water. The results obtained by Jalal for sulfadiazine and acetaminophen were well reproduced by the authors of the present invention.

O'Connor et al. in Drug. Devel. Indian. Pharm (1985) _U (9 & 10) pages 1837-1857 reviewed in-vitro drug release profiles for uncoated tablets containing various drugs and fillers (microcrystalline cellulose and two types of water dispersible cellulose) in different proportions prepared by wet granulation followed by extrusion and shaping. Unfortunately, the prepared tablets did not dissolve rapidly.

(i. Barato et al. in I.abo-Pharma (1984) 32, No. 342, pages 401-403) disclose granules containing a large amount of drug with a solubility of 1: 10 carboxymethylcellulose and polyvinylpyrrolidone, prepared by conventional wet granulation. prepared from this granulate did not dissolve until after 13 minutes.

DE-4310963 describes the preparation of supposedly rapid release tablets of propalenone hydrochloride. According to Figure 7, only 10% of the active ingredient was released after 30 minutes.

IJS 4911921 discloses tablets containing high doses of ibiiprolene. Tablets were prepared by conventional wet granulation from the drug, binder and wet granulation binder. Although rapid release of the active ingredient was achieved, the tablets disintegrated slowly.

A.A. Chalmers et al. in J. Pharm. Pharmac. (1976) 28 pages 234-238, describes formulations containing a high amount (> 90%) of oxytetracycline and optionally intragranular microcrystalline cellulose (7.2%) and / or alginic acid (2.7%). Tablets were prepared by pouring or conventional wet granulation techniques using water and a 2.5 wt% solution of polyvinylpyrrolidone in water. Very rapid tablet disintegration was achieved only with tablets prepared by casting, when alginic acid was incorporated into the granulate. When these techniques were applied to, for example, amoxicillin, which is also an antibiotic, there was no rapid disintegration of the tablets.

US patent 1560475 discloses tablets containing more than 90% by weight of orally active cephalosporin and thus less than 10% by weight of carriers (binder, disintegrant and lubricant). Tablets may be prepared by mixing cphalosporin and carriers and then compressing the mixture. Preferably, however, tablets are prepared by dissolving or dispersing the binder in water or in a suitable organic solvent and then using the liquid to granulate cfalphorin. The dried granules are then mixed with a disintegrant and a lubricant and compressed into tablets. However, the release time of these tablets, measured in distilled water at 37 ° C, ranges from 2 to 13 minutes.

DU-2259646 discloses tablets containing about 90% cphalosporin and about 10% carriers (crystalline cellulose, ultraamylopectin and lubricant). Tablets are prepared by mixing the above components, forming a dry granulate, and compressing the granules so obtained into tablets. The tablets are said to disintegrate in an artificial gastric juice at 37 ° C for 3 minutes.

LP-0200252 discloses tablets containing 80-98% of a mixture of trimethoprim or a salt thereof, a sulfonamide or a salt thereof in a ratio of 1:20 to 20: 1 and a polymeric resin ion exchanger such as Amberlite® IRP 88. The tablets are prepared by wet granulation technique with using a binder solution for wet granulation in ethanol or a mixture of ethanol and water. The described disintegration times were generally less than 1 minute. However, the procedures of this administration have proved to be unsuitable for other drugs or combinations of drugs.

A formulation technique that is generally applicable to different drugs with a water solubility of less than 10% is described in EP-0330284-B. The drug is admixed with 20-100% by weight of the cellulosic product, which is microcrystalline cellulose, microfine cellulose, or a mixture of both. The mixture is granulated with an aqueous solution containing up to 0.5% by weight of the granulating binder (all ratios based on the weight of the active ingredient). In order to obtain rapidly disintegrating tablets, the granules may be mixed with suitable carriers such as disintegrants, lubricants and flavors after drying and screening. A specific example of this procedure is described in EP-0281200-B. The present invention provides fast disintegrating tablets comprising an amphoteric beta-lactarn antibiotic, 24-70% by weight of a first disintegrant which is microcrystalline cellulose and / or microfine cellulose and a second disintegrant. The described disintegration times were generally within 1 minute. The bioavailability, for example, of amoxicillin trihydrate was as good as that of a commercially available suspension and was independent of the route of administration of the tablets (as a suspension after disintegration of tablets in water or as an orally administered tablet). However, according to the experience of the present inventors, this formulation technique has proven unusable in the preparation of fast-disintegrating and fast-dissolving tablets containing greater amounts of active ingredient and consequently considerably less cellulosic product.

