IE53393B1 - The use of an aromatase-inhibitor for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of prostatic hyperplasia - Google Patents

Description

The present invention ia concerned with the use of a compound for the manufacture of a medicament for the prophylaxis and/or treatment by therapy of prostatic hyperplasia. j Prostatic hyperplasia involves a benign enlargement of the prostate glands which starts in the so-called inner prostate gland. Discomfort can be attributed primarily to the obstructions of the urethra that occur. Voiding of the bladder is impeded and residual urire is retained. Without surgical treatment uraemia may occur.

Up to now it has been almost impossible to treat this very freguent disorder in older men using medicaments. The phyto-preparations used for this purpose, such as, for example, β-sitosterin, mixtures of various plant extracts and combinations of plant extracts with the neurotropic spasmolysant azoniaspirochloride have proved ineffective in a one year study. Although the patients under therapy experienced an improvement in the micturition symptom, a regression of the hyperplastic prostate gland was not achieved.

Hormones too find application in the treatment of prostatic hyperplasia; of these substances the depot gestagen gestonorone caproate should be given especial mention. Compared with the phyto-preparations, an improved action is obtained with gestonorone eaproate. The prolonged duration of micturition before the treatment is distinctly shortened and the maximum flow value (flow of writ» per unit of ti··) io improved. A distinct reduction 4a the sise of tho adenoma cannot, however, bo detected in this esse either· United States Patent Specification Mo. 3,425,507 daecrlbee the treetnont of proetetic hypertrophy with the gestagenlcally end aatiandrogenlcally active esters of6-chlero-17-hydroxy-ls,2a-aethylene-pregna-4,6-dlene?3O-dlone (cyproteroae eetere). However, it has been S?®und that even under this treat sent, only a partial re1© greesion of the hyperplasia occurs.

“German Offenlegungaeehrlft Mo. 28 17 157 proposes the ess of antioestrogens in combination with antiandrogenleally active substances for the prophylaxis end therapy of proetetic hyperplasia. She use of antloestrogena la passible, however, only in a specific dosage range elnce at relatively high doses antloestrogena too act agonisti@©lly (®s oeatrogens).

Proetetic hyperplasia involves a benign enlargement @f the prostate gland, in which the interstice (stroma) 2© sai. the epithelium participate to a varying degree. A shifting of the oestrogen/androgen ratio in favour of the ©estrogens nay be regarded inter sila as the cause.

Wirioua investigations have shown that in older men the ©oncentrations of serum testosterone fall off; at the §5 ease tine the proportion of SHBG (sex hormone binding glebnlin, specific transport protein for steroids) in©roaaes, eo that the biological availability of androgens decreases «till further.

The oestrogens preeent ia sen originate predominantly from the peripheral aromatisation of androgenio horaonee and not froa teetioul&r bioeynthseie (B.U. Schvelkert: Befunde sum indrogenmetabollsnus ia 'dn&rogenlslerungeerecheiaungen bsi der Trau’, editor· s J. Hammsratein, U. Lachnit-Pixson, P. Baumann and 9. Plevig, pages 42 50, Bxcerpta Medica (1979), Amsterdam, Oxford, Princeton; MacDonald, P.C., Rombaut, R.P. and P.K. Siiteri (1967): Plasma precursors of estrogen. I. Bxtsnt of conversion of plasma A^-androstsnedions to estrone in normal sales and nonprsgnant noraal, castrate and adrenalactoaleed females. J. Clin. Rndocrlnol. Metab. 27, 1105 - 1111; Weinstein, H.I., Keich. R.P., Jenner, M.R., Kaplan, 3.1. and M.M.

Grumbach (1974): Secretion of unconjugated androgens and estrogens by the normal and abnormal testis before and after human chorionic gonadotropin. J. Clin. Invest. 55, 1 - 6).

It has also been found that oestrogens are formed by the aromatisation of androgens also in the prostate gland itself and it has been established that fibroblast cultures from human prostatic hyperplasia tissue aromatise testosterone to form oestrogens sore strongly than fibroblast cultures originating from healthy prostate tissue (Β.Π.

