ZA200602577B - Microparticles comprising somatostatin analogues - Google Patents

Description

MICROPARTICLES COMPRISING SOMATOSTATIN ANALOGUES

The present invention relates to microparticles comprising a somatostatin analogue and to pharmaceutical compositions comprising the same.

Somatostatin is a tetradecapeptide having the structure

H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Somatostatin analogues of particular interest have been described e.g. in WO 97/01579 and

WO 02/10192. Said somatostatin analogues comprise the amino acid sequence of formula (D/L)Trp-Lys-X, -X2 - I wherein X, is a radical of formula (a) or (b) — co— —NH——CO— oon, @ tH: (®)

CH, R, wherein R, is optionally substituted phenyl, wherein the substituent may be halogen, methyl, ethyl, methoxy or ethoxy, ' Ryis -Z—CHzR;, -CHzCO-O-CHzR;,

Ore, = A wherein Z, is O or S, and

X, is an a-amino acid having an aromatic residue on the C, side chain, or an amino acid unit selected from Dab, Dpr, Dpm, His, (Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala and t-butyl-Ala, the residue Lys of said sequence corresponding to the residue Lys? of the native somato- statin-14.

These compounds are referred to hereinafter as compounds of the invention.

By somatostatin analogue as used herein is meant a straight-chain or cyclic peptide derived from that of the naturally occurring somatostatin-14, comprising the sequence of formula and wherein additionally one or more amino acid units have been omitted and/or replaced by one or more other amino acid radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. in general the term covers all modified derivatives of the native somatostatin-14 comprising the above sequence of formula i which have binding affinity in the nM range to at least one somatostatin receptor subtype as defined hereinafter.

Preferably, the somatostatin analogue is a compound in which the residues at positions 8 through 11 of the somatostatin-14 are represented by the sequence of formula | as defined above.

More preferably, the somatostatin analogue is a compound as disclosed above comprising a hexapeptide unit, the residues at positions 3 through 6 of said hexapeptide unit comprising the sequence of formula |. Particularly preferred is a somatostatin hexapeptide wherein the residues at positions 1 and 2 of the hexapeptide unit may be any of those as known in the art, e.g. as disclosed by A.S. Dutta in Small Peptides, Vol. 19, 202-354, Elsevier, 1993, or as substituents for, Phe® and/or Phe’ of somatostatin-14.

More particularly the somatostatin analogue is a compound in which the hexapeptide unit is cyclic, e.g. having a direct peptide linkage between the a-carbonyl group of the residue at position 6 and the a-amino group of the residue at position 1.

While Lys, X, and X; in the sequence of formula | have the L-configuration, Trp may have the D- or L-configuration. Preferably Trp has the D-configuration.

X, is preferably a residue of formula (a) or (b), R; being preferably zc, R, or <O)-0GHR,

When Xz comprises an aromatic residue on the C, side chain, it may suitably be a natural or unnatural a-amino acid, e.g. Phe, Tyr, Trp, Nal, Pal, benzothienyl-Ala, Tic and thyronin, preferably Phe or Nal, more preferably Phe. X; is preferably an a-amino acid bearing an aromatic residue on the C, side chain.

When R, Is substituted phenyl, it may suitably be substituted by halogen, methyl, ethyl, methoxy or ethoxy e.g. in ortho and/or para. More preferably R, is unsubstituted phenyl.

Z, is preferably O.

