FR2648349A1 - PROCESS FOR OBTAINING PHARMACEUTICAL FORMS OF FLUTAMIDE WITH CONTINUOUS AND / OR PROLONGED RELEASE - Google Patents

Abstract

The invention relates to a process for obtaining a pharmaceutical form of flutamide with continuous and / or sustained release, comprising mixing the flutamide and other pharmaceutically acceptable components contained in this pharmaceutical form with a delay component consisting of an anionic copolymer. formed of methacrylic acid and methyl methacrylate, alone or in combination with other retarding components. A flutamide release test and a method for determining the bioavailability thereof are also described, both carried out by extraction of the flutamide with methanol and high pressure liquid chromatography of the solution obtained. The pharmaceutical forms obtained in this way, in particular tablets, make it possible to achieve a longer duration of the stay of flutamide in the blood stream, which results in better bioavailability of the latter and a reduction in the doses to be administered to the patient, and they are suitable for the treatment of prostatic hyperplasia and advanced prostate cancer.

Description

PROCESS FOR OBTAINING PHARMACEUTICAL FORMS FROM

  FLUTAMIDE WITH CONTINUOUS AND / OR PROLONGED RELEASE

  The invention relates to a process for obtaining pharmaceutical forms with continuous and / or prolonged release of an active element, and in particular, a process for obtaining a continuous and / or prolonged release pharmaceutical form in which Use flutamide as an active ingredient. In addition, the nventlon concerns new pharmaceutical forms

obtained according to this process.

  The invention also relates to an analytical method for determining the amount of flutamide in continuous release tablets, and a test of

  dissolution of sustained release tablets.

  Flutamid, whose chemical name is "N-

  Isobutyryl-4-nitro-3-trifluoromethyl-anilide, or blen

  according to the nomenclature of the Chemical Abstract, "2-methyl-N-

  (4-Nitro-3- (trifluoromethyl) -phenyl) -propanamide, has the following formula: CH 2 O 2

CH3

  and it is a blen compound known as an oral steroids anti-androgenic anti-androgen and suitable for the treatment of prostate hyperplasia and advanced prostate cancer. For the treatment of these diseases, conventional tablets containing flutamide as an active ingredient are available. The usual treatment consists in the daily administration to the patient of up to three conventional tablets, the amount of flutamide per tablet being 250 mg, which means a quantity

  total of 750 mg of flutamide per day of treatment.

  In addition, flutamide is an insoluble drug, rapidly absorbed in the intestines, which has a very short residence time in the bloodstream. In addition, as a consequence of the disintegration of a conventional tablet, the flutamide contained therein is released at one time, which produces a high level of flutamide in the bloodstream, which could lead to serious side effects in the patient. Examples of these serious side effects are: hydrosaline retention due to increased blood levels of testosterone and estradiol; a mammary sensibility, sometimes accompanied by galactorrhea; we sometimes observe. during prolonged treatment, decreased sperm production and transient liver function disorders, which require perlodic control of liver function and sperm count, sometimes leading to

  recommendation to alleviate or stop treatment.

  Therefore, it is necessary to have novel fl uid containing dosage forms suitable for the treatment of prostate hyperplasia and advanced prostate cancer in order to overcome the above-mentioned difficulties. The Applicant's researches concerning new pharmaceutical forms containing flutamide as an active ingredient and overcoming these difficulties have been directed towards obtaining new pharmaceutical forms of flutamide. allowing the release

  gradual and continuous process of this one in gastric juices.

  intestlnaux. As a result, new pharmaceutical forms of continuous and / or prolonged release flutamid have been obtained. which have the following advantages: a) increased residence time and use of flutamide in the bloodstream; b) malntlen of a uniform level of flutamlde in the plasma: c) reduction of the possibilities of troublesome side effects in the patient; and d) therefore, improving the effectiveness of the treatment and improving the bioavailability of flutamide. The solution proposed by this invention consists in the preparation of new pharmaceutical forms containing flutamide as active principle, releasing said active ingredient in a prolonged and / or continuous manner, and for the preparation of these pharmaceutical forms, the invention recommends the use of a polymeric matrix resin, in combination with other inert, retarding and soluble agents in the intestines, which

  allows a gradual release of flutamlde.

