AP497A

AP497A - Novel subcutaneous implants based on nomegestrol derivatives and the processes for their production.

Info

Publication number: AP497A
Application number: APAP/P/1993/000576A
Authority: AP
Inventors: Michel Lanquetin; Jean-Louis Thomas; Jacques Paris; Elsimar Coutinho
Original assignee: Laboratoire Theramex
Priority date: 1992-09-21
Filing date: 1993-09-21
Publication date: 1996-05-28
Also published as: BR9305642A; RU2120797C1; US5565443A; DZ1717A1; NO941900D0; KR100255700B1; SK54694A3; CA2122827A1; EP0613372A1; BG62317B1; CN1094284A; WO1994006437A1; RO115783B1; FR2695826B1; CZ116494A3; ATE198275T1; CZ284806B6; HUT67044A; EP0613372B1; JPH08506318A

Abstract

There is provided a novel subcutaneous implant containing an effective

Description

NOVEL SUBCUTANEOUS IMPLANTS BASED ON NOMEGESTROL DERIVATIVES

AND THE PROCESSES FOR THEIR PRODUCTION

AP.00497

This invention relates to novel subcutaneous implants endowed with progestative action and the processes for their production.

It has more particularly as a subject matter novel subcutaneous implants intended to insure protracted contraception.

( Specifically it has as subject matter subcutaneous implants containing an effective amount of a derivative of 3-substituted 6-methyl 17O-0R, 20-oxo 19-nor pregna

4,6-dien selected from the group consisting of

a) 3,20-dioxo 6-methyl 17a-0R₁ 19-nor pregna 4,6-diens of general formula I

carbon atoms

AP/P/ »3 / 0 0 5 7 6 wherein R_x is a hydrogen, or the acyl moiety of an organic aliphatic, aromatic or cyclanic carboxylic acid having from 2 to 16

wherein R_x has the above-given definitions

19-nor pregna (Π)

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X 73907047 CBB1NET SEF1B and R_} Is a hydrogen, llie acyl moieiy ol a carboxylic acid, or an alkyl radical having from 1 lu 8 carbon atoms and

c) the 3-R₃R₄ 6-methyl 17<<-OR_l 20-oxo 19-nor pregna 4,6-diens of general

wherein R_x is defined as above

Rj and R₄ together torn either an oxinido grouping oi formula -N-O-R_swherein R_s is a hydrogen, a lower alkyl or a carboxyalkyl group or an alkyleuedioxy grouping which may be substituted or each are a lover alkoxy radical, in admixture or conjunction with a carrier and with a biologically acceptable diluent According to another aspect of the invention there is provided a method of making an implant which consists in that a hollow tube of polymeric material having an internal channel, is cut at a length of between 20 and 50 mm, in that the internal channel is filled with an effective amount of a composition as described above, then the ends of the tube are sealed with a specific glue and the tube is sterilized by physical means.

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According to a further aspect of the invention there is provided a method of contraception in a woman which consists of implanting in the subcutaneous tissues, a subcutaneous implant containing a 3-substituted 6-methyl 17<£-OR^ 19-nor pregna 4,6-dien in which the substituents are as defined above.

The implants according to this inventions are made of polymeric materials (hydrophobic, hydrophilic or biodegradable) used as vectors I of pharmacologically-actlve compounds previously included In the formulae I, Il or III. The carrier material may be a biocompatible and sterilizable polymer selected from the group consisting of hydroxyethyl polymethacrylates, polycaprolactones, polylacticpolyglycolic acid copolymer, and polydimethyl siloxanesft*^

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AP.00497

- 2A The inplants namely are oi the container type or of the matrix type.

Among the implants which use hydrophobic materials it may be cited :

the Inplants of container type prepared from polydimethyl slloxanes such as for example SILASTIC produced by the company Dov Corning. This kind of implant is shown in the form of a tube having an external diameter comprised between 2 and 4 mm and having a thickness of about 0,4 mm. The portions of tubing are cut at the selected lengths as a function of the amount of nor pregnadienic compound

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S 23907047 CHBINEI QEF[B which is desirably incorporated. The ends of these portions of tube are closed using a glue of medical quality also sold by the company Dow Corning and which belongs to the group of silicones RTV (Boo* Temperature Vulcanizing).