Representative compounds of the invention are e.g. compounds of formula (lI) /

cyclofA -2ZZ - (DA)Trp - Lys-X - X J an 1 2 3 4 L] [J] wherein

X, and X2 are as defined above,

Als a divalent residue selected from Pro, (Ry-NH-CO-O)Pro-, Rg-N-R,-Pro-, HO-R-Pro-, (co

R,(CH,),,N - N

Re

RoaRaN-A(CHy)- CONHPIO-, RuRgNACH,), oS Pro-

RyNH-CO-O-Ry-CH(NR,}-CO- , RyrCHNR,)-CO- and -NR,-CH,-CO- wherein Rs is NRsRo-Caealkylene, guanidino-Cealkytene or C.ealkylene-COOH, Rs, is H,

C,alkyl or has independently one of the significances given for Ry Reis H or Cy.alkyl, R, is

OH or NRsRs, Ry is -(CHz)s.s~ of -CH(CHs)-, Ry is H or CHa, Raa is optionally ring-substituted benzyl, each of Rg and Re independently is H, Cialkyl, o-amino-Cy.alkylene, o-hydroxy-

C,.alkylene or acyl, R; is a direct bond or C,.ealkylene, each of Rs and Ry independently is

H, C,4alkyl, o-hydroxy-C..alkylene, acyl or CHOH-(CHOH)-CH wherein c is 0, 1, 2, 3 or 4, or Rs and Ry form together with the nitrogen atom to which they are attached a heterocyclic group which may comprise a further heteroatom, and Ry; is optionally ring-substituted benzyl,(CHz)1.s-OH, CHs-CH(OH)- or -(CH2)1.5-NRgRs, and

ZZ, is a natural or unnatural a-amino acid unit.

ZZ. may have the D- or L-configuration. When ZZ, is a natural or unnatural a-amino acid unit, it may suitably be e.g. Thr, Ser, Ala, Val, lle, Leu, Nie, His, Arg, Lys, Nal, Pal, Tyr, Trp, optionally ring-substituted Phe or N*-benzyl-Gly. When ZZ, is Phe, the benzene ring thereof may be substituted by e.g. NH;, NO, CHs, OCH; or halogen, preferably in para position.

When ZZ, is Phe, the benzene ring thereof is preferably unsubstituted.

When A comprises a Pro amino acid residue, any substituent present on the proline ring, e.g. R&-NH-CO-O- etc., is preferably in position 4. Such substituted proline residue may exist in the cis form, e.g. > ce

N i ) o as well as in the trans form. Each geometric isomer individually as well as mixtures thereof are compounds of the invention.

When Als (NRgRy Ca galkylene-NH-CO-O)Rro- where NRsR, forms a heterocyclic group, such group may be aromatic or saturated and may comprise one nitrogen or one nitrogen and a second heteroatom selected from nitrogen and oxygen. Preferably the heterocyclic group is e.g. pyridyl or morpholino. CzeAlkylene in this residue is preferably -CH-CHz-.

Any acyl as Rs, Re, Rsand R; in A may be e.g. R,.CO- wherein Ryz is H, Ci4alkyl, Ca4alkenyl,

Csecycloalkyl or benzyl, preferably methyl or ethyl. When Ry, or Ry, In A is ring-substituted benzyl, the benzene ring may be substituted as indicated above for ZZ,.

Particularly preferred are compounds of formula Ill i : N 2 NM

Ao(Y i ° b) ° ° o= . 0) i Me [11]

A

OO wherein the configuration at C-2 is (R) or (S) or a mixture thereof, and wherein R is NR;oRy:-Coealkylene or guanidine-Cealkylene, and each of Ry and Ry independently is H or Cy4alkyl, in free form, in salt form or protected form.

Preferably R is NR;oR41-Czsalkylene. Preferred compounds of formula Ii are those wherein

R is 2-amino-ethyl, namely cyclof{4-(NH-C.H-NH-CO-O-)Pro}-Phg-DTrp-Lys-Tyr(4-Bz)-

Phe] (referred herein to as Compound A) and cyclo{{4-(NHz-C.H,-NH-CO-O-)Pro}-DPhg-

DTrp-Lys-Tyr(4-Bzl)}-Phe], in free form, salt form or protected form. Phg means -HN-

CH(CeHs)-CO- and Bzi means benzyl.

