WO2006034661A1

WO2006034661A1 - A method for producing oral solid dosage form and oral solid dosage form prepared thereby

Info

Publication number: WO2006034661A1
Application number: PCT/CZ2005/000073
Authority: WO
Inventors: Ales Franc; Borek Zaludec; Zdenek Novotny; Hana Brzobohata; Anna Petrovicova; Leos Stejskal
Original assignee: Pliva-Lachema A.S.
Priority date: 2004-09-30
Filing date: 2005-09-30
Publication date: 2006-04-06
Also published as: CZ297446B6; CZ20041002A3

Abstract

The invention relates to a method for producing an oral solid dosage form capable of instantaneous release of the active substance which is a sparingly water-soluble antiestrogen, particularly tamoxifen citrate, characterized in that the antiestrogen is pre-mixed with a water-insoluble and/or alcohol-insoluble filler and optionally with at least one further pharmaceutically acceptable excipient, 80 % of particles of the filler or its mixture with at least one further pharmaceutically acceptable excipient being smaller than 355 micrometers and at most 10 % of these particles being smaller than 40 micrometers, whereupon the triturate obtained is mixed with a water-insoluble and/or alcohol-insoluble filler and with a water-soluble and/or alcohol-soluble binder and optionally with at least one further pharmaceutical excipient, 80 % of particles of the mixture of the filler and binder and optionally of at least one further pharmaceutically acceptable excipient being smaller than 355 micrometers and at most 10 % of these particles being smaller than 40 micrometers, and the mixture obtained is granulated in the presence of water and/or alcohol which are used in an amount smaller than or equal to 8 % by weight, based on the total weight of the wet granulated mixture, whereupon the granulate obtained is dried. The invention also relates to the thus-obtained oral solid dosage form.

Description

A Method for Producing Oral Solid Dosage Form and Oral Solid Dosage Form Prepared Thereby

Field of Invention

The invention relates to a method for producing an oral solid dosage form and an oral dosage form prepared thereby.

Background of the Invention

An example of a sparingly water-soluble antiestrogen is tamoxifen citrate of chemical name (Z)-2- [4-(l,2-diphenyl-l-butenyl)phenoxy] -N,N-dimethylethanamine citrate, of summary formula C₃₂H₃₇NOs, relative molecular mass 563.64 and structural formula

Tamoxifen citrate is a synthetic non-steroid antiestrogen characterized by competition with estradiol in interaction with cytoplasmic estrogen receptor. In the preparation of oral solid dosage forms containing as the active substance tamoxifen citrate, but also other sparingly water-soluble antiestrogens, one is confronted with undesirable properties of tamoxifen citrate such as its low solubility in water and extremely high electrostatic charge. The mentioned low solubility of tamoxifen citrate in water would result in its incomplete dissolution from the dosage form unless a special modification is provided, which would lead to an insufficient plasma level of tamoxifen citrate in blood, whereas in compressing into tablets the mentioned high electrostatic charge causes adhesion of tamoxifen citrate on the punches of the compressing press, resulting in an uneven surface of tablets, loss in their weight and thus a lower amount of tamoxifen citrate in the tablet. Moreover, the high electrostatic charge of tamoxifen citrate reduces content uniformity of the tablet because during mixing with other excipients this electrostatic charge causes aggregation of particles of tamoxifen citrate into zones of its higher concentration. All that has been said for tamoxifen citrate holds in principle also for other sparingly water-soluble antiestrogens.