The aaount of nor pregnadienic compound of formulae I, II or III incorporated in the portion of tube ranges from 30 to 80 mg and preferably from 35 to 65 mg. This content of active ingredient is namely determined by the granulometric properties of the active ingredient which may be mlcronlzed or mlcrocrlstalllzed and by the physico-chemical characteristics (molecular weight, solubility, dlffusibllity, partition index). The way of in corporation of the active ingredient may be done either in the solid state or dispersed In a biologically acceptable and inert carrier.

The manner of preparation and Isolating of the mierocrystellized forms of the compounds of this invention have been already described in the french patent application 2.668.945 in the name of this applicant.

- implants of the container type produced from ethylene/vlnyl acetate copolymers such as for example the material sold under the Trade Name ELVAX'*’ MD 40 by the company DUPONT de NEMOURS.

This kind of implant has already been utilized for the intra uterine device Progestasert'** made by Alza, but contrarlly to Progestasert in the case of the implants of this invention, the active Ingredient is Introduced in a solid fora.

- Implants of the matrix type, produced from polydimethyl slloxanes. This kind of implant has already been used in the men (Nash, Robertson and cowork -Contraception 18 (1978) p.367). This Implant of the matrix type namely presents the inconvenient of e high rate of release of the active ingredient. In order to compensate this disadvantage, the implants according to this invention have been produced in Introducing one of the derivatives according to the formulae I, II or III suspended in a hydrophilic liquid in vhlch the to r-.

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AP . 0 0 4 9 7 active ingredient is insoluble.

This suspension is admixed to the poly dimethyl siloxanes then the vhole mass is cross-linked before to proceed to the extrusion of the elastomer in the form of a cylindrical thread having the choosen measures. This process allows this obtention of a release kinetic of zero order and no longer as a function of the square root of time such es the cited matrix by Nash and co-workers.

- implants of the matrix type produced fro· ethylene-vinyl acetate copolymers. In this case the implant is prepared by caeting. Due to Its monolithic structure, this implant releases the active ingredient along a kinetic of the type square root of the time. The partial coating using a membran which serves to control the release from the matrix, may be realized either with an EVA polymer having a lower concentration of vinyl acetate or in Introducing the matrix in a tube of polydimethyl siloxane (type SILASTIC) to obtain release curves of zero order.

Among the. implants using hydrophilic materials it may be cited t implants of matrix type produced from hydroxyethyl polymethacrylates such as for example HYDRON^1Bl manufactured by the company HYDRON HED SCIENCES.

This kind of Implant is produced in polymerizing in alcohol followed by a cross-linking by means of ethylene glycol dlmethylacrylate. After desolvatatlon in a mold, it is obtained In the dry form (vitreous) an implant, the kinetics of which 1$ close to zero order. The process of manufacturing is somewhat Inspired from that described by GHXEN Y.V for Norgestomet (J. Pharm. Sci. 65 (1976) 48B).

Among the Implants using biodegradable materials, it may be cited :

AP/P/ 93/00576

Implant of manufactured Pharm. Sci. extruding,

SEP ’93 9:31 the contained type prepared from polycap..olactones following the process disclosed by PITT and Cowork (J. 68 (1979) 1534). These cylindrical implants obtained by contain between 30 and 50 mg of one of the nor

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S 73907047 CABINET BEFIB ·· 5 pregnadienic derivatives ot formulae 1, Il or III suspended In an Inert solvent. They have a dlaaeter of 2,4 ma.

Implants of matrix typ, produced from a polylactic-polyglycollc acid system 50/50 having a molecular velght In tha order of 180.000.

This kind of Implant Includes from 20 to 40X of a norpregnadlenic derivatives of formula 1, Il or III. It is prepared In dissolving tha biodegradable system In methylene chloride to which tha active Ingredient Is added, then in evaporating the solvent.

