GB2222947A

GB2222947A - Continuous/controlled release flutamide formulations

Info

Publication number: GB2222947A
Application number: GB8914039A
Authority: GB
Inventors: Luis Of Prizont
Original assignee: DATSA LAB
Current assignee: DATSA LAB
Priority date: 1989-06-19
Filing date: 1989-06-19
Publication date: 1990-03-28
Also published as: IT9067447A0; GB8914039D0; DE4019512A1; IT1240954B; IT9067447A1; FR2648349A1; ES2013970A6

Description

2222947 A PROCESS FOR THE OBTAINING OF PHARMACEUTICAL FORMS OF

CONTI'.7JOUS AND/OR CONTROLLED RELEASE OF FLUTAMIDE PURPOSE OF T= INVE NTION The invention is referred to a process for the obtaining of pharmaceutical forms of continuous and/or controlled release of an active element, and particulary, to a process to obtain a pharamceutical form of continuous and/or controlled release where it is used flutamide as an active element. Besides, the invention is referred to the new pharmaceutical forms obtained in this way.

The invention also provides an analytical method to determine the quantity of flutamide in tablets of continuous release and a test of solution of continuous release tablets.

BACKGROUND OF TITE INVENTION

The f 1 u t a m i d c, which chemical name i S N-isobutyryl-4-nitro-3trifluoromethylanilide, or using the nomenclature of the Chemical Abstract, 2-methyl-N-[4-nitro-"5-(trifluoromethyl) phenyl] propanamide, has the following formula:

- 0 11 3 CH N11 NO 3 11 0 2 .;kl 3 and it is well-known as a non-steroid antiandrogen, active by oral way, and appropiate for the treatment of prostate hyperplasia and advanced prostate carcinoma. For the treatment of these diseases it is dispensed conventional tablets including flutamide as an active element. The usual treatment consists in a daily dispensing to the patient up to three conventional tablets, with a quantity of flutamide pertabletof 25Orng, which means a total quantityof 750 mgof flutamide per each day of treatment.

Besides. the flutamide is an insoluble drug of fast absorption in the intestine, which produces a very reduced stay time in the bloodstream and besides, as a consecuence of the disintegration of the conventional tablet, the flutamide content is released in one time, which produces a high level of flutamide in the bloodstream that could originates harmful collateral effects in the patient. These are examples of the harmful collateral effects:

hydrosaline retention due to the increasing of testoterone and estradiol in the plasmatic levels; mamary sensibility sometimes accompnied by galactorrhea; sometimes during a long period of treatment it is observed a decreasing in the production of spermatozoons and transitional disorders of the hepatic function that forces to do periodical hepatic functional controls and recounts of spermatozoons with results that sometimes recommend to decrease or to cancel the treatment.

Consecuently, it arises the necessity of providing new pharmaceutical forms, containing flutamide, appropiated for the treatment of the prostate hyperplasia and the advanced prostate carcinoma to overcome the before mentioned difficulties. In ourintention to find new pharmaceutical forms containing flutamide as an active principle and overcoming these difficulties we have been intended for the obtaining of new pharmaceutical forms of flutamide allowing its gradual and continuous release in the gastrointestinal juices. As a consecuence of this, it has been obtained new pharmaceutical forms of continuous and/or controlled release of flutamide that present the following advantages:

a) increasing the use and stay time of flutamide in the bloodstream; b) mantaining a uniform level of flutamide in the plasma; c) decreasing the possibilities of harmful collateral effects in the patient; and e) consecuently, it is improved the effectiveness of the treatment and it is obtained a better bioavailability of flutamide.

The solution proposed by this invention consists in the preparation of new pharamaceutical forms containing flutamide as an active principle having a confluous and/or controlled release of the mentioned active principle, and for the preparation of these pharmaceutical forms the invention recommends the use of a polymeric matrix resin in combination with other inert retarding agents and soluble in the intestine that allows a gradual release of the flutamide.

Consecuently, it is a purpose of the present invention the preparation of pharmaceutical forms of continuous and/or controlled release of flutamide. It is an additional purpose to provide pharmaceutical forms of continuous and/or controlled release of flutamide presently not available in the market.