The difficulties due to the above-mentioned undesirable properties of tamoxifen citrate are to a certain extent overcome by precautions described in WO 03/035043 according to which the sticking of tamoxifen citrate to compressing machine punches can be inhibited by lower humidity of granulate of tamoxifen citrate and by controlled specific surface of its granules. According to the mentioned patent, good content uniformity is achieved by the dispersion granulation method and good dissolution is obtained by a highly effective disintegrant, used on the intragranular as well as extragranular level. Thus, the mentioned patent document protects the composition and preparation of oral solid dosage form in the form of tablets comprising tamoxifen citrate in an amount higher than 15 % by weight, based on the total weight of the final oral solid dosage form, using a pharmaceutically acceptable and advantageous amount of a filler, or a mixture of two fillers, amounting to 60 to 80 % by weight, a disintegrant in an amount of 2 to 5 % by weight, a binder in an amount of 1 to 4 % by weight and a lubricant in an amount of 0.5 to 2 % by weight, in all cases based on the total weight of the final oral solid dosage form. As filler may serve a mixture of lactose monohydrate and microcrystalline cellulose, as binder povidone, as disintegrant crosslinked salt of carboxymethyl cellulose and as a lubricant magnesium stearate. Tablets are manufactured by the dispersion granulation method, suitable size of the granules being achieved by passing the wetted tablet material through a sieve of suitable mesh size. The granules obtained are then dried, mixed with the lubricant and milled to granules of reduced size. The final humidity of the granulate obtained must not be higher than 2 % by weight, based on the weight of the granulate, and the specific area of the granules must be in the range 30 000 to 55 000 cm²/100 g of tamoxifen citrate. The granulate is then compressed and the tablets are coated with a usual coating mixture consisting of hydroxypropyl methyl cellulose, polyethylene glycol and titanium(IV) oxide. Another solution of this problem is provided in patent document US 2002/031548 describing a composition of an oral solid dosage form comprising tamoxifen citrate as active substance, wherein the undesired properties of tamoxifen citrate, particularly its high electrostatic charge and low wettability, are eliminated by use of a suitable composition of the carrier with addition of a wetting agent which increases the wettability of tamoxifen citrate and lowers its surface charge, thus enabling preparation of a uniform and rapidly soluble oral solid dosage form of tamoxifen citrate in the form of tablets or capsules. The mentioned patent document thus protects a composition comprising a mixture of tamoxifen citrate, a pharmaceutically acceptable filler and a disintegrant, the latter two being employed in an amount of 4 to 82 % by weight, based on the total weight of the final oral solid dosage form, of which 4 to 40 % by weight, based on the total weight of the final oral solid dosage form, is formed by at least one disintegrant. This mixture may optionally further contain 0.2 to 5 % by weight of a wetting agent, 0.2 to 10 % by weight of a lubricant and 0.1 to 10 % by weight of a lubricant, in all cases based on the total weight of the final oral solid dosage form. To ensure higher stability of the mentioned dosage form, an antioxidant in an amount of 0.5 to 15 % by weight, based on the total weight of the oral dosage form, is added. A mixture of lactose monohydrate and microcrystalline cellulose serves as a filler, modified maize starch as binder, sodium lauryl sulfate as a wetting agent, sodium salt of carboxymethyl starch as a disintegrant, magnesium stearate as a lubricant, and colloidal silicon oxide as a lubricant . Ascorbic acid is used as antioxidant. Analogously as in the preceding case, the mentioned oral solid dosage form in the form of tablets is manufactured by dispersion granulation using an aqueous solution of sodium lauryl sulfate. The desired size of the granules is achieved by pressing the wetted tablet material through a sieve of suitable mesh size whereupon the granules obtained are dried to humidity ranging from 2 to 3 % by weight, based on the weight of granules, milled and mixed with part of the filler, with lubricant, disintegrant and glydant , and the mixture obtained is compressed.

As evident from the above-mentioned facts, tablets comprising tamoxifen citrate as the active substance are so far manufactured by dispersion granulation followed by drying of the granulate obtained, its milling with lubricants and disintegrants, and subsequent compressing of the milled mixture. Thus, the existing state of art enables to produce an oral solid dosage form, containing tamoxifen citrate of originally very unfavorable properties. In the formulation of tablets, the preparation consists in wet dispersion granulation of a mixture of pharmaceutically acceptable excipients and tamoxifen citrate to give a granulation paste in which tamoxifen citrate, and possibly also the excipients, lose their original undesirable physicochemical properties, whereupon extrusion and subsequent drying of the mentioned paste afford a material the physicochemical properties of which are different from those of the individual components of the mentioned paste. The thus-obtained new properties of the mentioned material enable a more facile processing of tamoxifen citrate into oral solid dosage form.

However, the employed dispersion granulation method which has several obvious advantages represents a relatively complicated and time- and energy-consuming procedure, necessarily connected with extensive manipulation with the material processed, including particularly extrusion, drying and milling of the granulate. In addition to these time and energy demands, the granulate processing is accompanied by considerable amount of dust which can be limited but not completely eliminated. Since the above procedures concern the preparation of tablets containing a substance of hormonal effect, there is a risk of working environment contamination and thus a health hazard to the operating personnel. The possibility of working environment contamination also compels the operating personnel to take great care to decontamination of the working environment and equipment and all the instruments used. From what has been said above, the dispersion granulation method used in producing oral solid dosage forms containing toxic and particularly cytotoxic and hormonally active substances suffers from disadvantages that make it a relatively hazardous method.