The Implant according to the invention le put In the right place using a very large needle after local anesthaesla in the subcutaneous tissue of the region of the buttocks or in the forearm In the women. At the end of the treatment or at any time the Implant may be cleared out using a limited surgical intervention under light local anaesthesia.

Among the pharmacologically-active compounds which It Is possible to Insert in the implants according to this invention, it may be cited :

3,20-dioxo 6-methyl 17β-hydroxy 19-nor pregne 4,6-dlen 3,20-dioxo 6-aethyl 17a-acetoxy 19-nor pregna 4,6-dlen

3-hydroxy 6-methyl 17a-acetoxy 20-oxo 19-nor pregna 4,6-dlen 3,17a-dlacetoxy 6-methyl 20-oxo 19-nor pregna 4,6-dlen

3-pivaloyloxy 6-methyl 17a-acetoxy 20-oxo 19-nor pregna 4-6-dlen

3,3-ethylenedioxy 6-methyl 17a-acetoxy 20-oxo 19-nor pregna

4,6-dlen

3-methoxyimino 6-methyl 17a-acetoxy 20-oxo 19-nor pregna 4,6-dlen

3-carboxymethoxylmlno 6-methyl 17a-acetoxy 20-oxo 19-nor pregna

4,6-dlen

3,3-ll,2-(R)(R) diethoxycarbonyl ethylene dioxy] 6-methyl 17«-acetoxy 20-oxo 19-nor pregna 4,6-dlen

The blologJcally-compatible diluents are pharmacologically-lnert powders or vehicles which are progressively degraded by the biological medium and which serve to dilute, to divide or to distribute the active

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- 6 ingredient-Examples of diluents or vehicles are lactose, mannitol, urea, olive oil or peanut oil.

Since about twenty years, a large number of studies have been performed all over the place to ascertain an efficient and long lasting way of contraception. The tests performed with very important injectible suspensions of progestatives (Provera^1R1...) the duration of which extend over about 6 months, frequently joined with significant side-effects.

This is the reason why the experimenters have been coming to the implants in biocompatible polymers which are inserted either in the uterine cavity (PROGESTASERT(R)) or in the subcutaneous tissues (implants).

It thus be experienced implants containing numerous steroidal active ingredients with progestational activity such as norgestrienone, norethindrome or levonorgestrol.

Hower with these products, it has been necessary for obtaining a significantly lenghth of duration, to incorporate a large amount of active ingredient in the implant or better to insert several implants.

Thus Norplant^(R) which contains as active ingredient Norgestrel has a mean duration of activity of five years for a set of 6 implants of Silastic¹*¹. Each implant is filled with 36 mg of crystallized norgestrel, which makes a while charge of 216 mg of active ingredient.

AP/P/ 9 3 / 0 0 5 7 6

Contrarily, this invention requires the insertion of only one implant measuring from 30 to 45 mm according t the kind of implant which has been chosen. This way of implantation is significantly simplified and the implant is more easily accepted. The utilization as active ingredient of a norpregnadienic derivative having the general formulae I, II or III as defined as previously, allows an efficient contraception, saddled with minimal side-effects. This

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- 7 utilization insure the persistence ot periodical bleedings similar to menses.

More precisely several clinical trials have demonstrated that an implant of the container type based on Silastic'*’ as previously described, containing as active ingredient, nomegestrol acetate, exhibits a contraceptive activity for a period of at least 12 months.

A period of 12 months moreover allows a better monitoring of the subjects.

The following examples are Intended to illustrate the invention vithout limiting it.

EXAMPLE I

PREPARATION OF TBB IMPLANTS OF THE CONTAINER TYPE BASED ON SILASTIC' *’ AND CLINICAL RBSULTS

The used material is a tube of dimethyl polysiloxane manufactured by the coapany Dov Corning type 602-265 (catalog reference)

Portions of this tube have been cul at the choosen dimensions. An end of this portion is sealed by an adhesive material suuch as Silastic'*¹type A or type RTV, of medical quality.

The portions are filled with the selected amount of nomegestrol acetate having a controlled granulometric quality. The portions are then closed with the adhesive material. The thus realized implants are thereafter sterilized.