Other purpose of the invention is the analytical detection of the quantity of flutamide present in a pharamceutical form using High Pressure Liquid Chromatography (HPLC).

Other purpose of the invention is contituted by a test of solution or release of the flutamide contained in a pharmaceutical form.

The way to achieve these purposes is described as follows:

DETAILED DESCRIMON OF THE INVENTION In one of its aspects, the invention is referred to a process to obtain pharamaceutical forms of continuous and/or ontrolled realease of flutamide by its formulation with a retarding agent that allows the gradual release of the flutamide. In the scope of the invention, as appropiate pharmaceutical forms of continuous and/or controlled release, it is included:

a Tablets with plastic matrixes; 9 Covered tablets; Tablets with a nucleus and a regulating cover of continuous or controlles release; Tablets with slow erosion matrixes; - Tablets with protection film; Tablets prepared with hydrophilic matrixes; Tablets elaborated with osmotic release system; Polystratified tablets; Tablets with microgranules; Other type of tablets; Rigid capsules with microgranules of continuous action or controlled release; Soft capsules with suspension of the active principle in a medium of continuous or controlled release.

- Granulated to be released into water providing a suspension of continuous or controlled release; - Spherized granulated to be incorporated to capsules, conventional tablets, covered tablets, stratified tablets; Granulated covered with different retarding agents in order to regulate its release in a continuous or controlled way; Microgranules with polymerizated agents to be incorpored into capsules, tablets, powders, suspensions, and/or other systems of application of flutamide in continuous and/or controlled action; - Microcapsules with retarding agents to be incorporated into capsules, tablets, powders, suspensions and/or other flutamide application systems in continuous or controlled action; - Transdermical systems constituted by cellulose, polypropilene, polycarbonate, polytetrafluorethylene or others; and in general; - Any other pharmaceutical form of continuous or controlled release where there is flutamide or by-products.

As an appropiate retarding agent it is used a polymerical matrix in combination with other inert retarding agents soluble in an intestinal medium (pHa7) that allows the gradual release of flutamide.

The polymeric matrix is contituted by an anionic copolymer constitued by methacrylic acid and methyl-methacrilate that has the following chemical structure 1 CH CH 1 3 3 c - CH 2 - c 1 C=0 011 OP11 3 with a relation of carboxyl groups of aproximately L2. This compound is soluble in pH=7 and in pH> 7 due to the formation of salts with alkalis and for this reason it is appropiate for its includingin a pharamccutical form thatwants a gradual release of an active principle in the intestine, since, as it has been mentioned before, the pH of the intestine, and particullary the one of the small intestine in its jejunurn and ileum sections, varies aproximately from 7 to 7.5, so this compound is soluble in the intestinal medium.

The resine of polymeric matrix of methacrylic acid and methyImethacrilate is obtained by conventional polymerization technics, controlling the proportion of monomerous in such a way to be possible the obtaining the appropiate proportion, since the release of the active principle, in this case flutamide, will be a function of the proportion between the easily permeable acrylic elements and the hardly permeable acrylic elements.

Besides, the retarding element could contain variable quantities of one or more of the ususal retarding agents selected from between microcritalline cellulose, stearic and palmitic acids, miristate of glyceryl and cetylic alcohol, hydrogenated caster acid, ethyl cellulose, glyceryl mono-stearate, Styrene copolymer of the hydrolizate maleic acid, shellac and polietilenglycol 6000, shellac and hydrogenated oil, various plastifiers, glycerol and sorbitol, tanates and polygalacturonic acid; polyetilene or others, polyvinif chloride ot others, polyvinil acetate or others, polioximetilemadipamide, sodium dioctilsulfusccinate, hexadetil trim eti lamoni urn, carboxymethyl cellulose, methyl cellulose, polyvinilpirrolidone, amylose and others.

The pharmaceutical forms of continuous and/or controlled release of this invention, could contain besides of the active principle (flutamide) and of the retarding element, other usable pharmaceutical elements, as diluents, for example, dyhidrated dicalcium phosphate, calciourn sulphate, lactose, cellulose, kaolin, mannitol, sodium chloride, cron starch and others; cohesive agents, for example, starch, gelatin, saccharose, glucose, lactose, gum arabic, sodium alginate, microcrystal line cellulose, carnauba wax, polletilenglycol 4000, hydroxyethylcellulose, polyvinilpirrolidone and others; lubricatns, for example, talcum, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and others; slipers, for example, colloidal silicon dioxide (CAB-O-SIL) or talcum; desintegrators, for example, corn starch, alginic acid, starch sodium glicate, methyl-cellulose, guar gum, carboxymetyl cellulose; and dyes. for example. 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.