The objective of the invention is thus to find a novel method for producing oral solid dosage forms containing in water sparingly soluble antiestrogens, particularly tamoxifen citrate, by which it would be possible to prepare an oral solid dosage form containing the mentioned sparingly soluble antiestrogens and which would be capable of instantaneous release of the active substance, without involving the hazards mentioned above in connection with the dispersion granulation.

This objective has been achieved by the method for producing an oral solid dosage form according to the present invention. Summary of the Invention

The invention relates to a method for producing an oral solid dosage form capable of instantaneous release of the active substance which is a sparingly water-soluble antiestrogen, particularly tamoxifen citrate, characterized in that the antiestrogen is pre-mixed with a water- insoluble and/or alcohol-insoluble filler and optionally with at least one further pharmaceutically acceptable excipient, 80 % of particles of the filler or its mixture with at least one further pharmaceutically acceptable excipient being smaller than 355 micrometers and at most 10 % of these particles being smaller than 40 micrometers, whereupon the triturate obtained is mixed with a water-insoluble and/or alcohol-insoluble filler and with a water-soluble and/or alcohol-soluble binder and optionally with at least one further pharmaceutical excipient, 80 % of particles of the mixture of the filler and binder and optionally of at least one further pharmaceutically acceptable excipient being smaller than 355 micrometers and at most 10 % of these particles being smaller than 40 micrometers, and the mixture obtained is granulated in the presence of water and/or alcohol which are used in an amount smaller than or equal to 8 % by weight, based on the total weight of the wet granulated mixture, whereupon the granulate obtained is dried.

The obtained granulate, after optional mixing with at least one disintegrant and/or at least one lubricant , is advantageously compressed into tablets.

Suitable pharmaceutical excipient, with which the antiestrogen and a water-insoluble and/or alcohol-insoluble filler are optionally pre-mixed, is advantageously an intragranular swelling disintegrant.

The weight ratio of the antiestrogen to a water-insoluble and/or alcohol-insoluble filler, optionally to its mixture with at least one further pharmaceutically acceptable excipient, in the pre-mixed mixture advantageously equals to 1 : 1 to 1 :6, preferably 1 :3.

The weight ratio of the water-insoluble and/or alcohol-insoluble filler to at least one further pharmaceutically acceptable excipient in the pre-mixed mixture advantageously equals to 1:10 to 1:50, preferably 1:33.

The water-insoluble and/or alcohol-insoluble filler or its mixture with at least one further pharmaceutically acceptable excipient which is pre-mixed with the antiestrogen has advantageously a density equal to 0.7 to 1.0 g.cm^"3. Suitable filler for pre-mixing with the antiestrogen can be advantageously calcium hydrogen phosphate dihydrate, and an intragranullar swelling disintegrant for pre-mixing with the antiestrogen can be cross-linked sodium salt of carboxymethyl cellulose.

Suitable pharmaceutically acceptable excipient with which the triturate is optionally mixed, can be advantageously an intragranular capillary disintegrant.

The ratio of the triturate to the mixture of a water-insoluble and/or alcohol-insoluble filler and a water-soluble and/or alcohol-soluble binder, or to their mixture with at least one further pharmaceutically acceptable excipient, is advantageously 1:1 to 1:3, preferably 1:2.

The mixture intended for mixing with the triturate advantageously contains a water-insoluble and/or alcohol-insoluble filler, at least one further pharmaceutically acceptable excipient and a water-soluble and/or alcohol-soluble binder in a weight ratio ranging from 14:7:0.5 to 14:28: 1₃ preferably in the weight ratio 14:14:1.

Advantageously, in the mixture intended for mixing with the triturate, the water-insoluble and/or alcohol-insoluble filler is calcium hydrogen phosphate dihydrate, the intragranular capillary disintegrant is microcrystalline cellulose, and the water-soluble and/or alcohol- soluble binder is povidone.

