AU2013201877B2 - Sustained release formulation comprising octreotide and three linear polylactide-co-glycolide polymers - Google Patents

Abstract

fi:% \Tutrwovo\N~ortl\DC \RBR50 1l.OC-2!/03/2013 The present invention relates to sustained release formulations comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and three different linear polylactide-co glycolide polymers (PLGAs).

Description

H:%\Tuerove\NRorbl\CC\BR50015__ doc-2I03/0_ Sustained release formulation conpisin g.octreotide and three linear polyiactideogycoide polymers This application is a divisional application of Australian Application No. 2009209594 the specification and drawings of which as originally filed are incorporated herein in their entirety by reference. The present invention relates to sustained release formulations comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and three different linear polylactide-co glycolide polymers (PLGAs). These pharmaceutical compositions according to the present invention are indicated for inter alia long-term maintenance therapy in acromegalic patients, and treatment of severe diarrhea and flushing associated with malignant carcinoid tumors and vasoactive intestinal peptide tumors (vipoma tumors). Peptide drugs are usually administered systemically, e.g. parenterally. However, parenteral administration may be painful and cause discomfort, especially for repeated daily administrations. In order to minimize the number of injections to a patient, the drug substance should be administered as a depot formulation. A common drawback with injectable depot formulations is the fluctuation in plasma levels such as high peak levels together with plasma levels close to zero during the entire release periode. Sustained release formulations comprising as active ingredient octreotide or a pharmaceutically acceptable salt thereof and two or more different polylactide--co-glycolide polymers (PLGAs) have, for instance, been also disclosed in W02007/071395. The present invention discloses a sustained release formulation comprising as active ingredient (drug substance) octreotide or a pharmaceutically-acceptable salt thereof. Octreotide is a somatostatin analog having the following formula: (D)Phe-Cvs-Phe-(D)Trp-Lvs-Thr-Cvs-Thr The active ingredient may be in the form of a pharmaceutically acceptable salt of octreotide. such as an acid addition salt with e.g. inorganic acid, polymeric acid or organic acid, for -2 example with hydrochloric acid, acetic acid, lactic acid, citric acid, fumaric acid, malorric acid, maleic acid, tartaric acid, aspartic acid, benzoic acid, succinic acid or pamoic (embonic) acid. Acid addition salts may exist as mono- or divalent salts, e.g. depending whether 1 or 2 acid equivalents are added. Preferred is the pamoate monosalt of octreotide. Accordingly, in a first aspect, there is provided a sustained release pharmaceutical composition comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and three different linear polylactide-co-giycolide polymers (PLGAs). The particle size distribution of the drug substance influences the release profile of the drug from the depot form. The drug substance which is used to prepare the depot formulation is crystalline or in the form of an amorphous powder. Preferred is an amorphous powder which has a particle of a size of about 0.1 microns to about 15 microns (99% > 0.1 microns, 99% < 15 microns), preferably from 1 to less than about 10 microns (90% > 1 microns, 90% < 10 microns). The drug substance preferentially undergoes a micronization process to present the required particle size distribution. The present invention further provides a sustained release pharmaceutical composition (depot) comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof incorporated in blends or mixtures of poly(lactide-co-glycolide)s (PLGAs), for instance in form of microparticles, implants or semisolid formulations. Alternatively to blends of PLGAs, in another aspect of the present invention the pharmaceutical composition comprises a mixture of PLGA polymers containing the active ingredient; i.e. the active ingredient may be incorporated into one or more PLGAs in form of microparticles, implants or semisolid formulations and is then mixed with another microparticle or implant or semisolid formulation also comprising the active ingredient and one or more PLGAs. The pharmaceutical composition according to the present invention allows a sustained release of the active ingredient over a period of more than three month, preferentially between three and six months. During the release of the active ingredient the plasma levels of octreotide are within the therapeutic range. It is understood that the exact dose of octreotide will depend on a number of factors, including the condition to be treated, the severity of the condition to be treated, the weight of the subject and the duration of therapy.

