GB2239798A

GB2239798A - Biodegradable injectable microspheres

Info

Publication number: GB2239798A
Application number: GB9024862A
Authority: GB
Inventors: Gerard Cohen; Jean-Luc Dubois
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1989-11-15
Filing date: 1990-11-15
Publication date: 1991-07-17
Anticipated expiration: 2010-11-15
Also published as: FR2654337A1; IT9048470A1; BE1005511A4; IT1242010B; IT9048470A0; ATA231390A; NL9002492A; LU87836A1; DK270990D0; DK270990A; SE9003570L; DE4036425A1; GB9024862D0; GB2239798B; AT400298B; FR2654337B1; CH681691A5; CA2029940A1; SE9003570D0; JPH03294229A

Abstract

Biodegradable microspheres contain a lactic acid and glycolic acid copolymer and an anti-oestrogen or anti-progestomimetic steroid. The microspheres can be formulated with an aqueous or oily vehicle to form an injectable suspension useful as a medicament. With such a medicament the release period of active ingredient can be from about 1 to about 3 months.

Description

BIODEGRADABLE INJECTABLE MICROSPHERES, A PROCESS FOR THEIR PREPARATION AND

INJECTABLE SUSPENSIONS CONTAINING THE SAME The present invention relates to new biodegradable injectable microspheres which can provide a medicament having an anti-oestrogen or antiprogestomimetic activity, a process for their preparation and injectable suspensi-ons containing the same.

It is known that to provide for the release of an active ingredient over a period of time of the order of 1 to 2 months poses a certain number of problems which are not always easy to solve. Such release should be regular and well-controlled with time in order to avoid any overdose of active ingredient. Moreover, the formulation which provides this spreading-out of the activity of the active ingredient in time must be well zolerated and bio- degradab3e, in order not to leave residues which could cause undesirable reactions.

The Applicants have thus been led to research an injectable formulation which seeks to avoid known disadvantages and they have found that microspheres containing a lactic acid and glycolic acid copolymer respond very well within the cont-ext of the present problem. When it is sought to administer an antioestrogen or anti-progestomimetic steroid, the immediate effects of which can be different from the effects shown in a long-term treatment, the microspheres of the invention have the additional advantage of preventing the diversion of the active ingredient from its long-term activity for which it may be prescribed.

Accordingly, the present invention provides microspher...s for providing a medicament having an antioestrogen or anti-progestomimetic activity, which microspheres comprise:

- a lactic acid and glycolic acid copolymer, and - an anti-oestrogen or anti-progestomimetic steroid.

Among the lactic acid and glycolic acid copolymers which may be used in the present invention are those in which the copolymer is a copolymer of D,L-lactic acid and glycolic acid and, more particularly, those containing fror. about 25 to about. 75% of D,L-lactic acid and fror. about 75 IL-o about 25% of glycolic acid.

Among such copolymeis, there are more particularly preferred the copolymers marketed under the Trademark - '756 by the company Boehringer Ingelheim.

RESOMER@ RG, Among the D,L-lactic acid and glycolic acid copolymers there are still more particularly preferred copolymers containing about 50% of D,L-lactic acid and about 50% of glycolic acid.

i Among such copolymers there are quite particularly preferred the copolymers marketed under the Trademark RESOMERCJRG 503, RG 504, RG 505, RG 506 or RG 508 by the company Boehringer Ingelheim. These copolymers offer a range of molecular mass weight (mw) spread between about 40,000 and about 93,000.

These latter polymers which are totally biodegradable and perfectly well tolerated p-trmit a release of act4-ve inaredlent to be obtained which can range over a period of time of about 1 to about 3 months.

In the microspheres of the invention, the antioestrogen or antiprogestomimetic steroid is preferably a 19-nor steroid or 19-nor D- homosteroid substituted in position 11beta and optionally in position 2.

In the present invention, there are more particularly preferred microspheres in which the antiprogestomimetic steroid is a compound corresponding to formula (,A):

1.

