US 2016O151447A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0151447 A1 BELSA GUIVERNAU et al. (43) Pub. Date: Jun. 2, 2016

(54) PHARMACEUTICAL COMPOSITION FOR A (30) Foreign Application Priority Data SUSTAINED RELEASE OF LANREOTDE Jul. 9, 2013 (EP) ...... 1329O156.2 (71) Applicant: IPSEN PHARMA S.A.S., Boulogne-Billancourt (FR) Publication Classification (72) Inventors: Ruth BIELSA GUIVERNAU, Palleja (51) Int. Cl. (ES); Roland CHERIF-CHEIKH, A638/08 (2006.01) Castelldefels (ES); Julie FOURNES, A647/12 (2006.01) Sant Pere de Ribes (ES); Daniel A619/00 (2006.01) MARTINEZ LORENTE, Sabadell (52) U.S. Cl. (ES); Anne PETIT, Leves (FR); Joel CPC ...... A61K 38/08 (2013.01); A61 K9/0019 RICHARD, Méré (FR) (2013.01); A61 K47/12 (2013.01) (21) Appl. No.: 14/903,010 (57) ABSTRACT A pharmaceutical composition for a Sustained release of pep (22) PCT Filed: Jul. 8, 2014 tide therapeutics, in particular for a Sustained release compat ible with therapeutic treatments of at least two months. In an (86). PCT No.: PCT/EP2014/064586 embodiment, the composition comprises lanreotide as an 371 (c)(1), active agent,9. a hydroSolubley co-solvent, and water with the 2) Date: Jan. 5, 2016 p H of the compositionp being9. from 4.0 to 7.5. Patent Application Publication Jun. 2, 2016 Sheet 1 of 6 US 2016/O151447 A1

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PHARMACEUTICAL COMPOSITION FORA 0010 Unless otherwise indicated the following definitions SUSTAINED RELEASE OF LANREOTDE are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. 0001. The present invention relates to a pharmaceutical (0011. The term “pH modifier” as used herein refers to a composition for a Sustained release of therapeutics, in compound or excipient used mainly to adjust or control the particular for a Sustained release compatible with therapeutic pH of the formulation. treatments of at least 2 months. In some preferred embodi 0012. The term “co-solvent as used in the present appli ments, the pharmaceutical composition comprises the pep cation refers to a solventor a mixture of solvents which allows tide lanreotide. Such pharmaceutical compositions are par the incorporation of the active ingredient in the composition ticularly useful for the treatment of diseases lanreotide is to obtain the required dose in a suitable Volume and matching indicated for. the injectability criteria. In the co-solvent, the solubility of 0002 Lanreotide is a marketed somatostatin analogue. It lanreotide or its salts used according to the present invention is a cyclic peptide with the amino acid sequence presented is preferably equal or higher than 8% (w/v) at room tempera below: ture (20-25°C.). 0013 The term “hydrosoluble' is understood to mean soluble in water. Preferably, the “hydrosoluble' co-solvent — has solubility in water measured at 25° C. higher than 10 mg/mL, and preferably higher than 30 mg/mL. 0014. The term “nonhydrosoluble' is understood to mean wherein Nal is the abbreviation for naphthylalanine, and there non soluble in water. Preferably, a “non hydrosoluble' (co) is a disulfide bridge between the two cysteine residues. polymer or excipient has solubility in water measured at 25° 0003 Lanreotide is indicated in the treatment of acrome C. less than 1 mg/mL, and preferably less than 0.1 mg/mL. galy due to both pituitary and non-pituitary growth hormone 0015 The term “low molecular weight' is understood to secreting tumors, the management of symptoms caused by mean that the molecular weight is less than 2,000 Da. neuroendocrine tumors (NET), particularly carcinoid tumors 0016. The term "aprotic' when used to describe a solvent and VIPomas (VIP=Vasoactive Intestinal Peptide), and in the is understood to mean a solvent unable to freely release a treatment of thyrotrophic adenoma. proton H+ in solution, and unable to modify the pH when 0004. The treatments require continuous or repeated added to a composition in the pH range of 4 to 8. administration to the patient over an extended period of time. 0017. The term "injectability” which can be determined As repeated injections cause both inconvenience and discom by measuring the injection force, refers to the suitability of fort to the patient, Sustained release preparations are desirable the formulation for parenteral administration using a device and have been the subject of development efforts. Thus lan for injection, like a syringe or an injector. reotide is available today in two formulations: a Sustained 0018. The term “stabilizer” as used herein means a phar release formulation which is injected intramuscularly every maceutically acceptable compound to prevent degradation, ten or fourteen days and an extended release formulation enhance the physical or chemical stability of the active sub which is administered subcutaneously once a month or once stance (e.g. a compound having antioxidant properties or every 2 months for certain acromegalic patients. However, Surfactants). even if this set of extended release formulations exists, a need 0019. The term “surfactant” as used herein refers to a remains to reduce both inconvenience and discomfort to the compound or excipient with surface active properties. When patient with extended release formulations covering more used in the present formulations, a surfactant may improve than 2 months or even 2 months for the patients not covered by the aqueous solubility of the active ingredient, help to protect the existing formulations. the active Substance against degradation, and/or limit active 0005 To extend the duration of treatment for more than ingredient precipitation if co-solvent alone is not sufficient. one month, in particular for at least two months, the amount of 0020. The term “antioxidant’ as used herein refers to a injected pharmaceutical active ingredient (injected dose) has compound having antioxidant properties. When used in the to be increased. On the other hand, to avoid further discomfort present formulations, the antioxidant may inhibit or prevent for the patient, the injected Volume must remain as low as oxidative degradation of the active ingredient and/or inhibit possible and compatible with the parenteral administration or prevent oxidative degradation of the excipients. route. Therefore, there is need for a new pharmaceutical com 0021. The term “(co)polymer means a polymer or position of lanreotide capable of delivering a Sustained copolymer or a mixture thereof. release over at least two months, preferably with a high dose 0022. The term “biocompatible” means biologically com of lanreotide (e.g. 120, 240 or 360 mg) while keeping a patible by not producing a medically significant toxic, inju convenient Volume of injection (e.g. equal or less than 2 mL). rious, or immunological response in living tissues, biological The present invention provides such pharmaceutical compo systems or biological functions. sitions. The Subject of the present invention is thus a pharma 0023 The term “biodegradable” means capable of being ceutical composition for a Sustained release of the active decomposed by biological agents, biological (micro-)organ ingredient for at least 2 months, comprising: isms, or when placed in biological fluids. 0006 lanreotide as the active ingredient, 0024. The term “essentially when used associated with 0007 a hydrosoluble co-solvent, and the expression “a composition consisting essentially of 0008 water, means that any additional components constitute only minor the pH of the composition ranging from 4.0 to 7.5. impurities, individually less than 2, preferably less than 1, 0009. In the text herein below, unless otherwise indicated, more preferably less than 0.5, 0.25% relative to the total the limits of a range of values are included in that range, weight of the composition, and in aggregate less than 3, 2, 1. especially in the expression “ranging from'. 0.5% relative to the total weight of the composition. US 2016/015 1447 A1 Jun. 2, 2016

0025. In a preferred embodiment, “a composition consist 0037. The co-solvent may be selected from low molecular ing essentially of means that any additional components weight hydroSoluble polymers such as polyvinylpyrrolidone constitute only minor impurities, individually less than 2% (PVP), polyethylene glycol (PEG) or a mixture thereof, and relative to the total weight of the composition, and in aggre in particular PEG 600, PEG 500-DME (dimethylether), PEG gate less than 3% relative to the total weight of the composi 500, PEG 400, PEG 300, PEG 200 or a mixture thereof. tion. 0038. The co-solvent may preferably be an aprotic sol 0026. In a preferred embodiment, “a composition consist vent. The aprotic co-solvent used according to the present ing essentially of means that any additional components invention does not significantly modify, or is unable to constitute only minor impurities, individually less than 1% modify, the pH value in the pH range of 4 to 8. Such aprotic relative to the total weight of the composition, and in aggre solvent may be selected from N-methyl-2-pyrrolidone gate less than 2% relative to the total weight of the composi (NMP), N-ethyl-2-pyrrolidone (NEP), glycofurol, propylene tion. glycol, ethanol, benzyl alcohol and mixtures thereof, 0027. In a preferred embodiment, “a composition consist 0039. In a preferred embodiment, the hydrosoluble co ing essentially of means that any additional components solvent is selected from the low molecular weight hydro constitute only minor impurities, individually less than 0.5% soluble polymers and mixtures thereof. relative to the total weight of the composition, and in aggre 0040. In a preferred embodiment, the hydrosoluble co gate less than 1% relative to the total weight of the composi Solvent is an aprotic solvent. tion. 0041. In another preferred embodiment, the co-solvent is 0028. In a preferred embodiment, “a composition consist selected from N-methyl-2-pyrrolidone (NMP), propylene ing essentially of means that any additional components glycol, glycerol, low molecular weight polyethylene glycols constitute only minor impurities, individually less than (PEG), glycofurol, ethanol and a mixture thereof, and more 0.25% relative to the total weight of the composition, and in preferably from NMP, low molecular weight PEG, glycofurol aggregate less than 0.5% relative to the total weight of the and mixtures thereof. composition. 0042. In a preferred embodiment, the co-solvent is present 0029. Unless otherwise stated, all percentages mentioned in a concentration ranging from 10 to 25% by weight, and in the present invention are weight/weight (w/w) percentages. more preferably from 15 to 22% by weight relative to the total 0030 The active ingredient lanreotide is in the form of a weight of the composition. salt or as a free-base. The salts of lanreotide which can be used 0043. In a more preferred embodiment, the co-solvent is for the invention are preferably pharmaceutically acceptable NMP. Preferably, the co-solvent is NMP and is present in a salts of organic acids, such as those of acetic, phenylacetic, concentration ranging from 15 to 20% by weight relative to lactic, malic, pamoic, ascorbic, Succinic, benzoic, methane the total weight of the composition. Sulphonic or toluenesulphonic acids, or pharmaceutically 0044. In another embodiment, the co-solvent is a low acceptable salts of inorganic acids, Such as those of hydro molecular weight PEG. Preferably, the co-solvent is a low chloric, hydrobromic, hydriodic, Sulphuric or phosphoric molecular weight PEG and is present in a concentration rang acids. ing from 15 to 22% by weight relative to the total weight of 0031. According to one preferred embodiment, lanreotide the composition. is in a salt form. 0045. In a more preferred embodiment, the co-solvent is 0032. Preferably, lanreotide is in the form of lanreotide glycofurol. Preferably, the co-solvent is glycofurol and is acetate. present in a concentration ranging from 16 to 22% by weight 0033 According to another preferred embodiment, lan relative to the total weight of the composition. Preferably, the reotide is as a free base. co-solvent is glycofurol and is present in a concentration 0034. Whatever the form of lanreotide, i.e. salt form or ranging from 16 to 20% by weight relative to the total weight free base, in the sense of the present invention, the amount of of the composition. lanreotide, expressed for instance as a concentration or a 0046. In another preferred embodiment, the co-solvent is percentage in the composition, refers to lanreotide as a free glycofurol of formula (1) base. 0035 Advantageously, lanreotide is present in a concen tration ranging from 35 to 55% by weight, preferably from 40 to 50% by weight, and more preferably from 42 to 48% by weight relative to the total weight of the composition. In CN- (OCH2CH-OH another preferred embodiment, lanreotide is present in a con O centration ranging from 42 to 46% by weight relative to the total weight of the composition. wherein n is an integer from 1 to 5, or a mixture thereof, 0036. A composition according to the present invention According to the present invention, the formula (1) covers the comprises a co-solvent which allows obtaining the required racemic as well as the enantiomeric forms of the compound. injectability criteria of the pharmaceutical compositions. The 0047. In another preferred embodiment, the co-solvent is co-solvent used in the composition according to the present glycofurol of formula (1) as defined above or a mixture invention is hydrosoluble. Moreover, the solubility, in the thereof, and is present in a concentration ranging from 16 to hydrosoluble co-solvent, of lanreotide or its salts used 20% by weight relative to the total weight of the composition. according to the present invention is equal or higher than 8% 0048. In another preferred embodiment, the co-solvent is (w/v) at room temperature. For comparison, the solubility of glycofurol of formula (1) as defined above or a mixture lanreotide acetate is less than 4% in water, aqueous acetic acid thereof, wherein n is an integer from 1 to 2, and is present in (at the concentration of 0.1 or 1 mol/mL), aqueous NaCl a concentration ranging from 16 to 20% by weight relative to (0.9%), or polysorbate (0.01%). the total weight of the composition. US 2016/015 1447 A1 Jun. 2, 2016