Schvelkert (1979): Conversion of androstenedlone to estrone in human fibroblasts cultured from prostate, genital and nongenital skin. Bora. Metab. Res. 11, 655 - 640 - 5 Sohweikert, B.U., Bela, H.J. and P.B. SchrOdsr: Androgen metabolism In flbroblasta from human benign proatatlc hyperplasia, proatatlc carcinoma and nonganltal akin in 'Steroid receptors, metabolism and proatatic cancer'. Iditora: P.H. SchrBdar and H.J. da Voogt, pages 126 - 155, Bxcerpta Medics (1980), International Congress Sarles Bo. 494, Amsterdam, Oxford, Princeton], Since the prostate gland of non possesses oestrogen receptors and the interstice (stroma) ie a target organ for oestrogens, the sestrogens bring about the stiaula-. tion of the fibromuscular tissue· Prom this it follows that, in humane, proatatlc hyperplasia le predominantly a disorder of the fibromuscular interstice (stroma) stimulated by oestrogens.

These findings are also supported by investigations carried out on dogs. It has been possible to show that oestrogen treatment leads to a stimulation of the interstice whereas androgen treatment leads to a stimulation of the glandular epithelium (parenchyma) [Tuan, U.V., Sehflring, B., Senge, Th,, Beumann, P., Schweikert, B.U. and B.P. Bohr (1981): Morphometric analysis of prostates in castrated dogs after treatment with androsfenediol, estradiol and cyproterone acetate, Invest. Urol. 18: 289 - 292].

—Also in autoradiographic studies on human prostatic hyperplasia tissue it has been possible to show that it is only ths glandular epithelium (parenchyma) that is a tar53393 “ get organ for androgen·, and not the interstice. It has also been found that fibroblast cultures from human prostatic hyperplasia tissue scomatise testosterone to form oestrogens more strongly than fibroblast cultures originating from healthy prostate tissue.

The aim upon which the present invention is based has been to develop an agent for men that leads to a regression of the fibromuscular part of the prostate gland.

This aim is achieved by preventing the formation of biologically active oestrogens by administering aromatase-inhibitors. The stimulation of the fibromuscular tissue is thereby prevented and regression results accompanied by a decrease in size.

This brings about the desired improvement in the clinical symptoms (micturition discomfort).

The present invention accordingly provides the use for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of prostatic hyperplasia, of an aromatase-inhibitor free of clinically significant oestrogenic or other hormonal action apart from its action on the aromatisation.

Suitable for use according to the present invention are all substances that act as aromatase25 inhibitors, that is to say that come into consideration as a substrate for the aromatase, without possessing oestrogenic or other hormonal actions in addition to their action on the aromatisation, for example - 7 testolactone (17a-oxa-D-homo-androata-l,«-diene-3,17dione).

There may also be mentioned as the aromataseinhibitor, for example, androsta-4,6-diene-3,17-dione, androsta-4,6-dien-17g-ol-3-one acetate, androsta-1,4,6,-triene-3,17-dione, androst-4-ene-19-chloro-3,17-dione, and androst-4-ene-3,6,17-trione, and also androst-4-en-4-ol-3,17-dione and esters thereof, for example the acetate, heptanoate, dodecanoate, hemisuccinate and benzoate.

In patients with decompensated benign prostatic hyperplasia (stage III), spontaneous micturition is no longer possible (urine retention). These patients are given a suprapubic vesical fistula catheter by means of suprepubic vesical paracentesis under local anaesthesia. The vesical fistula catheter therefore has 2 functions: 1. If urine retention continues, the bladder is emptied via the catheter; when the urinary bladder is full, the patient can open and close the fistula catheter by himself. 2. The functional effectiveness of an initiated therapy is indicated by the fact that the patient can again urinate spontaneously, since the vesical fistula catheter - β does not Interfere with spontaneous micturition. it the same time the patient can, on re-occurrence of spontaneous micturition, check the residual amounts of urine after each micturition hy means of the vesical fistula catheter.

The results of a testolaotone treatment (200 mg per daily) of 10 patients having benign proatatic hyperplasia (stage 111) are summarised in Table 1 below. . 9 .