Even previously it has been indicated that the pharmaceutical forms of continuous and/or controlled release could be very varies, following we will particularize the invention referred to tablets in general and we will detail some methods to obtain tablets according to the invention, although the rest of the pharamaccutical forms mentioned and recommended by the invention could be easily obtained using in each case the specified elaboration technic and the appropiate excipients.

In the scope of this invention and in the mean used following, the term "tablets of the invention" is referred to a pharmaceutical form, specifically a tablet already mentioned that contains flutamide as an active principle and it is provided by a continuous or controlled release of such active principle.

Generally, the tablets of the invention could be obtained according to conventional methods of tablet obtaining, such as direct compression methods, methods of granulating in dry or wet way, and indirect compression methods, with the particularity of that the active principle (flutamide) is mixed not only with the excipient and/or accepted pharmaceutical transmisors but also with a retarding element constituted by an anionic copolymer constituted by unit of methacrylic acid and methyl-methacrylate, that has the following structure:

CH CH CH 1 2 - c C11 c A 1 C 0 C 0 & OCH 3 con a proportion of carboxyl groups of 12.

Both the flutamide quantity and the one of the retarding component and the rest e lements of the tablet of the invention could vary according to the final dosage it is wanted to provide to the tablet. Neverthless, for therapy ends, it is appropiate to use a quantity of flutarnide to constitute aproximately 60-80% in weight of the tablet; a quantity of retarding element between 6 and 14 % in weight of the tablet, and the rest 6 to 34 % in weight of the tablet, constituted by the excipients and/or accepted pharmaceutical transmisors.

Once obtained the tablets of the invention. they are checked by the ususal tests of average weight, hardness, active principle valuation and release test.

In other aspect of the invention, it is provided a method to determine analyticaly the flutamide content of a tablet of the invention. it means, a method to determine the flutamide dosage in the tablets of the invention. The method is based in the application of High Pression Liquid Chromatography (HPLC) technics, applied on a flutamide solution, obtained by extraction of the flutamide with an organic diluent such as an alkanol, preferably methanol, and basicaly, it consists in comparing the obtained curve by a solution constituted by the weight equivalent to a creshed tabled and methanol with a master curve of a standard solution with a known concentration. Particulary, to determine the dosage of a tablet of the invention with 400 mg of flutamide, the carrying out of the mentioned method will includes:

a) Preparation of the sample (in triplicate) It is weighted exacly 20 tablets, to determine the average weight of a tablet; It is crashed in a mortar to obtain a fine powder; It is weighted exactly a quntity equivalent to the weight of a tablet, it is disolved in methanol and it is shaked during 30 minutes; It is filtrated the resulting solution in black strip filter paper, it is put in a gauged flask of 100 ml and it is completed in volume with methanol; b) Preparation of a standard solution of a known flutamide concentration.

Preferably it is formed the standard solution with a flutamide concentration equivalent to the one that it is waited to find in the sample-problem.

Once prepared the samples, it is made the high pression liquid chromatography on each one and it is comparted the obtained results. With this technic it is possible to determine the dosage of flutamide in any type of the before mentioned pharmaceutical forms. In the realization of the tests we have used a high pressure liquid chromatographer that includes a WATIERS M45 pump, and an UGK injector, an absorbance detector of a fixed wavelenght and register, although obviously it could be used another similar type with the necessary adjustments.

It has been used as eluante a mbdng of methanol/Water (60:40) with a flow rate of 1 mi/min and it has been measures of wavelenght of 365 nm. The registry speed was 5 mm/min.

Even it has been described the method to dosage the tablets of 250 mg offlutamide, obviously to determine the dosage of tablets with other quantities of flutamide, it must be done the described method but varying appropiately the dilutions.