WO 2009/095450 PCT/EP2009/051026 -3 Surprisingly fluctuations in plasma levels can significantly be reduced by using a suitable combination of three different linear PLGAs in the pharmaceutical composition according to the present invention. The drug substance is incorporated into a biodegradable polymer matrix consisting of three different linear polylactide-co-glycolide polymers (PLGAs). The PLGAs have a lactide: glycolide monomer ratio of 100:0 to 40:60, preferably 90:10 to 40:60, more preferably 85:15 to 55:35. The PLGAs according to the present invention have a molecular weight (Mw) ranging from 1,000 to 500,000 Da, preferably from 5,000 to 100,000 Da, The architecture of the polymers is linear. The inherent viscosity (IV) of the PLGAs according to the present invention is below 0.9 dlig in CHC3, preferentially below 0.8 di/g in CHCl 3 .The inherent viscosities can be measured by the conventional methods of flow time measurement, as described for example in "Pharmacopoee Europieenne" 1997, pages 17-18 (capillary tube method). Unless stated otherwise, these viscosities have been measured in chloroform at a concentration of 0.5% at 25"C or in hexaisofluoropropanol at a concentration of 0.5% at 30*C. End groups of the PLGAs according to the present invention can be but are not limited to Hydroxy, carboxy, ester or the like, The drug substance content of the depot formulation (the loading) is in a range of 1% to 30%, preferred 10% to 25%, more preferred 15% to 20%. The loading is defined as the weight ratio of drug substance as free base to the total mass of the PLGA formulation. Suitable polymers are commonly known but not limited to those commercially available as RESOMER® by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, LACTEL@ by Absorbable Polymers International (API), Pelham, AL, USA, MEDISORB@ by Alkermes, Inc., Cambridge, MA, USA, PURASORB@ by PURAC biochem BV, Gorinchem, The Netherlands. Examples of suitable polymers are listed in Table 1.