A compound of the invention in protected form corresponds to a somatostatin analogue wherein at least one of the amino groups is protected and which by deprotection leads to a compound of formula Ii or III, preferably physiologically removable. Suitable amino protecting groups are e.g. as disclosed in “Protective Groups in Organic Synthesis”, T. W. Greene, J. wiley & Sons NY (1981), 219-287, the contents of which being Incorporated herein by reference. Example of such an amino protecting group is acetyl.

A compound of the invention, e.g. a compound of formula Il, for instance Compound A, may exist e.g. in free or salt form. Salts include acid addition salts with e.g. inorganic acids, poly- meric acids or organic acids, for example with hydrochloric acid, acetic acid, lactic acid, aspartic acid, benzoic acid, succinic acid or pamoic acid. Acid addition salts may exist as mono- or divalent salts, e.g. depending whether 1 or 2 acid equivalents are added. Preferred salts, e.g. for Compound A, are the lactate, aspartate, benzoate, succinate and pamoate including mono- and di-salts, more preferably the aspartate di-salt and the pamoate monosalt.

The compounds of the invention may be prepared in accordance with conventional methods.

Typically, the compounds of the invention, are delivered systemically, e.g. parenterally.

However, parenteral administration may be very painful, especially in repeated administration. In order to minimize the number of injections to a patient, a suitable depot formulation should be administered. it has been found that administration of microparticles comprising a somatostatin analogue e.g. embedded in a biocompatible pharmacologically acceptable polymer, suspended in a suitable vehicle gives release of all or of substantially all of the active agent over an extended period of time, e.g. several weeks up to 6 months, preferably over at least 4 weeks.

Accordingly, the present invention provides microparticles comprising a compound of the invention e.g. embedded in a biocompatible pharmacologically acceptable polymer, and a pharmaceutical depot formulation comprising said microparticles.

The compound of the invention may be present in an amount of from about 1 to about 60%, more usually about 10 to about 50%, preferably about 20 to about 40%, even more preferably about 25% to about 35%, by weight of the microparticles dry weight.

Preferably, the compound of the invention used to prepare the microparticles is an amorphous powder having a particle of a size of about 0.1 microns to about 15 microns, preferably less than about 5 microns, even more preferably less than about 3 microns.

v The particle size distribution of the compound of the Invention may influence the release profile of the drug from the microparticles. Typically, the smaller the particle size, the lower is the burst and release during the first diffusion phase, e.g. the first 20 days. Preferably, particle size distribution is e.g. x10 < 0.8 microns i.e. 10% of the particles are smaller than 0.8 microns; x50 < 1.5 microns i.e. 50% of the particles are smaller than 1.5 microns; or x90 < 3.0 microns, i.e. 90% of the particles are smaller than 3.0 microns.

The polymer matrix of the microparticles may be a synthetic or natural polymer. The polymer may be either a biodegradable or non-biodegradable or a combination of biodegradable and non-biodegradable polymers, preferably biodegradable.

By "polymer" is meant an homopolymer or a copolymer.

The polymer matrix is designed to degrade sufficiently to be transported from the site of administration within one to 6 months after release of all or substantially all the active agent.

Suitable polymers include (a) linear or branched polyesters which are linear chains radiating from a polyol moiety, e.g. glucose, for example a polyester such as D-, L- or racemic polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polycaprolactone, polyalkylene oxalate, polyalkylene glycol esters of an acid of the Kreb's cycle, e.g. citric acid cycle, and the like or a combination thereof, (b) polymers or copolymers of organic ethers, anhydrides, amides and orthoesters, including such copolymers with other monomers, e.g. a polyanhydride such as a copolymer of 1,3-bis-(p-carboxyphenoxy)-propane and a diacid, e.g. sebacic acid, or a copolymer of erucic acid dimer with sebacic acid; a polyorthoester resulting from reaction of an ortho-ester with a triol, e.g. 1,2,6-hexanetriol, or of a diketene acetal, e.g. 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5,5]un-decane, with a diol, e.g. 1,6- dihexanediol, triethyleneglycol or 1,10-decanediol; or a polyester amide obtained with an amide-diol monomer, e.g. 1,2-di-(hydroxyacetamido)-ethane or 1,10-di- (hydroxyacetamido)decane; or (c) polyvinylalcohol.