0049. As the composition is intended for parenteral 0075. In a preferred embodiment, the present invention is administration, the pH of the composition must be controlled a pharmaceutical composition for a Sustained release of the for a local tolerance and tolerability point of view, and this active ingredient for at least 2 months, said composition com parameter plays also a role on active Substance Solubilisation prising or consisting essentially of or consisting of and drug product Sustained release properties. Thus the pH of 0.076 lanreotide as the active ingredient, the composition is between 4.0 and 7.5. 0.077 a hydrosoluble aprotic co-solvent, 0050. In a preferred embodiment of the invention, the pH 0078 a pH modifier, and of the composition is from 4.0 to 6.0 and preferably from 4.8 0079 water, to 5.4. the pH of the composition ranging from 4.0 to 7.5, and pref 0051) To reach a pH ranging from 4.0 to 7.5, depending on erably from 4.0 to 6.0. the lanreotide form and the salt form in particular, a pH 0080. In another preferred embodiment, the pharmaceuti modifier may be needed. cal composition according to the invention is for a Sustained 0052. In another embodiment, the composition according release of an active ingredient for at least 2 months and to the present invention comprises an optional pH modifier. comprises or consists essentially of, or consisting of 0053. In a preferred embodiment, the present invention is I0081 from 35 to 55% of lanreotide as the active ingre a pharmaceutical composition for a Sustained release of the dient, active ingredient for at least 2 months, said composition com I0082 from 10 to 25% of a hydrosoluble aprotic co prising or consisting essentially of, or consisting of Solvent, 0054 lanreotide as the active ingredient, I0083) a pH modifier, and 0055 a hydrosoluble co-solvent, I0084) water (qsp 100%), 0056 an optional pH modifier, and the pH of the composition ranging from 4.0 to 7.5, and pref 0057 water, erably from 4.0 to 6.0. the pH of the composition ranging from 4.0 to 7.5. I0085. In another embodiment, the pharmaceutical compo 0058. In a more preferred embodiment, the composition of sition of the present invention is for a Sustained release of an the present invention comprises an optional pH modifier and active ingredient for at least 2 months and comprises or con the pH is ranging from 4.0 to 6.0. sists essentially of or consisting of 0059 Another subject of the present invention is a phar I0086 lanreotide as the active ingredient, maceutical composition for a sustained release of an active 0.087 a hydrosoluble co-solvent, ingredient for at least 2 months, said composition comprising 0088 a pH modifier, and or consisting essentially of, or consisting of: I0089 water (for injection), the pH of the composition ranging from 4.0 to 7.5 and the pH 0060 lanreotide as the active ingredient, modifier being different from the hydrosoluble co-solvent. 0061 a hydrosoluble co-solvent, (0090 Preferably, the pH modifier is added to reach a target 0062 an optional pH modifier, and pH value ranging from 4.0 to 7.5, preferably from 4.0 to 6.0, 0063 water (for injection), and more preferably from 4.8 to 5.4. the pH of the composition ranging from 4.0 to 6.0. 0091. In another preferred embodiment, the pharmaceuti 0064. In a preferred embodiment, the present invention is cal composition according to the invention is for a Sustained a pharmaceutical composition for a Sustained release of the release of an active ingredient for at least 2 months and active ingredient for at least 2 months, said composition com comprises or consists essentially of, or consisting of prising or consisting essentially of, or consisting of 0092 from 35 to 55% of lanreotide as the active ingre 0065 lanreotide as the active ingredient, dient, 0.066 a hydrosoluble aprotic co-solvent, (0.093 from 10 to 25% of a hydrosoluble co-solvent, 0067 an optional pH modifier, and 0094) a pH modifier, and 0068 water, (0.095 water (qsp 100%), the pH of the composition ranging from 4.0 to 7.5, and pref the pH of the composition ranging from 4.0 to 7.5, more erably from 4.0 to 6.0. The pH modifier may be chosen, for preferably from 4.0 to 6.0, and the pH modifier being different instance, from acetic acid, citric acid, lactic acid, phosphoric from the hydrosoluble co-solvent. In a preferred embodiment acid, hydrochloric acid, Stearic acid and pamoic acid. Ifused, of the invention, the pH modifier is present and selected from the pH modifier may be different from the hydrosoluble co acetic acid, citric acid, lactic acid, phosphoric acid, hydro solvent. chloric acid, Stearic acid and pamoic acid, and preferably is 0069. In another embodiment, the composition according acetic acid. to the present invention comprises a pH modifier. In another 0096. In another preferred embodiment, the pharmaceuti preferred embodiment, the composition according to the cal composition according to the present invention is free of present invention comprises a pH modifier and said pH modi any non hydrosoluble, biocompatible and/or biodegradable, fier is different from the co-solvent. (co)polymer or a mixture thereof. This means that the content 0070. In another embodiment, the pharmaceutical compo of any non hydrosoluble, biocompatible and/or biodegrad sition of the present invention is for a Sustained release of an able, (co)polymer in the composition is less than 0.1% by active ingredient for at least 2 months, and comprising or weight (w/w). consisting essentially of, or consisting of: 0097. A classical and well-described way to provide a 0071 lanreotide as the active ingredient, pharmaceutical composition with a sustained release of an 0072 a hydrosoluble co-solvent, active pharmaceutical ingredient after administration is the (0073 a pH modifier, and use of biocompatible (co)polymers such as polylactides 0074 water (for injection), (PLA), polyglycolides (PLG), poly lactide-co-glycolides the pH of the composition ranging from 4.0 to 6.0. (PLGA), polyalkylcyanoacrylates, poly-s-caprolactones and US 2016/015 1447 A1 Jun. 2, 2016

any (co)polymer agents obtained by combination or modifi 0123 a pH modifier, and cation of these biocompatible (co)polymers. Such (co)poly 0.124 water (qsp 100%), mers which are not hydrosoluble form the biodegradable the pH of the composition ranging from 4.0 to 7.5, and more matrix of microparticles or solid implants, which is progres preferably from 4.0 to 6.0. sively eroded when administered into the body. 0.125. A composition according to the present invention 0098. In another preferred embodiment, the pharmaceuti may also contain other additives usually used in Such phar cal composition of the present invention is for a Sustained maceutical compositions such as, for instance, stabilizers, release of the active ingredient for at least 2 months, free of antioxidants or Surfactants. any non hydrosoluble, biocompatible and/biodegradable, 0.126 Stabilizers or surfactants may be selected from fatty (co)polymer, and comprising or consisting essentially of, or acids and salts thereof, polyoxyethers, poloxamers, polyols consisting of: Such as trehalose, mannitol, Saccharose and dextrose, 0099 lanreotide as the active ingredient, polysorbates, polyoxyethylene fatty acid esters, and mixtures 0100 a hydrosoluble co-solvent, thereof. 0101 an optional pH modifier, and I0127. Antioxidants may be selected from: amino acids 01.02 water, Such as methionine, histidine, tryptophan; polyamino acids the pH of the composition ranging from 4.0 to 7.5, Such as glutathione; chelating agents such as disodium ede and more preferably comprising or consisting essentially of tate (EDTA) and citric acid; sodium metabisulfite; butylhy or consisting of droxytoluene (BHT); butylhydroxyanisol; ascorbic acid; and (0103 from 35 to 55% of lanreotide as the active ingre mixtures thereof. Preferably, the antioxidant is selected from dient, amino acids, polyamino acids, and mixtures thereof, and 0104 from 10 to 25% of a hydrosoluble co-solvent, more preferably from methionine, histidine, tryptophan and 0105 an optional pH modifier, and glutathione. (0.106) water (qsp 100%), I0128 If present, the amount in weight (w/w) of these the pH of the composition ranging from 4.0 to 7.5, and more additives is lower than 5.0% of the pharmaceutical composi preferably from 4.0 to 6.0. tion, and preferably lower than 1.0%. 0107. In another preferred embodiment, the pharmaceuti I0129. In a preferred embodiment, the composition accord cal composition of the present invention is for a Sustained ing to the present invention comprises an additive selected release of an active ingredient for at least 2 months, free of any non hydrosoluble, biocompatible and/biodegradable, (co) from stabilizers, antioxidants, Surfactants, and mixtures polymer, and comprising or consisting essentially of, or con thereof, in an amount lower than 5.0% (w/w) of the pharma sisting of: ceutical composition, and preferably lower than 1.0%. 0.108 lanreotide as the active ingredient, 0.130. In a preferred embodiment, the composition accord 0109 a hydrosoluble co-solvent, ing to the present invention comprises an antioxidant, in an 0110 a pH modifier, and amount lower than 5.0% (w/w) of the pharmaceutical com 0111 water, position, and preferably lower than 1.0%. the pH of the composition ranging from 4.0 to 7.5 and the pH I0131. In another preferred embodiment, the composition modifier being different from the hydrosoluble co-solvent, according to the present invention comprises an antioxidant and more preferably comprising or consisting essentially of selected from amino acids, polyamino acids, and mixtures or consisting thereof, in an amount lower than 5.0% (w/w) of the pharma 0112 from 35 to 55% of lanreotide as the active ingre ceutical composition, and preferably lower than 1.0%. dient, 0.132. In another preferred embodiment, the composition 0113 from 10 to 25% of a hydrosoluble co-solvent, according to the present invention comprises an antioxidant 0114 a pH modifier, and selected from methionine, histidine, tryptophan and glu 0115 water (qsp 100%), tathione, and mixtures thereof, in an amount lower than 5.0% the pH of the composition ranging from 4.0 to 7.5, and more (w/w) of the pharmaceutical composition, and preferably preferably from 4.0 to 6.0, and the pH modifier being different lower than 1.0%. from the hydrosoluble co-solvent. I0133. In another preferred embodiment, the composition 0116. In another preferred embodiment, the pharmaceuti according to the invention is for a Sustained release of an cal composition of the present invention is for a Sustained active ingredient for at least 2 months and consists of release of an active ingredient for at least 2 months, free of any 0.134 from 35 to 55% of lanreotide as the active ingre non hydrosoluble, biocompatible and/biodegradable, (co) dient, polymer, and comprising or consisting essentially of or con 0135 from 10 to 25% of a hydrosoluble aprotic co sisting Solvent, 0117 lanreotide as the active ingredient, 0.136 a pH modifier, 0118 a hydrosoluble aprotic co-solvent, 0.137 from 0 to 5% of an additive selected from stabi 0119 a pH modifier, and lizers, antioxidants, Surfactants, and mixtures thereof, 0120 water, and the pH of the composition ranging from 4.0 to 7.5, 0138 water (qsp 100%), and more preferably comprising or consisting essentially of the pH of the composition ranging from 4.0 to 7.5. or consisting of 0.139. In another preferred embodiment, the composition I0121 from 35 to 55% of lanreotide as the active ingre according to the invention is for a Sustained release of an dient, active ingredient for at least 2 months and consists of 0.122 from 10 to 25% of a hydrosoluble aprotic co 0140 from 35 to 55% of lanreotide as the active ingre Solvent, dient, US 2016/015 1447 A1 Jun. 2, 2016