  Therefore, an object of the present invention is the preparation of continuous and / or prolonged release flutamide dosage forms. Another object of the present invention is to provide pharmaceutical forms of sustained release and / or extended release flutamide which are not currently available on the market. Another object of the invention is the analytical detection of the amount of flutamide present in a pharmaceutical form by means of chromatography.

  high pressure liquid phase (HPLC).

  Another object of the invention is constituted by a dissolution or liberation test of fiutamlde

  contained in a pharmaceutical form.

  According to one of these aspects, the invention relates to a process for obtaining pharmaceutical forms of flutamide with continuous and / or prolonged release, thanks to the formulation thereof with a retarding agent which allows the gradual release of flutamide. The invention encompasses in its scope, as appropriate pharmaceutical forms for continuous and / or prolonged release: plastic matrix tablets; 10. coated tablets; tablets comprising a core and a regulating coating for continuous or prolonged release; slow degradation matrix tablets; protective layer tablets; 15. tablets prepared using hydrophilic matrices; tablets made with an osmosis release system; polystratified tablets; 20. tablets with microgranules; other types of tablets; rigid capsules comprising microgranules with continuous action or sustained release; soft capsules comprising a suspension of the active ingredient in a medium, with continuous or prolonged release; granules for release into water, which is a continuous or extended release suspension; spherical granules for incorporation into capsules, conventional tablets, coated tablets, laminated tablets; 5.granules coated with different retarding agents, in order to regulate the release in a continuous or prolonged manner; microgranules comprising polymerized agents for incorporation into capsules, tablets, powders, suspensions, and / or other continuous and / or prolonged flutamide delivery systems; microcapsules containing retarders for incorporation into capsules, tablets, powders, suspensions, and / or other continuous or prolonged flutamide delivery systems; transdermal systems, consisting of cellulose, polypropylene, polycarbonate, polytetrafluoroethylene or others; and in general any other sustained or sustained release dosage form in which there is

flutamide or its by-products.

  As a suitable retarding agent, a polymer matrix is used in combination with other intestinal-soluble inerting agents (pH S 7), which allows the progressive release of flutamide. The polymer matrix consists of an anononic copolymer of methacrylic acid and methyl methacrylate, which has the following structural structure:

CH3 CH3

- CH2 - C - CH2 - C -

C = O C = O

OH OCH3

  the proportion of carboxyl groups being about 1: 2.

  This compound is soluble in a medium having a pH greater than or equal to 7, due to the formation of salts with alkalis, and for this reason. it is suitable for being contained in a pharmaceutical form intended for the progressive release of an active agent in the intestines, since, as mentioned above, the pH of the intestinal medium, in particular that prevailing in the intestine hail, in the jejunal and ileal sections, varies from 7 to about 7.5, so that this compound

  is soluble in the intestinal mill.

  The resin of the polymeric matrix of methacrylic acid and methyl methacrylate is obtained by conventional polymerization methods, adjusting the proportions of the monomers so that it is possible to obtain the appropriate proportions, since the release of the principle flutamide in this case will depend on the proportions between easily permeable acrylic elements and the elements

  acrylic permeable dlfflcllement.

  The retarding component may contain varying amounts of one or more of the usual retarding agents, including microcrystalline cellulose, stearyl and palmitic acids, glyceryl mylstate, cetyl alcohol, hydrogenated acid and the like. ethylcellulose, glyceryl monostearate, hydrolyzed styrene / malic acid copolymer, shellac and polyethylene glycol 6000, shellac and hydrogenated oil, various plasticizers, glycerol and sorbitol, tannates and polygalacturonic acid; polyethylene, poly (chloride of

  vinyl), polyvinyl acetate, polyoxymethylene

  adlpamlde, sodium dioctylsulfosuccinate.

  hexadecyltrimethylammonium, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, amylose and others. The pharmaceutical forms with continuous and / or prolonged release of this invention may contain, in addition to the active ingredient (flutamide) and the retarding component, other useful pharmaceutical components, such as diluents, for example dicalcium phosphate hydrate, 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 the like; lubricants, for example talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil and the like; slip agents, for example colloidal silicon dioxide (CAB-O-SIL) or talc: disintegrants, for example corn starch, alginic acid, sodium-amyl ammonium glycate, methylcellulose, guar gum, carboxymethylcellulose; and dyes, for example red FD and C N '3, red FD and C N' 40, yellow FD and C N '5, yellow FD and C N' 6, blue FD and C N '1, blue FD and C

N '2, green FD and C N' 3.