Advantageously, the at least one lubricant , optionally mixed with the dry granulate, can be magnesium stearate, zinc stearate, aluminum stearate, colloidal silicon oxide, stearic acid, sodium stearyl fumarate, polyethylene glycol or sodium lauryl sulfate, this at least one lubricant being used in an amount equal to 0.1 to 5 % by weight, based on the total weight of the mixture obtained.

Advantageously, the at least one disintegrant, optionally mixed with the dry granulate, can be ultraamylopectin, cross-linked sodium salt of carboxymethyl cellulose or cross-linked polyvinylpyrrolidone, this at least one disintegrant being used in an amount equal to 1 to 10 % by weight, preferably 2 % by weight, based on the total weight of the mixture obtained.

The method for producing according to this invention, with the exception of compressing, is advantageously carried out in one apparatus.

In compressing of the dry granulate, the pressing power, compressing rate and total compressing time are advantageously adjusted so that the die surface temperature does not exceed 40 °C. The compressing of the granulate is advantageously carried out using chrome plated punches. The invention also relates to an oral solid dosage form, prepared according to the invention.

The method according to the invention enables preparation of a highly uniform dosage form with an instant release of the active substance, particularly in the form of tablets, which as the active substance contains in water sparingly soluble nonsteroid antiestrogens, particularly tamoxifen citrate, in a strength of 10 to 40 mg in a unit dose, and thus eliminates the above described properties of the mentioned active substances. According to the invention, this is achieved by preparation of the solid dosage form, using water-insoluble and/or alcohol- insoluble granulate whose relatively large surface area due to its fine granulation, defined by the condition that 80 % of its particles are smaller than 355 micrometers and at most 10 % of these particles are smaller than 40 micrometers, suppresses the undesired effect of the high surface charge of the antiestrogen and thus enables its good wetting with water and rapid dissolution. Besides, the high flow rate of the granulate mentioned which is about 10 g.s^"1, in combination with its relatively high bulk density amounting to 0.7 to 0.8 g.cm^'3, enables a dependant, rapid and continuous manufacturing of oral solid dosage form, particularly tablets, of high quality.

During the preparation of oral solid dosage form by the method according to the invention, the water-insoluble and alcohol-insoluble components of oral solid dosage form, particularly the filler and disintegrant, practically enable retention of constant particle size distribution and shape of the granules independently of the mixing equipment and amount of the granulation liquid employed because during the processing according to the invention the granules do not undergo such interaction with the granulation liquid that could bring about changes in magnitude and shape of the granules.

The method according to the invention enables production of tablets satisfying the strict regulations of correct production practice requiring that the manufactured tablets meet the given pharmacopoeial criteria. A critical parameter for a tablet is particularly the content uniformity of the active substance in the tablet. Thus, for example, according to the Pharmacopoeia (USP), the content of the active substance in individual ten tablets must be in the range from 85 to 115 % by weight, based on the average content of the active substance in the mentioned ten tablets, and the standard deviation RSD should not exceed 6 %. However, this pharmacopoeial limit is already unsatisfactory from the viewpoint of GMP (good manufacturing practice). The method of producing tablets must guarantee that a statistically conclusive amount of all tablets produced in one batch meets the given pharmacopoeial limit. To this end, the preparation of tablets is advantageously evaluated by the Bergum method, which represents the most reliable and the strictest method in this field. The Bergum criterion for a given number of tablets, usually ranging from 10 to 150, guarantees at 90% confidence level that with 95% probability all tablets of the given batch, from which the samples were taken, meet the content uniformity test according to the Pharmacopoeia (USP). It should be noted that tablets manufactured according to this invention meet the Bergum criterion. In producing oral solid dosage forms with low content of the active substance it is generally difficult to reach this limit in cases where the content of the active substance in the dosage form obtained does not reach even 15 %, based on the total weight of the dosage form. In producing the mentioned dosage form, this problem is usually overcome by mixing the active substance with other components of the dosage form in high-speed mixers, by cross-linking the active substance with other components of the dosage form and subsequent mixing the obtained mixture and using the dispersion or fluid granulation method, or dry granulation. Such procedures and methods, however, not always give the desired result, and moreover they are laborious and time-consuming.