R 2 1 0 A B 1 1 is R (,A) - 1 1 1 in which R, represents an organic radical containing from 1 to 18 carbon atoms and optionally one or more heteroatoms, the atom immediately adjacent to the carbon in position 11 being a carbon atom, R2 represents a hydrocarbon radical containing from 1 to 8 carbon atoms, X represents the remainder of a pentagonal or hexagonal ring optionally substituted and optionally carrying an unsaturation, the rings A and B having one of the following structures:

a) - either A and B represent the group:

1 R "" A B 0 R in T.,;hich R' and R", which may be the same or different, tiaving represent a hydrogen atom, or an alkyl radical L from 1 to 4 carbon atoms; b) - or A and B represent the group:

1 Rx".W - Rx representing a hydrogen atom or a group -ORe, in which Re represents a hydrogen atom, an optionally substituted alkyl radical having from 1 to 6 carbon atoms or an acyl radical; c) - or A and B represent the group..

6 A B 0._ as well as the addition salts of the compounds of formula ('A) with acids.

The addition salts with acids of the compounds of formula (,A) can be, for example, the salts formed with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, f ormic, propionic, benzoic, maleic, fumaric, succinic.. tartaric, citiic, oxalic, glyoxylic, aspartic, alkane sulphonic such as methane- or ethane-sulpbonic, arylsulphonic such as benzene- or paratoluene-sulphonic, and arylcarboxylic.

Among the compounds of formula %) for use in the invention there are preferred in particular those in w h ic. h:

- R, contains a heteroatom, preferably nitrogen or sulphur, - R2 represents a methyl or ethyl radical, - X represents the remainder of a ring R 2 1% &1 1 0 R 4 R 3 in which "R2 keeps the same Tmeaning as previously, R3 and R4, which may be the same or different, represent either a hydrogen atom, or an OH, Oalk 4. O-CO-alk-5 radical, alk4 and alk5 representing an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, 0 or a --:-UM2--uti radical, or a -COCH20Coalk6 radical, in which alk6 represents an optionally substituted alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or a CO-CO2H)r CO-CO2-alk.7 radical, in which alk 1 7 represents an alkyl radical containing from 1 to 8 carbon atoms, H NHalk.

1 1 or a -C=0 radical, or a radical, in which alk8 represents an alkyl radical containing from 1 to 8 7 - carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or a -C-=N radical, or R3 and R4 together form a radical:

1 CH3 1 LIC-U-Z1 1 -;-'2 1 in which Z1 represents a hydrogen atom. an alkyl radical cr an acyl radical containing from 1 to 8 carbon atoms and Z2 represents an alkyl radical containing from 1 to 8 carbon atoms and preferably those in which X represehts the remainder of a ring:

R 2 R 3 000 R 4 in WIlic.'i R. keeps the same meaning as previously, Re3 represents an OH radical and R'4 represents an alkynyl or alkenyl radical containing up to 4 carbon atoms.

Among these latter there are quite particularly preferred for use in the invention the following, namely:

17beta-hydroxy-llbeta-[4-(diinethylamino)-phenyl]17alpha- (1-propynyl)estra-4,9-dien-3-one; - i 17beta-hydroxy-llbeta-[4-[(methyl)(1-methylethyl)amino]- phenyl]-17alpha(1-propynyl)-estra-4,9-dien-3one; (Z)-11-beta--[4-(dimethylamino)-phenyl]-17betahydroxy-17alpha-(1propenyl)-estra-4,9-dien-3-one.