WO 2009/095450 PCT/EP2009/051026 -4 Table 1: Examples of suitable polymers No I Product name Polymer Inherent Producer viscosity [dLfg] Supplier 1 Resomer® R 202 H Linear Poly(D,L-lactide) 0.16 - 0,24) Boehringer free carboxylic acid end group 2 Resomer@ R 202 S Linear Poly(),L-lactide) 0.16 - 0.24 9 Boehringer 3 Resomer@ R 203 S Linear Poly(D,L-lactide) 0,25 0. 35 Boehringer 4 Resomer@ RG 752 H Linear Poly(D,L-lactide-co- 0.14 - 0.22 Boehringer glycolide) 75:25 free carboxylic acid end group 5 Resomer@ RG 752 S Linear Poly(DL-lactide-co- 0.16 - 0.24 Boehringer glycolide) 75:25 6 Resomer@ CR RG Linear Poly(DL-lactide-co- 0.32 - 0.44 Boehringer 75:25 or Resomer@ glycolide) 75:25 RG Typo 75:25 S / Resorner @ RG 753 S 7 Lactel@ 100D020A Linear Poly(DL-lactide) 0.15-0.25 API/Durect free carboxylic acid end group 8 Lactel@ 100D040A Linear Poly(DL-lactide) 0.26 - 0.54 API/Durect free carboxylic acid end group 9 Lactel@ 100D040 Linear Poly(D,L-lactide) 026 - 0.54 2 API/Durect 10 Lactel@ 1 00D065 Linear Poly(DL-lactide) 0.55 - 0.75 2 API/Durect 11 Lactel@ 85DG040 Linear Poly(D,L-lactide-co.- 0.26 -0.54 4 APiDurect glycolide) 85:15 12 Lactel@ 85DG065 Linear Poly(DL-lactide-co- 055 0.752) API/Durect glycolide) 85:15 13 Lactel@ 75DG065 Linear Poly(D,L-lactide-co- 0.55 - 0.75 2 API/Durect glycolide) 75:25 14 Lactel@ 65DG065 Linear Poly(DL-lactide-co- 0.55 - 0.75 0 API/Durect glycolide) 65:35 15 Lactel 50DG065 Linear Poly(D,L-lactide-co- 0.'55- 0.75 API/Durect glycolide) 50:50 16 Medisorb@ Linear Poly(DL-lactide) 10,66 - 0.80 Alkermes 100 DL HIGH IV 17 Medisorb@ Linear Poiy(D,L-lactide) 0.50 - 0.65 Alkermes 100 DL LOW IV 18 Medisorb@ Linear Poly(DLlactide-co- 0.66 - 0.80 Aikermes 8515 DL HIGH iV glycolde) 85:15 19 Medisorb@ Linear Poly(DL-lactide-co- 0.50 - 0.65 Aikermes 8515 DL LOW IV glycolide)85:15 WO 2009/095450 PCT/EP2009/051026 -5 No Product name Polymer Inherent Producer viscosity [dUg] Supplier 20 Medisorb@ Linear Polv(DL-actide-co- 066 - 0.80 Akermes 7525 DL HIGH IV g!ycolide) 75:25 21 Medisorb@ Linear Poly(D,L-iactide-co- 0.50 -0.65 Alkermes 7525 DL LOW IV glycolide) 75:25 22 Medlsorb@ Linear Poly(D,L-lactide-co- 0.66 - 0-80 Alkermes 6535 DL HIGH IV glycolide) 65:35 23 Medisorb@ Linear Poly(DL-lactide-co- 0.50 -0.65 Alkermes 6535 DL LOW IV glycolide) 65:35 24 Medisorb@ Linear Poly(D,L-lactide-co- 0.66 -0.80 Alkermes 5050 DL HIGH IV glycolide) 50:50 25 Medisorb@ Linear Poly(D,L-lactide-co- 0.50 -0.65 Alkermes 5050 DL LOW IV glycolide) 50:50 1) IV has been determined in chloroform at a concentration of 0.1 % at 25"C 2) IV has been determined in chloroform at a concentration of 0.5 g / dL at 30*C 3) IV has been determined in Hexafluoroisopropanol at a concentration of 0.5 g 1 dL at 300 Plasma levels with low variability can be achieved over a time period of more then three month, preferentially between three and six month, only with with pharmaceutical compositions according to the present invention, not with formulations containing only one single polymer from the table above. in addition, the pharmaceutical composition according to the present invention can be manufactured aseptically or non-aseptically and sterilized terminally by gamma irradiation. Preferred is terminal sterilization by gamma irradiation, resulting in a product with the highest sterility assurance possible. The pharmaceutical composition according to the present invention may also contain one or more pharmaceutical excipients modulating the release behavior in an amount of 01% to 50%. Examples of such agents are: Poly(vinylpyrrolidone), carboxymethyl cellulose sodium (CMC-Na), dextrin, poly(ethyleneglycol), suitable surfactants such as poloxamers, also known as poly(oxyethylere-block-oxypropylene), Poly(oxyethylene)-sorbitan-fatty acid esters WO 2009/095450 PCTEP2009/051026 known and commercially available under the trade name TWEEN@ (e.g. Tween 20, Tween 40, Tween 60, Tween 80, Tween 65 Tween 85, Tweer 21, Tween 61, Tween 81), Sorbitan fatty acid esters e.g. of the type known and commercially available under the trade name SPAN, Lecithins, inorganic salts such as zinc carbonate, magnesium hydroxide, magnesium carbonate, or protamine, e.g. human protamine or salmon protamine, or natural or synthetic polymers bearing amine-residues such as polylysine The pharmaceutical composition according to the present invention can be a depot mixture or a polymer blend of different polymers in terms of compositions, molecular weight and/or polymer architectures. A polymer blend is defined herein as a solid solution or suspension of three different linear polymers in one implant or microparticle. A mixture of depots in contrast is defined herein as a mixture of two or more depots like implants or microparticles or semisolid formulations of different composition with one or more PLGAs in each depot. Preferred is a pharmaceutical composition wherein the three PLGAs are present as polymer blend. The pharmaceutical composition according to the present invention can be in the form of implants, semisolids (gels), liquid solutions or suspensions which solidify in situ once they are injected or microparticles. Preferred are microparticles. Preparation of microparticles comprising octreotide or a pharmaceutically-acceptable salt