New composition

Abstract

The present invention relates to a pharmaceutical composition comprising biodegradable polymeric microparticles containing a somatostatin analog or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition preferably providing sustained release of the somatostatin analog or a pharma- ceutically acceptable salt thereof for 30 days or more.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition comprising biodegradable polymeric microparticles containing a somatostatin analogue or a pharma- ceutically acceptable salt thereof.The present invention further relates to said pharmaceutical composition for use as a medicament. [Background technology]

[0002] Somatostatin analogues, such as octreotide, lanreotide, and pasireotide, are peptide drugs that can be used in a variety of therapeutic applications, such as the treatment of acromegaly, carcinoid syndrome associated with neuroendocrine tumors, and vasoactive intestinal peptide tumors. Often, such peptide drugs require treatment and are usually administered parenterally, e.g., by injection, which can be a drawback, especially when repeated and frequent administration over an extended period of time, e.g., daily or weekly, is required. Considering the drawbacks associated with frequent parenteral administration, pharmaceutical manufacturers have been developing sustained release compositions that can help reduce the number of doses required over a long period of time. Such sustained release pharmaceutical compositions are often based on polylactic-co-glycolic acid (PLGA). However, it is difficult to formulate a PLGA sustained release pharmaceutical composition with an acceptable somatostatin analog release profile, especially when the desired sustained release profile is longer than one month (30 days), such as two months (60 days) or more, or even three months (90 days) or more. In this case, a particular challenge is to avoid an unacceptably high initial release (burst) of somatostatin analog after administration and ensure sufficient and stable release over the entire sustained release period. In response to the above problems, formulators have developed sustained release pharmaceutical compositions that contain blends of microparticles made from different PLGAs. However, such compositions can be complex and expensive to manufacture. In addition, the desired sustained release period may require the administration of high doses of somatostatin analogs (and thus large amounts of PLGA microparticles), which may cause needle passability and injectability problems for the formulation. Summary of the Invention [Problem to be solved by the invention]

[0003] Thus, there remains a need for novel sustained release pharmaceutical compositions that can provide sustained release of somatostatin analogues, particularly over extended periods, such as periods greater than one month, such as periods greater than two months, three months, or even longer. In particular, there is a need for somatostatin sustained release compositions that provide acceptable somatostatin release profiles, such as sufficient release of somatostatin analogues throughout the desired sustained release period, and acceptable bursts (which can minimize or minimize the risk of side effects / adverse reactions associated with administration of somatostatin analogues). Furthermore, there is a need for pharmaceutical compositions that are not complicated to manufacture, inexpensive, convenient to use, have an acceptable shelf life, are safe, are well tolerated by patients, and minimize patient discomfort and / or needleability and injectability issues that may occur with repeated administrations associated with long-term treatment, for example.

[0004] The aim of the following invention is to address one or more of the above problems. The inventors have surprisingly found that the pharmaceutical composition described herein can meet one or more of the above-mentioned problems.In particular, the inventors have found that the pharmaceutical composition according to the present invention can release somatostatin analogues for 30 days or more, for example, 60 days or more, 90 days or more, or even more, and the bursts can be tolerated.In addition, the inventors have also surprisingly found that the bioavailability of the somatostatin analogues contained in the pharmaceutical composition of the present invention can be surprisingly increased compared to currently marketed somatostatin analogues, such as octreotide, sustained release formulations, such as Sandostatin® LAR®, thereby allowing the administration of a reduced dose of somatostatin analogue (i.e., a reduced amount of PLGA microparticles) while achieving the effect of a higher dose than in other formulations. [Means for solving the problem]

[0005] 1. A pharmaceutical composition comprising biodegradable polymer microparticles containing a somatostatin analog or a pharma- ceutically acceptable salt thereof, wherein the biodegradable polymer comprises: The molar ratio of lactide to glycolide is 80:20 to 90:10; The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.2 to 0.4 dl / g. PLGA, and The biodegradable polymer microparticles The drug loading was 10-15 w / w%; Dv50 is 30 μm to 90 μm; and The specific surface area measured by gas adsorption is 0.50 m 2 / g, preferably less than 0.40m 2 / g, preferably The pharmaceutical composition, wherein the somatostatin analog or a pharma- ceutical acceptable salt thereof is sustained-released for 30 days or more, more preferably for 30 to 200 days, or for 60 days or more, more preferably for 60 to 200 days, or for 90 days or more, more preferably for 90 to 200 days. 2. The pharmaceutical composition according to item 1, wherein the somatostatin analog is sustained-released for 60 days or more, preferably for 60 to 200 days. 3. The pharmaceutical composition according to item 1, wherein the somatostatin analog is sustained-released for 90 days or more, preferably 90 to 200 days. 4. The pharmaceutical composition according to any one of the above items, wherein the molar ratio of lactide and glycolide in the PLGA according to item 1 is 83:17 to 87:13, and the intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g. 5. A pharmaceutical composition according to any of the preceding clauses, wherein the PLGA according to any of the preceding clauses contains less than 0.5 w / w% residual lactide and / or glycolide monomers.

[0006] 6. The pharmaceutical composition according to any one of the above items, wherein the drug loading of the biodegradable polymer microparticles according to any one of the above items is 11 to 14 w / w%, or 11.5 to 12.5 w / w%. 7. A pharmaceutical composition according to any of the preceding clauses, wherein the biodegradable polymer microparticles according to any of the preceding clauses are biodegradable polymer microspheres. 8. The biodegradable polymer microparticles according to any one of the above items, Dv50 is 50 μm to 80 μm, preferably 60 μm to 75 μm, and / or Specific surface area measured by gas adsorption is 0.05 to 0.3 m 2 / g, The pharmaceutical composition according to any one of the above items. 9. A pharmaceutical composition according to any of the preceding clauses, wherein the somatostatin analogue is octreotide or a pharma- ceutically acceptable salt thereof, preferably a pharma- ceutically acceptable salt of octreotide selected from the group consisting of octreotide acetate and octreotide pamoate. 10. A pharmaceutical composition according to any of the preceding clauses, wherein the biodegradable polymer according to any of the preceding clauses comprises at least 50 w / w%, preferably at least 85 w / w%, or more preferably 100 w / w% PLGA.