0141 from 10 to 25% of a hydrosoluble aprotic co acid, citric acid, disodium edetate, sodium metabisulfite, Solvent, butylhydroxytoluene, butylhydroxyanisol, and mixtures 0.142 a pH modifier, thereof, and 0.143 from 0 to 1% of an additive selected from stabi (0168 water (qsp 100%), lizers, antioxidants, Surfactants, and mixtures thereof, the pH of the composition ranging from 4.0 to 6.0. and 0169. In a preferred embodiment, a pharmaceutical com 0144) water (qsp 100%), position of the present invention is free of any non hydro the pH of the composition ranging from 4.0 to 6.0. soluble, biocompatible and/or biodegradable, (co)polymer, 0145. In another preferred embodiment, the composition and comprises or consisting essentially of or consisting of according to the invention is for a Sustained release of an 0170 lanreotide as the active ingredient, active ingredient for at least 2 months and consists of 0171 acetic acid as pH modifier, 0146 from 35 to 55% of lanreotide as the active ingre 0172 glycofurol as hydrosoluble co-solvent, and dient, (0173 water for injection, the pH of the composition ranging from 4.0 to 6.0. 0147 from 10 to 25% of a hydrosoluble co-solvent, 0.174. In another preferred embodiment, a pharmaceutical 0148 a pH modifier, composition of the present invention is free of any nonhydro 0149 from 0 to 5% of an additive selected from stabi soluble, biocompatible and/or biodegradable, (co)polymer, lizers, antioxidants, Surfactants, and mixtures thereof, and comprises or consisting essentially of or consisting of and 0.175 lanreotide as the active ingredient, (O150 water (qsp 100%), 0176 acetic acid as pH modifier, the pH of the composition ranging from 4.0 to 7.5, and the pH 0.177 glycofurol as hydrosoluble co-solvent, and modifier being different from the hydrosoluble co-solvent. (0178 water for injection, 0151. In another preferred embodiment, the composition the pH of the composition ranging from 4.0 to 6.0, and lan according to the invention is for a Sustained release of an reotide being in an acetate form, active ingredient for at least 2 months and consists of and more preferably comprises or consists essentially of or 0152 from 35 to 55% of lanreotide as the active ingre consisting of dient, (0179 from 40 to 50% (w/w) of lanreotide, (O153 from 10 to 25% of a hydrosoluble co-solvent, 0180 from 16 to 22% (w/w) of glycofurol, and 0154) a pH modifier, 0181 qsp 100% of water for injection. 0155 from 0 to 1% of an additive selected from stabi 0182. In a particular embodiment, a pharmaceutical com lizers, antioxidants, Surfactants, and mixtures thereof, position of the present invention is free of any non hydro and soluble, biocompatible and/or biodegradable, (co)polymer, 0156 water (qsp 100%), and comprises or consists essentially of or consisting of the pH of the composition ranging from 4.0 to 6.0, the pH 0183 from 42 to 48% (w/w) of lanreotide, modifier being different from the hydrosoluble co-solvent. 0.184 from 16 to 22% (w/w) of glycofurol, 0157. In another preferred embodiment, the composition 0185 from 5 to 7% (w/w) of acetic acid, and according to the invention is for a Sustained release of an 0186 qsp 100% of water for injection, active ingredient for at least 2 months, consisting of: the pH of the composition ranging from 4.8 to 5.4, and lan 0158 from 35 to 55% of lanreotide as the active ingre reotide being in its acetate form. dient, 0187. In a particular embodiment, a pharmaceutical com 0159 from 10 to 25% of a hydrosoluble co-solvent position of the present invention is free of any non hydro selected from NMP, low molecular PEG, glycofuroland soluble, biocompatible and/or biodegradable, (co)polymer, mixtures thereof, and comprises or consists essentially of or consisting of 0160 a pH modifier selected from acetic acid, citric 0188 from 42 to 46% (w/w) of lanreotide, acid, lactic acid, phosphoric acid, hydrochloric acid, (0189 from 16 to 20% (w/w) of glycofurol, Stearic acid and pamoic acid, 0.190 acetic acid, and 0.161 from 0 to 5% of an additive selected from stabi (0191) qsp 100% of water for injection, lizers, antioxidants, Surfactants, and mixtures thereof, the pH of the composition ranging from 4.8 to 5.4, lanreotide and being in its acetate form, and glycofurol being of formula (1) (0162 water (qsp 100%), as defined above or a mixture thereof. the pH of the composition ranging from 4.0 to 6.0. 0.192 In another particular embodiment, a pharmaceutical 0163. In another preferred embodiment, the composition composition of the present invention is free of any nonhydro according to the invention is for a Sustained release of an soluble, biocompatible and/or biodegradable, (co)polymer, active ingredient for at least 2 months, consisting of: and comprises or consists essentially of or consisting of 0164 from 35 to 55% of lanreotide as the active ingre (0193 from 42 to 46% (w/w) of lanreotide, dient, (0194 from 16 to 20% (w/w) of glycofurol, (0165 from 10 to 25% of a hydrosoluble co-solvent 0.195 acetic acid, and selected from NMP, low molecular PEG, glycofuroland (0196) qsp 100% of water for injection, mixtures thereof, the pH of the composition ranging from 4.8 to 5.4, lanreotide 0166 a pH modifier selected from acetic acid, citric being in its acetate form, and glycofurol being of formula (1) acid, lactic acid, phosphoric acid, hydrochloric acid, as defined above wherein n is an integer from 1 to 2 or a Stearic acid and pamoic acid, mixture thereof. 0.167 from 0 to 1% of an antioxidant selected from 0.197 In the case where lanreotide is in its acetate form and methionine, histidine, tryptophan, glutathione, ascorbic acetic acid is used as pH modifier, the acetate content in the US 2016/015 1447 A1 Jun. 2, 2016

composition, coming from lanreotide under its salt form and 0226 a pH modifier, and from acetic acid, can be measured. 0227 water (qsp 100%), 0198 When lanreotide is in its acetate form, acetic acid as the pH of the composition ranging from 4.0 to 7.5, more pH modifier may be added in Such a manner that the concen preferably from 4.0 to 6.0. tration of acetate content in the composition is ranging from 0228. In another preferred embodiment, the composition 2 to 10% by weight, and preferably from 6 to 10% by weight according to the invention is for a Sustained release of an relative to the total weight of the composition. active ingredient for at least 2 months, consisting of: 0199. In another embodiment, a pharmaceutical composi 0229 from 42 to 46% of lanreotide as the active ingre tion of the present invention is free of any non hydrosoluble, dient, biocompatible and/or biodegradable, (co)polymer, and com 0230 from 16 to 20% of glycofurol of formula (1) as prises or consisting essentially of or consisting of defined above, or a mixture thereof, 0200 lanreotide in its acetate form, 0231 acetic acid as pH modifier, 0201 acetic acid as pH modifier, 0232 from 0 to 5% of an additive selected from stabi 0202 glycofurol as hydrosoluble co-solvent, and lizers, antioxidants, Surfactants, and mixtures thereof, 0203 water for injection, and the acetate content in the composition being ranged from 2 to 0233 water (qsp 100%), 10% by weight, and preferably from 6 to 10% by weight, the pH of the composition ranging from 4.0 to 6.0. and more preferably 0234. In another preferred embodiment, the composition (0204 from 42 to 48% (w/w) of lanreotide, according to the invention is for a Sustained release of an (0205 from 16 to 22% (w/w) of glycofurol, active ingredient for at least 2 months, consisting of: 0206 acetic acid, and 0235 from 42 to 46% of lanreotide as the active ingre 0207 qsp 100% of water for injection, dient, in acetate form, the pH of the composition ranging from 4.8 to 5.4, and the 0236 from 16 to 20% of glycofurol of formula (1) acetate content in the composition being ranged from 6 to above wherein n is an integer from 1 to 2, or a mixture 10% by weight. thereof, 0208. In another embodiment, a pharmaceutical composi 0237 acetic acid as pH modifier, tion of the present invention is free of any non hydrosoluble, 0238 from 0 to 1% of an additive selected from stabi biocompatible and/or biodegradable, (co)polymer, and com lizers, antioxidants, Surfactants, and mixtures thereof, prises or consists essentially of or consisting of and 0209 lanreotide in its acetate form, 0239 water (qsp 100%), 0210 acetic acid as pH modifier, the pH of the composition ranging from 4.8-5.4. 0211 glycofurol as hydrosoluble co-solvent, and 0240. In another preferred embodiment, the composition 0212 water for injection, according to the invention is for a Sustained release of an the acetate content in the composition being ranged from 2 to active ingredient for at least 2 months, consisting of: 10% by weight, and preferably from 6 to 10% by weight, and 0241 from 42 to 46% of lanreotide as the active ingre glycofurol being of formula (1) or a mixture thereof, dient, in acetate form, and more preferably comprising or consisting essentially of 0242 from 16 to 20% of glycofurol of formula (1) or consisting of above wherein n is an integer from 1 to 2, or a mixture 0213 from 42 to 48% (w/w) of lanreotide, thereof, 0214 from 16 to 22% (w/w) of glycofurol, 0243 acetic acid as pH modifier, 0215 acetic acid, and 0244 from 0 to 1% of an antioxidant selected from 0216 qsp 100% of water for injection, methionine, histidine, tryptophan, glutathione, ascorbic the pH of the composition ranging from 4.8 to 5.4, the acetate acid, disodium edetate, citric acid, sodium metabisulfite, content in the composition being ranged from 6 to 10% by butylhydroxytoluene (BHT), butylhydroxyanisol, and weight, and glycofurol being of formula (1) or a mixture mixtures thereof, and thereof wherein n is an integer from 1 to 2. 0245 water (qsp 100%), 0217. In another particular embodiment, a pharmaceutical the pH of the composition ranging from 4.8-5.4. composition of the present invention is free of any nonhydro 0246 A pharmaceutical composition according to the soluble, biocompatible and/or biodegradable, (co)polymer, present invention is a semi-solid formulation. A semi-solid and comprises: composition can be injected using a standard device for injec 0218 lanreotide as the active ingredient, tion Such as a Syringe connected to a needle. The Viscosity and 0219 acetic acid as pH modifier, other physical state characteristics of the compositions can be 0220 glycofurol as hydrosoluble co-solvent, assessed as the injectability, when the administration step is 0221 an additive selected from stabilizers, antioxidants evaluated. The injectability can be determined conducting and Surfactants, and simulated injection tests and according to different physical 0222 water for injection, methods. The injectability can be reported as injection the pH of the composition ranging from 4.0 to 7.5, and lan strength or Syringe injection force (SIF). reotide being in an acetate form. 0247 The SIF can be determined using a dynamometer 0223) In another preferred embodiment, the composition (L1000R, Lloyd Instruments Ltd.) equipped with a calibrated according to the invention is for a Sustained release of an cell (NLC 100N, Lloyd Instruments Ltd.). The pharmaceuti active ingredient for at least 2 months, consisting of: cal composition conditioned in a 4.5 mm diameter Syringe 0224 from 35 to 55% of lanreotide as the active ingre coupled with a 20 mm lengthx 1.2 mm ID needle is tested for dient, its injectability during a simulated discharge at a 100-200 0225 from 10 to 25% of a hydrosoluble co-solvent, mm/min speed range where the force applied by the instru US 2016/015 1447 A1 Jun. 2, 2016

