KR100475260B1 - Granulate for the preparation of fast-disintegrating and fast-dissolvingcompositions containing a high amount of drug - Google Patents

Abstract

For the preparation of fast-disintegrating and fast-dissolving compositions, granules are provided which contain the active ingredient with a water solubility of 1:> 10 in a mixture with 15 wt% of water dispersible cellulose.

Description

GRANULATE FOR THE PREPARATION OF FAST-DISINTEGRATING AND FAST-DISSOLVING COMPOSITIONS CONTAINING A HIGH AMOUNT OF DRUG}

The present invention relates to granules containing an active ingredient having a water solubility of 1:> 10 in a mixture with water dispersible cellulose, and to a quickly-disintegrating and dissolving composition containing said granules.

It is well known that high doses of drugs and especially antimicrobial compounds may need to be administered for effective treatment of the disease. In addition, it is necessary to reduce the frequency of administration from 4 or 3 to 2 or 1 times a day in order to increase the patient's medication adherence. The daily administration of the drug may therefore be divided into one or two doses instead of three or four doses, which means that the amount of drug per dose-form should be increased. Some drugs may be suitably included in so-called modified-release preparations depending on their efficacy and pharmacokinetic properties. Some other drugs, for example amoxicillin, appear to provide the best bioavailability when included in a composition that releases only the active ingredient immediately (Scand. J. Gastroentererol. (1996) 31 (1), 49-53). Eating two or more small agents that contain the same agent instead of one large agent at the same time is not convenient for patients, especially for middle-aged people who need to take several medications regularly, so that they contain the desired amount of drug and the minimum amount of excipients There has always been a need for easily swallowable such dosage forms with disintegration and rapid solubility. Numerous attempts to realize such dosage forms have been undertaken since the seventies, but as can be seen the developed compositions and methods of preparation were only applicable to the particular drug selected.

IMJalal et al., J. Pharm Sci (1972) 61 : 9, contain 80% of the drug of magnesium hydroxide, sulfadiazine, or acetaminophen, and a binder of Avicel ^R RC581 (microcrystalline cellulose and carboxymethyl cellulose sodium). The tablet containing% is started. Tablets are prepared by mixing the drug with the binder, mixing with water to granulate, drying the granules and tableting them with tablets. The disintegration time varies from 0.8 minutes (magnesium hydroxide) to 3.5 minutes (sulphadiazine). In our experience, it has been clarified that the results are highly dependent on the nature of the drug: 12½ minutes disintegration time, for example, when applying the method to produce tablets containing 80% of amoxicillin trihydrate. It was observed that tablets containing ibuprofen disintegrated after at least 5 minutes, and tablets containing sulfamemethazole required 35 minutes to disintegrate in water. The results could be reproduced rather well by the inventors of the present invention, as obtained by Jalal for sulfadiazine and acetaminophen.

Drug Devel. Ind. Pharm (1985) 11 (9 & 10), pp. 1837-1857, O'Connor et al. Consist of different drugs with different proportions and diluents (microcrystalline cellulose and two types of water dispersible cellulose), followed by wet granulation followed by extrusion and spherical. The ex vivo drug release profile for uncoated pellets prepared by spheronisation was obtained.

G.Barato et al., Labo-Pharma (1984) 32 , no 342 401-403, consist of a high amount of drug, carboxymethyl cellulose and polyvinylpyrrolidone with a water solubility of 1:> 10, and conventional wet granulation. It describes a granule produced by Tablets made of granules have been reported to disintegrate only after 13 minutes.

In DE-4310963, propaphenone-HCl tablets are claimed to be fast-released. According to Figure 7, the percentage release of active ingredient after 30 minutes was only 10%.

US 4911921 discloses tablets containing high doses of ibuprofen. The tablets may be prepared by conventional wet granulation of drugs, binders, and wet granulation binding agents. Although the active ingredient could be fast-released, the tablet did not disintegrate quickly.

J. Pharm. Pharmac. (1976) Tablet preparations containing high amounts (> 90%) of oxytetracycline and optionally intragranular microcrystalline cellulose (7.2%) and / or alginic acid (2.7%) except for AAChalmers on pages 28, 234-238. Start water. Tablets were prepared by slugging or by conventional wet granulation techniques, using water or an aqueous 2.5 wt% polyvinylpyrrolidone solution. If alginic acid is included in the granules, very fast disintegration times can be reached by tablets made only by the slugging method. When these techniques were applied, for example, to amoxicillin and antibiotic compounds, no fast-disintegrating tablets could be obtained.