Among the ricrospheres of the invention there are also preferred those in which the anti-oestrogen steroid is a compound corresponding to formula (IB):

RA-N-C 1 9 -,\ z RA 0 111\ y \ X R17 R'17 CA B (,B) in w,iich the rings A and B have one of the f ol lowing structures: a) either A and B represent the group:

R2 R'2" ' A: 0 - 9 in which R2 and R'2, which may be the same or different, represent a hydrogen atom or an alkylradical having from 1 to 4 carbon atoms; or b) A and B represent the group:

HO 5:p, A B .. kI R17 and R117 are such that: - either R17 and 'R'17 together form a ketone function, - or R17 is a hydroxyl radical or an acyloxy radical and R117 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, X, Y and Z are such that:

- X represents a methylene radical, an arylene group, a CH2-0 radical or an arylenoxy radical linked to the steroid by a carbon atom, - Y represents a single bond or a saturated or unsaturated, linear or branched aliphatic chain containing from 1 to 18 Qarbon atoms, optionally interrupted by one or more radicals chosen from arylene or oxygen radicals and optionally terminated by an 1 i 1 i 1 - arylene radical, - Z represents a single bond or a CH2-0 radical linked to the Y radical by a carbon atom, it being understood that when Y and Z are a single bond, X does not represent a methylene or CH2-0 radical, RA and RA', which may be the same or different, represent a hydrogen atom, a linear or branched alkyl 4 onally iadical containing from 1 to 8 carbon atoms, opt substituted by an aryl, alkyl or dialkylamino radical or an esterified hydroxy or carboxyl radical, or RA and RA' form, with the nitrogen atom to which they are linked, a saturated or unsaturated heterocycle with 5 or 6 links, optionally containing one or more other heteroatoms chosen f rom oxygen, nitrogen and sulphur atoms and optionally substituted by an alkyl radical having from 1 to 4 carbon atoms, it being understood ti-iat at least one of the substituents RA or RA' is not a hydrogen atom.

Among these latter, there are preferred those in wh ich:

- Z represents a single bond, - R2 and R2 are identical. and represent a hydrogen atom or a methyl radical, - R17 represents a hydroxyl radical, R117 represents a hydrogen atom, an ethynyl radical 11 - or a propynyl radical, - X represents a methylene radical and Y is a saturated linear chain containing froin 5 to 10 carbon atoms, or X represents a phenylene radical and Y is a saturated linear chain containing from 3 to 10 carbon atoms and preferably N-butyl- 4-(3,17beta-dihydroxy-estra-1,3,5 (10)-trien-lllieta- yl)-N-methyl benzeneoctanamide.

The compounds of formula (,A) can thus, for example, be the compounds described in the French Patents Nos. 2,497,807, 2,566,179 and 2,625,505. The compounds of formula (,A) can also be the compounds described in the French Patent No. 2,528,434.

In addition, the compounds of formula (IB)r for example, can be the compounds described in the French Patent Application published under the number 2,643,638.

The invention also provides a process for the preparation of microspheres as defined above, which process c=prises preparing:

an aqueous phase containing an emulsifying agent, and - an organic phase containing an anti-oestrogen or anti- progestomimetic steroid, a lactic acid and glycolic acid copolymer, and a solvent which is nonmiscible with the aqugous phase, adding the organic phase to the aqueous phase under strong agitation in order to obtain an emulsion, evaporating off the i solvent under reduced pressure, filtering off the thusobtained microspheres, and washing and drying them.

The preferred conditions for carrying out the above-described processare as follows: - the phases are prepared simultaneously, - the lactic acid and glycolic acid copolym er is a copolymer of IIPLGA Polylactic Glycolic Acid" type such as a RESOMER\:;/copolymer, - the non-miscible solvent is a solvent which is nonmiscible with the dispersed phase such as chloroform or dichloromethane, - the emulsifying agent is a polyoxy- ethylene sorbitan monooleate, sodium alginate or a polyvinyl alcohol, - the evaporation of the solvent under reduced pressure is advantageously carried out with gentle heating.

When the above-described process is carried out, the copolymers marketed under the Trademark RESOMERkZ/ RG 503, RG 504, EG 505, RG 506 or RG 508 are preferably used in order to obtain microspheres which release the active ingredient over a period of about one month.

Among the previously-mentioned non-miscible solvents, dichloromethane is preferably used.