thereof is known and for instance disclosed in US5,445,832 or US5,538,739. The following part of the invention is focused on polymer microparticles although the descriptions are applicable for implants, semisolids and Equids as well. The microparticles according to the present invention may have a diameter from a few submicrons to a few millimeters, e.g. from about 0.01 microns to about 2 mm, e.g. from about 0.1 microns to about 500 microns, For pharmaceutical microparticles, diameters of at most about 250 microns, e.g. 10 to 200 microns, preferably 10 to 130 microns, more preferably 10 to 90 microns. The microparticles according to the present invention may be mixed or coated with an anti agglomerating agent or covered by a layer of an anti-agglomerating agent, e.g. in a prefilled WO 2009/095450 PCT/EP2009/051026 -7 syringe or vial. Suitable anti-agglomerating agents include, e.g. mannitol, glucose, dextrose, sucrose, sodium chloride, or water soluble polymers such as polyvinylpyrrolidone or polyethylene glycol, e.g. with the properties described above. For microparticles according to the present invention in dry state preferably an anti agglomerating agent is present in an amount of about 0.1 to about 10%, preferentially about 3% to 5%, e.g. about 4% by weight of the microparticles. A preferred anti-agglomerating agent in this respect is mannitol. Alternatively, an anti-agglomerating agent can be applied to the microparticles during their manufacturing process. For example, at the step of filtering / washing the microparticles they can be additionally rinsed with an aqueous solution of an anti-agglomerating agent, Thus, a layer of the anti-agglomerating agent is formed on the surface of the microparticles. Preferably, the anti-agglomerating agent is present in the microparticles at an amount of less than 10%, more preferred less than 2%, most preferred less than 0.5% by weight of the microparticles. A preferred anti-agglomerating agent in this respect is mannitol. The manufacturing process for the depot formulation of the current invention is described in detail for rnicroparticles: The microparticles may be manufactured by several processes known in the-art, e~g., coacervation or phase separation, spray drying, water-in-oil (W/O) or water-in-oil-in-water (WIO/W) or solids-in-oil-in-water (S/ONV) emulsion/suspension methods followed by solvent extraction or solvent evaporation. The emulsion/suspension method is a preferred process, which comprises the following steps: (i) preparation of an internal organic phase comprising (ia) dissolving the polymer or polymers in a suitable organic solvent or solvent mixture; optionally dissolving/dispersing suitable additives; (ib) dissolving/suspending/emulsification of the drug substance in the polymer solution obtained in step (la); (ii) preparation of an external aqueous phase containing stabilizers and optionally but preferably buffer salts; (iii) mixing the internal oganic 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 -8 (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, and sieving the microparticles through 140 pm. Suitable organic solvents for the polymers include e.g. ethyl acetate, acetone, THF, acetonitrile, or halogenated hydrocarbons, e.g. methylene chloride, chloroform or hexafluoroisopropanol. Suitable examples of a stabilizer for step (iib) include Poly(vinylalcohol) (PVA), in an amount of 0.1 to 5%, Hydroxyethyl cellulose (HEC) and/or hydroxypropyl cellulose (HPC), in a total amount of 0.01 to 5%, Polyvinyl pyrolidone), Gelatin, preferably porcine or fish gelatin. The dry microparticles composition can be terminally sterilized by gamma irradiation (overkill sterilization), optionally in bulk or after filling in the final container resulting in the highest sterility assurance possible. Alternatively the bulk sterilized microparticles can be resuspended in a suitable vehicle and filled as a suspension into a suitable device such as double chamber syringe with subsequent freeze drying. The pharmaceutical composition according to the present invention containing microparticles may also contain a vehicle to facilitate reconstitution. Prior to administration, the microparticles are suspended in a suitable vehicle for injection. Preferably, said vehicle is water based containing pharmaceutical excipients such as mannitol, sodium chloride, glucose, dextrose, sucrose, or glycerins, non-ionic surfactants (e.g. poloxamers, poly(oxyethylene)-sorbitan-fatty acid esters, carboxymethyl cellulose sodium (CMC-Na), sorbitol, poly(vinylpyrrolidone), or aluminium monostearate in order to ensure isotonicity and to improve the wettability and sedimentation properties of the microparticles. The wetting and viscosity enhancing agents may be present in an amount of 0.01 to 1%; the isotonicity agents are added in a suitable amount to ensure an isotonic injectable suspension. The invention further provides the use of a pharmaceutical composition according to the present invention in the manufacture of a medicament for inter alia long-term maintenance therapy in acromegalic patients, and treatment of severe diarrhea and flushing associated with malignant carcinoid tumors and vasoactive intestinal peptide tumors (vipoma tumors).

