DE4019512A1 - METHOD FOR MAINTAINING PHARMACEUTICAL PHARMACEUTICAL FORMS WITH CONTINUOUS AND / OR CONTROLLED RELEASE OF FLUTAMIDE - Google Patents

Abstract

A continuous and/or controlled release form of flutamide is obtained by mixing flutamide and conventional pharmaceutical excipients with a retarding element constituted by an anionic copolymer of methacrylic acid and methyl methacrylate, alone or in combination with other retarding elements. A test to measure release of flutamide and a method to determine the bioavailability of it comprises extraction of the flutamlde with methanol and high pressure liquid chromatography on the resulting solution. The pharmaceutical forms obtained in this way, specifically the tablets, have a longer residence time in the bloodstream, have greater bioavailability and allow decreasing of the dose. They are useful in the treatment of prostate hyperplasia and advanced prostate carcinoma.

Description

The invention relates to a method for preservation pharmaceutical dosage forms with continuous and / or controlled release of an active ingredient, and more particularly to a method of obtaining a pharmaceutical dosage form with continuous and / or controlled release, at the flutamide is used as an effective ingredient. Furthermore, the invention relates to new, in this way received pharmaceutical dosage forms.

The invention also provides an analytical method for Determine the amount of flutamide in tablets with continuous Release on and a dissolution test of Continuous release tablets.

The flutamide whose chemical name is N-isobutyryl-4 nitro-3-trifluoromethylanilide, or by use the nomenclature according to Chemical Abstract, 2-methyl-N- [4- nitro-3- (trifluoromethyl) phenyl] -propanamide, has the the following formula  

and is well known as a non-steroidal antiandrogen, It is orally effective and suitable for treatment of prostate hyperplasia and advanced Prostate carcinoma. To treat these diseases be conventional tablets, the flutamide as effective Containing ingredient administered. The usual Treatment consists in a daily administration to the patient of up to three conventional tablets, with a quantity of 250 mg flutamide per tablet, which means a total of 750 mg of flutamide per day of treatment.

Furthermore, the flutamide is an insoluble drug with rapid absorption in the gut, which is a very diminished Dwell time in the bloodstream causes and continues is, as a result of the dissolution of the conventional Tablet releasing flutamide content at once, causing a high level of flutamide in the bloodstream causes what harmful side effects in the patient could cause. Examples of harmful Side effects are the following:

• - Water retention (hydrosaline behavior) due the rise of testosterone and oestradiol in the Plasma levels;
• - Hypersensitivity of the breast, sometimes of milk flow accompanied;  
• - sometimes during a long period of treatment a decrease in sperm production and transient disorders of liver function observed resulting in periodic liver function checks and sperm counts forces with results that It is sometimes recommended to do the treatment to reduce or cancel.

As a result, there is a need for new, flutamide containing pharmaceutical dosage forms to provide for the treatment of the prostate Hyperplasia and advanced prostate carcinoma are suitable to the previously listed difficulties to overcome. In our intention, new ones pharmaceutical dosage forms, the flutamide as an effective basic ingredient and to overcome these difficulties, we were to the preservation of new pharmaceutical dosage forms considered by Flutamid, which is its gradual and continuous release into the stomach Intestinal juices allowed. As a result, new ones pharmaceutical dosage forms with continuous and / or controlled release of flutamide that have the following advantages.

• a) Increase of the working and dwell time of Flutamide in the bloodstream
• b) maintaining a uniform mirror of flutamide in the plasma  
• c) reducing the potential for harmful side effects in the patient
• d) consequently, the effectiveness of the treatment improved and better bioavailability obtained from flutamide.

The solution proposed by this invention consists in the production of new pharmaceutical dosage forms, the flutamide as an effective principle included, with continuous and / or controlled release of said active ingredient, and for the preparation of this pharmaceutical Dosage forms recommends the invention the use of a polymer matrix resin in conjunction with other inert delays, the is soluble in the intestine and the gradual release the flutamide allowed.

Consequently, an object of the present invention the production of pharmaceutical dosage forms with continuous and / or controlled release of flutamide. It is another task pharmaceutical dosage forms with continuous and / or controlled release of flutamide to create, currently not available in the market are.

Another object of the invention is the analytical Detection of the amount of flutamide used in a pharmaceutical Dosage form is present using of high pressure liquid chromatography (HPLC).  