In other aspect of the invention, it is provided a dissolution or realease of flutamide. In order to determine the grade of realese of flutamide in the gastrointestinal juices it has been prepared a solution of artificial intestinal juice containing 2.5 mgfinl of pancreatine and a surface-active agent as polysorbate 80 or sodium dioctilsulfosuccinate among others, in a proportion of aproximately 1 %.

The composition of this solution allows to achieve a good correlation between the obtained in vitro data and the real results.

The dissolution technic of control of release in the indicated in the USP = Ed., even obviously it could be used any other similar one adapting the equipment to the release test in each case.

The results of the dissolution test are included in the following table:

RELEASE minutes: 32.5% 1 hour:

2 hour:

3 hour:

4 hour:

hour:

6 hour:

7 hour:

8 hour:

hour:

36.86% 39.08% 51.54% 59.85% 71.62% 76.34% 78.77% 81.66% 90.30% It is seen consecuently that unlike the conventional tablets of flutamide, where the realease of flutamide in made in one time y in a big quantity, in the continuous and/or controlled realease tablets of the invention, it is observed a gradual realease of the flutamide, that originates a more uniform presence of flutamide in the plasma and longer stay time in the bloodstream, so it is ovecome some difficulties indicated in the begining of this description generated by the administration of conventional tablets of flutamide.

In other aspects of the invention, it is described a method to determine the flutamide and its metabolites in plasma, using High Pression Liquid Chromatography (HPLC) technics. In order to study the bioavailability of the flutamide in tablets of continuous and/or controlled release it has been prepared samples of plasma previously heparinized adding to them specif quantitites of flutamied and its metabolites (hydroxyflutamide and trifluorphenylnitroaniline (TTNMA)) and they has been subjected to an extraction with a organic dissolvent as an alkanol preferably methanol. Following, it has been established the detection limits and the recall factor and it has been studied the reproducing of the obtained registries. Previously, it has been determined the calibration curve, both of the flutamide and its metabolites. In order to do the high pression liquid chromatography it has been used a WATTER M45 chromatographer, and UGK injector, a fixed wave absorbance detector and a register. It has been used as an eluante a mixing of methanol/water (60:40) with a flow rate of 1 ml/min and it has been measured the absorbance at a wavelength of 365 nm. It has been prepared the equipment to operate with a registry speed of 5 mm/min.

Operating in these conditions, the retention times obtained for the flutamide and its metabolites were:

RETENTIONTIMES Flutamide: 6.4 min TFNMA: 2.8 min Hydroxyflutamide: 4.2 min Carrying out the determination method of flutamide and its metabolites in plasma It has been the calibration curve of the flutamide, TFNMA, and hydroxyflutamide. For this it has been prepared the following solutions:

& Flutamide, main solution of 10 ng/,gl 'ITNMA main solution of 0.2 ngigi Hydroyflutamide, main slution 10 ng-lul W- and it has been injected fractions of 1, 2, 5, 10, 25, 35, 50 and 100 gl of each one of these solutions in order to obtain the correspondent calibration curve of each element.

Preparation of the samples It is homogenized by Vortex 2 ml of hepaynizcd plasma of patients treated with tablets of flutamide of continuos and/or controlled action and mantianed at -4 oC and it is added to 3 ml of dichloromethane (of analitic purity); following, it is shaked by Vortex during 1 minute, it its centrifugated at 3500 r.p.m. during 5 minutes and it is separated the organic phase which is passed to a glass tube of conical bottom; following, it is dry evaporated and it is redissolved to the solid residue in 100 Al of methanol (of analitic purity). 71be solution obtained in this way is injected in the chromatographer as it is.

Determination of the detection limit It is taken proportions of plasma of non-treated voluntaries adding them decreasing quantities of each one of the elements to be studied. It is prepared the samples following the method before indicated and they are carried out the correspondent chromatograms.

It has been considered as a detection limit for each element the value which signal had a relation signallnoise higher or equal to 2, and it has been obtained the following results:

Detection limit for flutamide:

Detection limit for TFNMA:

ng/gi plasma 0.2 ng/gl plasma Detection limit for hydroxyflutarnide: 20 ng/gl plasma Determination of the recall factor It is taken proporcions of plasma of non-treated voluntaries adding them the elements to be studied. It is prepared the samples according to the method previously described, specificaly, it is taken proportions of 2 mI of plasma and it is added 100 mg of flutamide, 10 ng of MMA and 100 ng of hydroxyflutamide, being subjected to an extraction process by the before indicated soleven and the obtained solutions are chromatographied comparing themn with masters.