The choice of a definitive size for this Implant made of Silastic'*¹has been realized following preliminary studies performed on volunteers with implants according to example I, of various sizes (20, 30 or 40 mm).

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- 8 - vith those of 20 na lenghth, it occured two pregnancies

- vith those of 30 am, pregnancies also occured

- “ith those of 40 na it did not appear any conception but the percentage of amenorrhea vas high.

The choice has thus been given to an Inplant of 35 na lenghth of filling, containing 50 ± 5 ng of nonegestrol acetate.

This Implant has been the subject natter of a study performed on 100 voaan 1.· 1085 months/vomen. The laplants have bean inserted by subcutaneous vay, after local anaesthesia using e 2Z procaine solution, in tha buttocks area. The subjects were women with genital activity, young (86X vere less than thirty years old), in the course of ovarian activity vith steady cycles.

subjects still take place in this study after one year. 11 subjects have aade expelled the iaplant between 6 and 11 months and only 9 subjects before 6 months.

The reasons for this vithdraval vere :

- 9 cases ι preference tor another method

- 3 cases : occurance of menstrual unpunctualltles

- 2 cases : velght taking

- 3 cases : desire of a pregnancy

- 3 cases : side-effects (vertigos, dysmenorrheas, head aches).

On a total of 1085 months/vomen, only one pregnancy occured providing a Pearl's Index of 1.1X.

Bleeding similar to menses occured in all the vomen but along a rythm which varies iron one to another. Out the 80 women which have had one year of implantation, the mean number of bleeding periods is about 12.24 ± 0.29 vith a mean duration (in days) of 5.24 ± 0.11. Table I gathers the characteristics of this action in the treated women.

AP/P/ 93/00576

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Figure 1. gathers the menstrual abnormalities (amenorrheas, metrorrhagias, spottings) in the first twenty women which have reached one year of implantation.

An amenorrhea occured in 19 out 100 women on the first month, then the occurance decreases with the time (4.7X on the list month). The frequency of the intermonthly bleedings also decreased with the time (from 11X the first cycle to IX on the last month of utilization).

The third Implant of the matrix kind has provided a profile of release somewhat different with a more significant Immediate release.

APiPl 33/00576

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- 10 TABLE I

IMPLANT CONTAINING NOKEGKSTROL ACETATE

Parameters	Mean	S.D
Number of episods of bleeding (*)	12.24	0.29
Mean duration of the bleedings (days)	5.24	0.11
Total number of the days of bleeding	64.19	2.75
Total number of the days of spotting	7.24	1.50
Total number of the days of bleeding and spotting	71.42	3.22
Kean duration between two consecutive bleeding periods (++)	24.51	0.60
Mean duration of the cycles in days (+++)	29.80	0.60
Longest episod of bleeding (in days)	10.70	0.92
Longest Intervall without bleeding (in days)	57.86	4.13

9ZS00/£6 /d'dV (*·) an episod of bleeding is shown with one or several consecutive days of bleeding (with the exception of spotting) (++) an intervall without bleeding is the iniervall between two episods of bleeding (+♦+) a cycle includes an episod of bleeding and an intervall without bleeding

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- 11 Figure 2. shows the variation of body weight (n-77) and of arterial pressure In the women which have beared the Implant for one year. It appears a statiscally-signiflcalive decrease of the systolic pressure (p»0.02). The body weight Increased 1« average of 1.1 kg In a significative manner (p>0.05).

Hormones determination have been carried out In the women having an Implant..

m) punctual determinations of progesterone in the second moiety of the cycle” in twelve subjects and sixty cycles, have first been carried out.

in thirty six cycles, the progesterone level higher to 3 ng/al testifies the occurance of an ovulation. These values are indicated in table 3.

b) In six women, at least weekly samplings for estradiol and progesterone determinations have been carried out during the control cycle for the five or six first cycles of treatment then for the eleventh and tvelvth cycles.