[0007] 11. A pharmaceutical composition according to any of the preceding clauses, wherein the biodegradable polymer microparticles according to any of the preceding clauses constitute at least 50 w / w%, preferably at least 75 w / w%, or more preferably at least 80 w / w% of the total of all biodegradable polymer microparticles contained in the pharmaceutical composition. 12. The composition meets the following criteria: Releases less than 7% of the somatostatin analogue over a 5-hour period; Measured in vitro (in 900 mL of 100 mM acetate buffer, pH 4, at 37°C) by the method described in European Pharmacopoeia 10, 2.9.3; Tested at a dose equivalent to 30 mg of somatostatin analogue; releases a somatostatin analogue that satisfies wherein the somatostatin analogue is preferably octreotide. The pharmaceutical composition according to any one of the above items. 13. The composition meets the following criteria: Releases less than 3% of the somatostatin analogue over a 5-hour period; Measured in vitro (in 900 mL of 100 mM acetate buffer, pH 4, at 37°C) by the method described in European Pharmacopoeia 10, 2.9.3; Tested at a dose equivalent to 30 mg of somatostatin analogue; releases a somatostatin analogue that satisfies wherein the somatostatin analogue is preferably octreotide. The pharmaceutical composition according to any one of the above items. 14. The pharmaceutical composition according to any of the preceding claims, which is a liquid suspension containing the biodegradable polymer microparticles, or a dried product of the biodegradable polymer microparticles. 15. The pharmaceutical composition according to item 14, comprising a liquid suspension comprising the biodegradable polymer microparticles, the biodegradable polymer microparticles being suspended in an aqueous vehicle or a non-aqueous vehicle, preferably the non-aqueous liquid vehicle being a pharma- ceutically acceptable oil consisting essentially of one or more medium chain triglycerides.

[0008] 16. The pharmaceutical composition according to item 15, wherein the microparticles contained in the liquid have a concentration of 100 mg / mL to 500 mg / mL, preferably 100 mg / mL to 375 mg / mL, and more preferably 125 mg / mL to 375 mg / mL. 17. A pharmaceutical composition according to any of the preceding clauses, which is sterilized by irradiation. 18. A pharmaceutical composition according to any of the above clauses for use as a medicament. 19. The pharmaceutical composition according to any one of items 1 to 17, for use in the treatment of a disease for which a somatostatin analog or a pharma- ceutical acceptable salt thereof has a therapeutic effect, wherein the disease is selected from the group consisting of autosomal dominant polycystic kidney disease, Cushing's disease, polycystic liver, acromegaly, gigantism, TSH-secreting pituitary adenoma, carcinoid syndrome, vasoactive intestinal peptide tumor, and neuroendocrine neoplasms including neuroendocrine tumors including gastroenteropancreatic neuroendocrine tumors, preferably selected from acromegaly and gastroenteropancreatic neuroendocrine tumors. 20. The pharmaceutical composition as defined in any one of clauses 1 to 17 for use according to clause 18 or 19, which sustains release of the somatostatin analogue over 60 days or more and is administered once about every 60 days at a dose equivalent to a dose of 25 mg to 105 mg of octreotide or an equivalent dose of a pharma- ceutical acceptable salt thereof, and is administered once every 84 days at a dose equivalent to a dose of 60 mg, 90 mg, or 120 mg of octreotide or an equivalent dose of a pharma-ceutical acceptable salt thereof.

[0009] 21. The pharmaceutical composition as defined in any one of clauses 1 to 17 for use according to clause 18 or 19, which sustains release of the somatostatin analogue over 90 days or more and is administered once about every 90 days at a dose equivalent to a dose of 25 mg to 105 mg of octreotide or an equivalent dose of a pharma- ceutical acceptable salt thereof. 22. A pharmaceutical composition for use according to any one of items 18 to 21, wherein the pharmaceutical composition is administered to a patient parenterally, preferably by intramuscular or subcutaneous injection, the subcutaneous injection being preferably deep subcutaneous. 23. The following: (i) the pharmaceutical composition according to any one of items 1 to 17; (ii) optionally, a vehicle for reconstitution; and (iii) a vial or syringe, optionally pre-filled with the pharmaceutical composition of (i); Kit including: 24. A method for making biodegradable polymeric microparticles according to any of the preceding paragraphs, wherein the biodegradable polymer comprises at least 50 w / w%, 85 w / w%, or 100 w / w% of PLGA according to any of the preceding paragraphs, and wherein the method comprises the following steps: (i) preparing an organic phase comprising an organic solvent mixture, preferably a mixture of dichloromethane and methanol in a weight ratio of 80:20 to 95:5, said biodegradable polymer in a concentration of 10 w / w% to 30 w / w%, and a somatostatin analog or a pharma- ceutically acceptable salt thereof in a concentration sufficient to achieve a pre-determined drug loading of 10 w / w% to 15 w / w%; (ii) preparing an aqueous phase containing water, 0.1 w / v% to 10 w / v% of a stabilizer, preferably PVA, and 2 w / w% to 5 w / w% of a salting-out agent, preferably sodium chloride; (iii) continuously mixing the organic phase and the aqueous phase of (i) and (ii) in a volume ratio of 1:80 to 1:250 to form an emulsion; (iv) removing the organic solvent from the emulsion of (iii) by solvent evaporation or solvent extraction; (v) drying the biodegradable polymer microparticles obtained in (iv) and sieving them through a suitable size sieve; (vi) optionally repeating (v) until the residual organic solvent is below a predetermined level; wherein all w / w% and w / v% in the above process other than drug loading are based on mass or volume of each solution. An embodiment of the present invention will be described with reference to the drawings. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the in vivo pharmacokinetic release profile of a suspension of microspheres of Composition D (Example 4). [Diagram 2] FIG. 1 shows the in vivo pharmacokinetic release profile of a suspension of microspheres of Composition A (Example 5). [Diagram 3] FIG. 13 shows the in vivo pharmacokinetic release profiles of aqueous and non-aqueous suspensions of Composition D microparticles by route of administration and reconstitution vehicle (Example 9). [Figure 4] FIG. 10 shows the mean plasma octreotide levels over the study period (Example 10B) resulting from a single dose of Composition D microparticles (90 mg octreotide) or 3×30 mg (once per month) of Sandostatin LAR. [Diagram 5] FIG. 13 shows the change in IGF1 serum levels over the study period resulting from a single dose of Composition D microparticles (90 mg octreotide) or 3×30 mg (once per month) of Sandostatin LAR (Example 10B). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In a first aspect of the present invention, there is provided a pharmaceutical composition comprising biodegradable polymer microparticles comprising a somatostatin analogue or a pharma- ceutically acceptable salt thereof, the biodegradable polymer comprising: The molar ratio of lactide to glycolide is 80:20 to 90:10; The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.2 to 0.4 dl / g. PLGA, and The biodegradable polymer microparticles The drug loading was 10-15 w / w%; Dv50 is 30 μm to 90 μm; and The specific surface area measured by gas adsorption is 0.50 m 2 / g, preferably less than 0.40m 2 / g or less.