The present invention provides a novel technology of producing an oral solid dosage form, in which the active substance is evenly aggregated to the surface of excipient particles of defined size distribution, and in the course of preparation of the mentioned dosage form the particle size distribution of the excipients is not changed. This method does not represent a classical process of granulate preparation and therefore no lengthy preparation of the binder is necessary. In the method according to the invention, there is also no need for technologically demanding extrusion of the granulation mixture and laborious and time-consuming milling or grading of the granulate obtained. To obtain the desired quality of the oral solid dosage form, it is necessary in mixing of the active substance with excipients to achieve the desired uniformity of the blended mixture before wetting the mentioned mixture with water and/or alcohol. According to this invention, this is achieved by pre-mixing the active antiestrogen substance with a water-insoluble and/or alcohol-insoluble filler and optionally with at least one further pharmaceutical excipient. In the pharmaceutical practice, this pre-mixing process is denoted as trituration and is used in cases where an even distribution of the active substance in at least one powdery excipient has to be achieved. In this procedure, the ratio of the active substance to the excipient or excipients in the individual trituration steps is lowered by dividing the excipient or a mixture of excipients into several parts. The active substance is there successively mixed until the desired concentration of the active substance in the excipient, or in a mixture of excipients, is achieved. According to the invention, such mixture of excipients can be a water-insoluble and/or alcohol-insoluble filler and optionally at least one pharmaceutically acceptable excipient, wherein the particles of the filler or mixture of the filler with at least one further excipient have the above defined size distribution. The mentioned filler is insoluble in the granulation liquid and in order to ensure an even mixing of the filler with the active substance the filler must have the above defined bulk density and a flow rate of about 10 g.s^"1. Otherwise, during mixing of the active substance with the filler and optionally with at least one further excipient there would be no movement and thus no disintegration of aggregates of the active antiestrogen component, and also no disintegration of electrostatic aggregates, spontaneously formed in the course of mixing. Such advantageous filler is calcium hydrogen phosphate dihydrate. Also an intragranular swelling disintegrant, which advantageously is a further excipient that together with the filler is pre-mixed with the antiestrogen, must not be activated by the granulation liquid employed and must exhibit a high swelling ability ensuring later a good release of the active substance by swelling mechanism. The presence of this intragranular swelling disintegrant in the system active substance/filler/disintegrant must also enable adhesion of particles of the active substance to particles of the filler. Such requirements are met particularly by cross-linked sodium salt of carboxymethyl cellulose.

Also the mixture of water-insoluble and/or alcohol-insoluble filler, water-soluble and/or alcohol-soluble binder and optionally at least one further pharmaceutically acceptable excipient, with which the triturate of the active substance, obtained in the above-described manner, is subsequently mixed, must have such particle distribution that 80 % of particles of this mixture are smaller than 355 micrometers and at most 10 % of these particles are smaller than 40 micrometers, such particle size distribution in the mentioned mixture guaranteeing both good mixing of components of this mixture with components of the triturate and the final granularity of the resulting granulate. In the mixture to be mixed with the triturate, the filler is preferably calcium hydrogen phosphate dihydrate and the water-soluble and/or alcohol- soluble binder is preferably povidone, particularly povidone, commercially available as Kollidon 90 F, and the further pharmaceutically acceptable excipient is preferably an intragranular capillary disintegrant, preferably microcrystalline cellulose. The mentioned binder Kollidon 90 F, the building unit of which is polyvinylpyrrolidone of molecular mass about 1 000 000, is specially pulverized to enable addition to the inner phase without dissolving, and also good mixing. Since it is a highly efficient and very well soluble binder, it is activated already by use of such a small amount of the granulation liquid that does not make it possible to form a solution of the binder.

The granulation liquid can be water or alcohol or a combination thereof containing water and alcohol in any desired ratio. The amount of water and/or concentrated alcohol is at most 8 % by weight, based on the total weight of the wet granulated mixture. In wetting of the mixture, obtained by mixing of the triturate with a mixture of water-insoluble and/or alcohol-insoluble filler, water-soluble and/or alcohol-soluble binder and optionally at least one pharmaceutically acceptable excipient, by the mentioned small amount of the granulation liquid, there is already no increase in the particle size of the mentioned mixture. There is only an even adhesion of the active substance and disintegrant to the surface of the filler particles takes place, which enables a very good uniformity of the oral solid dosage form obtained and a rapid release of the active substance from this dosage form. In this case, no lengthy granulation extrusion is necessary which represents a very sensitive process concerning the cleanness of the working environment and which was indispensable in the hitherto existing methods of producing oral solid dosage forms containing in water sparingly soluble antiestrogens, particularly tamoxifen citrate, as active substance. After drying of the obtained granulate, without further milling, grinding, grading or sieving, a granulate of an excellent flow rate of about 10 g.s^"1 is obtained. Already this granulate can be used as an oral solid dosage form, e.g. after filling into capsules.