The emulsifying agent can advantageously be a polyvinyl alcohol such as the product marketed under the Trademark Mowiol(Dby the Hoechst company. This latter can be used at a concentration close to 0.3 w/v.

- 13 The reaction is advantageously carried out at a temperature of between about 5 and about 150C.

In order to carry out the evaporation of the solvent, the operation is done advantageously under reduced pressure, progressively increasing the temperature of the reaction medium. After the evaporation stage, the microspheres can be filtered over sintered glass, washed, and dried in an oven for about 24 hours. Th3 Picrospheres can be sterilized by radiosterilization.

Also included in the present invention is a variant of the preparation process for microspheres as described above, in which process an organic phase is prepared containing:

- an anti-oestrogen or anti-progestomimetic steroid, - a lactic acid and glycolic acid copoymer, and - an organic solvent, then the organic phase is nebulized straightaway in order to obtain the desired microspheres, and they are washed and dried.

In carrying out this process variant, the organic solvent is preferably an organic solvent such as acetone, ethanol, tetrahydrofuran, dichloromethane or chloroform.

Also included as part of the invention are microspheres as prepared using the above-described i process and its variant.

The microspheres which are the subject of the present invention can be used in the long-term treatment of illnesses necessitating a very progressive and continuous release of active ingredient. As indicated above the microspheres are biodegradable and can be administered by injection.

The microspheres containing an anti- progestomimetic steroid can be used, for example, in the treatment of hormonal disorders, in the treatment of endometriosis or in the treatment of hormonedependent tumours.

In the same way, the microspheres containing an anti-oestrogen steroid can be used, for example, to combat disorders due to a hyper-secretion of glucocorticoids and in particular to combat ageing in general and more particularly hypertension, atherosclerosis, os'k--eoporosis, diabetes and obesity, as well as the depression of the immune system and insor.nia.

These products can also be useful in the treatment of certain hormonedependent tumours.

The -microspheres which are the subject of the invention can be administered by sub-cutaneous or intra-muscular route.

Thus, included as part of the invention are - is injectable compositions containing microspheres according to the invention. Such compositions typically suspensions which can be aqueous or oily or based on any other pharmaceutically-acceptable liquid vehicle. The suspensions can advantageously contain from about 20 to about 100 mglml of microspheres in the chosen vehicle. Also, they can be prepared according to the usual methods.

As indicated in the French Patent Application filed by the Applicants on 24 February 1989 under the number 89-02384, the compounds of formula (,B) can be prepared by a process in which a compound of formula (II):

CH20H Y "..I R17 R'17 0 wherein X, Y, R.7 and R1.7 have the meaning already indicated, it being understood that R17 cannot represent a hydroxyl radical, is subjected - either to the action of an oxidizing agent in order to obtain a compound of formula (III):

1 COOH 0 X R17 R17 (III) which is subjected to the action of an agent which allows the carboxyl function to b-s activated, then to -the action of a compound of formula (IV):

RA 1..10, (IV) RA 1 in which RA and RA' have the meaning already indicated in order to obtain a compound of formula (IB) corresponding to the compound of formula (I) in which Z is a single bond and the rings A and B represent the group:

R2 1 R'O) A B in which R 2 and R'2 are a hydrogen atom, - or to a reaction for the introduction of the radical - 17 RA _>N-CO- RA:_1 in order to obtain the compound of formula (Ila) corresponding to a compound of formula (I) in which Z is a methylenoxy radical and the rings A and B have the same meaning as in the compounds of formula (IB), the thus-produced compounds of formulae (Ia) and (Ila) being, if desired, - either subjected to a reducing agent when R17 and R'17 together form a ketone function, or subjected to to an acylation agent when R17 represents a hydroxy function, - or subjected to a saponif ication agent when R17 represents an acyloxy function, - or subjected to an alkylation in position 2, when at least one of the radicals R2 hydrogen atom, - or subjected to an aromatization agent of ring A, then to a saponification agent contrived in order to obtain a compound of formula (Ib) corresponding to the compound of formula (Ia) and a compound of formula (Ilb) corresponding to the compound of formula (Ila) and in which the rings A and B represent the group:

and RI.