[0012] The term "biodegradable polymer" as used herein refers to a polymer or mixture of polymers that degrades in response to contact with body fluids, for example after injection into a patient. Non-limiting examples of biodegradable polymers include polylactic acid, poloxamer, polyglycolic acid, polycaprolactone, polycarbonate, polyesteramide, polyanhydride, polyamino acid, polyethylene glycol (PEG), polyorthoester, polycyanoacrylate (and copolymers), PLGA, and mixtures of any of the above, as well as copolymers based on two or more repeating units forming the above-listed polymers. In the context of the present invention, preferred biodegradable polymers are polylactic acid, polyglycolic acid, PEG, PLGA, and mixtures of any of the above, as well as copolymers based on two or more repeating units forming the above-listed preferred polymers. For example, biodegradable polymers may include PLGA in a mixture with any other biodegradable polymer, and in particular PLGA in a mixture with any of the above-listed biodegradable polymers other than PLGA.

[0013] As used herein, the term "biodegradable polymeric microparticles" refers to monolithic microparticles formed from a biodegradable polymer. The microparticles have an internal continuous biodegradable polymer matrix. The microparticles can be of any shape, including spherical or irregular. The term includes microspheres and microgranules. The biodegradable polymer used to form the biodegradable polymer microparticles contained in the pharmaceutical composition of the present invention includes PLGA having a molar ratio of lactide and glycolide of 80:20 to 90:10 and an intrinsic viscosity of 0.2 to 0.4 dl / g measured in chloroform at a concentration of 0.5 w / w% at 25°C. In one embodiment, the PLGA has a molar ratio of lactide to glycolide of 82:18 to 88:12, such as 83:17 to 87:13. In one embodiment, the intrinsic viscosity of the PLGA measured in chloroform at a concentration of 0.5 w / w % at 25° C. is 0.2 to 0.4 dl / g. In a more specific embodiment, the PLGA has a lactide to glycolide molar ratio of 83:17 to 87:13 and an intrinsic viscosity of 0.25 to 0.35 dl / g measured at 25° C. at a concentration of 0.5 w / w % in chloroform. The PLGA may be linear or branched, hyperbranched, comb-branched, dendrimer-like branched, T-shaped, star-shaped, or any mixture thereof. In one embodiment of the invention, the PLGA is a linear PLGA. The PLGA may be a poly D,L-lactide-co-glycolide copolymer.

[0014] The PLGA may contain less than 5% w / w, such as less than 3% w / w, of residual lactide and / or glycolide monomers. In one embodiment, the PLGA contains less than 0.5 w / w% residual lactide and / or glycolide monomers. Most preferably, the PLGA is free of residual lactide and / or glycolide monomers, i.e., 0% residual lactide and / or glycolide monomers. The end groups of the PLGA are not limited, and examples of possible end groups include hydroxy, ester (e.g., stearyl), acidic (e.g., carboxy) groups, and the like. In one embodiment of the present invention, the end groups of the PLGA are acidic, preferably carboxyl groups. The lactide to glycolide molar ratio of PLGA can be measured using conventional methods, for example, nuclear magnetic resonance (1H NMR).

[0015] In the present invention, the intrinsic viscosity of PLGA is measured in chloroform at a concentration of 0.5 w / w% at 25° C. The intrinsic viscosity can be measured by conventional methods, for example, using the Capillary Viscometer Method described in Chapter 2.2.9 of the European Pharmacopoeia 10.0. As will be appreciated by one of skill in the art, the intrinsic viscosity and the molar ratio of lactide to glycolide of PLGA are averages over a certain range, for example, as indicated in the manufacturer's specifications for PLGA. As described herein, any PLGA having the requisite attributes, such as lactide to glycolide molar ratio and intrinsic viscosity, can be used to form the biodegradable polymers defined herein, i.e., biodegradable polymer microparticles defined herein, and included in the biodegradable polymers included in the pharmaceutical compositions of the present invention. Non-limiting examples of commercially available PLGA include RESOMER® from Evonik, LACTEL® (Evonik), MEDISORB® from Evonik, PURASORB® from Corbion, and Expansorb® from Seqens.

[0016] The biodegradable polymer microparticles contained in the sustained release pharmaceutical composition of the present invention contain a somatostatin analog or a pharma- ceutical acceptable salt thereof. The somatostatin analog or a pharma- ceutical acceptable salt thereof can be loaded into the biodegradable polymer microparticles at a drug loading of 10 to 15 w / w%. As used herein, the term "drug loading" refers to the mass ratio (expressed as a percentage) of the somatostatin analog mass to the total mass of the biodegradable polymeric microparticle, i.e., according to the following formula: Mass ratio=m(SA) / T(BPM) (wherein m(SA) represents the mass of the somatostatin analogue and T(BPM) represents the mass of the biodegradable polymer microparticles). It is expressed by: When a pharma- ceutically acceptable salt of a somatostatin analog is used, the mass ratio is calculated based on the mass of the molar amount of the free base of the somatostatin analog that is the same molar amount as the pharma- ceutically acceptable salt of the somatostatin analog contained in the biodegradable polymeric microparticles. Drug loading can be measured using conventional methods, e.g., high performance liquid chromatography (HPLC), for example, an appropriate mass of biodegradable polymeric microparticles, e.g., 20 mg, can be weighed out and dissolved in dimethylsulfoxide (DMSO), and the sample analyzed by HPLC assay, e.g., according to the method described in the European Pharmacopoeia, e.g., the Octreotide General Monograph for Octreotide.