British Patent 1560475 discloses a tablet containing at least 90% by weight of orally active cephalosporins and consequently up to 10 wt% of excipients (binders, disintegrants and lubricants). Tablets may be prepared by mixing cephalosporin with excipients and then tableting the mixture, but preferably tablets dissolve or disperse the binder in water or a suitable organic solvent and use this liquid to granulate the cephalosporin. It is manufactured by. The dried granules are then mixed with disintegrants and lubricants and compressed into tablets. However, the disintegration time of the tablets measured in distilled water at 37 ° C. ranged from 2 minutes to 13 minutes.

DE-2259646 discloses a tablet containing about 90% cephalosporin compound and about 10% excipients (crystalline cellulose, ultraamylopectin, and lubricant). This tablet is made by mixing the components, making dry granules, and tableting the granules so obtained.

EP-0200252 is a mixture of trimethoprim or a salt thereof and sulfonamide or a salt thereof in a ratio of 1:20 and 20: 1, and an ion-exchange compound of a processed resin type such as Amberlite ^R IRP 88, 80-98. The tablet containing% is started. The tablets are prepared by wet granulation technology using a solution containing wet granulation binding agents in ethanol or a mixture of ethanol and water. Disintegration times are generally reported to be less than one minute, but the teachings of this application do not appear to be applicable to other drugs or combinations of drugs.

Formulation techniques that can generally be applied to other drugs having a water solubility of less than 10% are disclosed in EP-0330284-B. The drug is mixed with 20-100 wt% of microcrystalline cellulose, microfine cellulose or a mixture of cellulose products thereof and granulated with an aqueous solution containing up to 0.5 wt% of a wet granulation binding agent (all percentages based on the weight of the active ingredient). The granules can be dried and sieved and then mixed with appropriate excipients such as disintegrants, lubricants and fragrances to obtain fast-disintegrating tablets. Specific examples thereof are disclosed in EP-0281200-B, which comprises a primary disintegrant and a secondary disintegrant which are amphoteric beta-lactam antibiotics, microcrystalline cellulose and / or ultrafine cellulose. Fast-disintegrating tablets containing 70 wt% are described. Disintegration times were generally reported to be within 1 minute. For example, the bioavailability of amoxicillin trihydrate has been shown to be as good as commercially available suspensions, independent of the mode of administration of the tablets (in suspension or after swallowing, allowing the tablets to disintegrate in water). . However, in the experience of the inventors of the present invention, it appears that this preparation technique is not applicable to the preparation of quick-disintegrating and quick-dissolving tablets containing high amounts of active ingredient and consequently low amount of cellulose product.

WO 92/19227 discloses tablet formulations with high drug content. The tablet was manufactured by the dry tableting technique including manufacture of granules. Although it was certainly possible to obtain fast-disintegrating tablets, it was not clear which method was used for the evaluation and which requirements were met. No results of solubility studies were provided.

The problem solved by the present invention is to provide a composition or method of preparation which can be generally applied to all kinds of active ingredients having a water solubility of less than 10%, so as to contain a high amount of active ingredients while using conventional production equipment. To yield a rapidly-disintegrating and quick-dissolving composition.

It is an object of the present invention to contain an active ingredient having a water solubility of 1:> 10 in a mixture with water dispersible cellulose of ≦ 15 wt%, most preferably 2-5 wt%, as a percentage based on the weight of the active ingredient. To provide granules.

Another object of the present invention is to provide a quick-disintegrating and quick-dissolving composition containing the granules.

Now mix the active ingredient with water solubility of 1:> 10 contained in a mixture with water dispersible cellulose of ≤15 wt% as a percentage based on the weight of the active ingredient, granulate the mixture with water or an aqueous solution, and It has then been found that by drying the wet granules, granules are obtained which can be advantageously used for the preparation of the rapidly-disintegrating and quick-dissolving compositions.