Another object of the invention is illustrated by a test for solution or release of in a pharmaceutical dosage form contained Flutamide.

The way to solve these tasks is below described:

In a relationship, the invention relates to Process for the preservation of pharmaceutical dosage forms with continuous and / or controlled Release of flutamide by its formulation with a retarding agent that releases gradually the flutamide allowed. Within the scope of the invention are as suitable pharmaceutical dosage forms with continuous and / or controlled release contain:

• - tablets with plastic bases;
• - coated tablets;
• - tablets with a core and a regulating coating with continuous or controlled release;
• - tablets with basic masses, which are slowly removed become;
• - tablets with protective film;  
• - Tablets made with hydrophilic bases;
• - equipped with osmotic release system tablets;
• - multi-layered tablets;
• - tablets with microgranules;
• - other types of tablets;
• - solid capsules with microgranules with continuous Effect or controlled release;
• Soft capsules with a suspension of the active ingredient in a medium with continuous or controlled release;
• - Granules to be given in water, with a Suspension with continuous or controlled Release is created;
• - Rounded granules for inclusion in capsules, conventional Tablets, coated tablets or layered tablets;
• - Granules containing different retarders are coated to their release in continuous or to regulate in a controlled way;
• - Microgranules with polymerized substances for absorption in capsules, tablets, powders, suspensions and / or other flutamide application systems with continuous  or controlled mode of action;
• - percutaneous, made of cellulose, polypropylene, Polycarbonate, polytetrafluoroethylene or other formed systems; and generally;
• - any other pharmaceutical dosage form continuous or controlled release, in the flutamide or by-products are included.

As a suitable retarder is a polymeric Ground substance in combination with other inert, in a visceral medium (pH <7) of soluble delaying agents used that the gradual release allowed by flutamide.

The basic polymer substance is characterized by an anionic, formed from methacrylic acid and methyl methacrylate Copolymer formed, which is the following chemical structure

with a carboxyl group ratio of approximately 1: 2 has. This connection is because of the Formation of salts with alkalis at pH = 7 and at pH 7 soluble and for this reason it is suitable for inclusion in a pharmaceutical dosage form, the gradual release of a effective ingredient in the intestine wants, as before was mentioned, the pH of the intestine, and in particular of the small intestine in its jejunum and ileal Sections fluctuates approximately from 7 to 7.5, so that this compound is soluble in the intestinal medium.

The resin from the polymeric ground substance Methacrylic acid and methyl methacrylate is replaced by conventional Obtained by polymerization such controlling the ratio of the monomers, that it is possible the appropriate ratio since the release of the effective basic substance, in this case, flutamide, a function of Relationship between the easily penetrable acrylic components and the hard-to-penetrate acrylic components will be.

Furthermore, the retarding ingredient could be different Quantities of one or more of the usual Contain delay agents selected from microcrystalline cellulose, stearic and palmitic acids, Myristates of glyceryl and cetyl alcohol, hydrogenated oleic acid (caster acid), ethyl cellulose, glyceryl monostearate, Styrene copolymer of the hydrolyzed Maleic acid, shellac and polyethylene glycol 6000, Shellac and hydrogenated (hydrogenated) oil, various Plasticizers, glycerol and sorbitol, Tanate  (tanates) and polygalacturonic acid; Polyethylene or other, polyvinyl chloride or other, polyvinyl acetate or others, polyoxymethylene adipamide, Sodium dioctylsulfosuccinate, hexadetyltrimethylammonium, Carboxymethyl cellulose, Methylcellulose, polyvinylpyrrolidone, amylose and others.

The pharmaceutical dosage forms according to the invention with continuous and / or controlled Release could be beyond the active ingredient (Flutamide) and the delay agent others contain useful pharmaceutical ingredients, such as diluents, for example, dihydrogenated dicalcium phosphate, Calcium sulfate, lactose, cellulose, Kaolin, mannitol, sodium chloride, corn starch and other; Binders, for example starch, gelatin, Sucrose, glucose, lactose, gum arabic, sodium alginate, microcrystalline cellulose, carnauba wax, Polyethylene glycol 4000, hydroxyethyl cellulose, polyvinyl pyrrolidone and other; Lubricant, for example Talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated (hydrogenated) vegetable oils and others; Release agent (slipers), z. For example, colloidal silica (CAB-O-SIL) or talc; Resolution means for example Cereal starch, alginic acid, sodium glycate starch, Methylcellulose, guar gum, carboxymethylcellulose; and dyes, e.g. Red FD and C No. 3, red FD and C No. 40, yellow FD and C No. 5, yellow FD and C No. 6, blue FD and C No. 1, blue FD and C No. 2, green FD and C No. 3.  