I-,:\rumen'CvemNu ronoi u\K i tAj Un zi.da cx-un o/zI /4 -9 There is further provided a method of administering octreotide or a pharmaceutically acceptable salt thereof for long-term maintenance therapy in acromegalic patients, and treatment of severe diarrhea and flushing associated with malignant carcinoid tumors and vasoactive intestinal peptide tumors (vipoma tumors), said method comprising administering to a patient in need of octreotide or a pharmaceutically-acceptable salt thereof a pharmaceutical composition according to the invention. The utility of the pharmaceutical compositions according to the present invention can be shown in standard clinical or animal studies. The invention further provides a kit comprising the depot formulation in a vial, optionally equipped with a transfer set, together with a water-based vehicle in an ampoule, vial or prefilled syringe or as microparticles and vehicle separated in a double chamber syringe. Experimental Part The following examples are illustrative, but do not serve to limit the scope of the invention described herein. The examples are meant only to suggest a method of practicing the present invention. Example 1 : Microparticle preparation An appropriate amount of the PLGA polymers is dissolved in an appropriate amount of dichloromethane to give an appropriate polymer concentration as stated in column "PLGA cone." in Table 2. An appropriate amount of drug substance is weight into a glass beaker and the polymer solution is poured over the drug substance so that the resulting microparticles have a drug load as stated in column "drug load". E.g. for microparticles with a drug load of 20% and a polymer concentration of 20% the numbers are as the following: 3.547 g of the PLGA polymers are dissolved into 17.7 ml dichloro methane to give a 20 % (w/v) polymer solution. 1.453 g of octreotide pamoate (corresponding to 1.00 g = 20% octreotide free base) is weight into a glass beaker and the polymer solution is poured over the drug substance.