However, this granulate can be advantageously mixed with at least one pharmaceutically acceptable disintegrant, such as preferably ultraamylopectin, cross-linked sodium salt of carboxymethyl cellulose or cross-linked polyvinylpyrrolidone, and/or with at least one pharmaceutically acceptable lubricant such as preferably magnesium stearate, zinc stearate, aluminum stearate, colloidal silicon oxide, stearic acid, sodium stearyl fumarate, polyethylene glycol or sodium lauryl sulfate, whereupon the mixture obtained is compressed into tablets.

With the exception of compressing into tablets, the method according to the invention can thus be carried out in one apparatus in a manner known as "one step process". Within the framework of the invention it was found that when in the compressing into tablets the surface of the stamping tools is warmed above 40 °C, a film of the active substance may be formed on the surface of the punches. This undesired phenomenon can be prevented by adjusting the compression force, and rate and total time of the compressing so that the punches do not warm above the mentioned temperature limit. Another possibility is to employ commercially available chromium plated punches on which no film of the active substance is formed even at temperatures exceeding the above mentioned temperature limit. In this way, tablets with great range of radial strength, from 30 to 120 N, are obtained that satisfy well the given physicochemical requirements.

In the following part the invention is explained in more detail using examples of its execution, which however are only illustrative and do not limit its scope.

Examples Example 1

Preparation of tablets containing tamoxifen citrate as active substance in 10, 20 and 40 mg strength

To a mixture of 2.554 kg of tamoxifen citrate, 5.600 kg of calcium hydrogen phosphate dihydrate and 0.168 kg of cross-linked sodium salt of carboxymethyl cellulose is added 6.664 kg of calcium hydrogen phosphate dihydrate, 6.720 kg of microcrystalline cellulose Avicel PH 102 and 0.470 kg of povidone Kollidon 90 F, whereupon the mixture obtained is mixed. The mixture obtained is then wetted with 1.680 kg of 96% ethanol and is mixed again. The granulate obtained is then dried in vacuo to humidity ranging from 4 to 6 % and then 0.168 kg of magnesium stearate and 0.336 kg of cross-linked sodium salt of carboxymethyl cellulose are added to this dried granulate, and the mixture obtained is mixed and subsequently compressed into tablets weighing 135 mg, 270 mg and 540 mg, which corresponds to 10 mg, 20 mg and 40 mg, respectively, of tamoxifen citrate in one tablet.

Example 2

Content uniformity of tablets

Results of determination of content uniformity for 10 tablets prepared by the procedure described in Example 1 are given in Table 1

Table 1

Example 3

Dissolution of tablets containing lO mg of tamoxifen citrate in dependence on their radial strength

Conditions used:

Medium: 1000 ml of0.02M HCl

Method: paddle

Speed: 100 r.ρ.m.

Temperature: 37 °C

Wavelength: 274 - 276 nm

Limit: 75 % within 30 min.

The results obtained are given in Table 2

Table 2

These results are presented graphically in Figure 1.

Claims

PATENT CLAIMS

1. A method for producing an oral solid dosage form capable of immediate release of the active substance which is a sparingly water-soluble antiestrogen, particularly tamoxifen citrate, characterized in that the antiestrogen is pre-mixed with a water- insoluble and/or alcohol-insoluble filler and optionally with at least one further pharmaceutically acceptable excipient, 80 % of particles of the filler or its mixture with at least one further pharmaceutically acceptable excipient being smaller than 355 micrometers and at most 10 % of these particles being smaller than 40 micrometers, whereupon the triturate obtained is mixed with a water-insoluble and/or alcohol-insoluble filler and with a water-soluble and/or alcohol-soluble binder and optionally with at least one further pharmaceutical excipient, 80 % of particles of the mixture of the filler and the binder and optionally of at least one further pharmaceutically acceptable excipient being smaller than 355 micrometers and at most 10 % of these particles being smaller than 40 micrometers, and the mixture obtained is granulated in the presence of water and/or alcohol which are used in an amount smaller than or equal to 8 % by weight, based on the total weight of the wet granulated mixture, whereupon the granulate obtained is dried.