Just above it was stated that the pharmaceutical Dosage forms with continuous and / or controlled release very differently could be. In the following, although the invention described in detail with reference to tablets in general and there will be some conservation procedures of tablets according to the invention exactly described, but the others mentioned and by the invention recommended pharmaceutical dosage forms can be easily obtained by in any case, the displayed execution technique and the suitable binders are used.

In the context of this invention and in the following used Meaning refers to the expression "inventive Tablets "on a pharmaceutical Dosage form, in particular an already mentioned Tablet, the flutamide as an effective ingredient contains and is equipped with a continuous or controlled release of such effective ingredient.

In general, the tablets according to the invention according to usual methods for tablet production obtained, such as direct compaction, dry or wet granulation and indirect Compaction process, with the special feature that the active ingredient (flutamide) not only with the binder and / or the permitted pharmaceutical Transfer media is mixed, but also with a retarding agent consisting of an anionic Copolymer consisting of units of methacrylic acid and methyl methacrylate is constructed and the following  Structure possesses:

with a carboxyl group ratio of 1: 2.

Both the amount of flutamide and that of the inhibiting Constituent and the other constituents of the invention Tablet can be used accordingly the final dosage with which the tablet is provided should be, vary. Nonetheless, it is suitable for therapeutic purposes, a Flutamidmenge too use, which is approximately 60 to 80 wt .-% of Makes up the tablet; an inhibitor amount between 6 and 14 wt .-% of the tablet, and from the Binders and / or licensed pharmaceutical Carrier existing residue 6 to 34 wt .-% of the tablet.  

Upon receipt of the tablets of the invention tested according to the usual average weight tests, Hardness, content of effective Component and Release Test.

In other respects, the invention provides a method for the analytical determination of the flutamide content a tablet according to the invention, d. H. a method, the Flutamiddosierung in the inventive To determine tablets. The procedure based on the application of high pressure liquid chromatography (HPLC) techniques based on a by extraction of the flutamide with a organic solvents, such as an alkanol, preferably methanol, flutamide solution obtained be, and it essentially consists in comparing the one for the weight equivalent a crushed tablet and methanol formed solution with a formed solution Comparison curve of a standard solution known Concentration. To the content of an inventive To determine tablet with 400 mg flutamide will carry out the said process In particular include:

• a) Preparation of the sample (triplicate)
  Exactly 20 tablets are weighed to determine the average weight of a tablet;
  they are ground in a mortar to obtain a fine powder;
  an amount exactly equivalent to the weight of a tablet is weighed, dissolved in methanol and shaken for 30 minutes;
  The resulting solution is filtered through black-band filter paper, placed in a 100 ml volumetric flask and the volume made up with methanol.
• b) Preparation of a standard solution of known flutamide concentration
  Preferably, the standard solution is provided with a flutamide concentration which corresponds to that expected to be found in the sample problem.

When the samples are made, is added everyone's high-pressure liquid chromatography performed and the results obtained are compared. It is with this technique possible, the content of flutamide in each species the aforementioned pharmaceutical dosage forms to determine. In carrying out the Tests we have a high-pressure liquid chromatograph used a WATTERS M45 Pump, a UGK injector and an absorption detector with fixed wavelength and registration owns, but obviously another could similar type with the necessary settings Find use.  

The eluent was a mixture of methanol / water (60:40) at a flow rate of 1 ml / min and it was at a wavelength of Measured 365 nm. The registration speed was 5 mm / min.

If the procedure also with tablet contents of 250 mg of flutamide has been described obviously for the determination of the content of tablets with other amounts of flutamide the method described with appropriate change of dilution be performed.

In other respects, according to the invention Dissolution or release test of flutamide created. To determine the release rate of flutamide in the gastrointestinal juice was a solution of made of artificial intestinal juice, which is 2.5 mg / ml pancreatin and a surfactant as well as other polysorbate 80 or sodium dioctylsulfosuccinate in a proportion of approximately 1% contained.