,, represents a EO 1 1 1 1 i A 1 B I. 111 18 - the thus-produced compounds of formulae (Ib) and (1 1 b) being, if desired, - either, when R17 and R117 together form a ketone function, subjected to.a. reduction agent or subjected to a metal complex of formula (V):

M-RI17 (V) in which M represents a metal atom and R',-, has the same meaning as above, it being understood that it is not a hydrogen atom, or, when R17 is a hydroxyl radical, are subjected to a selective acylation agent in position 17, - or, when RA or RA' is a hydrogen atom, subjected to an alkylation agent.

19 - The invention will now be described by wa-y-of illustration only with reference to the specificExamples which follow. Example 1: Microspheres of 17beta-hydrolcy.-Ilbeta-r4- (dimethylamino)-phenyll-17alpha-(Ipropynvl)-estra-419dien- 3-one (hereinafter compound A) An organic solution of known viscosity containing 1 g of D,L-lactic acid and glycolic acid copolymer (RESOMERV-/503) in 17 g of dichloromethane and 0.5 g of compound A is introduced into a temperature-contro 1 led reactor at 100C containing 250 ml of an aqueous solution at 0.3% w/w of hydrolyzed polyvinyl alcohol (Mowiol 8/88) maintained at 100C.

The whole is enulsified for 15 minutes under strong agitation (250 rpm). Agitation is maintained (250 rpm) and the temperature i3 raised to 170C for one hour.

While maintaining agitation, the temperature is ra,sed to 220C under redt!ced pressure at 550 mm of Hg for 15 minutes. The pressure is then lowered to 500 mra of 14g for 45 minutes while maintaining the other parameters. Next, the pressure is lowered to 400 Pm. of Hg for 2 hours 30 minutes while maintaining agitation in the temperature-controlled chamber at 220C.

At the end of these cycles, the pressure and temperature are returned to ambient.

The microspheres thus obtained are filtered under i 4 1 1 1 - reduced pressure (filter porosity 3), washed, and dried in an oven under reduced pressure. Example 2: Microspheres of 17beta-hydroxy-libeta[4(dimethylamino)-phenyl]-17alpha-(1-propynyl)-estra-4,9dien- 3-one (hereinafter compound A) operating as in Example 1, but starting with an organic solution containing 1 g of D,L-lactic acid and glycolic acid copolymer (RESOMERV- Y505) in 27 g of dichloromethane and 0.5 g of compound A, m-Icrospheres were obtained containing compound A. Example 3: Microspheres of 17betahydroxy-libeta-[4[(methyl)(1-methylethyl)-amino]-phenyl]-17alpha(1propynyl)-estra-4,9-dien-3-one (hereinafter compound B) operating as in Example 1, but starting with an organic solution containing 1 g of D,L-lactic acid and AS---\ glycolic acid copolymer (RESOMERV-V504) in 17.5 g of dichloromethane and 0.5 g of compound B, microspheres were obtained containing compound B. Examp e_4: M-4cros heres of (Z)-11beta-[4- _ (dipiethylamin-o)-:phep beta-hydroxv-17alpha-(1 y11-17 - -------propenyl)-estra-4,9-dien-.3-one (hereinafter compound C) Operating as in Example 1, but starting with an organic solution containing 1 g of D,L-lactic acid arid /Sh glycolic acid copolymer (RESOMERk,9 506) in 28 g of dichloromethane and 0.75 g of compound C, microspheres were obtained containing compound C.