The water dispersible cellulose used is also known as "microcrystalline cellulose and carboxymethyl cellulose sodium", as in the US Pharmacopoeia / International Formulary. Microcrystalline cellulose is a partially purified and depolymerized form of α-cellulose and is obtained by treating pulp derived from fibrous plant material with a dilute mineral acid solution. This acid exposes and frees crystalline sites by attacking more irregular or amorphous regions of the cellulose polymer chain to form cellulose crystal aggregates. The reaction mixture is washed to remove the collapsed by-products and the resulting wet-cake removes water and spray-dried to form dry porous particles having a wide size distribution. Microcrystalline cellulose is a white, odorless, tasteless, relatively free flowing powder and insoluble in water, organic solvents, dilute alkalis and dilute acids. It is possible to have wide use as pharmaceutical excipients, ie as binders / diluents in the preparation of tablets by direct tableting and wet granulation, as tablet disintegrants, as tablet glidants / semi-adhesives, and as capsule diluents. . Microcrystalline cellulose is commercially available in different particle size grades with different properties (eg, Avicel ^R PH 101 and 102). Carboxymethyl cellulose sodium is prepared by the action of sodium monochloro acetate on alkalized cellulose. It is a white to light yellow, colorless, hygroscopic powder or granular material and is commercially available in numerous different grades with regard to degree of substitution, viscosity, particle size and the like. It is well known as a suspending agent and / or thickening agent and as a wet granulation binding agent. Cross-linked products are used as tablet disintegrants. Water dispersible cellulose is a colloidal form of microcrystalline cellulose prepared by chemical depolymerization of highly purified wood pulp, and the original crystalline region of the fiber is combined with the carboxymethyl cellulose sodium and spray-dried. They can also be widely used as pharmaceutical and cosmetic excipients, ie as oil-in-water emulsifiers, emulsions or foam stabilizers, as suspensions in pharmaceutical suspensions (recoverable and already made suspensions) and as thickening agents. Since the carboxymethyl cellulose sodium component improves the binding properties and improves the plasticity of the agglomerated pellets, water dispersible cellulose is also considered to be an excellent excipient in the compositions prepared by wet granulation and subsequent extrusion and spheronization. Water dispersible cellulose can therefore be advantageously used in the preparation of compositions having sustained release of the active ingredient. The four types of cellulose are Avicel ^R RC-501 (containing 7.1-11.9% carboxymethyl cellulose sodium), Avicel ^R RC-581 (containing 8.3-13.8% carboxymethyl cellulose sodium), Avicel ^R RC-591 (8.3) -13.8% carboxymethyl cellulose sodium) and Avicel ^R CL-611 (containing 11.3-18.8% carboxymethyl cellulose sodium). All types are hygroscopic powders, insoluble in organic solvents and dilute acids, partially soluble in dilute alkalis and water (due to the carboxymethyl cellulose sodium component). In view of the above properties, it is surprising that all four types can be used to prepare granules according to the invention which enable the preparation of fast-disintegrating compositions and which release the active ingredient quickly. Of the above grades, preferably the Avicel ^R RC-581 type is used, most advantageously the Avicel ^R RC-591 type is included in the granules. Water dispersible cellulose can be used in an amount of up to 15 wt% based on the weight of the active ingredient, but preferably the cellulose is used in a concentration of 1 to 7.5 wt%, more advantageously in a concentration in the range of 2 to 5 wt% And all percentages are based on the weight of the active ingredient. Surprisingly, in our experience, the preparation of granules from the active ingredient and the corresponding amount of microcrystalline cellulose and carboxymethyl cellulose sodium, respectively, did not produce a quickly-disintegrating and rapidly-dissolving composition.

The active ingredient included in the granules has a water solubility of 1:> 10 at room temperature, but preferably solubility is 1: ≧ 100. Advantageously, the active ingredient is a drug that must be administered at a high dosage in order to be effective. Examples of such drugs include a group of beta-lactam compounds such as penicillin (amoxicillin, ampicillin) and cephalosporin (sepachlor); A group of macrolides such as erythromycin and probemycin; Group of sulfonamides such as sulfamemethazole; A group of quinolones and hydroxyquinolones such as ciprofloxacin; Groups of imidazoles and nitroamidazoles such as metronidazole and tinidazole; And general antimicrobial compounds selected from a variety of other compounds such as nalidic acid and nitrofurantoin. However, other drugs that do not belong to antimicrobial compounds may also be successfully granulated by the present invention: antacids such as hydrotalcite, analgesic and anti-inflammatory drugs such as ibuprofen, acetaminophen and acetylsalicylic acid, diabetes such as tolbutamide Drugs such as drugs, antimalarial drugs such as amodiaquin hydrochloride, mycobacterium tuberculosis inhibitors such as rifampicin and mycobacterium tuberculosis drugs, anticonvulsants such as carbamazepine, and dopaminergic drugs such as levodopa. Alternatively, the active ingredient is not a drug but a compound that can enhance the efficacy of the drug when administered with the drug (simultaneously or sequentially). An example is a beta-lactamase inhibitor such as clavulanic acid or a pharmaceutically acceptable salt thereof that has shown a significant improvement in the efficacy of beta-lactam antibiotic compounds. The high active ingredient content of the granules also makes it possible to bind active ingredients, such as drugs, in the same granules, unless compatibility is compromised.