ment on the plunger and its displacement are recorded. The (NET), particularly carcinoid tumors and VIPomas, and in the simulated injection is performed vertically in the air. The treatment of thyrotrophic adenoma. maximum injection force (in N) is derived from the data 0258. A pharmaceutical composition according to the collected during the discharge. present invention may be useful in the treatment of acrome 0248. In a preferred embodiment, a pharmaceutical com galy due to both pituitary and non-pituitary growth hormone position according to the present invention presents an inject secreting tumors, the management of symptoms caused by ability defined by a SIF ranging from 5 to 50 N when tested neuroendocrine tumors (NET), particularly carcinoid tumors with the method defined above with a dose up to 500 mg of and VIPomas, and in the treatment of thyrotrophic adenoma. lanreotide. Preferably the SIF of the pharmaceutical compo In a preferred embodiment, a pharmaceutical composition sition is ranging from 10 to 35 N. according to the present invention is useful in the treatment of 0249. A pharmaceutical composition according to the acromegaly or NET. The NET can e.g. be selected from present invention is administered by the parenteral route. In a functioning and non-functioning gastroenteropancreatic neu preferred embodiment, the composition of the present inven roendocrine tumors. tion is administered by Subcutaneous, intramuscular or deep 0259. The invention therefore also relates to a method of Subcutaneous injection, and more preferably subcutaneous or treatment of a patient suffering from acromegaly by admin deep-subcutaneous injection. istering atherapeutically active amount of the pharmaceutical 0250 For the sub-cutaneous route, and deep-subcutane composition described in any one of the embodiments ous in particular, which remains the preferred one, the Volume described above. of injection is preferably not greater than 2 or 1.9 or 1.8 or 1.7 0260. In an embodiment, the pharmaceutical composition or 1.6 or 1.5 or 1.4 or 1.3 or 1.2 or 1.1. or 1 mL. In order to load in accordance with the present invention is administered or up to 500 mg of lanreotide in such a volume, specific formu injected, or prepared for administration or injection into a lations had to be defined as the controlled-release properties patient in need thereof, no more frequently than every 8 had to be combined with the high concentration of active weeks or preferably every 9 or 10 or 11 or 12 or 13 or 14 or 15 ingredient and an acceptable injectability. Such a situation is or 16 weeks. Preferably, it is administered or injected every 13 a challenge as a significant proportion of specific excipients weeks. aimed to provide the Sustained release properties is usually 0261. In a further preferred embodiment, the pharmaceu required and this amount removes capacity of loading for the tical composition of the invention is administered or prepared active ingredient. for administration as a single injection. 0251 A pharmaceutical composition according to the 0262 Preferably, the method comprises administering the present invention allows a Sustained release of lanreotide in pharmaceutical composition at least once every 9 weeks or 10 humans for at least 2 months. Such release is obtained without weeks or 12 weeks or 13 weeks or 14 weeks or 15 weeks or 16 any (co)polymeric matrix in the composition, in particular weeks. More preferably, the method comprises administering without any nonhydrosoluble, biocompatible and/biodegrad the pharmaceutical composition at least once every 13 weeks. able, (co)polymeric agents usually used in Sustained release 0263. In another embodiment, the pharmaceutical compo composition Such as polylactides (PLA), polyglycolides sition is administered by single injection. Preferably, it is (PLG), poly lactide-co-glycolides (PLGA), polyalkylcy injected intramuscularly, Subcutaneously or deep Subcutane anoacrylates, poly-s-caprolactones and any (co)polymer ously. agents obtained by combination or modification of these bio 0264. In yet another embodiment, the pharmaceutical compatible (co)polymers. composition is administered at a dose of 60.90, 120 or 240 or 0252. In a preferred embodiment, the sustained release of 360 mg of active pharmaceutical ingredient, i.e. lanreotide. lanreotide is of at least 2 to 6 months in humans. Preferably, the pharmaceutical composition is administered at a dose of 120, 240, or 360 mg of lanreotide. 0253) In a preferred embodiment, the sustained release of 0265. The invention also relates to a method of treatment lanreotide is of at least 2 months in humans. or prevention of a patient Suffering from a neuroendocrine 0254. In a preferred embodiment, the sustained release of tumor (NET) by administering a therapeutically active lanreotide is of at least 3 months in humans. amount of the pharmaceutical composition described in any 0255. The composition according to the invention allows a one of the embodiments above. Preferably, symptoms caused sustained release for at least 63 days, 70 days, 77 days, 84 by neuroendocrine tumors (NET) are being treated or pre days, or 90 days and preferably 91 days. vented. In an embodiment, these symptoms are selected from 0256 In a preferred embodiment, the composition accord flushing, diarrhea, and abdominal cramping. ing to the invention allows a sustained release for at least 63 0266 The invention also relates to a method of treatment days. In another preferred embodiment, the composition or prevention of a patient Suffering from thyrotrophic according to the invention allows a Sustained release for at adenoma by administering atherapeutically active amount of least 70 days. In another preferred embodiment, the compo the pharmaceutical composition described in any one of the sition according to the invention allows a Sustained release for embodiments above. at least 77 days. In a more preferred embodiment, the com 0267. The invention also relates to a pharmaceutical com position according to the invention allows a Sustained release position according to any one of the embodiments described for at least 84 days. In another more preferred embodiment, above for use in medicine. In an embodiment, the pharma the composition of the present invention allows a Sustained ceutical composition of the invention is for use in treating or release for at least 91 days. preventing acromegaly. In a further embodiment, the phar 0257 Lanreotide is a marketed somatostatin analogue. It maceutical composition is for use in treating or preventing a is indicated in the treatment of acromegaly due to both pitu neuroendocrine tumor (NET). The NET can e.g. be selected itary and non-pituitary growth hormone-secreting tumors, the from functioning and nonfunctioning gastroenterointestinal management of symptoms caused by neuroendocrine tumors neuroendocrine tumors. Preferably, the pharmaceutical com US 2016/015 1447 A1 Jun. 2, 2016 position is for use in treating or managing a symptom of a use in the treatment of acromegaly due to both pituitary and NETSuch as a symptom selected from flushing, diarrhea, and non-pituitary growth hormone-secreting tumors, said compo abdominal pain. In a further embodiment, the pharmaceutical sition consisting of: composition of the invention is for use in treating or prevent 0292 from 42 to 46% (w/w) of lanreotide, ing a thyrotrophic adenoma. In a preferred embodiment, the 0293 from 16 to 20% (w/w) of glycofurol of formula present invention relates to a pharmaceutical composition as (1) as defined above and n is an integer from 1 to 2, defined above for use in the treatment of acromegaly due to 0294 acetic acid, both pituitary and non-pituitary growth hormone-secreting 0295 from 0 to 1% of an additive selected from stabi tumors, said composition consisting of lizers, antioxidants, Surfactants, and mixtures thereof, 0268 from 35 to 55% of lanreotide as the active ingre and dient, 0296 qsp 100% of water for injection, 0269 from 10 to 25% of a hydrosoluble co-solvent, the pH of the composition ranging from 4.8 to 5.4, and lan (0270 a pH modifier, reotide being in its acetate form. 0271 from 0 to 5% of an additive selected from stabi 0297. In a preferred embodiment, the present invention lizers, antioxidants, Surfactants, and mixtures thereof, also relates to a pharmaceutical composition as defined above and for use in the management of symptoms caused by neuroen (0272 water (qsp 100%), docrine tumors (NET), said composition consisting of the pH of the composition ranging from 4.0 to 7.5, and the pH modifier being different from the hydrosoluble co-solvent. 0298 from 42 to 46% (w/w) of lanreotide, 0273. In a preferred embodiment, the present invention 0299 from 16 to 20% (w/w) of glycofurol of formula also relates to a pharmaceutical composition as defined above (1) as defined above and n is an integer from 1 to 2, for use in the the management of symptoms caused by neu 0300 acetic acid, roendocrine tumors (NET), said composition consisting of 0301 from 0 to 1% of an additive selected from stabi 0274 from 35 to 55% of lanreotide as the active ingre lizers, antioxidants, Surfactants, and mixtures thereof, dient, and (0275 from 10 to 25% of a hydrosoluble co-solvent, 0302) qsp 100% of water for injection, (0276 a pH modifier, the pH of the composition ranging from 4.8 to 5.4, and lan reotide being in its acetate form. A pharmaceutical composi (0277 from 0 to 5% of an additive selected from stabi tion according to the present invention provides after the first lizers, antioxidants, Surfactants, and mixtures thereof, week of release a pharmacokinetic profile with a very con and stant and reproducible absorption rate and a specific negative (0278 water (qsp 100%), slope which allow suitable scenarios when repeated admin the pH of the composition ranging from 4.0 to 7.5, and the pH istrations are applied to address chronic and long-term treat modifier being different from the hydrosoluble co-solvent. ments. This specific pattern of pharmacokinetic profiles over 0279. In a preferred embodiment, the present invention a period of several weeks (FIG. 1) where the plasmatic levels relates to a pharmaceutical composition as defined above for of lanreotide decrease steadily, can be used to cover different use in the treatment of acromegaly due to both pituitary and durations of treatment and this for patients with different non-pituitary growth hormone-secreting tumors, said compo therapeutic windows. This modulation of the duration can be sition consisting of: obtained using a single pharmaceutical composition at a (0280 from 42 to 46% (w/w) of lanreotide, defined and unique dose (FIG. 2). (0281 from 16 to 20% (w/w) of glycofurol of formula 0303. The specific pharmacokinetic pattern is usually (1) as defined above, obtained from 2 weeks to 6 months and more preferably from 0282 acetic acid, 1 to 4 months. This allows defining new personalized treat 0283 from 0 to 5% of an additive selected from stabi ments for patients and indications such as acromegaly and lizers, antioxidants, Surfactants, and mixtures thereof, NET. and 0304 Furthermore the invention relates to a process for 0284 qsp 100% of water for injection, the preparation of a pharmaceutical composition for the pH of the composition ranging from 4.0 to 6.0. parenteral applications as described above. 0285. In a preferred embodiment, the present invention 0305 Preferably, the invention relates to a process for the also relates to a pharmaceutical composition as defined above preparation of a pharmaceutical composition as described for use in the management of symptoms caused by neuroen above, said process comprising the following steps: docrine tumors (NET), said composition consisting of 0306 preparation of a co-solvent mixture including the (0286 from 42 to 46% (w/w) of lanreotide, pH modifier and other additives when needed, (0287 from 16 to 20% (w/w) of glycofurol of formula 0307 introduction of the active ingredient in a suitable (1) as defined above, container, 0288 acetic acid, 0308 hydration of the active ingredient and homogeni 0289 from 0 to 5% of an additive selected from stabi Zation of the composition by means of a mixing process lizers, antioxidants, Surfactants, and mixtures thereof, at a temperature between 5 and 70° C., preferably at and room temperature. 0290 qsp 100% of water for injection, 0309 Preferably, the invention relates to a process for the the pH of the composition ranging from 4.0 to 6.0. preparation of a pharmaceutical composition for parenteral 0291. In a preferred embodiment, the present invention applications as described above, said process comprising the relates to a pharmaceutical composition as defined above for following steps: US 2016/015 1447 A1 Jun. 2, 2016

0310 preparation of a co-solvent mixture including the to-use presentation. It may also be available as a ready-to pH modifier and other additives when needed, and intro reconstitute presentation where a freeze-dried product con duction of the mixture into a syringe or a syringe-like taining the active ingredient can be extemporaneously container, reconstituted with the mixture of the co-solvent, the optional 0311 introduction of the active ingredient into a second pH modifier and other additives if needed as solvent for Syringe or a syringe-like container, reconstitution. 0312 connection of the 2 Syringes or Syringe-like con 0329. As a further embodiment the pharmaceutical com tainers with a 2-way connector, position may be packaged in pre-filled Syringes. 0313 hydration of the active ingredient and homogeni 0330. In a preferred embodiment, the present invention Zation of the composition by a kneading process also relates to a pre-filled Syringe, said Syringe containing the between the 2 containers and through the connector at a pharmaceutical composition as define above for a Sustained temperature between 5° C. and 70° C., preferably at release of an active ingredient for at least 2 months and room temperature. consisting of: 0314 Preferably, the invention relates to a process for the 0331 from 35 to 55% of lanreotide as the active ingre preparation of a pharmaceutical composition for parenteral dient, applications as described above, said process comprising the 0332 from 10 to 25% of a hydrosoluble co-solvent, following steps: 0333 a pH modifier, 0315 preparation of a co-solvent mixture including the 0334 from 0 to 5% of additive or mixture thereof pH modifier and other additives if needed and introduc Selected from stabilizers, antioxidants and Surfactants tion of the mixture into a syringe or a syringe-like con and tainer, 0335) water (qsp 100%), 0316 introduction of the active ingredient into a second the pH of the composition ranging from 4.0 to 7.5, and the pH Syringe or a syringe-like container, modifier being different from the hydrosoluble co-solvent. 0317 connection of the 2 syringes or syringe-like con 0336. In another preferred embodiment, the present inven tainers with a 3-ways connector fitted with a 2-way tion also relates to a pre-filled Syringe, said Syringe containing valve, a pharmaceutical composition as defined above for a Sus 0318 removing the air from the system by a suitable tained release of an active ingredient for at least 2 months and method, for instance applying vacuum to the free port of consisting of: the connector, 0337 from 42 to 46% (w/w) of lanreotide, 0319 hydration of the active ingredient and homogeni 0338 from 16 to 20% (w/w) of glycofurol of formula Zation of the composition by a kneading process (1) as defined above, between the 2 containers and through the connector at a 0339 acetic acid, temperature between 5 and 70° C., preferably at room 0340 from 0 to 5% of an additive selected from stabi temperature. lizers, antioxidants, Surfactants, and mixtures thereof, 0320 In addition the whole preparation process can be and controlled regarding the critical process parameters such as 0341 qsp 100% of water for injection, temperature, pressure, number of cycles and Syringe-to-valve the pH of the composition ranging from 4.0 to 6.0. diameter ratio, with equipment common to the skilled prac 0342. In another preferred embodiment, the present inven titioner. tion also relates to a pre-filled Syringe, said Syringe containing 0321 Alternatively, the preparation of the pharmaceutical a pharmaceutical composition as defined above for a Sus compositions as described above may be carried out extem tained release of an active ingredient for at least 2 months and poraneously, i.e. before administration. consisting of: 0322. In a preferred embodiment, the preparation of the (0343 from 42 to 46% (w/w) of lanreotide, pharmaceutical compositions as described above is carried 0344 from 16 to 20% (w/w) of glycofurol of formula out extemporaneously, i.e. before administration by a knead (1) as defined above and n is an integer from 1 to 2, ing process between: (0345 acetic acid, 0323 a pre-filled syringe containing the suitable dose of 0346 from 0 to 1% of an additive selected from stabi active ingredient, and lizers, antioxidants, Surfactants, and mixtures thereof, 0324 a syringe containing the mixture of the co-sol and vent, the optional pH modifier and other additives if (0347 qsp 100% of water for injection, needed (used as vehicle for reconstitution). the pH of the composition ranging from 4.8 to 5.4, and lan 0325 In a further embodiment of the invention, the active reotide being in its acetate form. ingredient can be previously treated for instance by freeze 0348. In a preferred embodiment both freeze-dried prod drying, drying, grinding, granulation, compaction, sieving, uct and solvent for reconstitution are packed in Syringes before the preparation of the pharmaceutical composition. which can be connected and used as a mixing device to 0326. Any sterilization technique Such as gamma irradia facilitate the reconstitution process and the final administra tion, electron beam irradiation, steam or sterile filtration for tion of the reconstituted formulation. part of the process can be used to obtain a sterile pharmaceu 0349 Another subject of the present invention is a phar tical composition. maceutical composition for a Sustained release of the active 0327. In a further embodiment of the invention, the prepa ingredient for at least 2 months, comprising, consisting essen ration of the pharmaceutical composition is conducted under tially of or consisting of aseptic conditions. 0350 as the active ingredient, a hydrosoluble peptide or 0328. A pharmaceutical composition according to the any pharmaceutically acceptable salt thereof, present invention may be available as a pre-filled and ready 0351 glycofurol as co-solvent, US 2016/015 1447 A1 Jun. 2, 2016