21 - Example 5: Microspheres of 17beta-hydroxy-llbeta-r4(dimethylamino)phenyll-17alpha-(1-propynyl)-estra-4,9dien- 3-one (hereinafter compound A) g of D,L-lactic acid and glycolic acid copolymer (RESOMER\j-/503), 55 g of methylene chloride and 1.5 g of compound A are introduced into a reactor. The organic solution thus obtained is agitated vigorously and nebulized. The microspheres thus obtained are filteted, washed, and dried in an oven.

Example 6:

An aqueous injectable composition was prepared containing:

- microspheres obtained in Example 1 200 mg - sterile aqueous excipient q.s. for 2 ml Example 7:

An oily injectable composition was prepared taining:

cont - microspheres cbtaired in Example 3 - sterile oily excipient q.s. for........

Pharmacokinetic Study Material and method:

........ 150 -ng 1 2 m female rats were used, divided into 5 groups of 5 animals. One group served as the control.

The rats of the other 4 groups received a single administration of 33 mg of compound A contained in the i i i i 1 1 i 22 - microspheres.

on day 1, each of these 4 groups received a different treatment.

- Group A: microspheres obtained in Example 1 administered by subcutaneous route.

- Group B: microspheres obtained in Example 1 administered by intranuscular route- - Group C: microspheres obtained in Example 2 admin-!.s'--e-,-ed by sub- cutaneous route.

- Group D: microspheres obtained in Example 2 administered by intranuscular route.

Blood samples were taken from the orbicular retro sinus on the following days:

day 1, before administration days 4 - 8 - 12 - 19 - 26.

Compound A was determined in the plasma by U.V. spectro-photometry after extraction and separation by HPLC.

Results:

Compound A was not detected on day 1 before treatment nor in the samples of the control group.

The averages and the typical variation of the averages of the plasma concentrations of compound A of the treated groups from day 4 to day 26 are shown in the following table:

DAYS OF SAMPLE TREATMENT D 1 D 4 D 8 D 12 D 19 D 26 1Group A 1 0.003 10.0551 0.0781 0.101 0.046 0.043 1 1 1 t 1 1 ICONC(M9-1-1)l 0.003 10.0151 0.0181 0.021 1 0.007 1 0.012 Group B 0.000 10.1241 0.1321 0.127 0.039 0.023 g 1 0 000 10 - 008 1 0. 0181 0 - 019 1 0. OOB 1 0 - 002 CONCla 1-11 1 i - i -L- 1 1 1Group C 1 0.000 10.0531 0.0251 0.020 1 0.154 0.063 1CONC(mg.1-1) 1 0.000 10.0051 0.0031 0.004 1 0.013 1 0.016 1Group D 0.000 10.0441 0.0331 0.014 0-073 0.080 1CONC(Mg-1-1)l 0.000 JO.0041 0.0091 0.004 '! 0.011 1 0.008 1 A Conclusion:

The various treatments permit a slow and permanent release of compound A to be obtained which is shown as a pharmacological activity and measurable plasma concentrations for at least 26 days.

1 i 1 1 i i 1 1 1 1 i 24 -

Claims

1. Microspheres fEor providing a medicament having an anti-oestrogen or anti- progestomimetic activity, which microspheres comprise:

- a lactic acid and glycolic acid copolymer, and - an anti-oestrogen or anti-progestoinimeti steroid.

2. Microspheres according to claim 1, wherein the lactic acid and glycolic acid copolymer is a copolymer of D,L-lactic acid and glycolic acid.

3. Microspheres according to claim 1 or claim 2, wherein the copolymer contains from about 25 to about 75% of DL-lactic acid and from about 75 to about 25% of glycolic acid.

4. Microspheres according to claim 3, wherein the copolymer corit&ins about 50% of D,L-lactic acid and about 50% of glycolic acid.

5. Microspheres according to any one of the preceding claims, wherein the molecular mass weight of t copolymer is from about 40,000 to about 93,000.