Before Implantation of the said implant, the cycles were always ovulatory with a level of progesterone of 8.1 t 4.2 ng/ml and 10.1 t

3.5 ng/ml respectively at the 18th and at the 24 th day of the cycle. Under treatment with an implant of nomegestrol acetate, the levels of progesterone have been lowered but the difference in comparison with the inclusion rate, did become significative only from the 24 th day of the second cycle (p < 0.05).

in the whole, the lowest levels have been reached in the course of the four first cycles of treatment. At the twelth cycle of treatment the mean values have been normal, respectively 7.1 ± 1.1 and 15.6 ± 4.7 ng/al at the 18th and at the 24th day.

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- 12 As a vhole during the studied thirty eight cycles only one ovulation (progesterone level higher or equal to 5 ng/ml) has been evidenced on 24 cases (64.2X).

In the course of the first cycles of treatment of each of the five patients, the progesterone levels have alvays been lover than 5 ng/ml. In the course of the 12th cycle, the plasmatic levels of progesterone were alvays compatible with the occurance of an ovulation.

Conclusively the implant of 35 mm lenghth containing 48 mg nomegmstrol acetate is an efficient contraceptive for a period of time of at least tvelve months, without causing amenorrheas, which have been known to be heavily accepted by the women.

The tolerancy as well as gynaecologlc as general, has been good.

BXBMPLB II

IMPLANTS OF NOMBGBSTROL ACKTATB OF A MATRIX TTPB

It has been prepared a general mass which forns the elastomer from 70 to 75X of a polyorgano siloxane derivative having silanol end groupings and 24 to 29X silica containing fro· 0.2 in 0.5X of a selected catalyst.

On the other part it has been prepared a mixture containing SOX of one of the active ingredients having the foraulae I, II or III suspended in an hydrophilic solvent and the vhole is lntlmely admixed in 50X of a polydlorgano-s1loxane

The mixture containing the active ingredient has been Incorporated in the composition vhlch forms the elastomer, according to the classical methods known in this art.

The vhole mixture is loaded in an extruder to obtain a continuous extrudate, having a diameter of between 2 and 3 mm, depending on the type of Implant.

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- 13 This extrudate is cross-linked by passing in a ventilated oven at a temperature comprised between 30 and 80°C.

This extrudate is then cut ted at the selected dimensions In order to obtain Implants of tubular appearance containing from 30 to 60 mg of active Ingredient.

For the in vitro testa they have been used implants of an approximative weight of 120 mg containing 25X of active ingredient.

EXAMPLE IH

STUDT ON THE IN VITRO RELEASE OF NOMEGBSTROL ACETATE (3,20-DIOZO

6-MBTHTL 17a»-ACBTOXY 19-NOR PRBGNA 4,6-DIEN) IN SEVERAL IMPLANTS

It has been performed a comparison of the speed of release of the active ingredient which has been incorporated in three different Implants of the matrix type and in one implant of the container type.

These implants have been put In containers containing a knovn amount of water which has previously been filtered and degazed. This medium is changed every 24 hours and the tested lasted over 4 days.

Nomegestrol acetate released in this medium, has been determined by UV spectrophotometry at 296 nm. For each formulation the determination has bean repeated three times. The result are expressed in the form of an average of three determinations and In pg of active ingredient relased per 24 hours. These result are gathered In Tables II and III

Two out three release profile the end of 14 released.

AP/P/ 93/00576

Implants of the matrix type have shown a very similar with a release of 110 pg/day at the steady state. At days about 14X of the active ingredient have been

The release of the active Ingredient in the implant of the container type has been twice lover. In every cases the kinetics were parallel.

AP.00497

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- 14 The third inplant of the natrix type supplied with a profile of release somewhat different with a more iaportani Immediate release.

EXAMPLE IV

PREPARATION OP IMPLANTS OP TH8 MATRIX TTPB BASED ON COPOLYMER BTBTLENB/VINTL ACBTATE (EVA). Results of the release study ”in vitro” of noaegemtrol acetate

The Implants are prepared by grinding and washing of EVA then drying and nixing with noaegestrol acetate in the proportions of 165 ng EVA for 55 ng active ingredient (i.e 3 parts of EVA for one pert of nonegestrol acetate). The alxiure being honogeneous is casted, extrudeted and coapressed at temperatures comprised between 50 and 65*C to produce a cylindrical extrudate of 2.3 mm diameter.