[0017] In one embodiment of the present invention, the drug loading of the biodegradable polymer microparticles contained in the pharmaceutical composition of the present invention is 11 w / w% to 14 w / w%, for example, 11 w / w% to 13 w / w%, 11.5 w / w% to 13 w / w%, or 12 w / w% to 13 w / w%. In a more specific embodiment, the drug loading of the biodegradable polymer microparticles is 11.5 to 13%, for example, 12 to 13 w / w%, and in an even more specific embodiment, it is 11.5 w / w% to 12.5 w / w%, for example, 12 w / w% to 12.5 w / w%. As used herein, the term "biodegradable polymer microspheres" refers to non-spherical, irregularly shaped, monolithic microparticles formed from one or more biodegradable polymers, the microspheres having an inner continuous biodegradable polymer, e.g., PLGA, matrix.

[0018] As used herein, the term "biodegradable polymer microspheres" refers to spherical or substantially spherical, regularly shaped, monolithic microparticles formed from one or more biodegradable polymers, the microspheres having an inner continuous biodegradable polymer, e.g., PLGA, matrix. Biodegradable polymer microgranules may be made, for example, by dry processes such as extrusion and grinding, and biodegradable polymer microspheres may be made, for example, by wet processes such as emulsification and precipitation. In certain embodiments of the present invention, the biodegradable polymeric microparticles are biodegradable polymeric microspheres. The median particle size, i.e., Dv50, of the biodegradable polymer microparticles, for example, biodegradable polymer microspheres, contained in the pharmaceutical composition of the present invention can be 30 μm to 90 μm, for example, 30 μm to 80 μm, 40 μm to 90 μm, 40 μm to 80 μm, 50 μm to 90 μm, 60 μm to 80 μm, for example, 60 μm to 70 μm, 60 μm to 65 μm. The biodegradable polymer microparticles also have the following particle size values: Dv90 is 70 μm to 200 μm, preferably 100 μm to 150 μm, for example, 100 μm to 140 μm, 100 μm to 130 μm, or 100 μm to 125 μm; Dv10 is 5 μm to 50 μm, preferably 20 μm to 40 μm, for example, 20 μm to 30 μm, 20 μm to 25 μm; The device may further comprise one or more of the following: In a specific embodiment, the Dv50 of the biodegradable polymer microparticles contained in the composition of the present invention is 60 μm to 80 μm, for example, 60 μm to 75 μm, for example, 60 μm to 70 μm, for example, 62 μm to 65 μm; the Dv90 is 80 μm to 200 μm, preferably 100 μm to 150 μm, for example, 100 μm to 140 μm, 100 μm to 130 μm, 100 μm to 125 μm; and the Dv10 is 5 μm to 50 μm, preferably 20 μm to 40 μm, for example, 20 μm to 30 μm, 20 μm to 25 μm. DvX means that X% of the volume of a biodegradable polymeric microparticle sample is less than the indicated particle size value, for example, Dv50 of 90 μm means that 50% of the volume of a biodegradable polymeric microparticle sample is less than 90 μm, for example, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm. DvX, for example Dv50, is determined by wet laser diffraction, for example as described in the European Pharmacopoeia V.10.8 Chapter 2.9.31. DvX can be determined, for example, as described in Example 3. Particle size measurement can be performed by wet laser diffraction, for example, using a Malvern Mastersizer 3000 equipped with a HydroMediumVolume (MV) dispersion unit. After suspending the biodegradable polymer microparticles in an aqueous medium containing a surfactant, e.g., polysorbate 80 (0.1%) (at room temperature, e.g., 20-25°C), the sample may be dispersed in purified water in a hydroMV dispersion unit (stirring speed 2000 rpm) until 10%-20% obscuration is reached, after which the sample is sonicated for 3 minutes (hydroMV dispersion unit setting medium (50%)) and then analyzed using a Malvernmastersizer3000. The results are calculated based on the Mie theory (real particle refractive index of 1.52 and imaginary particle refractive index of 0.001). A general-purpose analytical model may be used. In one embodiment, the biodegradable polymer microparticles have a Dv50 of 50 μm to 80 μm, more specifically 60 μm to 80 μm.

[0019] The average specific surface area of ​​the biodegradable polymer microparticles defined herein and contained in the pharmaceutical composition of the present invention is 0.5 m 2 / g, e.g., 0.49m 2 / g, 0.48m 2 / g, 0.47m 2 / g, 0.46m 2 / g, 0.45m 2 / g or less, for example, 0.44m 2 / g, 0.43m 2 / g, 0.42m 2 / g, 0.41m 2 / g, 0.4m 2 / g, e.g., 0.4m2 / g, e.g., 0.39m 2 / g, 0.38m 2 / g, 0.37m 2 / g, 0.36m 2 / g, 0.35m 2 / g, 0.34m 2 / g, 0.33m 2 / g, 0.32m 2 / g, 0.31m 2 / g, 0.3 or less, e.g., 0.29m 2 / g, 0.28m 2 / g, 0.27m 2 / g, 0.26m 2 / g, 0.25m 2 The specific surface area may be, for example, 0.05 to 0.5 m 2 / g, e.g., 0.05 to 0.45 m 2 / g, 0.05~0.4m 2 / g or less, 0.05~0.35m 2 / g or less, 0.05~0.3m 2 / g or less, 0.05~0.25m 2 / g or less, where the specific surface area is determined by gas, e.g., nitrogen or krypton gas adsorption, e.g., using the N2-BET or Kr-BET adsorption methods as described in the European Pharmacopoeia 10.8, chapter 2.9.26, e.g., as described in Example 3. Specific surface area is defined herein and refers to the total surface area per unit mass of the biodegradable polymer microparticles contained in the composition of the present invention.Specific surface area value can be the average calculated over multiple batches of biodegradable polymer microparticles, for example, 2, 3, 4, 5, or 6 batches.In one embodiment, specific surface area is determined by nitrogen adsorption using the Brunauer-Emmett-Teller (N2-BET) theory, for example as described in Example 3. In one embodiment, the specific surface area of ​​the biodegradable polymeric microparticles as defined herein is between 0.05 and 0.3 m 2 / g, more specifically 0.1 to 0.28 m 2 / g. In a more specific embodiment, the biodegradable polymer microparticles contained in the composition of the present invention have a Dv50 of 50 μm to 80 μm, for example, 60 μm to 75 μm, for example, 60 μm to 70 μm, for example, 62 μm to 65 μm, and an average specific surface area of ​​0.05 to 0.3 m. 2 / g, e.g. 0.1~0.28m 2 / g, 0.1-0.25m 2 / g, 0.20~0.21m 2 / g, e.g. 0.15m 2 / g, 0.2m 2 / g, 0.21m 2 / g, 0.206m 2 / g, 0.25m 2 / g, where the specific surface area is measured by gas, e.g., nitrogen gas or krypton gas adsorption, e.g., as determined using the N2-BET or Kr-BET adsorption methods as described in Example 3. In an even more specific embodiment, the biodegradable polymer microparticles contained in the composition of the present invention have a Dv90 of 60 μm to 80 μm, for example, 60 μm to 75 μm, for example, 60 μm to 70 μm, for example, 62 μm to 65 μm, a Dv50 of 80 μm to 200 μm, preferably 100 μm to 150 μm, for example, 100 μm to 140 μm, 100 μm to 130 μm, 100 μm to 125 μm, and a Dv10 of 5 μm to 50 μm, preferably 20 μm to 40 μm, for example, 20 μm to 30 μm, 20 μm to 25 μm, and an average specific surface area of ​​0.05 to 0.3 m. 2 / g, e.g. 0.1~0.28m 2 / g, where the specific surface area is measured by gas, e.g., nitrogen gas or krypton gas adsorption, e.g., as determined using the N2-BET or Kr-BET adsorption methods as described in Example 3.