The polymers may be cross-linked or non-cross-linked, usually not more than 5%, typically less than 1%.

The preferred polymers of this invention are linear polyesters and branched chain polyesters.

The linear polyesters may be prepared from a-hydroxy carboxylic acids, e.g. lactic acid

: and/or glycolic acid, by condensation of the lactone dimers, see e.g. US 3,773,919, the contents of which are incorporated herein by reference. The preferred polyester chains in the linear or branched (star) polymers are copolymers of the a-carboxylic acid moieties, lactic acid and glycolic acid, or of the lactone dimers. The molar ratio of lactide: glycolide of polylactide-co-glycolides in the linear or branched polyesters is preferably from about 75:25 to 25:75, e.g. 60:40 to 40:60, with from 55:45 to 45:55, e.g. 52:48 to 48:52 the most preferred.

Linear polyesters, e.g. linear polylactide-co-glycolides (PLG), preferably used according to the invention have a weight average molecular weight (Mw) between about 10,000 and about 500,000 Da, e.g. about 50,000 Da. Such polymers have a polydispersity M,/M,, e.g. between 1.2 and 2. Suitable examples include e.g. poly(D,L-lactide-co-glycolide), e.g. having a general formula —{(CsHsO(CsH4Os)}r- (each of x, y and n having a value so that the total sum gives the above indicated Mws), e.g. those commercially available, e.g. Resomers® from Boehringer Ingelheim, in particular Resomers® RG, e.g. Resomer® RG 502, 502H, 503, 503H, 504, 504H.

Branched polyesters, e.g. branched polylactide-co-glycolides, preferably used according to the invention may be prepared using polyhydroxy compounds e.g. polyol e.g. glucose or mannitol as the Initiator. These esters of a polyol are known and described e.g. in GB 2,145,422 B, the contents of which are incorporated herein by reference. The polyol contains at least 3 hydroxy groups and has a molecular weight of up to 20,000 Da, with at least 1, preferably at least 2, e.g. as a mean 3 of the hydroxy groups of the polyol being in the form of ester groups, which contain poly-lactide or co-poly-lactide chains. Typically 0.2% glucose is used to initiate polymerization. The branched polyesters (Giu-PLG) have a central glucose moiety having rays of linear polylactide chains, e.g. they have a star shaped structure.

The branched polyesters having a central glucose moiety having rays of linear polylactide- co-glycolide chains (Glu-PLG) may be prepared by reacting a polyol with a lactide and preferably also a glycolide at an elevated temperature in the presence of a catalyst, which makes a ring opening polymerization feasible.

The branched polyesters having a central glucose moiety having rays of linear polylactide- co-glycolide chains (Glu-PLG) preferably have an weight average molecular weight M,, in the range of from about 10,000 to 200,000, preferably 25,000 to 100,000, especially 35,000 to 60,000, e.g. about 50,000 Da, and a polydispersity e.g. of from 1.7 to 3.0, e.g. 2.0 to 2.5.

The intrinsic viscosities of star polymers of M,, 35,000 or M,, 60,000 are 0.36 or 0.51 dl/g,

respectively, in chloroform. A star polymer having a M,, 52,000 has a viscosity of 0.475 dVg in chloroform.

The desired rate of degradation of polymers and the desired release profile for compounds of the invention may be varied depending on the kind -of monomer, whether a homo- or a copolymer or whether a mixture of polymers is employed.

A mixture of polymers may comprise at least two different kinds of polymers, e.g. as listed under (a) to (e) above, or two polymers of the same palymer class with different properties.