0352 optionally a pH modifier, and are preferably pharmaceutically acceptable salts of organic 0353 water, acids, Such as those of acetic, phenylacetic, lactic, malic, the pH of the composition ranging from 4.0 to 8. pamoic, ascorbic, Succinic, benzoic, methaneSulphonic or 0354 Suitable that can be used in the invention toluenesulphonic acids, or pharmaceutically acceptable salts include growth hormone (GH), growth hormone releasing of inorganic acids, such as those of hydrochloric, hydrobro peptide (GHRP), growth hormone releasing factor (GRF), mic, hydriodic, Sulphuric or phosphoric acids. epidermal growth factor, interferon, insulin, Somatostatin, 0360. In accordance with the present invention, such phar bombesin, calcitonin, calcitonin gene related peptide maceutical compositions are preferably for use as a medica (CGRP), amylin, parathyroid hormone (PTH), parathyroid ment or are used in a method of treating a disease in a patient hormone related peptide (PTHrp), gastrin, gastrin releasing in need thereof. peptide (GRP), melanocyte stimulating hormone (MSH), 0361. Another subject of the present invention is a phar adrenocorticotrophic hormone (ACTH), maceutical composition for a Sustained release of the active (LH), luteinizing hormone-releasing hormone (LHRH), ingredient for at least 2 months, comprising, consisting essen cytokinases, Sorbine, cholecystokinin (CCK), glucagon, glu tially of or consisting of cagon-like peptide (GLP), gastrin, enkephalin, neuromedin, 0362 as the active ingredient, a hydrosoluble peptide endothelin, substance P. neuropeptide Y (NPY), peptide YY selected from lanreotide, octreotide, pasireotide, buser (PYY), vasoactive intestinal peptide (VIP), pituitary adeny elin, , , and , or late cyclase activating polypeptide (PACAP), bradykinin, any pharmaceutically acceptable salt thereof, thyrotropin releasing hormone (TRH), beta-cell tropin (a 0363 glycofurol as co-solvent, fragment of ACTH), or biologically active analogs of any of 0364 optionally a pH modifier, and the foregoing. 0365 water, 0355 The terms “biologically active analog and “ana the pH of the composition ranging from 4.0 to 8, log are used interchangeably hereinto cover naturally occur and preferably comprising, consisting essentially of or con ring, recombinant, and synthetic peptides, or derivatives or sisting of: fragments of such peptides, that exhibit substantially the 0366 as the active ingredient, a hydrosoluble peptide same agonist or antagonist effect of unmodified, or naturally selected from lanreotide, octreotide, pasireotide, buser occurring peptides, including e.g., those in which one or more elin, goserelin, leuprorelin, nafarelin and triptorelin, or of the naturally occurring amino acid residues has been any pharmaceutically acceptable salt thereof, deleted, substituted, or modified, or the N- or C-terminal 0367 glycofurol as co-solvent, group has been structurally modified. The agonist or antago 0368 a pH modifier, and nist effect of a peptide on its ligand or receptor can be mea 0369 water, Sured e.g. in in vitro or in vivo assays, such as cell-based 0370 Advantageously, the peptide or its pharmaceutically assays or experimental animal models adapted to the particu acceptable salt is present in a concentration ranging from 20 lar peptide. Such assays are well within the knowledge of the to 60, preferably from 35 to 55% by weight, and more pref skilled person. erably from 40 to 50% by weight, relative to the total weight 0356. Preferred hydrosoluble peptide salts according to of the composition. the present invention include salts of growth hormone (GH), 0371. In a preferred embodiment, the glycofurol is present growth hormone releasing peptide (GHRP), growth hormone in a concentration ranging from 10 to 35% by weight, and releasing factor (GRF), insulin, Somatostatin, parathyroid more preferably from 10 to 25% by weight relative to the total hormone (PTH), adrenocorticotrophic hormone (ACTH), weight of the composition. luteinizing hormone (LH), luteinizing hormone-releasing 0372. In accordance with the present invention, such phar hormone (LHRH) or -releasing hormone maceutical compositions are preferably for use as a medica (GnRH), glucagon-like peptide (GLP), or biologically active ment or are used in a method of treating a disease in a patient analogs of any of the foregoing. In a more preferred embodi in need thereof. ment, the hydroSoluble peptide salts according to the present 0373) Another subject of the present invention is a phar invention include salts of growth hormone (GH). Somatosta maceutical composition for a Sustained release of the active tin, adrenocorticotrophic hormone (ACTH), luteinizing hor ingredient for at least 2 months, comprising or consisting mone-releasing hormone (LHRH), glucagon-like peptide essentially of or consisting of (GLP), or biologically active analogs of any of the foregoing. 0374 as the active ingredient, a hydrosoluble peptide 0357. In another preferred embodiment, the active ingre selected from lanreotide, octreotide, pasireotide, buser dient is a Somatostatin analog selected from lanreotide, oct elin, goserelin, leuprorelin, nafarelin and triptorelin, or reotide, pasireotide, or any pharamaceutically acceptable salt any pharmaceutically acceptable Salt thereof, present in thereof a concentration ranging from 20 to 60% by weight, 0358. In another preferred embodiment, the active ingre relative to the total weight of the composition, dient is a LH-RH analog selected from avorelin, , 0375 glycofurol as co-solvent, present in a concentra , , goserelin, , leuprorelin, tion ranging from 10 to 35% by weight relative to the lutrelin, nafarelin, peforelin, triptorelin, , , total weight of the composition , detirelix, , iturelix, , praZarelix, 0376 a pH modidier, and ramorelix, teverelix, or any pharamaceutically acceptable salt 0377 water, thereof, and more preferably from buserelin, goserelin, leu the pH of the composition ranging from 4.0 to 8. prorelin, nafarelin, triptorelin, or any pharamaceutically 0378. In accordance with the present invention, such phar acceptable salt thereof. maceutical compositions are preferably for use as a medica 0359 Pharmaceutically acceptable salts which can be ment or are used in a method of treating a disease in a patient used for the peptides inaccordance with the present invention in need thereof. US 2016/015 1447 A1 Jun. 2, 2016

0379 Unless otherwise indicated, all technical and scien through the connector. Once the active ingredient is hydrated, tific terms used herein have the same meaning as commonly the whole product is kept in the 5 mL syringe and the 20 mL understood by a specialist in the domain associated with this Syringe is replaced by a new empty 5 mL syringe for the final invention. stage of the mixing process. 0380. The following examples are presented to illustrate 0389. Once homogeneous, the formulation is collected in the above procedures and should not be considered as limiting one of the two 5 mL syringes and then filled in 1 mL plastic the scope of the invention. syringes fitted with a 1.2 mm internal diameter (ID)*20 mm length (L) needle, to a 240 mg lanreotide dose. The needle is EXPERIMENTAL PART then capped with a needle shield. 0390 The individual doses filled in the syringes are sealed 1—Preparation Process in aluminium bags and gamma-irradiated (dose >25 kGy). Example la Example 1c 0381 Different batches are prepared using an acetate salt 0391 A pharmaceutical composition using dual-syringe of lanreotide as active pharmaceutical ingredient (API). The system and vacuum is prepared as follows: required amount of lanreotide acetate is hydrated and homog 0392) 32.73 grams of WFI are mixed with 22.86 grams of enized with the corresponding mixture of water for injection NMP and 4.32 grams of acetic acid in a glass bottle. 30.55 (WFI)/NMP/acetic acid in a suitable container. grams of the mixture are transferred in a 250 mL stainless 0382. Both acetate and water contents of the formulation steel syringe. are adjusted taking into account the contribution of the API 0393 38.06 grams of lanreotide acetate are introduced which also contains these 2 components. into a 250 mL stainless steel syringe. Using a plastic plunger 0383. Once homogeneous media are obtained, the differ and a spatula, the active ingredient introduced in the Syringe ent formulations are aliquoted in Syringes Suitable for pre is gently compacted. filled product and preferably compatible with a terminal ster 0394 Both syringes are fitted with a 3-way valve. Vacuum ilization using gamma-irradiation. is applied to the Syringe containing the active ingredient to a 0384 Part of the individual doses obtained at the end of the value lower or equal to 0.600 mbar during 30 min, using a filling step are sterilized by gamma-irradiation (dose >25 pump connected via the 3-way valve. kGy). 0395. Then, the valve is commuted to connect both 0385. Several formulations according to the invention are syringes and initiate the hydration of the active ingredient. thus prepared. The information related to these examples is The homogenization of the formulation is achieved by a push compiled in Table 1. pull kneading process between the 2 Syringes and through the valve. TABLE 1. 0396. When a homogeneous mixture is obtained, the for mulation is collected in one of the two 250 mL syringes and Content% (ww then filled in 1.0 mL plastic syringes fitted with a 1.2 mm Batch Lanreotide Acetate NMP WFI internal diameter (ID)*20 mm length (L) needle, to a 360 mg lanreotide dose. The Syringes are then capped with a needle B1 46.7 a.S. 7.5 6.9 a.S. 100 shield. B2 47.1 a.S. 7.5 6.9 a.S. 100 B3 4.1.8 a.s. 6.5 7.0 a.S. 100 0397 57 individual doses of 360 mg of lanreotide are B4 38.1 a.s. 6.1 7.4 a.S. 100 prepared. B5 44.6 a.s. 6.2 6.4 a.S. 100 B6 SO.8 a.s. 6.3 S.6 a.S. 100 0398. The individual doses filled in the syringes are sealed B7 39.8 a.s. 5.0 7.4 a.S. 100 in aluminium bags and gamma-irradiated (dose >25 kGy). B8 47.2 a.s. 6.3 21.8 a.S. 100 B9 49.6 a.S. 7.7 S.6 a.S. 100 Example 1d B10 47.6 a.S. 7.7 21.8 a.S. 100 B11 38.9 a.s. 6.2 2.5 a.S. 100 0399. A pharmaceutical composition using dual-syringe B12 47.8 q.S. 7.4 4.9 a.S. 100 system and vacuum is prepared as follows: B13 46.9 q.S. 7.4 8.9 a.S. 100 B14 43.6 a.s. 6.8 7.0 a.S. 100 (0400 78.82 grams of WFI are mixed with 51.12 grams of B15 39.6 a.s. 6.2 S.O a.S. 100 NMP and 8.88 grams of acetic acid in a glass beaker. 94.27 B16 39.8 a.s. 6.2 9.1 a.S. 100 grams of the mixture are transferred into a 750 mL stainless steelsyringe. 0401 110.14 grams lanreotide acetate are introduced in a Example 1 b 750 mL stainless steelsyringe. Using a specific rod and a spatula the active ingredient introduced in the Syringe is gen 0386 A pharmaceutical composition using dual-syringe tly compacted system is prepared as follows: 0402. Both syringes are fitted with a 3-way valve. Vacuum (0387 1.966 grams of a WFI:NMP 60:40 v/v mixture are is applied to the Syringe containing the active ingredient to a introduced in a 5 mL plastic syringe. value lower than or equal to 0.600 mbar during 35 min, using 0388 3.033 grams of lanreotide acetate are introduced in a pump connected via the 3-way valve. 20 mL plastic syringe fitted with a 2-way connector. The 0403. Then, the valve is commuted to connect both Syringe containing the liquid mixture is connected to the free Syringes and initiate the hydration of the active ingredient. port of the connector to initiate hydration of the active ingre The homogenization of the formulation is achieved by a push dient. The homogenization of the formulation is achieved by pull kneading process between the 2 Syringes and through the a push-pull kneading process between the 2 Syringes and valve. US 2016/015 1447 A1 Jun. 2, 2016