[0020] In another embodiment, the biodegradable polymeric microparticles included in the composition of the present invention are: The molar ratio of lactide to glycolide is 83:17 to 87:13; and The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g; There is PLGA, Dv50 is 60 μm to 75 μm, for example, 60 μm to 70 μm, for example, 62 μm to 65 μm; The average specific surface area is 0.05 to 0.3 m 2 / g, e.g. 0.1~0.28m 2 / g, 0.1-0.25m 2 / g, 0.20~0.21m 2 / g, e.g. 0.15m 2 / g, 0.2m 2 / g, 0.21m 2 / g, 0.206m 2 / g, 0.25m 2 / g, where the specific surface area is measured by gas, e.g., nitrogen or krypton gas adsorption, e.g., as determined using the N2-BET or Kr-BET adsorption methods as described in Example 3. Drug loading is 11.5-13%, e.g., 11.5 w / w%-12.5 w / w%, e.g., 12 w / w%-12.5 w / w% It is.

[0021] In another embodiment, the biodegradable polymeric microparticles included in the composition of the present invention are: The molar ratio of lactide to glycolide is 83:17 to 87:13; and The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g; There is PLGA, Dv50 is 60 μm to 75 μm, for example, 60 μm to 70 μm, for example, 62 μm to 65 μm; Dv90 is 100 μm to 150 μm, for example, 100 μm to 140 μm, 100 μm to 130 μm, or 100 μm to 125 μm; Dv10 is 20 μm to 40 μm, for example, 20 μm to 30 μm, 20 μm to 25 μm, The average specific surface area is 0.05 to 0.3 m 2 / g, e.g. 0.1~0.28m 2 / g, 0.1-0.25m 2 / g, 0.20~0.21m 2 / g, e.g. 0.15m 2 / g, 0.2m 2 / g, 0.21m 2 / g, 0.206m 2 / g, 0.25m 2 / g, where the specific surface area is measured by gas, e.g., nitrogen or krypton gas adsorption, e.g., as determined using the N2-BET or Kr-BET adsorption methods as described in Example 3. Drug loading is 11.5-13%, e.g., 11.5 w / w%-12.5 w / w%, e.g., 12 w / w%-12.5 w / w%, It is.

[0022] In another embodiment, the biodegradable polymer microparticles comprised in the composition of the present invention comprise a biodegradable polymer and a somatostatin analogue, preferably octreotide, or a pharma- ceutically acceptable salt thereof, wherein the biodegradable polymer is comprised of PLGA, which has the following structure: The molar ratio of lactide to glycolide is 83:17 to 87:13, and The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g, and The biodegradable polymer microparticles Dv50 is 60 μm to 75 μm, The average specific surface area is 0.05 to 0.3 m 2 / g, where the specific surface area is measured by gas, e.g., nitrogen or krypton gas adsorption, e.g., as determined using the N2-BET or Kr-BET adsorption methods, e.g., as described in Example 3; and Drug loading is 11.5-13%.

[0023] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention comprise a biodegradable polymer and a somatostatin analog, preferably octreotide, or a pharma- ceutically acceptable salt thereof, the biodegradable polymer being comprised of PLGA, the PLGA being The molar ratio of lactide to glycolide is 83:17 to 87:13; The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g, and the biodegradable polymer microparticles Dv50 is 60μm to 70μm, For example, as described in Example 3, the average specific surface area as measured by gas, e.g., nitrogen or krypton gas adsorption, as determined using, e.g., N2-BET or Kr-BET adsorption methods, is 0.1 to 0.28 m 2 / g, and The drug loading is 11.5 w / w% to 12.5 w / w%.

[0024] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention comprise a biodegradable polymer and a somatostatin analog, preferably octreotide, or a pharma- ceutically acceptable salt thereof, the biodegradable polymer being comprised of PLGA, the PLGA being The molar ratio of lactide to glycolide is 83:17 to 87:13; The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g, and the biodegradable polymer microparticles Dv50 is 62μm to 65μm, For example, as described in Example 3, the average specific surface area as measured by gas, e.g., nitrogen or krypton gas adsorption, as determined using, e.g., N2-BET or Kr-BET adsorption methods, is 0.1 to 0.25 m 2 / g, e.g. 0.15m 2 / g, 0.2m 2 / g, 0.20m 2 / g, 0.206m2 / g, 0.21m 2 / g, 0.25m 2 / g, and The drug loading is 12 w / w% to 12.5 w / w%.

[0025] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention comprise a biodegradable polymer and a somatostatin analog, preferably octreotide, or a pharma- ceutically acceptable salt thereof, the biodegradable polymer being comprised of PLGA, the PLGA being The molar ratio of lactide to glycolide is 83:17 to 87:13; The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g, and the biodegradable polymer microparticles Dv50 is 60μm to 75μm, Dv90 is 100 μm to 150 μm, Dv10 is 20 μm to 40 μm, For example, as described in Example 3, the average specific surface area as measured by gas, e.g., nitrogen or krypton gas adsorption, as determined using, e.g., N2-BET or Kr-BET adsorption methods, is between 0.05 and 0.3 m 2 / g, and The drug loading is 11.5 w / w% to 13 w / w%.