It has been obtained the following results:

Element Recall factor Flutamide 92.1 3.8 % MMA 88.5 -t-4.7 % Hydroxyflutamide 86.6 t: 7.2 % Observing these values it is seen than at least the 80 % of each studied element will be detected if it is free (not-conjugated) and being its concentration higher than this of the detection limit.

Study of the reproduction It is treated 6 samples of plasma of non-treated voluntaries with the elemets to be studied and they are analyzed accoding to the before indicated method.

The obtained results for each sample, once corrected the obtained values by each correspondent recall factor were the following:

FLUTAMIDE MMA =ROXYFLUTAMIDE 100.2% 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% 100.0% 103.6% 96.5% X= 102.37 % -1= 2.10 % C.V. = 2.05 % 101.75% 101.18% 3.39% 3.07% 3.33) % 3.03% From the reproduction and recall coefficient it is observed that the proposed analitic method is appropiated for the valuation of the studied to be studied in the plasma.

The present description is completed with the following examples that particularize specified ways to carry out the invention, specially it is referred to the obtaining of tablets including flutamide as an active principle with continuous and/or controlled action obtained carrying out the different methods of preparation of the tablets.

EXAMPLES

A) Elaboration of tablets by granulating EXAMPLE I

It is prepared tablets of continuous and/or controlled release containing 400 mg of flutamide as an active principle.

The composition of the tablet is:

Flutamide Lactose Talcum Aerosil 200 400 mg 43.1 mg 31.2 mg 2.0 mg Anionic copolymer 33.4 mg Magnesium stearate 5.2 mg TOTAL WEIGHT 514.9 mg 3 1 Elaboration:

a) MIXED, they are sieved by no.20 or 60, flutamide, lactose, aerosil 200 and talcum. Following, it is mixed in a V type, double or similar mixer, 400 gr of flutamide.43.1 oflactose. 15.6 gr of talcum and 2.0 of aerosil 200 during 30 minutes, to obtain a good mixing of the elements.

b) GRANULATED SOLUTION, it is prepared a solution of polymerous (acrylate resines) containing: anionic copolymer 33.4 gr solved in a mixin of equal parts of alcohol and methylene chlorade (0.050 gr of each one).

c) GRANULATION, it is granulaed the mixing obtained in the phase a) with the granulating solution, humidizing appropiately the elements. Following, it is passed by a sieve no. 6 and afterwards by a oscillating mill with sieve of no. 18 or 20.

d) DRYING, the obtained granulated is dryied in a dryier of fluid bottom at 40-50 oC and once the powders are dryied they are sieved in no. 18 or 20. Fllowing, it is added 3.304 gr of magnesium stereate and 15.6 gr of talcum and it is mixed during 15 minutes.

e) COMPRESSION, the powders are compressed in a rotative compressor, mantaining the specified weights and it is controlled the weight, the dissolution test, the valution, the aspect and the hardness.

f) Afterwards, the obtained tablets are put in a drum of the appropiate size and on them it is pulverized a solution of a polymeric resin of speed release in acetone alcohol (constitutes by 1.5 gr of resine and 0. 11 gr of alcohol and acetone). Afterwards it is added 1.896 gr of magnesium steorate, it is dryied during 2 hours in trays at 60 oC and following during 24 hours at 37 oC.

Finally, it is made the aspect test, valutaion, hardness and relaese.

EXAMPLE2

It is prepared tablets of continuous and/or controlled release containing 160 mg of flutamide, according to the method indicated in the example 1, adectiating appriopiately the weights of the elements to the new formulation. The obtained tablet has the following composition:

Flutamide Lactose Talcum Aerosil 200 mg 17.2 mg 12.4 mg 2.8 mg Anionic copolymer 5.6 mg Magnesium stearate 2.0 mg TOTAL WEIGHT 200 mg B) ELABORATION OF TALBETS BY DIRECT COMPRESSION EXAMPLE 3

It is prepared tablets of continuos and/or controlled release containing 400 mg of flutamide as an active principle.