For example, a mixture of polymers may comprise a polymer having a medium weight average molecular weight, e.g. from about 30,000 to about 60,000 Da, e.g. of about 50,000

Da, and of a polymer having a low weight average molecular weight, e.g. of about 2.000 to about 20,000 Da, e.g. of about 10,000 Da.

Preferably, the polymer matrix comprises a linear and/or branched polylactide-co-glycolide.

More preferably, the polymer matrix comprises a Resomer® RG, a star polylactide-co- : glycolide polymer having a weight average molecular weight of about 10,000 Da and/or a star polylactide-co-glycolide polymer having a weight average molecular weight of about 50,000 Da. The ratio of linear to branched polylactide-co-glycolide preferably is 0 : 100 to 100:0,e.9.50:50t025:75.

The polymer matrix may be present in a total amount of about 40 to 99% by weight of the microparticles.

The microparticles may further comprise an agent that may influence the porosity of the microparticles. Such an agent may be e.g. a) Polyvinyl pyrrolidone, preferably with a molecutar weight of between about 2,000 and about 20,000 Da. Suitable examples include those commonly known as Povidone K12 F with an average molecular weight of about 2,500 Da, Povidone K15 with an average molecular weight of about 8,000 Da, or Povidone K17 with an average molecular weight of about 10,000 Da. :

Preferably, the polyvinyl pyrrolidone is present in an amount of from about 0.1 to about 50%, e.g. about 10%, by weight of the microparticles. b) Carboxymethyl cellulose sodium (CMC-Na), preferably having a low molecular weight.

The viscosity may be, e.g. up to 20 cP for a 2% aqueous solution or a viscosity of from 8 to 25 mPa s. Convenlently the degree of substitution is from about 0.5 to about 1.45, preferably about 0.7. Typically the sodium content is about 5% to about 12%.

Preferably, the CMC-Na is present in an amount of from about 0.1 to about 20%, e.g. about 5%, by weight of the microparticles. c) Dextrin, e.g. with an average molecular weight ranging from 1,000 to 50,000 Da, preferably 5,000 Da. Preferably the dextrin has a fine particle size distribution, e.g. x90 less than 20 microns.

Preferably, the dextrin is present in an amount of from about 0.1 to about 10%, e.g. about 5%, by weight of the microparticles. d) Polyethyleneglycol, e.g. with weight average molecular weight ranging from about 1,000 to about 10,000 Da, preferably from about 1,000 to about 3,350 Da. Suitable examples include those commonly known and commercially available under the trade name

Carbowax® from Dow&Union Carbide, with e.g. Mw of 3,350 Da. Polyethyleneglycol with an weight average molecular weight of 3,350 Da has a viscosity of 76 to 110 cSt at 98.9 +- 0.3°C. Polyethyleneglycol with Mw ranging from 1000 to 3500 DA has viscosities ranging from 16 to 123 cSt 98.9 +/- 0.3°C.

The microparticles may further comprise a surfactant. Suitable surfactants include non-ionic surfactants such as a) Poloxamers, also known as polyoxyethylene potyoxypropylene block copolymers, e.g. having a molecular weight from about 2000 to about 8000 Da. The degree of polymerization of the ethylene moiety is typically 80 to about 110 units. The degree of polymerization of the propylene moiety is typically 20 to about 60 units. Examples of such compounds suitable for use in accordance with the present invention are those known and commercially available, e.g. under the trade name Pluronic® F68 available from BASF Germany. b) Polyoxyethylene-sorbitan-fatty acid esters e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters e.g. of the type known and commercially available under the trade name

TWEEN®, e.g. Tween 20 [polyoxyethylene(20)sorbitanmonolaurate], Tween 40 [poly- oxyethylene(20)sorbitanmonopalmitate], Tween 60 [polyoxyethylene(20)sorbitanmono- stearate], Tween 80 [polyoxyethylene(20)sorbitanmonooleate], Tween 65 [polyoxyethy- lene(20)sorbitantristearate], Tween 85 [polyoxyethylene(20)sorbitantrioleate], Tween 21 [polyoxyethylene(4)sorbitanmonolaurate], Tween 61 [polyoxyethylene(4)sorbitanmono- stearate], and Tween 81 [polyoxyethylene(5)sorbitanmonooleate]. Preferred are Tween and Tween 80.