  It has been previously stated that the pharmaceutical forms with continuous and / or prolonged release can be very diverse, and therefore the invention will be explained more particularly with regard to tablets in general, and a few methods of obtaining in detail will be described. of tablets according to the invention, although the other pharmaceutical forms mentioned and recommended by the invention can be easily obtained by using in each case the process

  particular preparation and appropriate excipients.

  In the context of this invention, as used herein, the term "tablets of the invention" denotes a pharmaceutical form, in particular a tablet, which contains flutamide as active ingredient and is endowed with the property of continuous release. or

prolonged of this active principle.

  In general, tablets of the invention can be obtained according to conventional tableting methods, for example direct compression methods, dry or wet granulation methods, and indirect compression methods, with In particular, the active ingredient (flutamide) is mixed not only with the excipient and / or the pharmaceutically acceptable carriers, but also with a retarding component consisting of an anionic copolymer consisting of methacrylic acid and methyl methacrylate units, and having the following structure:

CH3 CH3

l l

- CH2 - C - CH2 - C -

C = .O C = O

I

OH OCH3

  with a proportion of carboxyl groups of 1: 2.

  The amount of flutamide, as well as that of the retarding component and the other components of the tablet of the invention, may vary depending on the desired final dosage in the tablet. Nevertheless, for therapeutic purposes, it is appropriate to use an amount of flutamide accounting for about 60 to 80% by weight of the tablet: an amount of retarding component of between 6 and 14% by weight of the tablet, the remainder of the components representing 6 to 34% by weight of the tablet, and consisting of exclplents and / or

  pharmaceutically acceptable vehicles.

  Once the tablets of the invention obtained, they are subject to the usual controls as regards the average weight, the hardness. the active ingredient content and the

release of this one.

  According to another aspect of the invention, there is provided a method for analytically determining the flutamide content of a tablet of the invention, i.e., a method for determining the dose of flutamide in tablets of the invention. The method is based on the application of high pressure liquid chromatography (HPLC) techniques to a solution of flutamide, obtained by extraction of flutamide with an organic diluent, such as an alkanol, preferably methanol. and basically, it is to compare the curve obtained for a solution consisting of methanol and the mass equivalent to a crushed tablet, with a calibration curve obtained for a control solution of known concentration. In particular, in order to determine the dose present in a tablet of the invention at 400 mg of flutamide, the realization of the indicated process will include: a) Preparation of the sample (in triplicate) - weigh exactly 20 tablets, to determine the average polders of a tablet: - they are crushed in a mortar to obtain a fine powder; a quantity equivalent to the weight of a tablet is weighed exactly, dissolved in methanol and stirred for 30 minutes; the solution obtained is filtered on black band filter paper and placed in a volumetric flask

  100 ml, and complete the volume with methanol.

  b) Preparation of a control solution having a

known concentration of flutamlde.

  Preferably, a control solution having a concentration of flutamide equivalent to that expected in the sample of interest is prepared. Once the samples have been prepared, each of them is chromatographed in the high pressure liquid phase, and the results obtained are compared. According to this method, it is possible to determine the dose of flutamide in any

  type of pharmaceutical forms mentioned above.

  To carry out the tests, a high pressure liquid chromatograph was used, comprising a WATTERS M 45 pump and a UGK injector, a fixed wavelength absorbance detector, and a recorder, although can obviously use a device of a similar type, with the accommodations

required.

  As the eluent, a methanol / water (60/40) mixture was used at a flow rate of 1 ml / m 2 -n, and the measurements were made for a wavelength of 365 nm. The speed of

  scrolling of the recorder on the recorder is 5 mm / min.

  The method of dosing tablets containing 250 mg of flutamide has been described, but of course, in order to determine the doses of tablets containing other amounts of flutamid, the described procedure must be applied by modifying the dilutions appropriately. According to another aspect of the invention, there is provided

  an attempt to dissolve or release flutamide.

  In order to determine the degree of release of flutamide into the gastrointestinal juices, an artificial intestinal juice solution containing 2.5 mg / ml of pancreatin and a surfactant such as polysorbate 80 or sodium dloctylsulfosuccinate is prepared. ,

  among others, in a proportion of about 1%.

  The composition of this solution makes it possible to obtain a good correlation between the data obtained in vitro

and the actual results.

  The dissolution technique for the release control is that indicated in USP XXI Ed., Although, of course, any other similar technique can be used in adapting the apparatus to the test.

release in each case.