04.04. When a homogeneous mixture is obtained, the for 0417. The uncapped syringes are freeze-dried in order to mulation is collected in one of the two 750 mL syringes and obtain a solid cake of lanreotide in powder form. then filled in 1.0 mL plastic syringes fitted with a luer-lock 1.2 0418. After freeze-drying, the individual doses are stop mm internal diameter (ID)*20 mm length (L) needle, to a 360 pered with a Luer-lock stopper, and sealed in an aluminium mg lanreotide dose. The Syringes are then capped with a bag and gamma-irradiated (dose >25 kGy). needle shield. 0419. In parallel, the vehicle for reconstitution is prepared: 04.05) 197 individual doses of 360 mg of lanreotide are 6.40 grams of WFI are mixed with 3.60 grams of NMP in a thus prepared. volumetric flask. The solution is then aliquoted in 3.0 mL 0406. The individual doses filled in the syringes are sealed plastic syringes compatible with the ones used for the freeze in aluminium bags and treated by gamma-irradiation (dose dried product in terms of Syringe-to-Syringe connectivity. >25 kGy). 0420. The individual doses of the final formulation are Example le prepared as follows: 0421 connection of the 2 syringes, 0407. A pharmaceutical composition using both pre-mix 0422 hydration and homogenization by means of push ing and dual-syringe system is prepared as follows: pull kneading process between the 2 Syringes, 0408 8.445 grams of a WFI/NMP 10:90 v/v mixture is 0423 collection of the formulation in 1 of the 2 weighed in a glass beaker and 29.50 grams of lanreotide Syringes, acetate are weighed in another glass beaker. 20 grams of lanreotide acetate are added to the solvent while gently mix 0424 disconnection of the 2 Syringes and coupling of a ing with a spatula. Then, 12.15 grams of a WFI:NMP (95:5 Luer Lock needle for administration. V/v mixture are weighed in a glass beaker and around 5 grams of lanreotide acetate are added to the previous product and Example 1 q mixed with a spatula. Then, the rest of lanreotide acetate (up 0425. A pharmaceutical composition using a dual-syringe to 29.50 grams) is added while gently mixing with a spatula, system and vacuum is prepared as follows: and the rest of the WFI:NMP95:5 v/v mixture (up to 12.15 g) are added and mixed with a spatula. An overage of 1% is 0426 103.35 grams of WFI are mixed with 83.70 grams of applied for weighing the solvents. glycofurol and 12.95 grams of acetic acid in a glass bottle. 04.09. This hydrated product is transferred in a 50 mL 26.38 grams of the mixture are transferred in a 250 mL stainless steel syringe. This syringe is connected to another 50 stainless steel syringe. mL stainless steel syringe by means of a connector. The 0427 31.72 grams of lanreotide acetate are introduced in a homogenization of the formulation is achieved by a push-pull 250 mL stainless steel syringe. Using a plastic plunger and a kneading process between the 2 Syringes and through the spatula, the active ingredient introduced in the Syringe is COnnectOr. gently compacted. 0410. Once homogeneous, the formulation is collected in 0428 Both syringes are fitted with a 3-way valve. Vacuum one of the two 50 mL syringes and therefore aliquoted in 1 mL is applied to the Syringe containing the active ingredient using plastic syringes coupled with a 1.2 mm ID*20 mm L needle. a pump connected via the 3-way valve. The needle is capped with a needle shield. Individual doses of 0429 Vacuum is applied during 190 minto reach a value 240 mg of lanreotide are prepared. lower than or equal to 0.500 mBar. Then, the valve is com 0411. The individual doses filled in the syringes are sealed muted to connect both syringes and initiate the hydration of in aluminium bags and gamma-irradiated (dose >25 kGy). the active ingredient. The homogenization of the formulation is achieved by a push-pull kneading process between the 2 Example 1f Syringes and through the valve. 0412. A pharmaceutical composition suitable for extem 0430. Once homogeneous, the formulation is collected in poraneous reconstitution is prepared as follows: one of the two 250 mL syringes and then filled in 1.2 mL 0413 10.38 grams of lanreotide acetate are introduced in a plastic syringes with a 240 mg dose of Lanreotide. The 150 mL stainless steel syringe. 24.63 grams of acetic acid Syringes are capped with a needle shield. 0.2N is introduced into another 150 mL stainless steel 0431 68 individual doses of 240 mg of lanreotide having Syringe. a pH of 5.0 are prepared. 0414. The Syringe containing the active ingredient is fitted 0432. This composition according to the present invention with a 2-way valve and vacuum is applied during 30 min presents a maximum injection force defined by a SIF of 27 N using a pump. Once a vacuum lower than or equal to 0.600 at a 110 mm/min speed when tested with the method defined mBar is reached, the Syringe containing the 0.2N acetic acid above with a dose of 240 mg of lanreotide. is fitted with the free port of the valve. The valve is then 0433. The individual doses filled in the syringes are sealed opened to connect both syringes and initiate hydration of the in aluminum bags and gamma-irradiated (dose >25 kGy). active ingredient. The homogenization of the formulation is achieved by a push-pull kneading process between the 2 Example 1h Syringes and through the valve. 0415. Once homogeneous, the formulation is collected in 0434. A pharmaceutical composition using a dual-syringe one of the two Syringes and therefore aliquoted in 2.5 mL system and vacuum is prepared as follows: plastic syringes Suitable for freeze-drying process and fitted 0435 127.02 grams of WFI are mixed with 61.88 grams of with a Luer-lock tip. glycofurol and 11.09 grams of acetic acid in a glass bottle. 0416) Individual doses of 500 mg of lanreotide are pre 36.79 grams of the mixture are transferred in a 250 mL pared. stainless steel syringe. US 2016/015 1447 A1 Jun. 2, 2016

0436 32.21 grams of lanreotide acetate are introduced in a Example 1j 250 mL stainless steel syringe. Using a plastic plunger and a spatula, the active ingredient introduced in the Syringe is 0452. A pharmaceutical composition using dual-syringe gently compacted system and vacuum is prepared as follows: 0453 11.51 grams of WFI are mixed with 6.88 grams of 0437. Both syringes are fitted with a 3-way valve. Vacuum PEG 600 and 1.61 grams of acetic acid in a glass bottle. 17.79 is applied to the Syringe containing the active ingredient using grams of the mixture are transferred in a 250 mL stainless a pump connected via the 3-way valve. steel syringe. 0438 Vacuum is applied during 120 minto reach a value 0454 12.71 grams of lanreotide acetate are introduced in a lower than or equal to 0.500 mBar. Then, the valve is com 250 mL stainless steel syringe. Using a plastic plunger and a muted to connect both syringes and initiate the hydration of spatula, the active ingredient introduced in the Syringe is the active ingredient. The homogenization of the formulation gently compacted. is achieved by a push-pull kneading process between the 2 0455 Both syringes are fitted with a 3-way valve. Vacuum Syringes and through the valve. is applied to the Syringe containing the active ingredient using 0439. Once homogeneous, the formulation is collected in a pump connected via the 3-way valve. one of the two 250 mL syringes and then filled in 1.2 mL 0456 Vacuum is applied during 30 min to reach a value plastic syringes with a 240 mg Lanreotide dose. The Syringes lower than or equal to 0.600 mBar. Then, the valve is com are then capped with a needle shield. muted to connect both syringes and initiate the hydration of the active ingredient. The homogenization of the formulation 0440 75 individual doses of 240 mg of lanreotide having is achieved by a push-pull kneading process between the 2 a pH of 4.9 are prepared. Syringes and through the valve. 0441 This composition according to the present invention 0457. Once homogeneous, the formulation is collected in presents a maximum injection force defined by a SIF of 29 N one of the two 250 mL syringes and therefore aliquoted in 1.2 at a 110 mm/min speed when tested with the method defined mL plastic syringes. The Syringes are capped with a rubber above with a dose of 240 mg of lanreotide. stopper. 0442. The individual doses filled in the syringes are sealed 0458) 19 Individual doses of 240 mg of lanreotide having in aluminum bags and gamma-irradiated (dose >25 kGy). a pH of 4.68 are prepared. 0459. This composition according to the present invention Example li presents a maximum injection force defined by a SIF of 29.7 N at a 175 mm/min speed when tested with the method 0443 A pharmaceutical composition using dual-syringe defined above with a dose of 240 mg of lanreotide, and a SIF system and vacuum is prepared as follows: of 15.6 Nata 175 mm/min speed when tested with the method 0444 10.61 grams of WFI are mixed with 7.64 grams of defined above with a dose of 60 mg of lanreotide. PEG 600 and 1.75 grams of acetic acid in a glass bottle. 15.52 0460. The individual doses filled in the syringes are sealed grams of the mixture are transferred in a 250 mL stainless in aluminum bags and gamma-irradiated (dose >25 kGy). steel syringe. 0445 13.38 grams of lanreotide acetate are introduced in a Example 1k 250 mL stainless steel syringe. Using a plastic plunger and a 0461 A pharmaceutical composition using dual-syringe spatula, the active ingredient introduced in the Syringe is system and vacuum is prepared as follows: gently compacted 0462. 18.19 grams of WFI are mixed with 9.27 grams of 0446. Both syringes are fitted with a 3-way valve. Vacuum PEG 600 and 2.54 grams of acetic acid in a glass bottle. 20.42 is applied to the Syringe containing the active ingredient using grams of the mixture are transferred in a 250 mL stainless a pump connected via the 3-way valve. steel syringe. 0447 Vacuum is applied during 30 min to reach a value 0463. 14.58 grams of lanreotide acetate are introduced in a lower than or equal to 0.600 mBar. Then, the valve is com 250 mL stainless steel syringe. Using a plastic plunger and a muted to connect both syringes and initiate the hydration of spatula, the active ingredient introduced in the Syringe is the active ingredient. The homogenization of the formulation gently compacted. is achieved by a push-pull kneading process between the 2 0464 Both syringes are fitted with a 3-way valve. Vacuum Syringes and through the valve. is applied to the Syringe containing the active ingredient using 0448. Once homogeneous, the formulation is collected in a pump connected via the 3-way valve. one of the two 250 mL syringes and therefore aliquoted in 1.2 0465 Vacuum is applied during 30 min to reach a value mL plastic syringes. The Syringes are capped with a rubber lower than or equal to 0.600 mBar. Then, the valve is com stopper. muted to connect both syringes and initiate the hydration of the active ingredient. The homogenization of the formulation 0449 19 individual doses of 240 mg of lanreotide having is achieved by a push-pull kneading process between the 2 a pH of 4.84 are prepared. Syringes and through the valve. 0450. This composition according to the present invention 0466 Once homogeneous, the formulation is collected in presents a maximum injection force defined by a SIF of 61.9 one of the two 250 mL syringes and therefore aliquoted in 1.2 N at a 175 mm/min speed when tested with the method mL plastic syringes. The Syringes are capped with a rubber defined above with a dose of 240 mg of lanreotide, and a SIF stopper. of 24 Nat a 175 mm/min speed when tested with the method 0467 24 individual doses of 240 mg of lanreotide having defined above with a dose of 60 mg of lanreotide. a pH of 4.65 are prepared. 0451. The individual doses filled in the syringes are sealed 0468. This composition according to the present invention in aluminum bags and gamma-irradiated (dose >25 kGy). presents a maximum injection force defined by a SIF of 34.7 US 2016/015 1447 A1 Jun. 2, 2016