: c) Sorbitan fatty acid esters e.g. of the type known and commercially available under the trade name SPAN, for example including sorbitan monolauryl, monopalmityl, mono- stearyl, tristearyl, monooleyl and trioleyl esters. d) Lecithins, e.g. soy bean phospholipid, e.g. as known and commercially available under the trade name Lipoid® S75 from Lipoid; or egg phospholipid, e.g. as known and commercially available under the trade names Phospholipon® 90 from Nattermann,

Epikuron 100H or ‘Epikuron 145V, Epikuron 170 or Epikuron 200 from Degussa,

Bioactives.

Preferably, poloxamers, Tween 20 and/or Tween 80 are used. in case the polymer or polymers used to embed the compound of the invention is a polyester, the microparticles preferably further comprise a basic compound such as a basic salt or a base, e.g. basic zinc carbonate, magnesium hydroxide, magnesium carbonate or a protamine, e.g. human protamine or salmon protamine, or a natural or synthetic polymer bearing amine-residues such as polylysine or dimethylaminoethyimethacrylate.

Reference is made to the extensive literature on the subject for these and other excipients and procedures mentioned herein, see in particular Handbook of Phanmaceutical Excipients,

Second Edition, edited by Ainley Wade and Paul J. Weller, American Pharmaceutical

Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der

Hilfsstoffe for Pharmazie, Kosmetik and angrenzende Gebiete edited by H.P. Fiedler, 4th

Edition, Editio Cantor, Aulendorf and earller editions which are incorporated herein by reference.

Preferably, the microparticles of the invention contain as active ingredient only a compound of the invention, e.g. a compound of formula Il, preferably a compound of formula lil, even more preferably Compound A. Preferably, the microparticles of the invention contain a compound of the invention, e.g. a compound of formula Il or Ill, in form of the pamoate salt, even more preferably the pamoate salt of Compound A.

Procedures which may be used to prepare the microparticles of the invention may be conventional or known in the art or based on such procedures e.g. those described in L.

Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutische Technologie, Thieme, 1991, Hager's Handbuch der pharmazeutischen

Praxis, 4th Ed. (Springer Verlag, 1971), Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions and in E. Mathiowitz’s Encyclopedia of Controlled

Drug Delivery (John Wiley & Sons, Inc, 1999).

The present invention in another aspect provides a process for the preparation of microparticles of the invention comprising (i) preparation of an intemal organic phase comprising (a) dissolving the polymer or polymers in a suitable organic solvent or solvent “mixture, and optionally - dissolving/dispersing a porosity-influencing agent in the solution obtained in step (ia), or - adding a basic salt to the solution obtained in step (ia), - adding a surfactant to the solution obtained by step (ia); (ib) suspending the compound of the invention in the polymer solution obtained in step (ia), or dissolving the compound of the invention in a solvent miscible with the solvent used in step (ia) and mixing said solution with the polymer solution, or directly dissolving the compound of the invention in the polymer solution, or dissolving the compound of the invention in form of a water soluble salt in an aqueous phase and emulsifying said aqueous solution with the polymer solution (a); (ii) preparation of an extemal aqueous phase comprising (la) preparing a buffer to adjust the pH to 7-7.5, e.g. acetate or phosphate buffer, e.g. Na;HPO, and KH,PO,, and (ib) dissolving a stabilizer in the solution obtained in step (iia); (iii) mixing the intemal organic phase with the external aqueous phase e.g. with a device creating high shear forces, e.g. with a turbine or static mixer, to form an emulsion; and (iv) hardening the microparticles by solvent evaporation or solvent extraction, washing the microparticles, e.g. with water, collecting and drying the microparticles, e.g. freeze- drying or drying under vacuum.