The granules according to the invention are prepared according to conventional wet granulation methods, for example as known by I.M.Jalal et al. Preferably, the active ingredient and water dispersible cellulose are mixed in a suitable mixer (which may be a planetary mixer, high shear or high speed mixer, etc.). The mixing time depends on the specific device used. Water or aqueous solution is then added until the material is sufficiently wet. This process may be done in a mixer used to mix the components or else powder mixing may be transferred to a fluid bed granulator where an aqueous solution may be sprayed onto the material. The amount of water used may range from 20 to 30 wt% based on the weight of the granules. After partial drying, the wet mass is passed through the first screen and then further dried in the fluid bed dryer at an air injection temperature between 40 and 60 ° C. After the granules are dried to the required free humidity content, they are passed through a second screen. Or alternatively, the wet mass is transferred to a fluid bed dryer without wet screening. After drying, the granules are passed through the first and second screens, optionally through the third screen, respectively.

While many of the active ingredients mentioned above have undesirable flowability, the granules according to the invention have sufficient good flowability. Due to their good powder volume and suitable Hausner ratio, they can easily be made into the composition. Disintegration and dissolution activity of the granules is also satisfactory.

The granules according to the invention are very versatile in their application. Alternatively, after addition of suitable excipients such as lubricants, flow-promoters, anti-adhesives and the like, the granules may be filled into capsules or sachets. The composition based on the granules preferably contains granules in an amount of ≧ 80 wt% in order to obtain a high dose of the composition. However, due to the high active ingredient content and the limited number of excipients required to obtain fast-disintegrating and quick-dissolving compositions, mixing granules containing a particular active ingredient with other active ingredients outside the granules is a combination of drugs Or it is very advantageous if a combination of drugs and compounds that enhance the activity of the drug should be considered. It goes without saying that the granules may also be included in dosage form with a larger portion of excipients. This can be very advantageous if taste-blocking of the active ingredient is desired.

To prepare fast-disintegrating and quick-dissolving compositions containing high amounts of drug, the granules are advantageously mixed with primary and secondary disintegrants. The primary disintegrant is preferably a cellulose product, which is microcrystalline cellulose (Avicel ^R PH 101, Avicel ^R PH 102), ultrafine cellulose or mixtures thereof. The secondary disintegrant may be a starch such as Star-X 1500 ^R or a starch derivative such as sodium glycolate starch, but is preferably a superhard such as cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose. Selected from the group of disintegrants. Both primary and secondary disintegrants are advantageously added in an amount based on the weight of the composition, in an amount in the range of about 2, for example 1.5 wt%, to 8 wt%, more preferably in the range 3-6 wt%. . The ratio of the amounts of primary and secondary disintegrants in the composition may range from <4: 1 to 1: 4, but is preferably in the range of 1: 1. The composition may additionally contain lubricants such as saccharic acid, its sodium salt, or sweeteners such as aspartame, flavoring agents, colloidal silicon dioxide, stearic acid or its salts, but preferably such excipients are based on the weight of the composition In an amount of less than 4 wt%.

Alternatively, quick-disintegrating and quick-dissolving compositions can be prepared from two granules containing different active ingredients. It may also be advantageous to prepare granules from some of the excipients added to the granules according to the invention. Granules can be advantageously produced from perfumes, sweeteners, and one or two disintegrants, for example by means of dry granulation. Optionally, the granules can be mixed with compounds or drugs that enhance the activity of the active ingredient included in the granules, such as beta-lactamase inhibitors when the intra-granular active ingredient is a beta-lactam compound.