  The results of the dissolution test are given in the following table: Release minutes: 32.5% i hour: 36.86% 2 hours: 39.08% 3 hours: 51.54% 4 hours: 59.85% hours: 71.62% 6 hours: 76.34% 7 hours: 78.77% 8 hours: 81.66% hours 90.30% Therefore, we see that unlike conventional flutamide tablets that release it in only once and in a large amount, in the case of continuous and / or prolonged release tablets of the invention, there is a gradual release of flutamide which results in a more homogeneous concentration of flutamide in the plasma and a longer residence time in the bloodstream, and that we overcome a few

  difficulties indicated at the beginning of this description and

  generated by the admixture of conventional tablets

of flutamlde.

  According to another aspect of the invention, there is provided a method for assaying flutamide and its metabolites in plasma using high pressure liquid chromatography (HPLC) techniques. In order to study the blotting of flutamide in continuous and / or prolonged release tablets, plasma samples, previously heparinized, are prepared by adding specific amounts of flutamide and its

  metabolites (hydroxyflutamide and trifluorophenylnitro-

  aniline (TFNMA)), and they are extracted with an organic solvent such as an alkanol, preferably methanol. The limits of detection and the recovery factor (also called, in English terminology, "recall factor") are then determined, and

  studied the reproducibility of the recordings obtained.

  Previously, the calibration curve is determined for both flutamide and its metabolites. To perform the high-pressure liquid chromatography, a WATTER M45 chromatography apparatus, and a UGK injector, a detector are used.

  of fixed wavelength absorbance and a recorder.

  As the eluent, a mixture of methanol / water (60/40) was used at a flow rate of 1 ml / min, and the absorbance was measured at the wavelength of 365 nm. The apparatus was operated with a scrolling speed of

  recorder paper of 5 mm / min.

  Under these conditions, the retention times obtained for flutamide and its metabolites are: retention time flutamide: 6.4 min TFNMA: 2.8 min hydroxyflutamide: 4.2 min Realization of the method for the determination of flutamide and its metabolites in Plasma The calibration curves of flutamide, TFNMA and hydroxyflutamide are established. For these, the following solutions were prepared: flutamide: 10 ng / solution. TFNMA: solution of 0.2 ng / hl - hydroxyflutamide: solution of 10 ng / μl and fractions of 1, 2, 5, 10, 25, 35, 50 and 100 μl of each of these solutions were injected, to obtain the corresponding calibration curves for each component. Preparation of samples Using an appropriate apparatus (Vortex), 2 ml of heparinized plasma from patients treated with continuous and / or prolonged flutamide tablets maintained at -4 ° C were homogenized and add to 3 ml of dichloromethane (quality for analysis); then the whole is vortexed for 1 minute, centrifuged at 3500 rpm for 5 minutes, and the organic phase is separated and passed through a conical bottom glass tube; then evaporated to dryness and redissolved the solid residue in 100 μl of methanol (quality for analysis). The solution thus obtained is

  injected as such into the chromatography apparatus.

  Determination of detection limits Some amounts of untreated volunteer plasma are taken. and decreasing amounts of each of the test compounds are added. We

  prepares samples according to the procedure indicated below.

  above, and at the end the corresponding chromatograms are obtained. As the detection limit for each compound, the value whose signal corresponds to a signal-to-noise ratio greater than or equal to 2 is considered, and the following results are obtained: detection limit for flutamide: 10 ng / ul Plasma - detection limit for TFNMA: 0.2 ng / μl plasma - limit of detection for hydroxyflutamide: 20 ng / μl plasma Determination of recovery factor Plasma amounts of untreated volunteers are taken, and the compounds to be studied are added thereto. The samples are prepared according to the process described above, that is to say that 2 ml of plasma are taken and 100 mg of flutamide, 10 ng of TFNMA or 100 ng of hydroxyflutamide are added, followed by the whole is subjected to a method of extraction with the solvent indicated above, and the solutions obtained are subjected to chromatography and are compared with the standards. The following results were obtained: Compound Flutamide recovery factor 92.1 3.8%

TFNMA 88.5 4.7%

  Given these values, it is seen that at least 80% of each test compound will be detected if it is free (unconjugated) and if its concentration is greater than

limit of detection.

  Reproducibility study Six untreated volunteer plasma samples are treated with the test compounds and

  analysis according to the method indicated above.