2. The method according to claim 1, characterized in that the obtained granulate, after optional mixing with at least one disintegrant and/or at least one lubricant , is compressed into tablets.

3. A method according to claim Ior2, characterized in that the pharmaceutical excipient with which the antiestrogen and the water-insoluble and/or alcohol-insoluble filler are optionally pre-mixed is an intragranular swelling disintegrant.

4. A method according to any of claims Ito3, characterized in that the weight ratio of the antiestrogen to the water-insoluble and/or alcohol-insoluble filler, or optionally to its mixture with at least one further pharmaceutically acceptable excipient, in the pre- mixed mixture amounts to 1 :1 to 1 :6, advantageously 1 :3.

5. A method according to any of claims 1 to 4, characterized in that the weight ratio of the water-insoluble and/or alcohol-insoluble filler to at least one further pharmaceutically acceptable excipient in the pre-mixed mixture is 1:10 to 1:50, advantageously 1:33.

6. A method according to any of claims 1 to 5, characterized in that the water- insoluble and/or alcohol-insoluble filler or its mixture with at least one further pharmaceutically acceptable excipient, which is pre-mixed with the antiestrogen, has a density 0.7 to 1.0 g.cm^'3.

7. A method according to any of claims ltoό, characterized in that the filler for the pre-mixing with the antiestrogen is calcium hydrogen phosphate dihydrate and the intragranullar disintegrant for the pre-mixing with the antiestrogen is cross-linked sodium salt of carboxymethyl cellulose.

8. A method according to any of claims I to 7, characterized in that the pharmaceutically acceptable excipient with which the triturate is optionally mixed, is an intragranullar capillary disintegrant.

9. A method according to any of claims Ito8, characterized in that the weight ratio of the triturate to a mixture of water-insoluble and/or alcohol-insoluble filler and the water-soluble and/or alcohol-soluble binder, or to a mixture thereof with at least one further pharmaceutically acceptable excipient, is 1:1 to 1:3, advantageously 1:2.

10. A method according to any of claims Ito9, characterized in that the mixture intended for mixing with the triturate comprises a water-insoluble and/or alcohol-insoluble filler, at least one further pharmaceutically acceptable excipient and a water-soluble and/or alcohol-soluble binder in a weight ratio ranging from 14:7:0.5 to 14:28:1, advantageously in the weight ratio 14: 14: 1.

11. A method according to any of claims 1 to 10, characterized in thatinthe mixture, intended for mixing with the triturate, the water-insoluble and/or alcohol-insoluble filler is calcium hydrogen phosphate dihydrate, the intragranular capillary disintegrant is microcrystalline cellulose and the water-soluble and/or alcohol-soluble binder is povidone.

12. A method according to any of claims 2 to 11, characterized in that the at least one lubricant , optionally mixed with the dry granulate, is magnesium stearate, zinc stearate, aluminum stearate, colloidal silicon oxide, stearic acid, sodium stearyl fumarate, polyethylene glycol or sodium lauryl sulfate, this at least one lubricant being used in an amount of 0.1 to 5 % by weight, based on the total weight of the mixture obtained.

13. A method according to any of claims 2 to 12, characterized in that the at least one disintegrant, optionally mixed with the dry granulate, is ultraamylopectin, cross-linked sodium salt of carboxymethyl cellulose or cross-linked polyvinylpyrrolidone, this at least one disintegrant being used in an amount of 1 to 10 % by weight, advantageously in the amount of 2 % by weight, based on the total weight of the mixture obtained.

14. A method according to any of claims 1 to 13, characterized in that, with the exception of compressing into tablets, the processing is carried out in one equipment only.

15. A method according to any of claims 2 to 14, characterized in that in compressing the dry granulate into tablets the compressing force, compressing rate and total compressing time are adjusted so that the surface temperature of the stamping tools does not exceed 40⁰C.

16. A method according to any of claims 2 to 15, characterized in that the compressing of the dry granulate into tablets is carried out using chromium-modified punches.

17. An oral solid dosage form prepared by a method according to any of claims 1 to 16.