[0026] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention comprise a biodegradable polymer and a somatostatin analog, preferably octreotide, or a pharma- ceutically acceptable salt thereof, the biodegradable polymer being comprised of PLGA, the PLGA being The molar ratio of lactide to glycolide is 83:17 to 87:13; The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g, and the biodegradable polymer microparticles Dv50 is 60μm to 70μm, Dv90 is 100 μm to 140 μm, Dv10 is 20 μm to 30 μm, For example, as described in Example 3, the average specific surface area as measured by gas, e.g., nitrogen or krypton gas adsorption, as determined using, e.g., N2-BET or Kr-BET adsorption methods, is 0.1 to 0.28 m 2 / g, and The drug loading is 11.5 w / w% to 12.5 w / w%.

[0027] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention comprise a biodegradable polymer and a somatostatin analog, preferably octreotide, or a pharma- ceutically acceptable salt thereof, the biodegradable polymer being comprised of PLGA, the PLGA being The molar ratio of lactide to glycolide is 83:17 to 87:13; The intrinsic viscosity measured in chloroform at a concentration of 0.5 w / w% at 25°C is 0.25 to 0.35 dl / g, and the biodegradable polymer microparticles Dv50 is 62μm to 65μm, Dv90 is 100 μm to 130 μm, for example, 100 μm to 125 μm; Dv10 is 20 μm to 25 μm, For example, as described in Example 3, the average specific surface area as measured by gas, e.g., nitrogen or krypton gas adsorption, as determined using, e.g., N2-BET or Kr-BET adsorption methods, is 0.1 to 0.25 m 2 / g, e.g. 0.15m 2 / g, 0.2m 2 / g, 0.20m 2 / g, 0.206m 2 / g, 0.21m 2 / g, 0.25m 2 / g, and The drug loading is 12 w / w% to 12.5 w / w%.

[0028] The somatostatin analog, or a pharma- ceutically acceptable salt thereof, is comprised in a biodegradable polymer microparticle, e.g., a biodegradable polymer microsphere, contained in the pharmaceutical composition of the present invention. The somatostatin analog, or a pharma- ceutically acceptable salt thereof, can be dispersed, e.g., uniformly dispersed, within a continuous biodegradable polymer, e.g., PLGA, matrix of the biodegradable polymer microparticle, e.g., the biodegradable polymer microsphere. The term "somatostatin analog" as used herein refers to any pharmacologic active synthetic (as opposed to naturally occurring) compound designed to pharmacologically mimic somatostatin in binding to one or more of the five somatostatin receptor subtypes. If a somatostatin analog binds to at least one somatostatin receptor subtype, for example, to at least one of the five somatostatin receptor subtypes within the nM or μM range, it may be considered pharmacologic active if, for example, the IC50(nM) is less than 70, for example, less than 60, less than 50, less than 40, less than 30, less than 20, less than 10, for example, less than 6, for example, less than 5, less than 4, less than 3, less than 2, less than 1 for one or more of the five somatostatin subtypes. Preferably, the IC50(nM) is less than 6 for one or more of the five somatostatin subtypes, for example, less than 6 for subtype 2. The IC50 (nM) can be determined by known methods, for example, by measuring the binding of an I-labeled somatostatin analog to a cloned subtype receptor of interest in vivo, for example, by measuring binding in CHO-K1 (Chinese Hamster Ovary) cells transfected with the receptor of interest, e.g., subtype 2.

[0029] As used herein, the term "somatostatin" refers to any naturally occurring somatostatin, for example, somatostatin-14 or somatostatin-28. Non-limiting examples of somatostatin analogs include octreotide, lanreotide, pasireotide, and vapreotide. Any pharma- ceutically acceptable salt of somatostatin analogues may be included in the biodegradable polymeric microparticles, e.g., biodegradable polymeric microspheres, included in the pharmaceutical compositions of the present invention. Acceptable salts may be, for example, acid addition salts with inorganic, polymeric or organic acids, e.g., hydrochloric acid, acetic acid, lactic acid, citric acid, fumaric acid, malonic acid, maleic acid, tartaric acid, aspartic acid, benzoic acid, succinic acid or pamoic acid (embonic acid). The acid addition salts may be monovalent or divalent salts. The salts may be water-soluble or water-insoluble. In certain embodiments, the somatostatin analog contained in the biodegradable polymer PLGA microparticles, e.g., biodegradable polymer microspheres, contained in the pharmaceutical compositions of the present invention is octreotide or a pharma- ceutically acceptable salt thereof. A preferred pharma- ceutically acceptable salt may be the acetate or pamoate salt. In a more specific embodiment, the somatostatin analog is octreotide and / or a pharma- ceutically acceptable salt thereof, the pharma-ceutically acceptable salt thereof being selected from the group consisting of octreotide acetate, octreotide pamoate, and combinations thereof. Preferably, the pharma-ceutically acceptable salt thereof is octreotide acetate.

[0030] The advantage of the sustained release pharmaceutical composition of the present invention is that only biodegradable polymeric microparticles formed from PLGA as defined herein have the following properties: The desired sustained release, for example, 30 days or more, for example, 60 days or more, 90 days or more, or 120 days or more. Low initial release (burst), and Surprisingly high bioavailability of the somatostatin analogue or a pharma- ceutically acceptable salt thereof following administration to a patient; It is believed that one or more of these are required in the composition to achieve a certain composition. Thus, the biodegradable polymer used to form the biodegradable polymeric microparticles included in the pharmaceutical compositions of the present invention may comprise, or consist essentially of, PLGA as defined herein.