6. Microspheres according to any one of the preceding claims, wherein the anti-oestrogen or antiprogestomimetic steroid is a 19-nor steroid or 19nor D-homo steroid substituted in position 11beta and optionally in position 2. 7. Microspheres according to claim 6, wherein anti-progestominetic steroid is a compound corresponding to formula (,A):

R 1 2 A B (I A) in which R, represents an organic radical containing from 1 to 18 carbon atoms and optionally one or more heteroatoms, the atom immediately adjacent to the carbon in position 11 being a carbon atom, R2 represents a hydrocarbon radical containing from 1 to 8 carbon atoms, X represents the remainder of a pentagonal or hexagonal ring optionally substituted and optionally carrying an unsaturation, the rings A and B having one of the following structures:

a) - eitnerA and B represent the group:

R 1 5P, R "". A B Ili-11 0 j i 1 i X in which R' and R", which may be same or different, represent a hydrogen atom, or an alkyl radical having from 1 to 4 carbon atoms; b) - or A and B represent the group:

::%P, A 1 B Rx"_ Rx representing a hydrogen atom or a group -ORe, in which Re represents a hydrogen atom, an optionally substituted alkyl radical having from 1 to 6 carbon atoms or an acyl radical; c) - or A and B represent the group:

.6 A B 0 as well as the addition salts of the compounds cf formula (,A) with acids. 8. Microspheres according to claim 7, wherein in the compound of formula (,A), - R, contains a heteroatom, preferably nitrogen or sulphur, - R2 represents a methyl or ethyl radical, - X represents the remainder of a ring R R 3 1%. R 4 1% i i i in which R2 keeps the same meaning as in claim 7, R3 and R4, which may the same or different, represent either a hydrogen atom, or an OH, Oalk4 or O-CO-alk5 radical, alk4 and alk. representing an alkyl radicalcontaining from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, or a 11 -011 radical, or a -COCH 0COalk radical, in -C-CH2 2 6 -ituted alkyl which alk6 represents an optionally subst radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or a CO-CO2H or CO-CO2-alk7 radical, in which alk7 represents an alkyl radical containing from 1 to 8 0 - 28 carbon atoms, H ' NHalk 1 1 8 us. a -C=0 radical, or a -C=0 radical, in which alk 8 represents an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or a -C-=N radical, or R3 and R4 together form a radical:

CH3 MC-0-Z1 1 i;-Z2 in which Z1 represents a hydrogen atom, an alkyl radical or an acyl radical containing from 1 to 8 carbon atoms and Z2 represents an alkyl radical containing from 1 to 8 carbon atoms.

9. Microspheres according to claim 7 or claim 8, wherein in the compound of formula RA), X represents the remainder of a ring:

R 2 R ' -R # 29 - in which R2 keeps the same meaning as in claim 7, R'3 represents an OH radical and W4 represents an alkynyl or alkenyl radical containing up to 4 carbon atoms. 10. Microspheres according to any one of claims 7 to 9, wherein the compound of formula ('A) 's.

17beta-hydroxy-llbeta-[4-(dimethylamino)-phenyl]17alpha- (1-propynyl)estra-4,9-dien-3-one; 17beta-hydroxy-llbeta-[4-[(methyl) (1-methylethyl)amino]-phenyl]- 17a!pha-(!-propynyl)estra-4,9-dien-^)-one; or (Z)-llbeta-[4-(dimethylamino)-phenyl]-17betahydroxy- 17alpha-(1-propenyl)estra-4,9-dien-3-one. 11. Microspheres according to claim 6, wherein the anti-oestrogen steroid is a compound corresponding to formula (,B):

1 i RA-N-IC 0 1 c z RA NII Y (,B) X R17 % W17 CA i in which the rings A and B have one of the following structures: a) either A and B represent the group:

R2 R A B 2 0 in which R2 and R2, which may be the same or different, represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms; or b) A and B represent the group:

5pl.