Bosults of a testolsetono treatment with 200 ag daily air 2jj in the case of patients having benign prostate hyperplasia, atags XII a) Spontaneous micturition and siss of prostate gland a·rial no. Initials sgs duration of therapy (months) until spontaneous nicturition size of tho prostate gland - la grass initial after 8 months 1 J.O. 81 3 40 10 2 V.V. 77 4 80 20 3 O.L. 79 2 40 25 4 O.S. 81 4 70 25 5 V.S. 79 2 50 40 6 B.B. 69 5 50 40 7 H.M. 61 2 40 25 8 K.H. 73 4 40 20 9 B.H. 59 3 50 20 10 K.O. 75 4 60 30 z 73.40 3.30 52.00*) 25.50*) 3.D. 7.99 1.06 13.98 9.26 *) p <^0.001 -10 b) Oroflow-meaeureaent aerial i no. nitlain r age iroflov paraaetera (after 8 eonthe) residual urine (nl) sax. flow (al/aeo.) t (aee.) Biot. ▼ol. (ol5 1 J.O. 1 81 0 10 21 150 2 H.V. | 77 0 11 60 300 X ✓ O.L. 79 0 13 32 190 4 D.S. 1 81 0 21 40 300 5 4.3. 79 20 9 33 200 6 F.B. 1 69 50 6 60 180 7 H.H. 1 61 0 16 78 540 8 K.H. 73 20 13 62 480 9 B.H. 159 0 25 15 210 10 K.&. 175 0 14 65 450 X |73.4C 13.80 46.60 300.00 S.D. | 7.95 ) 5.67 21.13 141.26 - 11 In the case of the 10 patients studied, the average duration of therapy until the commencement of spontaneous micturition was 3.3 months (+ 1.1 months). After 8 months’ therapy 7 out of the 10 patients were able to urinate without leaving residual urine. In the case of 2 patients the residual urine was 20 ml in each case and in the case of 1 patient it was 50 ml. The urine flow parameters measured by s uroflowmeter gave on average a maximum flow rate of 13.8 ml/sec. (limit value: 6 to 25 ml/sec.) with an average micturition time of 46.6 seconds and an average micturition volume of 300 ml [see Table 1 b)].

The size of the prostate gland estimated by digito/rectal examination indicated a reduction in the size of the prostate gland of, on average, approximately half after 8 months* therapy. This should be qualified by mentioning that the subjective estimation of the volume of the prostate gland, even with great experience, is to be regarded only as a relative parameter.

The daily dose for male human beings of the aromatase-inhibitor when used in accordance with the present invention is 10 mg to 400 mg, preferably 50 mg to 250 mg, of testolactone (17a-oxa-D-homo-androsta-l,4diene-3,17-dione) or a biologically equivalent amount of another aromatase-inhibitor. Another aromataseinhibitor may be a single aromatase-inhibitor or a combination of 2 or more aromatase-inhibitors, one of which may, if desired, be testolactone. - 12 The medicament containing the aromatase-inhibitor is preferably administered orally but may also be administered parenterally, especially intramuscularly.

The medicament may be in a form suitable for oral 5 or parenteral administration and/or may be in unit dosage form.

The aromatase-inhibitor used according to the present invention may be processed by methods known per se into the usual forms of administration together with, for example, the additives, carrier substances and/or taste correctives customarily used in galenical pharmacy.

For the preferred oral administration there come into consideration, more especially, tablets, dragees, capsules, pills, suspensions or solutions.

For parenteral, especially intramuscular, administration, oily solutions are suitable, for example sesame oil or castor oil solutions.

Solubilizers, for example benzyl benzoate or benzyl alcohol, may be added to increase solubility. The oily solutions may, if desired, be stored in ampoules.

For use according to the present invention, the aromatase-inhibitor may be made up in the form of a unit dosage preparation containing in each dosage unit the daily amount of the aromatase-inhibitor required for the method of prophylaxis and/or of treatment by therapy of prostatic hyperplasia.

The unit dosage preparations formulated as indicated - 15 above contain per dosage unit, when in a form suitable for oral administration, preferably from 10 mg to 250 mg and, when in a fora suitable for parenteral administration, preferably from 20 mg to 200 mg of testolactone, or the biologically equivalent amount in each ease of another aromataseinhibitor.

The following Bxamplee illustrate the invention.

The Sxamples describe preparations aultable for use according to the present invention.