[0031] In one embodiment, the biodegradable polymer comprises at least 50% PLGA as defined herein, e.g., PLGA having a molar ratio of lactide to glycolide of 80:20 to 90:10 and an intrinsic viscosity of 0.2 to 0.4 dl / g measured at 25° C. in chloroform at a concentration of 0.5 w / w%. In more specific embodiments, at least 85 w / w%, such as at least 90 w / w%, at least 95 w / w% or 100 w / w% of the biodegradable polymer may be PLGA as defined herein. Preferably, 100% of the biodegradable polymer is PLGA as defined herein. As used herein above and below, particularly in the above two paragraphs and the following paragraph, "at least 50%" may in certain embodiments be at least 60 w / w%, at least 65 w / w%, at least 70 w / w%, at least 75 w / w%, at least 80 w / w%, at least 85 w / w%, at least 90 w / w%, such as at least 95 w / w%, for example 96 w / w% or more, 97 w / w% or more, 98 w / w% or more, 99 w / w% or more, such as 100 w / w%.

[0032] In the above embodiments where there is a biodegradable polymer that comprises less than 100% PLGA as defined herein, the remainder to 100% is preferably any one or more of the biodegradable polymers listed in the paragraph above defining the term "biodegradable polymer" (excluding PLGA as defined herein). The biodegradable polymer microparticles described herein may be the only biodegradable polymer microparticles contained in the composition of the present invention, or they may comprise at least 50 w / w%, for example at least 60 w / w%, at least 70 w / w%, at least 80 w / w%, at least 90 w / w%, at least 95 w / w%, at least 99 w / w%, at least 99.9 w / w% of the total of any biodegradable polymer microparticles contained in the composition. Preferably, the biodegradable polymer microparticles described herein comprise at least 80 w / w%, at least 85 w / w%, for example at least 90 w / w%, at least 95 w / w%, at least 99 w / w%, at least 99.9 w / w%. Most preferably, the biodegradable polymer microparticles described herein are the only biodegradable polymer microparticles contained in the composition of the present invention. When the biodegradable polymeric microparticles constitute less than 100 w / w% of the biodegradable polymeric microparticles contained in the pharmaceutical composition of the present invention, the remaining % of the biodegradable microparticles are "other" biodegradable microparticles as defined herein. The other biodegradable microparticles may also comprise PLGA. The PLGA may be the same as or different from the PLGA as defined herein. The other biodegradable microparticles may also comprise a somatostatin analogue, or a pharma- ceutically acceptable salt thereof. Preferably, the other biodegradable polymeric microparticles are formed from a biodegradable polymer comprising PLGA as defined herein, and preferably, they comprise a somatostatin analogue as defined herein, or a pharma- ceutically acceptable salt thereof. More preferably, the other biodegradable polymeric microparticles are formed from a biodegradable polymer comprising at least 50 w / w PLGA as defined herein, and preferably, they comprise a somatostatin analogue as defined herein, or a pharma- ceutically acceptable salt thereof. Other biodegradable polymeric microparticles may differ from the biodegradable polymeric microparticles defined herein by having different drug loading, DV50 or specific surface area. The other biodegradable polymeric microparticles may differ in one of the attributes / characteristics.

[0033] The compositions according to the invention may further comprise one or more other pharmaceutical excipients, such as pharmaceutical excipients normally included in the subject formulations, such as diluents, surfactants, stabilizers, release modifiers, preservatives, antioxidants, buffers, anti-aggregating agents, etc. Non-limiting examples of other pharmaceutical excipients include polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose (CMC-Na), dextrin, polyethylene glycol, suitable surfactants, such as poloxamers, also known as poly(oxyethylene-block-oxypropylene), commercially available surfactants known under the trade name TWEEN® (e.g., Tween 20, Tween 40, Tween 60, Tween 80, Tween 65, Tween 85, Tween 21, Tween 61, Tween 81). Examples of suitable anti-agglomerating agents include poly(oxyethylene) sorbitan fatty acid esters of the present invention, commercially available sorbitan fatty acid esters known under the trade name SPAN, lecithin, inorganic salts such as zinc carbonate, magnesium hydroxide, magnesium carbonate, or protamines, e.g., human protamine or salmon protamine, or natural or synthetic polymers containing amine residues, such as polylysine, hydroxyethyl cellulose (HEC) and / or hydroxypropyl cellulose (HPC), poly(vinylpyrrolidone), and gelatin, e.g., porcine or fish gelatin. Suitable anti-agglomerating agents include, for example, mannitol, glucose, dextrose, sucrose, sodium chloride, or water-soluble polymers such as polyvinyl alcohol, polyvinylpyrrolidone, or polyethylene glycol.

[0034] The pharmaceutical composition of the present invention can provide sustained release of a somatostatin analog or a pharma- ceutically acceptable salt thereof contained within biodegradable polymeric microparticles contained therein. The term "sustained release" as used herein refers to the continuous release of an amount of somatostatin analog or a pharma- ceutically acceptable salt thereof over or substantially over a predefined release period (e.g., 30 days or more, 60 days or more, 90 days or more, 120 days or more), as measured in vivo, for example, after administration by IM injection in a patient. The amount of somatostatin analog release can be an effective amount. For example, in one embodiment, sustained release can be determined by administering a 30 mg dose of somatostatin analog, preferably octreotide, or a pharma- ceutically acceptable salt thereof, to a patient by IM injection and determining that the plasma level of somatostatin analog, particularly octreotide, does not fall below 0.5 ng / mL for a period of at least 30 days.