The composition of the tablet is the following one:

Flutamide Anionic copolymer 400 mg 60 mg Sodium carboxymethyl cellulose 5 mg AvicelpHA01 Talcum U.S.P. Aerosil 200 Magnesium stearate TOTALWEIGHT mg 20 mg 3 mg 2 mg 580 mg Elaboration:

a) SIEVING, it is sieved all the powders by a sieve no. 20 or 40.

b) MINING, it is mixed in a mixer of V, double or similar type, 40 gr of flutamide, 6 gr of anionic copolymer, 0.5 gr of carboxymethyl cellulose and 9 gr of Avicel during 30 minutes.

In other mixer, it is mixed 2 gr of talcum and 0.3 gr ofAerosil 200 during 20 minutes. Afterwards, it is mixed both mixing during 15 minutes, adding 0.2 gr of magnesium z stearate and it is mixed during 5 minutes.

c) COMPRESSION, it is compressed this mixing in a rotative compressor with adecuate punches to mantain the specified weights.

Finally, it is controlled the average weight, the flutamide valuation, the dissolution test, the hardness and the aspect.

EXAMPLE4

It is prepared tablets of continuous and/or controlled releaseof 160 mgof flutamide following the method of the example 3.

The composition of the resulting tablet in the following one:

Flutamide Anionic copolymer Sodium carboxymethyl cellulose AvicelpH:101 Talcum Aerosil 200 Magnesium stearate TOTALWEIGHT EXAMPLES mg 32 mg 2mg 36 mg 8mg 1.2 ing 0.8 mg 240 mg It has been also prepared tablets of continuous and/or controlled relaese using gelatinized com starch. To do it, it weighted 16 gr of flutamide, 1. 6 gr of anionic copolymer, and 0.4 gr of gelatinized corn starch. It sieved in one sieve of no. 20 and they have been mixed during 30 minutes in an adectiate mixer. Afterwards it has been added 3.5 gr Avicel pH:101 and it has been mixed during 30 minutes. Afterwards, it has been added 0. 5 gr of talcum, 0,.1 gr of Aerosil 200 and 0.1 gr of magnesioum stearate, mixing them in a good way during 10 minutes before of the.compression of the mixer in a rotative compressor. Finally, it has been controlled the valuation of the flutamide, the aspect, the hardness and the dissolution test.

Although in the examples it has been indicated only particularways of carryingout the invention obviously any expert in htis technic could prepare any other pharmaceutical form containing different concentrating of flutamide and using the appropiate excipients and varying appropiately the quantities of them.

Once described the purpose of this invention it is said that what is new is what it is mentioned in the

Claims

1. A process to obtain a pharmaceutical form of continuous and/or controlled release of flutamide specified because it include the mixing of flutamide and the other accepted pharmaceutical transmisors and/or excipients with a redarding element contiotuted by an anionic copolymer composed by methacrylic acid and methyl methacrylate of structural form CH CH 3 1 3 -CH 2 =0 C=0 H U I, n only or in combination with other accepted pharmaceutical retarding agents.

2. A process according the claim 1, specified bexause the relation of the carboxyl groups of the anionic copolymer is L2.

3) A process according to the claim 1, specified because the pharmaceutical form is a tablet of continuous and/or controlled release.

4) A process according to claim 3, specified because the mentioned tablet is obtained by granulating.

5) A process according to claim 3, specified because the mentioned tablet is obtained by direct compression.

6) A process according to claim 3, specified because the tablet contains a quantity of flutamide between 60-80 % in weight of the tablet, and a quantity of retarding element between 6-14 % in weight of the tablet.

7) A pharmaceutical form of continuous and/or controlled release of flutamide, specified because it includes an appropiate quantity of a retarding component contituted by an anionic copolymer constituted by methacrylic acid and methyl methacrylate, only or in combination with other accepted pharmaceutical retarding agent.

8) A pharmaceutical form according to the claim 7, specified because the proportion of carboxyl groups in the mentioned anionic copolymer is 1:1 9) A pharmaceutical for according to the claim 7, specified because it is a continuous and/or controlled release.