Fast disintegration means that the time of disintegration in water at room temperature (20 ° C.) is less than 2 minutes, and preferably less than 1 minute. For the evaluation, while simulating the position of the user, the method according to the European Pharmacopoeia was used by changing the movement (22 mm instead of 55 mm). After 30 minutes at 37 ° C.,> 95% of the drug dissolved in the appropriate solvent (eg, as prescribed in US Pharmacopoeia 1995 for each particular drug) is considered to be a fast dissolution. Preferably, 90% of the drug dissolves after 10 minutes (in the same conditions).

The composition according to the invention shows many advantages. In bioequilibrium studies, the amoxicillin- and cefachlor-containing tablets according to the invention, whether taken as-is or dispersed first in water and then taken, have been found to be equivalent to commercially available compositions. Moreover, as shown by the conventional compositions described by Jalal et al, a significant variety in disintegration time and dissolution rate between compositions containing different agents in similar carriers was reduced. By using high dose granules, a significant reduction in the volume of the dosage form has been achieved. Reduced size is desirable from both the manufacturing and handling point of view and the patient's water solubility point of view. The benefits are numerous: the patient will be able to swallow the tablet composition more easily, resulting in increased patient adherence. Due to the reduction in the amount of excipients used, the new compositions are economically viable, such as significant savings in production costs and reduction of packaging materials, and from packaging materials that cannot be recycled, for example from aluminum and polyvinyl chloride. Economics also benefit from the reduction of waste.

Although the foregoing invention has been described in some detail by way of illustration and example for clarity and understanding, it is to be understood that any modifications or alterations may be made therein without departing from the scope and spirit of the appended claims. Will be readily apparent to those of ordinary skill in the art.

The following examples further illustrate the invention.

Example 1

970 g of Sephachlor (as monohydrate) and 30 g of dispersible cellulose (Avicel ^R RC591) were mixed in an oily mixer for 5 minutes. Approximately 320 ml of water was slowly added to this mixture and mixing continued for another 5 minutes. The wet granules were dried in a fluid bed dryer at an air injection temperature of 50 ° C. and then sieved through a 1.00 mm and 0.630 mm screen, respectively.

Example 2

864 g of the granules obtained in Example 1 were mixed for 10 minutes in a TURBULA-mixer with 98 g of a mixture of microcrystalline cellulose and cross-linked polypinylpyrrolidone (1: 1), a perfume and a sweetener. After adding the lubricant, mixing was continued for 3 more minutes and the mixture was compressed into tablets having an average weight of 625 mg.

The tablets obtained had the following characteristics:

Wear rate: <0.01%

Hardness: 6.9kP

Average tablet weight: 627 mg

Disintegration time (in water at 20 ° C): 22 seconds

Solubility: 98% Sephachlor dissolves after 10 minutes

99% Sephachlor dissolves after 30 minutes

Example 3

Sephachlor Monohydrate: 524.0mg

Dispersible Cellulose (Avicel ^R RC591): 15.7 mg

Microcrystalline Cellulose: 13.5mg

Low-Substituted Hydroxypropyl Cellulose: 13.5mg

Fragrance: 9.1mg

Sweetener: 9.1mg

Lubricant: 9.2mg

Granules and tablets were prepared from these components by the method described in Examples 1 and 2. The tablet so obtained had the following properties:

Wear rate: <0.01%

Hardness: 7.4 kP

Average tablet weight: 597 mg

Disintegration time (in water at 20 ° C): 100 seconds

Solubility: 92% Sephachlor dissolves after 10 minutes

96% Sephachlor dissolves after 30 minutes

Example 4

Amoxicillin (as trihydrate): 86.9%

Dispersible Cellulose (Avicel ^R RC591): 2.6%

Cross-linked polyvinylpyrrolidone: 3.8%

Microcrystalline Cellulose: 3.8%

Fragrance: 1.6%

Sweetener: 1.0%

Lubricant: 0.4%

Granules and tablets were prepared from these components by the method described in Examples 1 and 2. The tablet thus obtained had the following properties:

Wear rate: <0.01%

Hardness: 20kP

Average tablet weight: 1330 mg

Disintegration time (in water at 20 ° C): 48-50 seconds

Solubility: 98.5% of amoxicillin dissolves after 30 minutes

Example 5

From constituents such as those mentioned in Example 4, tablets and granules are prepared by the methods described in Examples 1 and 2, wherein amoxicillin trihydrate is ampicillin anhydride, acetaminophen, sulfamemethazole, ibuprofen and ciprofloxacin Substituted by another drug selected from. The tablet thus obtained had the following characteristics.

drug Hardness (kP) 20 ℃ In water Disintegration time (s) Solubility (% After 10 minutes) Solubility (30 minutes later %)  Amoxicillin Trihydrate 7.5 45 92.0 97.2  Ampicillin Anhydride 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 minutes)  Ibuprofen 5.5 54 98.0 101.8  Ciprofloxacin 6.0 32 95.9 99.3  Note: The solubility of all tablets except those containing amoxicillin is evaluated according to the method described in USP '95.

Example 6

As in Example 5, tablets and granules are prepared from the constituents as mentioned in Example 4 by the method described in Examples 1 and 2, wherein the amoxicillin trihydrate is ampicillin anhydride, sulfamethoxazole, eryth Substitution was also made by other drugs selected from romanic ethyl succinate and ciprofloxacin. The tablet thus obtained had the following characteristics.

drug Hardness (kP) 20 ℃ In water Disintegration time (s) Hardness (kP) 20 ℃ In water Disintegration time (s)  Amoxicillin Trihydrate 10.4 47 14.7 47  Ampicillin Anhydride 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

From the constituents as mentioned in Example 4, tablets and granules were prepared by the method described in Examples 1 and 2, but with other types of dispersible cellulose. The tablet thus obtained had the following characteristics.

Types of Dispersible Cellulose Hardness (kP) 20 ℃ in water Disintegration time (s) Avicel ^R RC-501 6.8 77 Avicel ^R CL-611 6.4 93

Example 8

Granules (= Amoxicillin Trihydrate / Dispersible Cellulose (Avicel ^R RC581) 98/2)

: 89.6%

Cross-linked polyvinylpyrrolidone: 3.9%

Microcrystalline Cellulose: 3.9%

Fragrance: 1.6%

Sweetener: 1.0%

Granules and tablets were prepared by the method described in Examples 1 and 2. The tablet thus obtained had a disintegration time of 92 seconds in water at 20 ° C. The hardness of the tablets observed was 7 kP.

Example 9

Granules (= Amoxicillin Trihydrate / Dispersible Cellulose (Avicel ^R RC581) 97/3)

: 84.75%

Cross-linked polyvinylpyrrolidone: 4%

Microcrystalline Cellulose: 11%

Lubricant: 0.25%

Tablets and granules were prepared by the method described in Examples 1 and 2. The tablet thus obtained had the following characteristics.

Hardness (kP) Disintegration time in water at 20 ° C (s) 61218 102120114

Example 10

Granules (= Amoxicillin Trihydrate / Dispersible Cellulose (Avicel ^R RC581) 96/4)

: 84%

Cross-linked polyvinylpyrrolidone: 4%

Microcrystalline Cellulose: 8.7%

Lubricant: 3.3%

Tablets and granules were prepared by the method described in Examples 1 and 2. The tablet thus obtained had the following characteristics.

Hardness (kP) Disintegration time in water at 20 ° C (s) 5915 9490115

Example 11

Granules (= Amoxicillin Trihydrate / Dispersible Cellulose (Avicel ^R RC581) 92/8)

: 89.3%

Cross-linked polyvinylpyrrolidone: 4.0%

Microcrystalline Cellulose: 6.4%

Lubricant: 0.2%

Tablets and granules were prepared by the method described in Examples 1 and 2. The tablet thus obtained had a disintegration time of 80 seconds in water at 20 ° C. The hardness of the tablets observed was 6 kP.

Example 12

From constituents such as those mentioned in Example 4, tablets and granules are prepared by the method described in Examples 1 and 2, varying the ratio of amoxicillin trihydrate and dispersible cellulose (Avicel ^R RC-591) in the granules. I was. The tablet thus obtained had the following characteristics.