WO 92/19227 discloses tablet formulations having a high drug content. Tablets were prepared by a dry compression technique, including the preparation of a granulate. Although fast-disintegrating tablets appear to have been prepared, it is not clear what method was used for evaluation and what requirements should be met. No results of solubility studies have been published.

The problem that is solved by the present invention is to provide a composition or manufacturing process that would be applicable to all kinds of active ingredients with a water solubility of less than 10%. The aim is to obtain fast-disintegrating and fast-dissolving compositions with a high content of active ingredient using standard production equipment.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a granulate comprising an active substance with a water solubility of 1:> 10%, in a mixture with <15% by weight, preferably 2-5% by weight, of water-dispersible cellulose (ratios based on the weight of said active substance). folders).

It is a further object of the invention to provide rapidly disintegrating and rapidly soluble compositions containing said granulate.

Detailed description of the invention

It has been found that by mixing the active ingredient having a water solubility of 1:> 10, with <15 wt% water-dispersible cellulose (ratios based on the weight of the active component), granulating the mixture with water or aqueous solution followed by drying the wet granulate a granulate is obtained, which can advantageously be used for preparing rapidly disintegrating and rapidly dissolving compositions.

Water-dispersible cellulose is also known as microcrystalline cellulose and sodium carboxymethylcellulose, for example in U.S. Pat. Phramcopoeia / National Formulary, Microcrystalline cellulose is a partially purified depolymerized form of α-cellulose.

which is obtained by processing paper derived from fibrous plant material with dilute mineral acid. Preferably, this acid attacks the less ordered or amorphous regions of the cellulosic polymer chain, thereby releasing crystallization centers that form cellulose crystalline aggregates. The reaction mixture is washed to remove by-products of degradation. The resulting wet cake is dewatered and spray dried to form porous particles with a wide size distribution. Microcrystalline cellulose is a white, relatively liquid powder, odorless, tasteless, insoluble in water, organic solvents, dilute leaches and dilute acids. It is widely used as a carrier in the pharmaceutical industry, for example as a binder, a diluent in the manufacture of tablets by direct compression and wet granulation, as a disintegrant, as a tablet glidant and as a diluent in capsules. Microcrystalline cellulose is commercially available in several particle size classes with different properties, eg Avicel®-PH 101 and 102. Carboxycellulose sodium is prepared by treating sodium alkalized cellulose with monochloroacetate. It is a white to slightly yellow, hygroscopic powder or granular material. It is commercially available in a variety of variants in terms of substitution range, viscosity, particle size, and the like. Carboxycellulose sodium is well known as a suspension and / or viscosity enhancing agent and as a binder for wet granulation. The crosslinked product is used as a disintegrant. Water-dispersible celluloses are colloidal forms of microcrystalline cellulose, prepared by chemical depolymerization of highly purified wood, where the original crystalline sites of the fibers are combined with sodium carboxycellulose and spray dried. Colloidal celluloses are also widely used as pharmaceutical or cosmetic carriers, e.g. as oil-in-water emulsifiers, emulsion or foam stabilizers, suspending agents in pharmaceutical suspensions (ready to use or as dilutable suspensions), and as thickening agents. Sodium carboxycellulose improves the binding properties and plasticity of the extruded mass. Therefore, water dispersible celluloses are also considered to be excellent carriers in compositions that are prepared by wet granulation followed by extrusion and shaping. Thus, the water-dispersible celluloses can advantageously be used to prepare compositions that exhibit sustained release of the active ingredient. Four types of these celluloses are available commercially under the trade names Avicel® RC-501 (containing 7.1-11.9% sodium carboxymethylcellulose), Avicel® ^! RC-581 (containing 8.3-13.8% sodium carboxymethylcellulose), Avicel® RC-591 (containing 8.3-13.8% sodium carboxymethylcellulose) and Avicel® CL-611 (containing 11.3-18.8) % sodium carboxymethylcellulose). All types are hygroscopic powders that are insoluble in organic solvents and dilute acids and partially soluble in both dilute alkali and water (due to the presence of sodium carboxymethylcellulose). In view of the aforementioned lasers, it is surprising that all four types can be used to prepare the granulate of the present invention and allow the preparation of rapidly disintegrating compositions that rapidly release the active ingredient. Of the above, Avicel® RC-581 is preferably used. Most preferably, Avicel® RC-591 is incorporated into the granulate. The water-dispersible celluloses may be used in an amount of up to 15% by weight (based on the weight of the active ingredient). Preferably, however, said celluloses are used in a concentration between 1 and 7.5 lunot%, most preferably in a concentration range of 2-5 wt%. All ratios are based on the weight of the active ingredient. Surprisingly, according to the experience of the present inventors, the preparation of a granulate from the active ingredient and an appropriate amount of microcrystalline cellulose or sodium carboxymethylcellulose did not lead to the formation of rapidly disintegrating and rapidly soluble mixtures.