10) A pharmaceutical form according to the claim 9, specified because it includes a quantity of flutamide between 60 - 80 % in weight of the tablet and a quantity of retarding element between 6 - 14 % in weight of the tablet.

11) A pharmaceutical form according to the claim 7, specified because the release of flutamide is done a gradual way and varies from aproximately 32.5 % at 30 minutes, to apro)dmately 90.30 % at 10 hours, in a medium equivalent to the one provided by the intestinal juices.

12) Amethod to determine the dosage of flutamide in a tabletof continuous and/or controlled of flutamide specified because it includes aprevious axtraction with an organic solvent, to subject to a high pression liquid chromatografy (HPLC) the resultant solution and to compare the obtained curve with a master curve of a known flutamide concentration.

13) A method according to the claim 12, specified because the organic solvent in an alkanol, preferably methanol.

I 2222947 14)A method to determine the bioavailability and the quantity of flutamide and its metabolite in plasma, released by a tablet of continuous and/or controlled release of flutamide. specified because it includes the extraction of a plasma extraction of a treated patient, to do an extraction with an organic dissolvent, to do a high pression liquid chromatogrphy on the resultant dissolution and to compare it with a master curve.

15) A method according to claim 14, specified because the organic solvent is an alkanol, preferably methanol.

16) A method to treat the prostate hyperplasia and/or of advanced prostate carcinoma that includes the administration to a patient a quantity therapeutically efficient in a pharmaceutical form of continuous and/or controlled release of flutamide according to the claim 7.

17) A method according to the claim 16, where the pharamceutical form is a tablet of continous and/or controlled release.

2 10 Amendments to the claims have been filed as follows 1. A process to obtain a pharmaceutical form of continuous and/or controlled release of flutamide specified because it include the mixing of flutamide and the other accepted pharmaceutical transmisors and/or excipients with a redarding element contiotuted by an anionic copolymer composed by methacrylic acid and methyl methacrylate of structural form CH CH 3 1 3 -CH A-CH,-C2 4. 1 =0 C=U 6 10CH only or in combination with other accepted pharmaccutical retarding agents.

i -12(- 7) A pharmaceutical form of continuous and/or controlled release of flutamide. specified because it includes an appropiate quantity of a retarding component contituted by an anionic copolymer constituted by methacrylic acid and methyl methacrylate. only or in combination with other accepted pharmaceutical retarding agent.

8) A pharmaceutical form according to the claim 7, specified because the proportion of carboxyl groups in the mentioned anionic copolymer is 12.

9) A pharmaceutical for according to the claim 7, specified because it is a continuous and/or controlled release.

11) A pharmaceutical form according to the claim 7, specified because the release of flutamide is done a gradual way and varies from apro3dmately 32-5 % at 30 minutes, to aprotmately 90.30 % at 10 hours, in a medium equivalent to the one provided by the intestinal juices.

12) A method to determine the dosage of flutamide in a tablet of continuous and/or controlled of flutamide specified because it includes aprevious axtraction with an organic solvent, to subject to a high pression liquid chromatografy (HPLC) the resultant solution and to compare the obtained curve with a master curve of a known flutamide concentration.

2 2 22-9 4 7 -2121- 14)A method to determine the bioavailability and the quantity of flutamide and its metabolite in plasma, released by a tablet of continuous and/or controlled release of flutamide. specified because it includes the extraction of a plasma extraction of a treated patien to do an extraction with an organic dissolvent, to do a high pression liquid chromatogrphy on the resultant dissolution and to compare it with a master curve.

15) A method a=rding to claim 14, specified because the organic solvent is an alkanol, preferably methanol.

16. A pharmaceutical form according to the claim 7 for treating prostate hyperplasia and/or of advanced prostate carcinoma.

17. A pharmaceutical form acording to the claim 16, where the phar#maceutical form is a tablet of continuous and/or controlled release.

Published 1990 at The Patent Office.State House, 66"71 MghHolborn, LondonWClR4TP. Further copies maybe obtainedfrom The PatentOffice. Sales Branch, St Mary Cray, Orpington. Kent BR5 3PM. Printed by Multiplex techniques ltd, St Mary Cray, Kent. Con. 1/87 1