The composition of this solution allows a good match between the obtained in vitro data and the real results too to reach.

The dissolution technique for controlling the release is the one in USP, XXI. Issue, stated, though obviously every other similar used could be, with adaptation of the equipment the release test in each case.  

The results of the dissolution test are as follows Table specified:

release 30 minutes | 32.5% 1 h 36.86% 2 h 39.08% 3 h 51.54% 4 h 59.85% 5 h 71.62% 6 h 76.34% 7 h 78.77% 8 h 81.66% 10 h 90.30%

Consequently, one sees that, unlike the usual Flutamide tablets in which the Flutamidfreisetzung at once in large quantity, at the tablets according to the invention with continuous and / or controlled release a gradual Release of the flutamide is observed, causing a more uniform presence of flutamide in the plasma and produces a longer residence time in the bloodstream, so that some stated at the beginning of this description, by the application of conventional Flutamide tablets caused difficulties be overcome.

In another aspect, the invention describes a Method for the determination of flutamide and its Metabolites in plasma using  of high pressure liquid chromatography (HPLC) - Techniques. To investigate bioavailability of flutamide in tablets with continuous and / or controlled release Samples from previously heparinized plasma by adding specific amounts of flutamide and its metabolites (Hydroxyflutamid and trifluorophenylnitroaniline (TFNMA)) made and extracted with one organic solvents, such as an alkanol, preferably methanol, subjected. Hereinafter were the detection limits and the recovery rate found and the reproducibility of the obtained Investigations examined. Before that was the calibration curve for both the flutamide and intended for its metabolites. To carry out high pressure liquid chromatography were a WATTER M45 chromatograph, a UGK injector and a fixed-absorption absorption detector Wavelength and a registration used. When Eluent was a mixture of methanol / water (60:40) at a flow rate of 1 ml / min used and the absorption was at a Wavelength of 365 nm measured. The device was set it to be at a registration speed of 5 mm / min worked.

In these operating conditions were the for the flutamide and its metabolites Retained retention times:

retention times Flutamide: | 6.4 min TFNMA: 2,8 min hydroxyflutamide: 4.2 min

Implementation of the method for the determination of Flutamide and its metabolites in plasma

It was the calibration curve of the flutamide, the TFNMA and the hydroxyflutamide. For this, the following solutions were prepared:
Flutamide, stock solution with 10 ng / μl
TFNMA, stock solution with 0.2 ng / μl
Hydroxyflutamide, stock solution with 10 ng / μl
and aliquots of 1, 2, 5, 10, 25, 35, 50 and 100 μl of each of these solutions were injected to obtain the corresponding calibration curve of each component.

Preparation of the samples

2 ml of heparinized plasma from with flutamide tablets with continuous and / or controlled action Treated patients were treated by vortex homogenized and kept at -4 ° C and 3 ml Dichloromethane (of analytical grade) added; then vortex was shaken for 1 min, centrifuged at 3500 rpm for 5 min, the organic Phase separated and placed in a glass tube with conical Ground transferred; then it is evaporated to dryness  and in 100 μl of methanol (from analytical Purity) dissolved again. The on this way The solution obtained is as it is in the Chromatograph injected.

Determination of the detection limit

There are plasma levels of untreated volunteers taken and given them decreasing amounts of each added to the constituents to be examined. The Samples are prepared according to the procedure previously described prepared and the corresponding chromatographies performed with them.

The detection limit for each component was the Value, where the signal is a signal Noise ratio greater than or equal to 2, and the following results were obtained:

Detection limit for flutamide: 10 ng / μl plasma Detection limit for TFNMA: 0.2 ng / μl plasma Detection limit for hydroxyflutamide: 20 ng / μl plasma

Determination of the recovery rate

There are plasma levels of untreated volunteers taken and the constituents to be determined added. The samples are after that described above Be made method, in particular Samples taken from 2 ml plasma and 100 mg flutamide, 10 ng of TFNMA and 100 ng of hydroxyflutamide added,  an extraction method by the above subjected to specified solvents, and the resulting Solutions are under comparison with calibration solutions Chromatograph.

The following results were achieved:

component Recovery Flutamide | 92.1 ± 3.8% TFNMA 88.5 ± 4.7% hydroxyflutamide 86.6 ± 7.2%

Looking at these values, you can see that at least Found 80% of each ingredient studied if it is free (not bound) and its concentration is higher than that of Detection limit.