A 1 B --- k.' ' R17 and R117 are such that: - either R17 and R117 together form a ketone function, - or R17 is a hydroxyl radical or an acyloxy radical and R117 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical having at. most 8 carbon atoms, X, Y and Z are such that:

- X represents a methylene radical, an arylene group, a CH2-0 radical or an arylenoxy radical linked_ to the steroid by a carbon atom, - Y represents a single bond or a saturated nr unsaturated, linear or branched aliphatic chain c,jiitaining from 1 to 18 carbon atoms, optionally interrupted by one or more radicals chosen from arylene or oxygen radicals and optionally terminated by an arylene radical, - Z represents a single bond or a CH2-0 radical linked to the Y radical by a carbon atom, it being understood that when Y and Z are a singe-bond, X does not represent a methylene or CH270 r'ical, al RA and RA', which may be the sane or differei,t, represent a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted by an aryl, alkyl or dialkylamino radical or an esterified hydroxy or carboxyl radical, or RA and RA' form, w - ith the n 1 itrogen atom to which they are linked, a saturated or unsaturated heterocycle with 5 or 6 links, optionally containing one or more other heteroatoms chosen from oxygen, nitrogen and sulphur z it.

1 i 1 1 1 1 i 1 i i i 1 i i atoms and optionally substituted by an alkyl radical having from 1 to 4 carbon atoms, it being understood that at least one of the substituents RA or RA' is not a hydrogen atom.

12. Microspheres according to claim 11, wherein in the compound of formula (%), - Z represents a single bond, - R. and R'2, are identical and represent a hydrogen atDm or a methyl radical, - R17 represents a hydroxyl radical, - R117 represents a hydrogen atom, an ethynyl radical or a propynyl radical, - X represents a methylene radical and Y is a saturated linear chain containing from 5 to 10 carbon atoms, or X represents a phenylene radical and Y is a saturated linear chain containing fror. 3 to 10 carbon atoms.

13. Microspheres according to claim 11 or claim 12, wherein -he compound of formula (,B) is N-butyl-4(3,17beta-dihydroxy-estra-1,3,5(10)-trienlibeta-yl)-Nmethyl benzeneoctanamide.

14. Microspheres according to claim 1 substantially as hereinbefore described specifically.

15. Microspheres substantially as hereinbefore decsribed with reference to any one of the specific Examples.

16. A process for the preparation of microspheres according to claim 1, which process comprises preparing:

- an aqueous phase containing an emulsifying agent, and - an organic phase containing an anti-oestrogen or anti- progestomimetic steroid, a lactic acid and glycolic acid copolymer and a solvent which is nonmiscible with the aqueous phase, adding the organic phase to the aqueous phase under strong agitation in order to t.)btain an emulsion, evaporating off the solvent under reduced pressure, filtering off the thusobtained microspheres and washing and drying them.

17. A process according to claim 16, wherein the lactic acid and glycolic acid copolymer is a copolymer as defined in any one of claims 2 to 5.

18. A process according to claim 16 or claim 17, wherein the non-miscible solvent is chloroform or dichloromethane.

1-9. A process according to any one of claims 16 to 18, wherein the emulsifying agent is a polyoy-y- ethylene sorbitan monooleate, sodium alginate or a polyvinyl alcohol.

20. A process according to any c-ne of claims 16 to 19, wherein the evaporation of the solvent under reduced pressure iscarried out with gentle heating.

21. A process for the preparation of microspheres according to claim 1, wherein an organic phase is 1 29. An injectable suspension according to claim 27 or claim 28, wherein the vehicle comprises water.

30. An injectable suspension according to claim 27 or claim 28, wherein the vehicle cc,mprises an oil.

31. An injectable composition acco-rding to claim 26 substantially as hereinbefore described in Example 6 or Example 7.

Published 1991 at The Patent Oflice. State House. 66/71 High Holborn. London WCIR47P. Further copies maybe obtained from Sales Branch. Unit 6. Nine Mile Point, Cwmfebnfach, Cross Keys, Newport. NP1 7HZ. Printed by Multiplex techniques lid, St Mary Cray. Kent.