The active ingredients which are incorporated into the granulate have a water solubility of 1:> 10 at room temperature, but preferably a solubility of 1:> 100. This procedure is preferred for drugs that must be administered in large doses to be effective. Examples of such drugs are generally atimicrobials selected from the group of beta-lactam compounds such as penicillins (amoxicillin, ampieilin) and cephalosporins (cefaclor); ntacrolides such as erythromycin and josamycin; sulfonamide groups such as sulfamethoxazole; hydroxyquinolones and quinolones such as ciprotloxacin; groups of imidazoles and nitroimidazoles such as mctronidazole and thmidazole; and various other substances such as nalidixic acid and nitrofurantoin. Also other non-antimicrobial drugs can be successfully granulated according to the present invention: antacids such as hydrotalcite, analgesics and anti-inflammatory drugs such as ibuprofen, acctaminophen and acetylsalicylic acid, antidiabetics such as tolbutamide, antimalarials such as amodiachine hydrochloride antituberculotics such as rifampicin, anticonvulsants such as carbamazepine and antiparkinsonian drugs such as levodopa. The active ingredient need not be a drug, but also compounds that are capable of enhancing drug efficacy when administered together with the drug (either simultaneously or sequentially). An example of such a substance is a beta-lactamase inhibitor, such as clavulic acid or a pharmaceutically acceptable salt thereof, which improves the efficacy of beta-lactam antibiotics. The high content of active ingredient in the granulate also makes it possible to combine active ingredients, such as pharmaceuticals, in that garment granulate, provided there are no reservations about their compatibility.

The granulates of the present invention are prepared by a conventional wet granulation method, for example according to I. M. Jalal et al. Preferably, the active ingredient is mixed with the water dispersible cellulose in a suitable mixer. The mixer can be either planetary, high shear or high speed. The mixing time depends on the particular apparatus used. Furthermore, water or an aqueous solution is added until the material is sufficiently wetted. This operation can be carried out either in the vessel used to mix the components, or the powder mixture can be transferred to a fluidized bed granulator where the aqueous solution is sprayed onto the materials. The amount of water used may range from 20 to 30% by weight (based on the weight of the granulate). After partial drying, the wet mass is passed through a first screen and then further dried in a fluid bed dryer at an inlet air temperature between 40 and 60 ° C. After drying the granules to the desired humidity, the granules are passed through a second screen. Alternatively, the wet mass can be transferred directly to a fluid bed dryer without wet screening. After drying, the granules pass through the first and second sieves. Three screens can also be used.