Example 1 Composition of a tablet .0 mg of 17a-oxa-D-homo-androsta-l,4-diene-3,17-dione (testolactone) 130.5 mg ef lactose 69.5 mg of maize starch 2.5 mg of poly-K-vinylpyrrolidone 25 2.0 mg of Aeroail (Trade Mark) 0.5 ax of magnesium stearate 225.0 mg total weight of the tablet, which was manufactured in the usual manner on a tablet press.

Example 2 Composition of a tablet 50.0 mg of l7a-oxa-D-homo-androeta-l,4-dlene-3,17-dione (teetolactone) 115.5 mg of lactose 54.5 mg of maize etarch - 14 2.5 ng of poly-H-vinylpyrrolldone 25 2.0 ag of Aerosil (Trade Mark) 0.5 as of aagneeiua stearate 225.0 ag total weight of the tablet, which waa aanu5 factored In the usual Banner on a tablet press.

Bxamole 5 Composition of an ollr aolutlon 50.0 ag of 17a-oxa-D-homo-androata-l,4-diene-3,17-dione 10 (testolactone/ 378.4 mg of castor oil 643.6 ag of benzyl benzoate 1072.0 ag 1 al solution The solution was introduced Into an ampoule and sterilized

Claims (7)

1. The use for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of prostatic hyperplasia, of an aromatase-inhibitor free of clinically

2. The use es claimed in claim 1, of the arom.ataselnhifcitor testolactone.

3. The use es claimed in claim 1, of the aromatase10 inhibitor androsta-4,6-diene-3,17-dione, androsta-4,6-dien17f-ol-3-one acetate, endroste-1,4,6-triene-3,17-dione, androst-4-ene-19-ehlore-3,17-cicne cr andrcst-4-ene-3,6,17tnone .

4. The use as claimed m claim l,cf the arometase15 inhibitor androst-4-er.-4-cl-3,1 7-dicne cr ar. ester thereof. 5. 13. The use of an aromatase-inhibitor as claimed in claim 12, wherein the medicament is m a form suitable for intramuscular administration. 14. The use of an aromatase-inhibitor as claimed in claim 12 or 13, wherein the medicament is m the form of an oily 10 solution. 15. The use of an aromatase-inhibitor as claimed ir. claim 14, wherein the oily solution is contained in ar. ampoule. 16. The use of ar. aromatase-inhibitor as claimed ir. any one cf claims 12 to 15, wherein the medicament is m the 15 form cf a unit dcsece preparation suitable for parenteral administration, each dosage unit containing ar. amount of the aromatase-inhibitor that is biologically equivalent to 20 mg to 200 mg cf testolectone. tially as described in any or.e of Examples 1 to 3 herein. 5 of testolactor.e or a biologically equivalent amount of another aromatase-inhibitor. 8. The use of an aromatase-inhibitor as claimed in any one cf claims 1 to 7, wherein the medicament is in the form of a unit dosage preparation containing m each 10 dosage unit the daily amount of the aromatase-inhibitor required for the treatment. 9. The use of an aromatase-inhibitor as claimed m any one of claims 1 to 8, wherein the medicament is in a form suitable for oral administration. 15 10. The use of an aromatase-inhibitor as claimed in claim 9, wherein the medicament is in the form of a tablet, dragee, capsule, pill, suspension or solution. 11. The use of an aromatase-inhibitor as claimed in claim 9 or 10, wherein the medicament is in the form of a unit 20 dosage preparation suitable for oral administration, each dosage unit containing an amount of ar. aromatase-inhibitor that is biologically eouivalent to 10 mg to 250 ng of testolectone. 12. The use of en aromatase-inhibitor as claimed m any one of claims 1 to 8, wherein the medicament is m a form suitable for parenteral administration.

5. The use as claimed m claim 4, wherein the ester is the acetate, heptanoate, docecanoate, hemisuccinate or benzoate. 20 5 significant oestrogenic or other hormonal action apart from its action on the aromatisation.

6. The use cf an eromatese-inhibitor es claimed m anyone of claims 1 tc 5, wherein the treatment uses daily S3393 - Ife10 mg to 400 mg of testolectcne or e biologically equivalent amount of another aromatase-inhibitor. 7. The use of an aromatase-inhibitor as claimed in claim 6, wherein the treatment uses daily 50 mg to 250 mg

7. ,7. The use cf an aromatase-inhibitor as claimed in claim 1, wherein the medicament has a composition substan20