WO 2009/095450 PCT/EP2009/051026 10 The suspension is homogenized with an Ultra-Turrax rotor-stator mixer with 20'000 rpm for 1 min under cooling with an ice/water mixture. This suspension is referred to as S1O suspension. 10.00 g of Polyvinylalcohol PVA 18-88, 3.62 g KH 2 P0 4 and 15.14 g NalHPO 4 are dissolved in 2.00 L deionized water to form a 0.5% PVA 18-88 solution buffered to pH 7.4. The S/O suspension is mixed with the 0.5 % PVA1 8-88 solution by pumping the S/O suspen sion with the help of a flexible tube pump (Perpex, Viton tube) at a rate of 10 ml/min into a turbine and by pumping the aqueous solution with a gear pump (Ismatec MV-Z/B with pumping head P140) at a rate of 200 mI/min into the same turbine. The two solutions are mixed in the turbine at 4'500 rpm. The homogenized S/0/W emulsion is collected into a 2 L glass beaker which is prefilled with 200 ml of the buffered PVA solution. The S/f0V emulsion is then heated up to 52"C in 5 h. The temperature of 52 0 C is hold for further 30 min. before the batch is cooled to room temperature again. During this process escaping dichloromethane is removed by vacuum and the batch is stirred by a 4 blade propeller-stirrer at 250 rpm. As a result, microparticles are formed out of the S/0/W emulsion, The microparticles are collected by filtration (5 pm), They are washed 5 times with 200 ml water and dried for 36 h at 20"C and 0.030 mbar. The dried microparticies are sieved through 140 prm and filled under nitrogen into glass vials. Prepared in that way, the microparticles are sterilized by gamma irradiation with a dose of 30 kGy. The particle size of the microparticles is measured by laser light diffraction. The microparticles are resuspended in white spirit using ultra sound. Table 2 gives the diameter xiO (90% of all particles are smaller than this value) after 120 seconds of ultra sound treatment. The assay of the microparticles is determined by HPLC after dissolving the microparticles with ultra sound in a 3:2 mixture of acetonitrile and methanol and further 1:1 dilution with a WO 2009/095450 PCT/EP2009/051026 - 11 sodium acetate buffer (pH 4). The solution is cleared from residual particulate matter by centrifugation. Table 2: Example 1-1: octreotide pamoate microparticles prepared by blend of three linear PLGAs. Drug PLGA Pro- Particle Batch Load cone. A B C cens size Asy (% (% Info xsa (pum) 1-1 20 20 33 34 33 738 68.4 19.6 A: PLGA 65:35 ester 0.6 dUg (%) B: PLGA 75:25 ester 0.4 dL/g (%) C: PLGA 85:15 ester 0.6 dUg (%) Process Info = Further Process Information: 7: 66 mM PBS pH 74 38: Turbine speed 3800 rpm instead of 4500 rpm Example 2: Vehicle compositions A to G CMC-Na, Mannitol and Pluronic F68 in an amount as given in Table 3 are dissolved in about 15 mi hot demonized water of a temperature of about 90*C under strong stirring with a magnetic stirrer. The resulting clear solution is cooled to 20"C and filled up with deionized water to 20.0 ml. Table 3: Suitable vehicles for the rnicroparticles (Arnounts given in g) A B C D E F G DCMC-Na 0 i 0:ao ~0,14 ai 8 -3 __t a-. 2 ,5 0.40 Mnitol 04 0.99 0.90 0.76 0 74 0 Pluronic F68 0.04 0.04 0.04 0.04 0.04 0.04 0.04 Example 3: Microparticle suspension 180 mg of microparticles of example 1-1 are suspended in 1.0 mi of a vehicle of composition D (Table 3) in a 6 R vials. The suspensions are homogenized by shaking for about 30 WO 2009/095450 PCT/EP2009/051026 -12 seconds by hand. The reconstituted suspension may be injected without any issues using a 20 Gauge needle. Ezixmple 4,Lypgh!isaion of the microparicles 180 mg of microparticles of example 1-1 are reconstituted in 1 ml of the vehicle composition F (Table 3), homogenized by stirring for I to 12 hours and then freeze-dried in a lyophilisator. Reconstitution of the lyophilized microparticies with 1 mi pure water (aqua ad injectabilia) resulted in fast and good wetting of the microparticles that may be injected without any issues using a 20 Gauge needle. Example 5: Release profile in vivo (rabbits) Microparticles containing octreotide are suspended in I ml of a suitable aqueous vehicle and the resulting suspension is injected intramusculary (i.m.) into male New Zealand White bastard rabbits in a dose of 12 mg/kg. For each dosage form (test group) 4 animals are used. After defined lime periods (indicated in the table 4) plasma samples are taken and analyzed for octreotide concentration. Table 4: Plasma levels (dose corrected values); concentration in ng/ml =x. Time after Administration (days) Batch 0.021 0,042 0.083 0.167 0,250 1 2 3 5 1 8 112 1-1 20,250 18.621 7 534 2.320 0. 96j 0 159 0.303 0.799 1.235 1.534 1.990 Ex. Time after Administration (days) Batch 19 27 33 40 47 54 61 60 75 82 189 96 1-1 1.557 1.404 0.947 0.903 1.224 3.204 2.381 1,887 2.142 1.511 0.512 0.284 - 13 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (22)