N at a 175 mm/min speed when tested with the method achieved by a push-pull kneading process between the 2 defined above with a dose of 240 mg of lanreotide, and a SIF Syringes and through the valve. of 19.9N at a 175 mm/min speed when tested with the method 0485. Once homogeneous, the formulation is collected in defined above with a dose of 60 mg of lanreotide. one of the two 750 mL syringes. 0469. The individual doses filled in the syringes are sealed 0486 A second sub-batch is prepared: in aluminum bags and gamma-irradiated (dose >25 kGy). 0487. 122.80grams of WFI are mixed with 87.01 grams of glycofurol and 16.53 grams of acetic acid in a glass bottle. Example 11 113.19 grams of the mixture are transferred in a 750 mL 0470 A pharmaceutical composition using a dual-syringe stainless steel syringe. system is prepared as follows: 0488 122.40 grams of lanreotide acetate are introduced in 0471 0.09 grams of methionine are dissolved in 9.74 a 750 mL stainless steel syringe. Using a plastic plunger and grams of WFI in a glass bottle. 8.44 grams of glycofurol and a spatula, the active ingredient introduced in the Syringe is 1.73 grams of acetic acid are added to the Solution. 4.28 grams gently compacted of the mixture are transferred in a 20 mL stainless steel 0489. Both syringes are fitted with a 3-way valve. Vacuum Syringe. is applied to the Syringe containing the active ingredient using 0472 5.22 grams of lanreotide acetate are introduced in a a pump connected via the 3-way valve. 20 mL stainless steelsyringe. Using a plastic plunger and a 0490 Vacuum is applied during 120 minto reach a value spatula, the active ingredient introduced in the Syringe is lower or equal to 0.500 mBar. Then, the valve is commuted to gently compacted. connect both syringes and initiate the hydration of the active 0473 Both syringes are fitted with a 3-way valve. Vacuum ingredient. The homogenization of the formulation is is applied to the Syringe containing the active ingredient using achieved by a push-pull kneading process between the 2 a pump connected via the 3-way valve. Syringes and through the valve. 0474 Vacuum is applied during 30 min to reach a value 0491. Once homogeneous, the formulation is collected in lower than or equal to 0.500 mBar. Then, the valve is com one of the two 750 mL syringes. muted to connect both syringes and initiate the hydration of 0492 Both sub-batches are mixed and homogenised by a the active ingredient. The homogenization of the formulation push-pull kneading process between the 2 Syringes through is achieved by a push-pull kneading process between the 2 the valve and then filled in 1.2 mL plastic syringes with a 450 Syringes and through the valve. mg lanreotide dose. The Syringes are then capped with a 0475 Once homogeneous, the formulation is collected in needle shield. one of the two 20 mL syringes and then filled in 1.2 mL plastic 0493 279 individual doses of 450 mg of lanreotide having Syringes with a 240 mg dose of lanreotide. The Syringes are a pH of 4.9 are prepared. capped with a needle shield. 0494. This composition according to the present invention 0476 13 individual doses of 240 mg of lanreotide having presents a maximum injection force defined by a SIF of 20N a pH of 5.11 are prepared. at a 110 mm/min speed when tested with the method defined 0477. This composition according to the present invention above with a dose of 450 mg of lanreotide. presents a maximum injection force defined by a SIF of 24N 0495. The individual doses filled in the syringes are sealed at a 110 mm/min speed when tested with the method defined in aluminum bags and gamma-irradiated (dose >25 kGy). above with a dose of 240 mg of lanreotide. 0478. The individual doses filled in the syringes are sealed Batch B18 in aluminum bags and gamma-irradiated (dose >25 kGy). 0496 121.73 grams of WFI are mixed with 86.40 grams of glycofurol and 16.41 grams of acetic acid in a glass bottle. Example 1m 112.32 grams of the mixture are transferred in a 750 stainless steel syringe. 0479. Two batches of a pharmaceutical composition (B17 0497 121.30 grams of lanreotide acetate are introduced in and B18) using a dual-syringe system and vacuum is prepared a 750 mL stainless steel syringe. Using a plastic plunger and as follows. a spatula, the active ingredient introduced in the Syringe is gently compacted. Batch B17 0498 Both syringes are fitted with a 3-way valve. Vacuum 0480. A first sub-batch is prepared. is applied to the Syringe containing the active ingredient using 0481) 122.83 grams of WFI are mixed with 87.19 grams of a pump connected via the 3-way valve. glycofurol and 16.53 grams of acetic acid in a glass bottle. 0499 Vacuum is applied during 120 minto reach a value 113.19 grams of the mixture are transferred in a 750 mL lower or equal to 0.500 mBar. Then, the valve is commuted to stainless steel syringe. connect both syringes and initiate the hydration of the active 0482 122.20 grams of lanreotide acetate are introduced in ingredient. The homogenization of the formulation is a 750 mL stainless steel syringe. Using a plastic plunger and achieved by a push-pull kneading process between the 2 a spatula, the active ingredient introduced in the Syringe is Syringes and through the valve. gently compacted 0500. Once homogeneous, the formulation is collected in 0483 Both syringes are fitted with a 3-way valve. Vacuum one of the two 750 mL syringes and then filled in 1.2 mL is applied to the Syringe containing the active ingredient using plastic syringes with a 270 mg Lanreotide dose. The Syringes a pump connected via the 3-way valve. are then capped with a needle shield. 0484 Vacuum is applied during 120 minto reach a value 0501. 278 individual doses of 270 mg of lanreotide having lower or equal to 0.500 mBar. Then, the valve is commuted to a pH of 4.9 are prepared. connect both syringes and initiate the hydration of the active 0502. This composition according to the present invention ingredient. The homogenization of the formulation is presents a maximum injection force defined by a SIF of 16 N US 2016/015 1447 A1 Jun. 2, 2016

at a 110 mm/min speed when tested with the method defined ration of calibrated Standard curves and the inclusion of qual above with a dose of 270 mg of lanreotide. ity control samples. The limit of quantification is 80 pg ml-1. 0503. The individual doses filled in the syringes are sealed 0516 A non-compartmental pharmacokinetic analysis of in aluminum bags and gamma-irradiated (dose >25 kGy). the individual serum concentration-actual time profile is applied by means of the WinNonlin V5.2 software in order to 2 Pharmacokinetic (PK) Studies obtain at least the following parameters: peak serum concen tration (Cmax), time to peak (Tmax), area under the time Example 2a concentration curve from 0 to t (AUCt) and mean residence 0504 The pharmaceutical composition identified as B1 in time from 0 to t (MRTt). Example la is injected in dog at a dose of 240 mg of lan 0517 Resulting meant-SD pharmacokinetic profiles reotide. obtained in dogs are presented in the FIG. 4. This PK study 0505. A total of six male Beagle dogs 16-23 kg body demonstrates the sustained release (SR) properties of this weight are used at the beginning of the study. They are main composition. tained with free access to a dry standard diet and to drinkable water. The animals are subcutaneously administered in the Example 2c inter Scapular area by trained personnel. 0518. The pharmaceutical compositions identified in 0506 Blood samples are obtained, through the cephalic Examples 1 g (G1) and 1h (G2) are injected in dog at a dose of veins, before injection (time 0), 15 and 30 minutes, 1, 2, 4, 8 240 mg of lanreotide. These compositions are reported in and 10 hours, 1, 2, 3, 7, 10, 14, 21 and 28 days, and then once Table 2. every 9-11 days (including if possible 56 and 84 days) until completing the experiment when lanreotide levels are unde TABLE 2 tected. 0507. The blood samples remain at room temperature for Content% (ww a minimum of 30 min and then they are centrifuged (1600 g for 20 min at 4°C.) in the centrifuge. Composition Lanreotide Acetate Glycofurol WFI 0508. The lanreotide serum concentration is determined G1 47.50 q.S. 7.50 19.00 q.S. 100.00 by means of a validated Radio Immuno Assay (RIA) method G2 40.00 q.S. 7.25 16...SO q.S. 100.00 that implies the preparation of calibrated standard curves and the inclusion of quality control samples. The limit of quanti 0519. A total of 12 Beagle dogs (six males and six fication is 80 pg. ml-1. females) 9-14 kg bodyweight performulation are used at the 0509. A non-compartmental pharmacokinetic analysis of beginning of the study. They are maintained with free access the individual serum concentration-actual time profile is to a dry standard diet and to drinkable water. The animals are applied by means of the WinNonlin V5.2 software in order to Subcutaneously administered in inter Scapular area by trained obtain at least the following parameters: peak serum concen personnel. tration (Cmax), time to peak (Tmax), area under the time 0520 Blood samples are obtained from unanesthetized concentration curve from 0 to t (AUCt) and mean residence animals by direct Venipuncture from the jugular vein, before time from 0 to t (MRTt). injection (time 0), 15 and 30 minutes, 1, 2, 4, 8 and 12 hours, 0510 Resulting meant-SD (standard deviation) pharma 1, 1.5, 2, 2.5, 3, 4, 5, 7, 10, 14, 21, 28, 35, 42, 49, 56, 63, 70, cokinetic profiles obtained in dogs are presented in the FIG.3. 77, 84,90, 105,119, 135, 150, 165 and 180 days after admin This PK study demonstrates the sustained release (SR) prop istration. erties of this composition. 0521. The blood samples remain at room temperature for a minimum of 30 min and then they are centrifuged (1600 g Example 2b for 20 min at 4°C.) in the centrifuge. 0511. The pharmaceutical composition containing 32.9% 0522 The lanreotide serum concentration is determined oflanreotide and 40.2% of propylene glycol acetate and WFI by means of a validated RIA method that implies the prepa q.S. 100% is injected in dog at a dose of 60 mg of lanreotide. ration of calibrated Standard curves and the inclusion of qual 0512. A total of three male Beagle dogs 16-23 kg body ity control samples. The limit of quantification is 80 pg ml-1. weight are used. They are maintained with free access to a dry 0523) A non-compartmental pharmacokinetic analysis of standard diet and to drinkable water. The animals are subcu the individual serum concentration-actual time profile is taneously administered in inter Scapular area by trained per applied by means of the WinNonlin V5.2 software in order to Sonnel. obtain at least the following parameters: peak serum concen 0513 Blood samples are obtained, through the cephalic tration (Cmax), time to peak (Tmax), area under the time veins, before injection (time 0), 15 and 30 minutes, 1, 2, 4, 8 concentration curve from 0 to t (AUCt) and mean residence and 10 hours, 1, 2, 3, 7, 10, 14, 17, 21, 24 and 28 days, and time from 0 to t (MRTt). then once every 9-11 days (including if possible 56 and 84 0524 Resulting meant-SD pharmacokinetic profiles days) until completing the experiment when lanreotide levels obtained in dogs for each formulation, i.e. G1 and G2, are are undetected. presented in FIGS. 5 and 6. This PK study demonstrates the 0514. The blood samples remains at room temperature for Sustained release (SR) properties of these compositions. a minimum of 30 min and then they are centrifuged (1600 g 0525 Data have been normalized at 15 kg dog body for 20 min at 4°C.) in the centrifuge. weight. Dogs showing discharge during experiment or puta 0515. The lanreotide serum concentration is determined tive antibody in serum associated to lanreotide were removed by means of a validated RIA method that implies the prepa for the analysis. US 2016/015 1447 A1 Jun. 2, 2016