  The results obtained for each sample, one the values obtained corrected by each corresponding recovery factor, are as follows: Flutamide TFNMA Hhydroxyflutamide

, 2% 98.7% 104.3%

103.1% 106.2% 98.9%

101.8% 103.7% 102.7%

105.4% 101.1% 101.0%

103.7% 97.2% 103.8%

, 0% 103.6% 96.5%

average = 102.37% 101.75% 101.18%

-1 = 2.10% 3.39% 3.07%

C.V. = 2.05% 3.33% 3.03%

  From the reproducibility and the recovery coefficient, it is observed that the proposed analytical method is suitable for the determination of the compounds studied

in the plasma.

  This description is illustrated with the aid of

  following examples, which describe particular embodiments of the invention. They particularly describe the production of tablets comprising flutamide as active ingredient, with continuous and / or prolonged action, according to different methods of preparation of tablets.

EXAMPLES

  A) Granulation of tablets

Example 1

  Continuous and / or prolonged release tablets containing 400 mg of flutamide are prepared as

active ingredient.

  The composition of the tablet is as follows: flutamide 400 mg lactose 43.1 mg talc 31.2 mg Aerosil 200 2.0 mg anionic copolymer 33.4 mg magnesium stearate 5.2 mg TOTAL WEIGHT 514.9 mg Preparation a) Mixture A flask, flutamide, lactose, aerosol 200 and talc are passed through a sieve of 20 mesh or 60 mesh. Then, 400 g of flutamide, 43.1 g of lactose, 15.6 g of talc and 2.0 g of Aerosil 200 are mixed in a V-shaped mixer or similar.

  minutes, to get a good mix of components.

  b) Granulation solution: a polymer solution (acrylate resin) containing 33.4 g of anionic copolymer dissolved in a mixture of equal parts of alcohol is prepared

  and methylene chloride (0.05 g each).

  c) Granulation: The mixture obtained in step a) is granulated using the granulation solution, wetting the components appropriately. Then the mixture is passed through a No. 6 mesh screen, and then into an oscillating mill equipped with a sieve.

mesh N '18 or 20.

  d) Drying: the granules obtained are dried in a fluid-bed dryer at 40-50 ° C. and once the powders are dried, they are passed through a No. 18 or 20 mesh screen. 3.304 is then added. g of magnesium stearate and 15.6 g of talc, and mixed for 15 minutes. e) Compression: the powders are compressed in a rotary compressor, keeping the indicated weights, and we control the polders, the dissolution, the dose, the appearance

and hardness.

  f) After which, the tablets obtained are placed in a cylinder of suitable dimensions, and a solution of a polymer of adjustment of the release rate in a mixture of acetone and alcohol (consisting of 1.5 g of resin and 0.11 g of alcohol and acetone). 1.896 g of manesium stearate is then added, dried for 2 hours on

  trays at 60 ° C, then for 24 hours at 37 ° C.

  Finally, the appearance, dose,

hardness and release.

Example 2

  Sustained-release and / or continuous release tablets containing 160 mg of flutamide are prepared according to the method set forth in Example 1, suitably adjusting the weights of the components of the novel formulation. The tablet obtained 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

  Continuous and / or sustained release tablets containing 400 mg of flutamide are prepared as

active ingredient.

  The composition of the tablet is as follows: flutamide 400 mg anionic copolymer 60 mg carboxymethyl cellulose soda 5 mg Avicel pH: 101 90 mg 53 talc U.S.P. 20 mg Aerosil 200 mg 3 mg magnesium stearate TOTAL WEIGHT 580 mg Preparation: a) sieving: all powders are passed through

a screen of mesh N 20 or 40.

  b) Mixing: in a twin V-blender, or similar type, 40 g of flutamide, 6 g of anionic copolymer, 0.5 g of carboxymethylcellulose are mixed.

and 9 g of Avicel for 30 minutes.

  In another mixer, 2 g of talc and

  0.3 g of Aerosil 200 for 20 minutes.

  After which, the two mixtures obtained are mixed for 15 minutes, by adding 0.2 g of sodium stearate.

  magnesium, and mixed for 5 minutes.

  c) compression: the resulting mixture is compressed in a rotary compressor, using adequate punches

to maintain the indicated weights.

  Finally, we control the average weight, the dose of

  flutamide, dissolution, hardness and appearance.

Example 4

  Continuous and / or sustained release tablets containing 160 mg of flutamide are prepared according to

method of Example 3.