While many of the above active ingredients have unsatisfactory transport properties, the granules prepared according to the present invention have these properties sufficient to good. Due to the good bulk volume and suitable Ilausner ratio, the granules can be easily formulated into compositions. The disintegration and dissolution behavior of the granules is also satisfactory.

The granulates prepared according to the present invention are very suitable for versatile use. After addition of suitable carriers such as lubricants, flow promoters, anti-adherents, etc., the granules may also be filled into capsules and sachets. Compositions based on the above granulate contain granules in an amount of> 80% by weight to obtain high dose compositions. Due to the high content of ingredients and the limited amount of carriers required to obtain rapidly disintegrating and rapidly dissolving compositions, it may be very advantageous to admix an additional active ingredient to the granulate when it is advantageous to combine drugs or combine the drug with an activity enhancer. pharmaceuticals. It goes without saying that the granulate can also be incorporated into a dosage form with a greater proportion of carriers. This can be very advantageous if taste masking of the active ingredients is required.

In order to prepare rapidly disintegrating and rapidly dissolving compositions containing a high amount of drug, it is preferred to mix the granulate with the first and second disintegrants. The first disintegrant is preferably a cellulosic product which is either microcrystalline cellulose (Avicel® PH 101, Aviccl® PH 102) or microfine cellulose, or a mixture of both. The second disintegrant may be a starch such as Star-X 1500, a starch derivative,

I 9 9 ft ft V such as sodium starch glycolate. The second disintegrant is preferably selected from the group of superdisintegrants such as crosslinked polyvinylpyrrolidone and low substituted hydroxypropylcellulose. It is preferred to add both the first and second disintegrant in an amount ranging from about 2, e.g. 1.5 wt%, to S wt%, more preferably in the range of 3-6 wt% (ratios based on the weight of the composition) . The ratio of the amount of the first and second disintegrants in the composition may range from < 4: 1 to 1: 4, but is preferably in a ratio of 1: 1. The compositions may further comprise flavoring agents, sweetening agents such as saccharinic acid, its sodium salt or aspartame, lubricants such as colloidal silica, stearic acid, and its salt. Preferably, such carriers are added in amounts of less than 4% by weight (ratios based on the weight of the composition).

Alternatively, the rapidly disintegrating compositions may be prepared from two granules containing different active ingredients. It may also be advantageous to prepare the granulate from some carriers which will later be added to the granulate prepared according to the present invention. For example, a granulate of flavors, sweeteners and one or both disintegrants can advantageously be prepared by the dry granulation method. The granulate may also be admixed with a drug or agent that increases the activity of the active ingredient incorporated into the granule, such as a beta-lactamase inhibitor, when the intra-granular active ingredient is a beta-lactam compound.

By rapid disintegration is meant disintegration in water at room temperature (20 ° C) with a disintegration time of less than 2 minutes, and preferably in less than 1 minute. The European Pharmacopoeia method is used to evaluate the disintegration process, but with additional movement modification (22 mm instead of 55 mm) simulating the user's situation. Rapid dissolution is defined as the dissolution of 95% of the drug in a suitable solvent, e.g. as prescribed in U.S. Pat. Pharmacopoeia 1995 for each individual drug, at 37 ° C after 30 minutes. Preferably, 90% of the drug was dissolved after 10 minutes (under the same conditions).