Example 2d 0535 A total of 16 Beagle dogs (eight males and eight females) 7-12 kg bodyweight performulation are used at the 0526. The pharmaceutical compositions identified in beginning of the study. They are maintained with free access Examples li (F1), 1j (F2) and 1k (F3) are injected in dog at a to a dry standard diet and to drinkable water. The animals are dose of 240 mg of lanreotide. These compositions are Subcutaneously administered in inter Scapular area by trained reported in Table 3. personnel. 0536 Blood samples are obtained from unanesthetized TABLE 3 animals by direct Venipuncture from the jugular vein, before Content% (w.fw injection (time 0), 15 and 30 minutes, 1, 2, 4, 8 and 12 hours, 1, 1.5, 2, 2.5, 3, 4, 5, 7, 10, 14, 21, 28, 35, 42, 49, 56, 63, 70, Composition Lanreotide Acetate PEG 600 WFI 77, 84,90, 105, 119 after administration. F1 40.00 q.S. 8.11 2O.S1 q.S. 100.00 0537. The blood samples remain at room temperature for F2 36.00 q.S. 7.75 2010 q.S. 100.00 a minimum of 30 min and then they are centrifuged (1600 g F3 36.00 q.S. 8.00 18.00 q.S. 100.00 for 20 min at 4°C.) in the centrifuge. 0538. The lanreotide serum concentration is determined 0527. A total of 12 Beagle dogs (6 males and 6 females) by means of a validated RIA method that implies the prepa 7-13 kg bodyweight performulation are used at the beginning ration of calibrated Standard curves and the inclusion of qual of the study. They are maintained with free access to a dry ity control samples. The limit of quantification is 80 pg. ml. standard diet and to drinkable water. The animals are subcu 0539 A non-compartmental pharmacokinetic analysis of taneously administered in inter Scapular area by trained per the individual serum concentration-actual time profile is Sonnel. applied by means of the WinNonlin V5.2 software in order to 0528 Blood samples are obtained from each dog through obtain at least the following parameters: peak serum concen the jugular veins, before injection (time 0), 15 and 30 min tration (C), time to peak (T,), area under the time utes, 1, 2, 4, 8 and 12 hours, 1, 1.5, 2, 2.5, 34, 5, 7, 10, 14, 21, concentration curve from 0 to t (AUCt) and mean residence 28, 35, 42,49,56, 63, 70, 77, 84,90, 105,120, 135, 150, 165 time from 0 to t (MRTt). and 180 days after administration. 0540 Resulting meant-SD pharmacokinetic profiles 0529. The blood samples remain at room temperature for obtained in dogs for each lanreotide dose, i.e. 270 and 450 a minimum of 30 min and then they are centrifuged (1600 g mg, are presented in FIG. 9 (lanreotide serum profiles deter for 20 min at 4°C.) in the centrifuge. mined in Beagle dogs following single SC Administration of 0530. The lanreotide serum concentration is determined G3 Formulation at the theoretical doses of 270 and 450 mg of by means of a validated RIA method that implies the prepa pure peptide per dog). This PK study demonstrates the Sus ration of calibrated Standard curves and the inclusion of qual tained release (SR) properties of these compositions. ity control samples. The limit of quantification is 80 pg ml-1. 0541 Data have been normalized at 15 kg dog body 0531. A non-compartmental pharmacokinetic analysis of weight. Dogs showing discharge during experiment or puta the individual serum concentration-actual time profile is tive antibody in serum associated to lanreotide were removed applied by means of the WinNonlin V5.2 software in order to for the analysis. obtain at least the following parameters: peak serum concen tration (Cmax), time to peak (Tmax), area under the time 3- Stability Study concentration curve from 0 to t (AUCt) and mean residence time from 0 to t (MRTt). Example 3a 0532 Resulting meant-SD pharmacokinetic profiles obtained in dogs for each formulation, i.e. F1, F2 and F3, are NMP Formulation presented in FIGS. 7 and 8. This PK study demonstrates the 0542. The pharmaceutical compositions of the present Sustained release (SR) properties of these compositions. invention are stable when tested overtime upon storage under 0533. Data have been normalized at 15 kg dog body the recommended 5° C. condition. weight. Dogs showing discharge during experiment or puta 0543. A stability study on the pharmaceutical composi tive antibody in serum associated to lanreotide have been tions identified as B2 in Example 1a is launched at 5° C. and removed for the analysis. 25°C/60% RH (RH: relative humidity). The pharmaceutical Example 2e composition is stored in pre-filled Syringes. 0544 The stability data are shown in Table 5 and Table 6. 0534. The pharmaceutical composition identified in Example 1 m (G3, batches B17 and B18) are injected in dog at TABLE 5 a dose of 270 and 450 mg of lanreotide. This composition is reported in Table 4. stability data at 5 it 3 C. Batch Parameter T = 0 T = 1 M T = 3 M T = 6 M T = 9 M TABLE 4 B2 Peptide 47.1 46.7 46.2 48.3 46.3 Content% (w.fw content (%) Composition Lanreotide Acetate Glycofurol WFI Purity 97.7 97.6 97.7 97.6 97.4 (RP G3 44.OO q.S. 8.00 18.50 q.S. 100.00 HPLC, % area) US 2016/015 1447 A1 Jun. 2, 2016 17

TABLE 5-continued Example 3c stability data at 5 it 3 C. Glycofurol Formulations Batch Parameter T = 0 T = 1 M T = 3 M T = 6 M T = 9 M Oligomers O.9 1.7 1.9 1.8 1.7 0547. Two different Lanreotide 3 months glycofurol for (SEC, mulations (G1: 47.5% of API and G2: 40% of API) were % area) selected for an accelerated stability study based on Arrhenius RE, 20.7 20.5 21.9 21.4 2O2 methodology. This study was designed to determine the Force kinetic of degradation at different storage conditions over a (SIF, N) Small duration period. 0548. The batches were stored for a 10 to 15-day period at 3 different storage conditions ranging from 40°C. to 55° C. TABLE 6 The results are provided in Table 8. stability data at 25 t 2 C, 60 it 5% RH TABLE 8 Batch Parameter T = O T = 1 M T = 3 M Arrhenius predictions based on sum of total impurities e0.1% B2 Peptide content (%) 47.1 46.5 45.5 Purity (RP-HPLC, 9% area) 97.7 96.8 96.2 Oligomers (SEC, % area) O.9 2.6 2.6 Formulation Degradation rate (k) at 5° C. (% impurity year) Syringe Injection Force (SIF, N) 20.7 22.1 27.7 G1 O.04 G2 O.O1 Example 3b PEG Formulations 0549 Based on the data obtained during this Arrhenius study, similar degradation rates were observed at 5°C. for G1 0545 Stability results were generated on three different and G2 formulations. In both cases, the shelf-life prediction Lanreotide 3 months PEG formulations F1 (at a dose of 60 based on the degradation rate observed supports a shelf-life mg of lanreotide), F2 (at a dose of 60 mg of lanreotide) and F3 prediction of approximately 24 months. This investigational (at a dose of 60 mg of lanreotide) stored at the recommended study carried out in accelerated temperature conditions dem 5° C. condition over a 9-month period. Some Syringes were onstrated the suitable stability of the proposed glycofurol also stored in accelerated temperature conditions at 25° based formulations. C/60% RH. Representative data at 5° C. is provided in Table 0550. The three different lanreotide glycofurol formula 7. tions (G1: 47.5% (w/w) of laneotide, G2: 40% (w/w) of 0546 Based on 9 months real time stability data, a provi- lanreotide and G3:44% (w/w) of lanreotide) were selected for sional shelf-life of 18 months at 2-8°C. is proposed for the a stability study at 5°C. The results are provided in tables 9 to Lanreotide 3-month PEG formulations. 11 below.

TABLE 7

stability data at 5° C.

Composition Parameter T = O T = 3 M T = 6 M T = 9 M F2 (at a dose Appearance of Syringe Off white Off white Off white Slightly of 60 mg of content yellow lanreotide) Syringe Injection Force 10.615.0 12.3.17.1 10.916.2 12.417.6 (SIF, N) Min/Max Peptide content (%) 33.9 34.0 34.3 34.1 Injected Dose 58.0 58.3 57.7 58.7 (mg?syringe) Mass injectable (mg) 171.4 171.4 168.2 1723 RP-HPLC (%) Each Individual Impurities O.3 O.3 O.3 O.3 Total impurities e0.1% 1.12 1.25 120 1.46 SE-HPLC Oligomers (%) 1.74 1.87 1.89 2.OO pH 4.7 4.7 4.7 Water Content (%) 40.6 US 2016/015 1447 A1 Jun. 2, 2016

TABLE 9 impurity relative to the peak area of lanreotide. A relative response factor of 1 is used. Total impurities are expressed as Stability Data at 5° C. conditions (G1 formualtion the sum of the impurity values above 0.1%. 1. A pharmaceutical composition comprising: Time point (months lanreotide, Test O 3 6 9 12 a hydroSoluble co-solvent, and water; Mean concentration of 44.0 42.5 42.3 43.4 42.8 wherein the pH of the composition is from 4.0 to 7.5, and lanreotide (% w/w) Total impurities e0.1% (% 4.2 5.9 7.3 6.3 7.8 the composition provides a Sustained release of lanreotide for area) at least 2 months after administration. pH S.O S.1 S.O S.1 S.O 2. The composition of claim 1, wherein lanreotide consti Maximum SIF (N) 27 29 24 28 27 tutes from 35% to 55% of the total weight of the composition. 3. The composition of claim 1, wherein the co-solvent is constitutes from 10% to 25% of the total weight of the com TABLE 10 position. 4. The composition of claim 1, wherein the pH of the Stability Data at 5° C. conditions (G2 formualtion composition is from 4.0 to 6.0. 5. (canceled) Time point (months 6. The composition of claim 1, further comprising a pH Test O 3 6 9 12 modifier.

Mean concentration of 38.5 38.1 37.8 38.7 38.2 7. (canceled) lanreotide (% w/w) 8. The composition of claim 6, wherein the pH modifier is Total impurities e0.1% (% 2.5 2.6 2.9 2.6 3.0 acetic acid, citric acid, lactic acid, phosphoric acid, hydro area) chloric acid, Stearic acid, or pamoic acid. pH 4.9 4.9 4.9 4.9 4.9 9. The composition of claim 1, wherein the composition Maximum SIF (N) 28 34 35 31 34 does not contain a non-hydroSoluble, biocompatible, or bio degradable (co)polymer. 10. The composition of claim 1, further comprising a sta TABLE 11 bilizer, antioxidant, and/or Surfactant. 11. The composition of claim 10, wherein the total amount Stability Data at 5° C. conditions (G3 formualtion of stabilizer, antioxidant, and/or surfactant in the composition Time point (months is less than 5% of the total weight of the composition. 12. (canceled) Test O 3 6 9 13. The composition of claim 1, wherein the composition Mean concentration of 43.1 43.2 42.9 43.2 provides a Sustained release of lanreotide in humans for 2 to lanreotide (% w/w) 6 months after administration. Total impurities e0.1% (% area) 1.7 1.4 1.4 1.6 14. The composition of claim 1, wherein the composition pH 4.9 4.9 4.9 S.O provides a Sustained release of lanreotide in humans for at Maximum SIF (N) 25 21 27 24 least 3 months after administration. 15. (canceled) 0551 Lanreotide mean concentration is performed by 16. The composition of claim 1, wherein the pH of the HPLC with a reverse phase method using a C18 stationary composition is from 4.8 to 5.4. phase with gradient elution. Quantitative analysis is carried 17. The composition of claim 10, wherein the total amount out using an external standard by comparing peak area (Col of stabilizer, antioxidant, and/or surfactant in the composition umn: Symetry C18 100 mmx4.6 mm; 3.5 um or equivalent; is less than 1% of the total weight of the composition. Flow rate: 1 mL/min: UV detection at 280 nmi; Mobile phase: 18. A method of treating acromegaly or NET, the method mixture of acetonitrile/water?trifluoroacetic acid; Reference comprising administering a therapeutically-effective amount standard and sample diluent: 0.1 M acetic acid). of the composition of claim 1 to a subject in need thereof. 0552. Impurities are tested using the same method as for 19. The method according to claim 18 wherein the compo mean concentration determination. The amount of an impu sition is administered parenterally. rity present in a sample is calculated from the peak area of the k k k k k