Examination of reproducibility

6 plasma samples will be non-treated volunteers treated with the components to be examined and according to the procedure given above analyzed.

The results obtained for each sample, corrected according to the respective recovery rate, were the following:  

From the reproducibility and the recovery rate it is noted that the proposed analytical procedures for the determination of in Plasma to be examined substances is suitable.

The present description is by the following Examples perfects the individual ways to Describe the implementation of the invention in detail, in particular, reference is made to conservation of tablets containing flutamide as an effective ingredient with continuous and / or controlled action contained by execution of the various processes for the production of Tablets.

Examples A. Preparation of tablets by granulation Example 1

There are tablets with continuous and / or controlled release, the 400 mg Flutamide contained as an effective ingredient. The Composition of the tablet is:

Flutamide | 400 mg lactose 43.1 mg talcum 31.2 mg Aerosil 200 2.0 mg Anionic copolymer 33.4 mg magnesium stearate 5.2 mg total weight 514.9 mg

execution

a) mixture; Flutamide, lactose, Aerosil 200 and talc are sieved by No. 20 or 60. Subsequently be 400 g in a V-blender, double or similar Flutamide, 43.1 g lactose, 15.6 g talc and 2.0 Aerosil 200 mixed for 30 minutes to get a good mix to get the ingredients.

b) granulated solution; it will be a solution of Polymers (acrylate resins) prepared containing: 33.4 g in a mixture of equal parts of alcohol and Methylene chloride (0.050 g each) dissolved anionic Copolymer.  

c) granulation; under suitable humidification of Ingredients is the mixture obtained in phase a) granulated with the granulating solution. Subsequently she is through a sieve No. 6 and then through a Shaker with sieve no. 18 or 20 happened.

d) drying; the granules obtained is in a Dryers with fluid bottom, in particular a rotary evaporator, dried at 40 to 50 ° C. and when the powders are dried, they will sieved by No. 18 or 20. Then be 3.304 g of magnesium stearate and 15.6 g of talc were added and it is mixed for 15 minutes.

e) pressing; the powders are under preservation of the certain weights pressed in a rotary press, and it will be the weight, the solubility test, the content, appearance and hardness controls.

f) Thereafter, the resulting tablets in a Drum of suitable size and placed on them becomes a solution of a polymeric resin with rapid dissolution in acetone / alcohol (composed of 1.5 g of resin and 0.11 g of alcohol and acetone). Thereafter, 1.896 g of magnesium stearate are added, dried on floors at 60 ° C for 2 h and then For 24 h at 37 ° C.

Finally, the test on appearance, content, Hardness and release made.  

example 2

After the procedure given in Example 1 are Tablets with continuous and / or controlled Release containing 160 mg flutamide, prepared, the weights of the ingredients in suitably adapted to the new formulation become. The resulting tablet has the following composition:

Flutamide | 160 mg lactose 17.2 mg talc 12.4 mg Aerosil 200 2.8 mg anionic copolymer 5.6 mg magnesium stearate 2.0 mg total weight 200 mg

B. Preparation of tablets by direct compression example 3

There are tablets with continuous and / or controlled release, the 400 mg Flutamide contained as an effective ingredient.

The composition of the tablet is the following:

Flutamide | 400 mg anionic copolymer 60 mg sodium 5 mg Avicel pH: 101 90 mg Talcum USP 20 mg Aerosil 200 3 mg magnesium stearate 2 mg total weight 580 mg

manufacturing

a) sieving; All powders are passed through a No. 20 sieve or sifted 40;

b) mixing; 40 g of flutamide, 6 g of anionic copolymer 0.5 g carboxymethyl cellulose and 9 g Avicel For 30 minutes in a double or similar Mixed V-mixers.

In another blender, add 2 g talc and 0.3 g Aerosil 200 mixed for 20 minutes. Then be both mixed for 15 minutes, 0.2 g magnesium stearate added and mixed for 5 minutes.

c) pressing; this mixture is mixed in a rotary Press with suitable stamps for the preservation of certain weights pressed.

Finally, the average weight, the Flutamide content, the solubility test, the hardness and appearance are controlled.

example 4

Following the procedure of Example 3, tablets are used with continuous and / or controlled  Release of 160 mg flutamide produced.