This is cut every 40 am to obtain an implant at the desired lenghth. This one is of a weight dose to 220 mg t 10 ag and contains 55 ag noaegestrol acetate (t 5 mg).

This matrix is ready to be coated with a porous membran in order that the rate of release will be controlled (PDHS or EVA).

Study of tha matrix release

Bach implant is placed in a 20 ml container having an aaount of deslonlzed water (for 24 hours).

This aedlua is replaced every 24 hours and the experience extends depending on the tests, from 15 to 31 days. The content of noaegestrol acetate in the medium is spectrophotoaetrically determined at 296 na.

The results are expressed In pg of active ingredient released per 24 hours. These results are gathered in the figure 4 in comparison with an implant based on BVA-copolymer. They show the regularity of the release of the active ingredient after encapsulation with a porous membran and

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- 15 at the sane tine, the lover release of nomegestrol acetate as a function of the time.

EXAMPLE V

PREPARATION OP THE IMPLANTS OF MATRIX TYPE BASED ON VINYL ACETATB/ZTHYLENE COPOLYMER PLACED UNDER A TUBING OP POLYDIMETHYL SILOXANE

The matrix is prepared according to example II and Introduced In · tubing of polydimethylsiloxane Medical Grade (Silastic) closed on the two ends vith the Silastic glue sterile type A Medical Adhesive ' silicone.

The finished implant Is of 3 mm diameter and consists in a cylindrical shape matrix of vinyl acetate/ethylene copolymer having about 2,3 mm diameter and 40 mm lengj/th.

The total lenghth is 42 mm after closing vith the glue at both ends.

RELEASE study

It is achieved according to the operational process and the dosage f method described at example III.

The results are expressed in ug of Nomegestrol acetate released per 24 hours. These results are figured on figure 5 in comparison with those obtained in a matrix based on EVA only.

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- 16 TABLE II

RELEASE OP NOMEGESTROL ACETATE (In Mg/day) FROM TBS MATRIX TYPE IMPLANTS (P 7571-113-11 : P 7571-113-13 : P 7571-113-15) and fro· container type (THERAMEX's implant) according to this Invention

DAY	Γ7371—113—11	77371-113-13	Γ7571-113-13	THERAMEX's Implant
1	184.4	210.2	186.0	103.4
2	142.9	206.7	146.1	71.4
3	128.4	209.2	132.0	65.5
7	492.6	663.7	490.0	201.5
8	111.9	189.2	116.5	54.4
9	113.7	187.5	114.2	55.5
10	113.0	181.8	113.9	54.5
13	325.8	444.0	344.4	143.0
14	107.9	130.5	109.4	50.1
		TABLE 111
CUMULATED RELEASE	(in yg) OF NOMEGESTROL ACETATE
	PROM TSE MATRIX TYPE	IMPLANTS
(P 7571-113-11 :	P 7571-113-13 : P 7571-113-15)
and from container type implants (THERAMEX's Implants)
	according to this Invention
	77571-113-11	77571-113-13	77571-113-13	THERAMEX's
DAYS				IMPLANT
1	184.4	210.2	186.0	103.4
2	327.3	416.9	332.1	174.8
3	455.7	626.1	464.1	240.3
7	948.3	1289.8	954.1	441.8
8	1060.2	1479.0	1070.6	496.2
9	1173.9	1666.5	1184.8	551.7
10	1286.9	1848.3	1298.7	606.2
13	1612.7	2292.3	1643.1	749.2
14	1720.6	2422.8	1752.5	799.3

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Claims

A subcutaneous implant containing an effective amount of a 3-substituted

6-methyl 170-01^ 20-oxo 19-nor pregna 4,6-dien selected from the group consisting of :

a) 3,20-dioxo 6-methyl 17a-0R₁ 19-nor pregna 4,6-diens of formula I wherein R₂ is a hydrogen or the acyl moiety of an aliphatic, aromatic or cyclanic organic carboxylic acid with from 2 to 16 carbon atoms

b) 3-0R₂ 6-methyl 20-oxo 17a-0R_x 19-nor pregna 4,6-diens of formula II

AP/P/ 93/00576 wherein R₂ has the above-given definitions and R₂ is a hydrogen, the acyl moiety of a carboxylic acid or an alkyl radical having from 1 to 8 carbon atoms and c) 3-R₃R₄ 6-methyl 17a-0R₁ 20-oxo 19-nor pregna 4,6-diens of general formula III