1. A sustained release pharmaceutical composition comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and three different linear polylactide-co-giycolide polymers (PLGAs).

2. The pharmaceutical composition according to claim 1 wherein the PLGAs are present as polymer blend.

3. The pharmaceutical composition according to claim 1 or 2 wherein the PLGAs have a lactide:glycolide monomer ratio of 90:10 to 40:60.

4. The pharmaceutical composition according to claim 3 wherein the PLGAs have a lactide:glycolide monomer ratio of 85:15 to 65:35.

5. The pharmaceutical composition according to any of claims 1 to 4 wherein the inherent viscosity of the PLGAs is below 0.9 dl/g in CHCl 3 .

6. The pharmaceutical composition according to claim 5 wherein the inherent viscosity of the PLGAs is below 0.8 dl/g in CHCl 3 .

7. The pharmaceutical composition according to any of claims 1 to 6 comprising the pamoate salt of octreotide.

8. The pharmaceutical composition according to any of claims 1 to 7 wherein the release of the active ingredient is three or more months,

9. The pharmaceutical composition according to claim 8 wherein the release of the active ingredient is between three and six months.

10. The pharmaceutical composition according to any of claims 1 to 9 in form of microparticles, a semisolid or an implant.

11. The pharmaceutical composition according to claim 10 in form of microparticles. - 15

12. The pharmaceutical composition according to claim 11 wherein the microparticles have a diameter between 10 pm and 90 pm.

13. The pharmaceutical composition according to claim 11 or 12 wherein the microparticles are additionally covered or coated with an anti-agglomerating agent.

14. The pharmaceutical composition according to claim 13 wherein the microparticles are coated with an anti-agglomerating agent and the anti-agglomerating agent is present in an amount of less than 2% by weight of the microparticles,

15. The pharmaceutical composition according to claim 13 or 14 wherein the anti agglomerating agent is mannitol.

16. The pharmaceutical composition according to any of claims 1 to 15 sterilized by gamma irradiation.

17. Use of a pharmaceutical composition according to any of claims I to 16 in the manufacture of a medicament for long-term maintenance therapy in acromegalic patients, and treatment of severe diarrhea and flushing associated with malignant carcinoid tumors and vasoactive intestinal peptide tumors (vipoma tumors).

18. A method of administering octreotide or a pharmaceutically-acceptable salt thereof for long-term maintenance therapy in acromegalic patients, and treatment of severe diarrhea and flushing associated with malignant carcinoid tumors and vasoactive intestinal peptide tumors (vipoma tumors), said method comprising administering to a patient in need of octreotide or a pharmaceutically-acceptable salt thereof a pharmaceutical composition according to any of claims 1 to 16.

19. A process of manufacturing microparticles according to claim 11 comprising (i) preparation of an internal organic phase comprising (ia) dissolving the polymer or polymers in a suitable organic solvent or solvent mixture; (ib) dissolving/suspending/emulsification of the drug substance in the polymer solution obtained in step (ia); (ii) preparation of an external aqueous phase containing stabilizers; - 16 (iii) mixing the internal organic phase with the external aqueous phase to form an emulsion; and (iv) hardening the microparticles by solvent evaporation or solvent extraction, washing the microparticles, drying the microparticles and sieving the microparticles through 140 pm.

20. Microparticles prepared according to the process of claim 19.

21. An administration kit comprising the pharmaceutical composition according to any of claims 1 to 16 in a vial, together with a water-based vehicle In an ampoule, vial or prefilled syringe or as microparticles and-vehicle separated in a double chamber syringe.

22. The sustained release composition according to claim 1; or the use according to claim 17; or the method according to claim 18; or the process according to claim 19; or the kit according to claim 21 substantially as hereinbefore described with reference to the Examples.