Amoxicillin Trihydrate / Dispersibility Cellulose (Avicel ^R Ratio of RC-591) Hardness (kP) In water at 20 ° C Disintegration time  95/5 7.3 77  92.5 / 7.5 7.1 87  85/15 6.5 127

Example 13

Granules (= Amoxicillin Trihydrate / Dispersible Cellulose (Avicel ^R RC591) 95/5)

: 84.1%

Cross-linked polyvinylpyrrolidone: 6.3%

Microcrystalline Cellulose: 6.3%

Fragrance: 1.6%

Sweetener: 1.0%

Lubricant: 0.7%

From the above components, tablets and granules were prepared by the method described in Examples 1 and 2. The tablet thus obtained had the following properties:

Hardness (kP) Disintegration time in water at 20 ° C. 71118 52-5656-6158-62

Example 14

The first granules were made from 300 g of amoxicillin trihydrate and dispersible cellulose (Avicel ^R RC-591) by the method described in Example 1. A mixture of microcrystalline cellulose (59.5 wt%), fragrance (23.3 wt%) and sweetener (5.5 wt%) is used to tablet tablets having a hardness of 1.5-2 kP from the mixture, and to break the tablets to break up the Frewitt vibration granulator. A second granule was made by forming granules by means. The first and second granules were mixed, then mixed with cross-linked polyvinylpyrrolidone and a lubricant, and then tableted from the mixture thus obtained. The tablet had the following characteristics:

Composition of tablets % % % %  Granules 1 79.6 84.6 89.5 94.5  Granules 2 12.5 9.4 6.4 3.1  Cross-linked Polyvinyl Pyrrolidone 7.4 5.6 3.8 1.9  slush 0.4 0.4 0.4 0.5 Nature of the tablet  Hardness (kP) 5.0 7.3 7.5 6.8  Disintegration time in water at 20 ° C 31.8 43.8 45.0 92.3

Example 15

From the constituents as mentioned in Example 4, tablets and granules are prepared by the method described in Examples 1 and 2, wherein the second granule-extradisintegrator, cross-linked polyvinylpyrrolidone, is prepared using starch ( Star-X 1500 ^R ), starch glycolate sodium, low-substituted hydroxypropyl cellulose, and other disintegrants selected from corn starch. The tablet thus obtained had the following characteristics.

Second extragranular disintegrant Hardness (kP) In water at 20 ° C Disintegration time (s) Starch (Star-X 1500 ^R ) 5.8 73  Starch sodium glycolate 4.8 124  Low-substituted hydroxypropyl cellulose 5.1 53  Corn starch 5.9 71

Claims (9)

For granules containing an active ingredient having a water solubility of 1:> 10 in a mixture with water dispersible cellulose which is microcrystalline cellulose and carboxymethyl cellulose sodium, the water dispersible cellulose is a percentage based on the weight of the active ingredient Granules, characterized in that present in an amount of ≤15wt%. A granule according to claim 1, which contains 1-7.5 wt% water dispersible cellulose. A granule according to claim 2, which contains 2-5 wt% water dispersible cellulose. The granules of claim 1, wherein the water dispersible cellulose contains 8.3% -13.8wt% sodium carboxymethyl cellulose. A granule according to claim 1, which is produced by wet granulation followed by sieving. At least one of claims 1 to 5 in a mixture with a pharmaceutically acceptable excipient comprising a disintegrant and optionally a drug or compound contained in granules to enhance the activity of the active ingredient. A fast-disintegrating and quick-dissolving composition containing granules, the composition being less than 2 minutes in water at room temperature (20 ° C.) when evaluated according to the method in the European Pharmacopoeia (movement is limited to 22 mm instead of 55 mm). A fast-disintegrating and quick-dissolving composition which exhibits a disintegration time of, moreover,> 95% of the active ingredient is dissolved in the dissolution medium after 30 minutes at 37 ° C. as assessed according to the methods of US Pharmacopoeia 1995. The method of claim 6, wherein the at least one granule according to any one of claims 1 to 5 is 2-8 wt% primary disintegrant and 2-8 wt% secondary as a percentage based on the weight of the composition. In a mixture with a disintegrant, present in a total amount of ≧ 80 wt%. 8. The method of claim 7, wherein the primary disintegrant is microcrystalline cellulose, ultrafine cellulose or mixtures thereof, and the secondary disintegrant is starch or starch derivative, cross-linked polyvinylpyrrolidone or low-substitution. Hydroxypropyl cellulose. 9. A composition according to claim 7 or 8, wherein the primary disintegrant and the secondary disintegrant are present in a ratio of 1: 1.