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2.

and Rj and R₄ together form an oximido grouping of formula =N-OR₅where R₅ is a hydrogen, a lower alkyl or a carboxyalkyl grouping or an alkylene dioxy group which optionally is substituted,

C or each of the substituents R₃ and R₄ is a lower alkoxy radical in admixture or conjunction with a physiologically-acceptable diluent in a physiologicaly-tolerable carrier.

2. An implant according to claim 1 wherein the active ingredient is in micronized, microcrystalline or ground form.
3. An implant according to claim 1 or claim 2 wherein the quality of the active ingredient is that obtained according to the process of microcrystallization.
4. An implant according to claims 1 and 2 wherein the carrier material is a

C biocompatible and sterilizable polymer selected from the group consisting of hydroxyethyl polymethacrylates, polycaprolactones, polylactic-polyglycolic acid copolymer, and polydimethyl siloxanes.
5. An implant according to any of the claims 1 to 4 wherein the active ingredient is 3,20-dioxo 6-methyl 17O-0R, 19-nor pregna 4,6-dien in which R·, is the acyl moiety of an organic aliphatic carboxylic acid or a hydrogen.
6. An implant according to claim 5 in which the active ingredient is 3,20-dioxo

6-methyl 17o-hydroxy 19-nor pregna 4,6-dien.

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7. An implant according to claim 5 in which the active ingredient is 3,20-dioxo

6-methyl 17o-acetoxy 19-nor pregna 4,6-dien.
8. An implant according to any of the claims 4 to 7 wherein the polymeric material is dimethylpoly siloxane.
9. An implant according to any of claims 1 to 8 in which the effective amount of 6-methyl 17o-OR, 20-oxo 19-nor pregnadienic derivative, ranges from 30 to 80 mg per subcutaneous implant.

c
10. An implant according to claim 9 in which the content of 6-methyl 17a-0R! 20-oxo 19-nor pregna 4,6-dien ranges from 35 to 65 mg per subcutaneous implant.
11. An implant according to claim 9 in which the content of 6-methyl 17σacetoxy 3,20-dioxo 19-nor pregna 4,6-dien ranges from 35 to 65 mg per subcutaneous implant.
12. An implant according to claim 11 in which the 6-methyl 17o-acetoxy 3,20dioxo 19-nor pregna 4,6-dien derivative is of a special quality such as provided by the process of microcrystallisation.
13. An implant according to any of the claims 1 to 12 in which the implant is made of a portion of polymeric material of cylindric shape, the length of which is comprised between 20 and 50 mm and the diameter of which between 2 and 4 mm.
14. An implant according to any of the claims 1 to 13 in which the implant is made of a portion of polymeric material based on ethylene/vinyl acetate copolymer (EVA) the length of which is comprised between 20 and 50 mm and the diameter of which ranges from 2 to 4 mm.

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15. An implant according to claim 14 which contains from 50 to 80 mg of active ingredient according to claim 1.
16. An implant according to claim 14, in which the carrier is based on ethylene/vinyl acetate copolymer with low concentration of vinyl acetate.
17. An implant according to one of the claims 14 to 16 in which the implant based on ethylene/vinyl acetate copolymer which contains the active ingredient, is introduced in a tubing of poly(dimethylsiloxane) and in which the thus-formed ensemble is closed at both ends by a siliconated glue.
18. A process for producing an implant according to any one of claims 1 to 13 which consists in that a hollow tube of polymeric material having an internal channel, is cut at a length comprised between 20 and 50 mm, in that the internal channel is filled with an effective amount of a derivative according to claim 1 or claim 2 then the ends of the tube are sealed with a specific glue and the tube is sterilized by physical means.