The compositions of the present invention exhibit many advantages. Studying the bioequivalence of the amoxieiline and cephalor containing tablets prepared according to the present invention, either as such or after prior dispersion in water, has shown results equivalent to commercially available compositions. In addition, the significant difference in spreading times and dissolution rates between compositions containing different medicaments in a similar carrier exhibited by the compositions described by Jalal et al. Has been reduced. By using granules with high doses of drug, a considerable reduction in the volume of the dosage form was achieved. Volume reduction is desired both in terms of production and handling and

In 9 9 * 9 9 4 ·

9 9 9 99 49 <<9 99 patient acceptance. The benefits of volume reduction are multiple. The patient can more easily swallow the composition. As a result, patient compliance is increased. Due to the reduction in the amount of carriers used, the new composition is advantageous both economically, by significantly reducing production costs and reducing the amount of packaging material required, and from an environmental point of view, by reducing the amount of wastes produced e.g. from aluminum and vinyl chloride poles. which cannot be recycled as packaging materials.

Although the present invention would! For clarity and understanding described in detail by way of illustrations and examples, those of ordinary skill in the art will appreciate that certain changes and modifications may be made without departing from the spirit and scope of the appended claims.

The following examples further illustrate the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

970 g of eephalor (as monohydrate) and 30 g of dispersible cellulose (Avicel® RC591) were mixed for 5 minutes in a planetary mixer. About 320 mL of water was gradually added to this mixture and stirring was continued for an additional 5 minutes. The wet granulate was dried in a fluid bed dryer at an inlet air temperature of 50 ° C and subsequently sieved through 1.00 mm and 0.630 mm screens.

Example 2

864 g of the granulate prepared according to Example 1 was mixed with 98 g of a mixture of microcrystalline cellulose and cross-linked polyvinylpyrrolidone (1: 1), flavors and sweeteners in a TURBFLA mixer for 10 minutes. Lubricant was then added and stirring continued for 3 minutes. The mixture was compressed into tablets having an average weight of 625 mg.

The tablets obtained had the following characteristics:

Tiny: <0.011%

Hardness: 6.9 kP

Mean tablet weight: 627 mg

Release time (in water 20 ° C): 22 seconds

Dissolution: 98% eephalor dissolved after 10 minutes: 99% eephalor dissolved after 30 minutes

AND

Example 3

Ccfalor monohydrate 524 mg

Dispersible cellulose (Avicel® RC591) 15.7 mg

Microcrystalline cellulose 13.5 mg

Low-substituted hydroxypropylcellulose 13.5 mg

Flavor 9.1 mg

Sweetener 9.1 mg

Lubricants 9.2 mg

The granules and tablets were prepared from the above components by the method described in Examples 1 and 2. The tablets thus obtained had the following characteristics:

Little bit

Hardness

Mean tablet weight Disintegration time (in water 20 ° C) Dissolution: <0.01%: 7.4kP: 597 mg: 100 seconds: 92% cefaclor dissolved in 10 minutes; 96% cefaclor dissolved in 30 minutes

Example 4

Amixicillin (as trihydrate) 86.9% Dispersible cellulose (Avicel® RC591) 2.6% Crosslinked polyvinylpyrrolidone 3.8% Microcrystatic cellulose 3.8% Flavors 1,6% Sweetener 1.0% Lubricant 0.4%

4 4

The granules and tablets were prepared from the above components by the method described in Examples 1 and 2. The tablets thus obtained had the following characteristics.

Opening time (in water 20 ° C)

Dissolution

Medium weight tablets

Hardness

Friability: 48-50 seconds: 98.5% amoxicillin dissolved in 30 minutes: 1330 mg: 20 kP: <0.01%

Example 5

The granules and tablets were prepared by the methods described in Examples 1 and 2 from the same components as described in Example 4. However, amoxicillin trihydrate was also substituted with another drug selected from ampicillin anhydrous, acetaminophen, sulfamethoxazole, ibuprofen and ciprofloxacinite. The tablets prepared by this route had the following characteristics:

drug hardness fkP) opening time in water 20 ° C ís) dissolution (% after 10 minutes) dissolution (% after 30 minutes) amoxicillin trihydrate 7.5 45 92.0 97.2 anhydrous ampicillin 7.1 41 86.7 97.2 acetaminophen 3.7 25 93.7 102.0 sulfamethoxazole 7.3 36 66.9 86.2 (after 20 min.) ibuprofen 5.5 54 98.0 101.8 ciprofloxacin 6.0 32 95.9 99.3

Note: dissolution of all tablets except those containing amoxicillin was determined by the methods described in USP '95.