Suitable organic solvents for the polymers include e.g. ethyl acetate, acetone, THF, acetonitrile, or halogenated hydrocarbons, e.g. methylene chloride, chloroform or hexafiuoro- isopropanol.

Suitable examples of a stabilizer for step (lib) include a) Polyvinyl alcohol (PVA), preferably having a weight average molecular weight from about 10,000 to about 150,000 Da, e.g. about 30,000 Da. Conveniently the polyvinyl alcohol has low viscosity having a dynamic viscosity of from about 3 to about 3 mPa s

Claims (17)

Claims

1. Microparticles comprising a somatostatin analogue comprising the amino acid sequence of formula -(DL)Trp-LYs-Xq -Xz - wherein X, is a radical of formula (a) or (b) a co— —NH—7—C0— oon, (@ : TH (®) CH, R, wherein R, is optionally substituted phenyl, Ryis —Z-CHrR;, -CH-CO-O-CHrR;, wherein Z, is O or S, and X, is an a-amino acid having an aromatic residue on the C, side chain, or an amino acid unit selected from Dab, Dpr, Dpm, His, (B)HyPro, thienyl-Ala, cyclohexyl-Ala and t- butyt-Ala, the residue Lys of said sequence corresponding to the residue Lys® of the native somatostatin-14 in free form, salt form, or protected form, embedded in a polymer matrix.

2. Microparticles according to claim 1 wherein the somatostatin analogue is a compound of formula Hi i : K NH ACT TL ° oo, fu 07 A 0 wherein the configuration at C-2 is (R) or (S) or a mixture thereof, and wherein R is NR,R,-C,alkylene, or guanidine C,salkylene, and each of R, and R; independently is H or C,_alkyl, in a free form, salt form or protected form.

3. Microparticles according to claim 1 or 2 wherein the somatostatin analogue is in pamoate salt form.

4. Microparticles according to any preceding claim wherein the polymer matrix comprises a linear or branched polyactide-co-glycolide.

5. Microparticles according to any preceding claim wherein the polymeric matrix comprises at least two different polymers.

6. Microparticles according to any preceding claim further comprising surfactant, a porosity influencing agent and/or a basic salt.

7. A pharmaceutical composition comprising microparticles of any preceding claim and a water-based vehicle comprising a wetting agent.

8. A composition according to claim 7 wherein the wetting agent comprises a poloxamer and/or a polyoxyethylene-sorbitan-fatty acid ester.

9. A composition according to any one of claims 7 or 8 wherein the vehicle comprises a tonicity agent.

10. A composition according to any one of claims 7 or 8 wherein the vehicle comprises a viscosity increasing agent.

11. A kit comprising microparticles according to any one of claims 1 to 6 and a water-based vehicle.

12. Use of microparticles according to any one of claims 1 to 6 or of a pharmaceutical composition according to any one of claims 7 to 10 for the preparation of a medicament for the treatment of a disease or disorder with an aetiology comprising or associated with excess GH- and/or IGF-1 secretion.

13. Microparticles according to any one of claims 1 to 6, or a pharmaceutical composition according to any one of claims 7 to 10, for use in treating a disease or disorder with an aetiology comprising or associated with excess GH- and/or IGF-1 secretion.

14. Microparticles according to any one of claims 1 to 6, substantially as herein described and exemplified. AMENDED SHEET

-22A-

15. A pharmaceutical composition according to claim 7, substantially as herein described and exemplified.

16. A kit according to claim 11, substantially as herein described and exemplified.

17. Use of microparticles according to claim 12, substantially as herein described and exemplified. AMENDED SHEET