  The composition of the tablet obtained is as follows: flutamide 160 mg anionic copolymer 32 mg sodium carboxymethyl cellulose 2 mg Avicel pH: 101 36 mg talc 8 mg Aerosyll 200 1.2 mg stearate magnesium 0.8 mg TOTAL WEIGHT 240 mg

Example -5

  Continuous and / or prolonged release tablets were also prepared using gelatinized corn starch. To do this, 16 g of flutamide, 1.6 g of anionic copolymer and 0.4 g of gelatinized corn starch are weighed. They are passed through a No. 20 mesh screen and mixed for 30 minutes in a suitable mixer. 3.5 g of Avicel pH: 101 are then added and the mixture is mixed for 30 minutes. 0.5 g of talc, 0.1 g of Aerosil 200 and 0.1 g of magnesium stearate are then added, and the mixture is thoroughly mixed for minutes before compressing the mixture in a rotary compressor. Finally, we control the dose of

  flutamide, appearance, hardness and dissolution.

  The examples mentioned above indicate only particular embodiments of the invention: -n, and are given for illustrative purposes only and not limltatlf. Any specialist can prepare any other dosage form containing different concentrations of flutamide, using the appropriate excipients and suitably varying their proportions.

Claims (17)

  A process for obtaining a continuous and / or sustained release pharmaceutical form containing flutamide, characterized in that it comprises the mixture of flutamide and other pharmaceutically acceptable excipients and / or carriers with a retarding component, consisting of an anionic copolymer formed of methacrylic acid and methyl methacrylate, of formula: CH3 CH3 I - CH2 - C - CH2 - C - C = O C = O ! I OH OCH3   alone or in combination with other retarding agents pharmaceutically acceptable.   2. Method according to claim 1, characterized in that the proportion of the groups   carboxylic acid in the anionic copolymer is 1: 2.   3. Process according to claim 1, characterized in that the pharmaceutical form is a   continuous and / or prolonged release tablet.   4. Method according to claim 3, characterized in that the tablet is obtained by granulation. 5. Process according to claim 3, characterized in that the tablet is obtained by direct compression.   6. Process according to claim 3, characterized in that the tablet contains a   proportion of flutamide between 60 and 80% by weight.   of the tablet, and a proportion of the retarding component between 6 and 14% by weight of the tablet. 7. Pharmaceutical form with continuous and / or prolonged release, containing flutamide, characterized in that it contains a suitable amount of a retarding component constituted by an anionic copolymer formed of methacrylic acid and methyl methacrylate, alone or in combination with other retarders pharmaceutically acceptable.   Pharmaceutical form according to claim 7, characterized in that the proportion of groups   carboxylic acid in the anionic copolymer is 1: 2.   9. Pharmaceutical form according to claim 7, characterized in that it is a form of   continuous and / or prolonged release.   10. Pharmaceutical form according to claim 9. characterized in that it contains a proportion of flutamide between 60 and 80% by weight of the tablet, and a proportion of retarding component   between 6 and 14% by weight of the tablet.   Pharmaceutical form according to Claim 7, characterized in that the release of the flutamide takes place gradually and ranges from about 32.5% after 30 minutes to about 90.30% after 10 hours. in a medium equivalent to that provided by the intestinal juices.   12. Method for determining the dose of flutamide in a continuous and / or prolonged release flutamide tablet, characterized in that it comprises a prior extraction with an organic solvent, the subjection of the solution obtained to a liquid chromatography high pressure (HPLC), and comparing the curve obtained with a curve   calibration for a known concentration of flutamide.   Process according to claim 12, characterized in that the organic solvent is a   alkanol, preferably methanol.   14. A method for determining the bioavailability and the amount, in the plasma, of flutamide and its metabolites, released by a flutamide tablet with continuous and / or prolonged release, characterized in that it comprises the removal of plasma from a patient treated, carrying out an extraction with an organic solvent, carrying out a high-pressure liquid chromatography of the solution obtained, and   comparison of the result with a calibration curve.   15. Process according to claim 14, characterized in that the organic solvent is a   alkanol, preferably methanol.   16. A method for treating prostatic hyperplasia and / or advanced prostate cancer, characterized in that it comprises administering to a patient a therapeutically effective amount of a pharmaceutical form. flutamide, continuous release   and / or prolonged, according to claim 7.   17. Process according to claim 16, characterized in that the pharmaceutical form is a   continuous and / or prolonged release tablet.