Examples

As in Example 5, the granules and tablets were prepared by the methods described in Examples 1 and 2 from the same components as described in Example 4. However, the amoxicillin trihydrate was replaced by another drug selected from anhydrous ampicillin, sulfamethoxazole. crytromycin ethyl succinate; and ciprofloxacin. The tablets obtained by this route had the following characteristics:

drug hardness (kP) opening time in water 20 ° C £ sl hardness (kP) opening time in water 20 ° C ω amoxicillin trihydrate 10.4 47 14.7 47 anhydrous ampicitin 10.6 40 15.4 59 sulfamethoxazole 10.1 (57) 13.8 66 erythromycin ethyl succinate 10.6 67 13.9 111 ciprofloxacin 9.1 34 14.1 65

Example 7

The granules and tablets were prepared by the methods described in Examples 1 and 2 from the components given in Example 4. However, another type of dispersible cellulose was used. The prepared tablets have the following characteristics:

type of dispersible cellulose hardness fkP) opening time in water 20 ° C (with) Avicei RC-501 6.8 77 Avicel RC-611 6.4 93

* 3 · 3 4 4 • 4 3 3 3 4 4 3 3 3 3

Example 8

Granulate (-amoxicillin trihydrate / dispersible cellulose (Avicel® RC581) 98/2) Cross-linked polyvinylpyrrolidone Microcrystalline c c 1 u lose Flavors

Sweeteners

89.6%

3.9% 3.9% 1.6% 1.0%

The granules and tablets were prepared by the methods described in Examples 1 and 2. The tablets thus obtained showed a disintegration time in water at 20 ° C of 92 seconds. The tablets had a hardness of 7 kP.

Example 9

Granulate (= amoxicillin trihydrate / dispersible cellulose (Avicel® RC581) 97/3) 84.75%

Cross-linked pylyvinylpyrrolidone 4.0%

Microcrystalline cellulose 11.0%

Lubricant 0.25%

The granules and tablets were prepared as described in Examples 1 and 2. The tablets thus obtained had the following characteristics:

hardness (kP) water opening time 20 ° C (s) 6 102 12 120 18 140

Example 10

Granulate (= amoxicillin trihydrate / dispersible cellulose (Avícel® RC581) 96/4) 84.0% Cross-linked polymers vinyl pyrrolidone 4.0%

Microcrystalline cellulose 8.7%

Lubricant 3,3%

The granules and tablets were prepared by the methods described in Examples 1 and 2. The tablets thus obtained had the following characteristics:

hardness (kP) water opening time 20 ° C (s) 5 94 9 90 15 Dec 115

Example 11

Granulate (= amoxicillin trihydrate / dispersible cellulose (Aviccl® RC581) 92/8) 89.3%

Cross-linked polyvinylpyrrolidone 4,0%

Microcrystalline cellulose 6.4%

Lubricant 0,2%

The granules and tablets were prepared as described in Examples 1 and 2. The tablets thus obtained had a disintegration time in water of 20 ° C for 80 seconds. The observed hardness was 6 kP.