The composition of the resulting tablet is the following:

Flutamide | 160 mg anionic copolymer 32 mg sodium 2 mg Avicel pH: 101 36 mg talc 8 mg Aerosil 200 1.2 mg magnesium stearate 0.8 mg total weight 240 mg

example 5

There were also tablets with continuous and / or controlled release using made of gelatinized cereal starch. To carry out were 16 g of flutamide, 1.6 g of anionic Copolymer and 0.4 g of gelatinized cereal starch weighed. They were sifted through a No. 20 sieve and Mixed for 30 minutes in a suitable blender. Thereafter, 3.5 g of Avicel pH: 101 was added and it was mixed for 30 minutes. Subsequently 0.5 g of talc, 0.1 g of Aerosil 200 and 0.1 g Magnesium stearate added, taking before pressing the mixture in a rotary press for 10 minutes were thoroughly mixed. Finally, the salary was on flutamide, the appearance, hardness and solubility test controlled.  

Although in the examples only certain ways to Implementation of the invention have been given obviously every expert on this technical Area any other pharmaceutical Formulation containing different concentrations of flutamide, manufacture and the appropriate Use binders and their quantities in appropriate Change way.

Claims (17)

A process for obtaining a continuous and / or controlled release pharmaceutical dosage form of flutamide, characterized in that it includes mixing flutamide and the other suitable pharmaceutical excipients and / or excipients with a retarding component consisting of one of methacrylic acid and methyl methacrylate composite anionic copolymer of the formula: is formed alone or in conjunction with other suitable pharmaceutical delay agents. 2. The method according to claim 1, characterized in that a ratio of the carboxyl groups of the anionic Copolymers 1: 2 is obtained.   3. The method according to claim 1 or 2, characterized in that as pharmaceutical dosage form a tablet with continuous and / or controlled release will be produced. 4. The method according to claim 3, characterized in that the tablet is obtained by granulation. 5. The method according to claim 3, characterized in that the tablet is obtained by direct pressing. 6. The method according to any one of claims 3 to 5, characterized in that the tablet with a flutamide amount between 60 and 80% by weight of the tablet and an amount of retarding ingredient between 6 and 14% by weight of the tablet will be produced. 7. Pharmaceutical dosage form with continuous and / or controlled release of flutamide, characterized in that an appropriate amount of retarding ingredient contains, from a methacrylic acid and Methyl methacrylate compound anionic Copolymer is formed, alone or in combination  with other suitable pharmaceutical delay agents. 8. Pharmaceutical dosage form according to claim 7, characterized in that the ratio of carboxyl groups in the anionic copolymer is 1: 2. 9. Pharmaceutical dosage form according to claim 7 or 8, characterized in that the release is a continuous and / or is controlled. 10. Pharmaceutical dosage form after a of claims 7 to 9, characterized in that a quantity of flutamide between 60 and 80% by weight the tablet and a lot of retarding ingredient between 6 and 14% by weight of the tablet. 11. Pharmaceutical dosage form after a of claims 7 to 10, characterized in that the release of the flutamide takes place gradually and approximately 32.5% at 30 min approximately 90.3% at 10 h changes, in one Medium, that created by the intestinal juices equivalent.   12. Method for determining the content of flutamide in a tablet with continuous and / or controlled release of flutamide, characterized in that it includes a previous extraction with an organic solvent, a submitting the resulting solution of high pressure liquid chromatography (HPLC) and comparing the obtained curve with a comparison curve for a known Flutamidkonzentration. 13. The method according to claim 12, characterized in that the organic solvent is an alkanol, preferably Methanol is. 14. Method for determining bioavailability and the amount of one tablet with continuous and / or controlled release flutamide released from flutamide and its Metabolites in plasma, characterized in that it includes extracting a plasma extract of a treated patient, extracting with an organic solvent, performing a high-pressure liquid chromatography with the resulting solution and their comparison with a Comparison curve.   15. The method according to claim 14, characterized in that the organic solvent is an alkanol, preferably Methanol is. 16. A pharmaceutical dosage form according to claim 7 for the treatment of prostate hyperplasia and / or advanced Prostate carcinoma with continuous and / or controlled release of a therapeutically effective Amount of flutamide. 17. A pharmaceutical dosage form according to claim 16, in which the pharmaceutical agent is a tablet with continuous and / or controlled release.