Example 12

The granulate and tablets were prepared by the methods described in Examples 1 and 2 from the components given in Example 4. Only the ratio of amoxicillin trihydrate to dispersible cellulose (Avicel® RC-591) in the granulate was variable. The tablets thus obtained had the following characteristics:

amoxicillin trihydrate / dispersible ratio cellulose (Avicel® RC-591) hardness (kP) opening time in water 20 ° C (s) 95/5 7.3 77 Q9 Γ / 7 n 1— | \ J / 1 7.1 87 85/15 6.5 127

Example 1 3

Granulate (= amoxicillin trihydrate / dispersible cellulose (Avicel® R.C591) 95/5) 84.1%

Lpyrrolidone Crosslinked Poles 6.3%

Microcrystalline cellulose 6.3%

Flavors 1,6%

Sweetener 1,0%

Lubricant 0,7%

The granules and tablets were prepared by the methods described in Examples I and 2 from the above components. The tablets thus obtained had the following characteristics:

hardness (kP) water opening time 20 ° C (s) 7 52-56 11 56-61 18 58-62

Example 14

The first granulate was prepared from 300 mg of amoxicillin trihydrate and dispersible cellulose (Avicel® RC-591) by the method described in Example 1. The second granulate was prepared by mixing

Rok φ φ mik mik mik φ φ φ φ φ · · · · · · · φ φ · · · φ φ φ φ φ mik mik mik mik mik mik mik mik mik mik mik mik mik mik mik rok rok rok rok rok rok rok rok rok 5.5% by weight), then compressing the mixture into tablets having a hardness of 1.5-2 kP and crushing the tablets using an oscillating Frewitt granulator. The first and second granules were mixed. The cross-linked polyvinylpyrrolidone and the lubricant were then mixed. Compressing the resulting mixture produced tablets having the following characteristics:

Tablet composition % % % % granulate 1 79.6 84.6 89.5 94.5 granulate 2 12.5 9.4 6.4 3.1 cross-linked polyvinylpyrrolidone 7.4 5.6 3.8 1.9 lubrikant 0.4 0.4 0.4 0.5 Tablet properties hardness (kP) 5.0 7.3 7.5 6.8 opening time in water 20 ° C 31.8 43.8 45.0 92.3

Example 15

The granulate and tablets were prepared by the methods described in Examples 1 and 2 / of the components given in Example 4. Only the second extragranular disintegrant was replaced with another disintegrant. selected from starch (Star-X 1500500), sodium starch glycolate, low-substituted cellulose and corn starch. The tablets thus obtained had the following characteristics:

second extraqranular disintegrant hardness (kP) opening time in water 20 ° C (s) Starch (Star-X 1500®) 5.8 73 sodium starch glycolate 4.8 124 low substituted hydroxypropylcellulose 5.1 53 cornstarch 5.9 71

• • ·

Claims (9)

Patent claims A granulate comprising an active ingredient having a water solubility of 1:> 10 in admixture with a water-dispersible cellulose, which is microcrystalline cellulose and sodium carboxymethylcellulose, characterized in that the water-dispersible cellulose is present in an amount of <15 % by weight (ratios based on the weight of the active ingredient). The granulate according to claim 1, characterized in that it contains 1-7.5% by weight of water-dispersible cellulose. Granulate according to claim 1 or 2, characterized in that it contains 2-5 wt. % water-dispersible cellulose. Granulate according to claims 1-3, characterized in that the water-dispersible cellulose is Aviccl® RC-591. A granulate according to any one of claims 1-4, characterized in that it has been prepared by conventional wet granulation. A rapidly disintegrating and rapidly dissolving composition comprising at least one granulate according to any one of claims 1-5 in admixture with pharmaceutically acceptable carriers and a drug or substance enhancing active ingredient incorporated into the granulate. AND Composition according to claim 6, characterized in that one or more of the granules according to any one of proposals I - 5 are present in a total amount of> 80% by weight, in admixture with 2 - 8% by weight of the first disintegrant and 2 - 8%. % by weight of the second disintegrant (ratios based on the weight of the composition). The composition of claim 7, wherein the first disintegrant is microcrystalline cellulose, microfine cellulose or a mixture of both and the second disintegrant is starch or starch derivative, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropylcellulose. ♦ »* 9. A composition according to designs 7 and 8, characterized by. wherein the first disintegrant and the second disintegrant are present in a 1: 1 ratio. AND