[0035] In other embodiments where the somatostatin analog is octreotide or a pharma- ceutically acceptable salt thereof, sustained release can be confirmed by administering to a patient, e.g., a patient in need thereof, e.g., a patient suffering from acromegaly or GEP-NETs, ​​an amount of a composition of the invention corresponding to a dose of 90 mg of octreotide by IM injection, and confirming that the plasma level of octreotide does not fall to a level below 0.5 ng / mL over the period from day 21 to day 84 following administration on day 0. This test, as well as other tests described herein above and below, can be performed with a larger number of patients (e.g., 5, 10, 15, 20, 50 or 100 patients) and then the results averaged to improve the quality and accuracy of the results obtained. An effective amount in the context of the present invention may be an amount that results in a patient having a therapeutically effective plasma level of a somatostatin analogue, such as octreotide, depending on the patient's existing plasma levels. An effective amount can be an amount that results in a somatostatin analog plasma level of 0.1 ng / mL, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 ng / mL or more. For somatostatin analogues such as lanreotide, octreotide, pasireotide, or vapreotide, a therapeutically effective plasma level can be, for example, 0.3ng / mL to 12ng / mL or more, such as 2ng / mL, 2.5ng / mL, 3ng / mL, 3.5ng / mL, 4ng / mL, 4.5ng / mL, 5ng / mL, 5.5ng / mL, 6ng / mL, 6.5ng / mL, 7ng / mL, 7.5ng / mL, 8ng / mL, 8.5ng / mL, 9ng / mL, 9.5ng / mL, 10ng / mL or more. For octreotide, a therapeutically effective plasma level may be, for example, 0.3ng / mL to 1ng / mL or more, for example, 0.3ng / mL to 3ng / mL, for example, 0.4ng / mL, 0.5ng / mL, 0.6ng / mL, 0.7ng / mL, 0.8ng / mL, 0.9ng / mL, 1.5ng / mL, 1.8ng / mL, 2ng / mL, 2.5ng / mL, 3ng / mL. A particularly effective plasma level may be 1ng / mL. What constitutes a therapeutically effective plasma level of a somatostatin analogue depends on the characteristics of the patient, for example, how well the patient responds to the somatostatin analogue in question. As used herein, the term "therapeutic effect or therapeutically effective" refers not only to a complete cure of a disease, but also to the alleviation or improvement of a disease or any symptoms associated therewith, such as an improvement in quality of life, or a delay in disease progression or stabilization of a disease. The efficacy of treatment in a patient can be monitored by any method known to those skilled in the clinical art of treating the disease in question.

[0036] In one embodiment of the present invention, an effective amount of the composition of the present invention may be an amount that results in a plasma level of a somatostatin analog (e.g., octreotide) that reduces insulin-like growth factor 1 (IGF1) serum levels in a patient (e.g., a patient suffering from acromegaly). For example, administration of an effective amount of a composition of the present invention comprising octreotide or a pharma- ceutically acceptable salt thereof may reduce serum IGF1 levels. There is no particular limit to the level of reduction achieved. In one embodiment, the reduction may be up to 50%, for example up to 40%, or up to 30% from baseline (IGF1 levels in the patient before administration of the pharmaceutical composition of the present invention), but the reduction is at least 1%, usually at least 15%, and particularly at least 20%. In the measurement, serum IGF1 levels may be measured using a validated IDS-iSYS method, such as the method described in Example 10B herein, or a validated LC-MS / MS method.

[0037] In an embodiment of the invention, an effective amount of the composition of the invention can be an amount that results in a somatostatin analog (e.g., octreotide) plasma level that reduces growth hormone (GH) serum levels in a patient (e.g., a patient suffering from acromegaly). For example, administration of an effective amount of the composition of the invention comprising octreotide or a pharma- ceutically acceptable salt thereof, in an embodiment, reduces GH serum levels to, for example, 3 μg / L or less, for example, 2.5 μg / L or less, for example, 2 μg / L or less, for example, 1.5 μg / L or less, or for example, 1 μg / L or less, with the minimum reduction being the level of detection. For such determination, serum human growth hormone (GH) levels can be determined using the IDS-iSYS Multi-Discipline Automated System, which is described in more detail below. In a preferred embodiment, an effective amount of a composition of the invention may be an amount that results in plasma levels of a somatostatin analogue, such as octreotide, that reduces IGF1 and / or GH serum levels in a patient suffering from acromegaly. The reduction may be as described above.

[0038] In one embodiment of the invention, an effective amount of the composition of the invention may be an amount that results in a somatostatin analogue, such as octreotide plasma level, that reduces chromogranin A (CgA) serum levels in a patient, such as a patient suffering from GEP-NET. There is no particular limit to the level of reduction achieved. CgA serum levels can be determined using the Time Resolved Amplified Cryptate Luminescence (TRACE) assay from the manufacturer BRAHMS, using the B·R·A·H·M·S CgA II KRYPTOR assay kit (reference number 839.050).

[0039] For example, sustained release of an effective amount of a somatostatin analogue over substantially a predetermined release period may be release over a predetermined release period minus a sustained release period, e.g., a period after injection before release of an effective amount is reached, e.g., the sustained release period may be 21 days or less, 18 days or less, 15 days or less, e.g., 14 days or less, 10 days or less, or 5 days or less. For example, if the predetermined release period is 90 days and the sustained release period is 5 days, then after administration of a first dose of a composition of the invention on day 0, the patient's plasma level of the somatostatin analogue is within a therapeutically effective range from day 5 to the end of the sustained release period. Typically, the sustained release period is only observed in patients who are not receiving a therapeutically effective plasma level of the somatostatin analogue the first time they receive a composition of the invention, e.g., in patients in need of treatment who have not been pretreated with a somatostatin analogue.

[0040] The term "patient" as used herein refers to a human or animal subject. In one embodiment of the present invention, the patient is a human. The human may be an adult or a child. Prior to administration of the composition of the present invention, the patient may be pre-treated (previously treated) with a somatostatin analog, or a pharma- ceutically acceptable salt thereof, and may have therapeutically effective plasma levels of the somatostatin analog, such as octreotide or lanreotide (the patient may, for example, be switching from one type of somatostatin analog treatment to treatment with the composition of the present invention, or may be pre-treated to ensure that the somatostatin analog is adequately supported by the patient). The therapeutically effective plasma levels of the somatostatin analog may be several weeks after the last administration of any pre-treatment. The patient may also be pre-treated to avoid any sustained release period after the first administration of the composition of the present invention.

[0041] The pharmaceutical compositions of the invention preferably provide sustained release of the somatostatin analogue or a pharma- ceutically acceptable salt thereof for 30 days or more, such as for 40 days or more, 50 days or more, 60 days or more, 70 days or more, 80 days or more, 90 days or more, 100 days or more, 110 days or more, 120 days or more, 150 days or more, 180 days or more, e.g., for 200 days. 30 days or more may be 30 to 200 days, for example, 30 to 180 days, for example, 30 to 126 days, for example, 30 to 120 days, for example, 30 to 90 days, for example, 30 to 60 days, for example, 56 days, 30 to 50 days, for example, 49 days, 42 days, 30 to 40 days, for example, 35 days, 30 days. 60 days or more may be 60 to 200 days, for example, 60 to 180 days, for example, 60 to 126 days, for example, 60 to 120 days, for example, 60 to 90 days, for example, 60 to 80 days, 77 days, 84 days, 60 to 70 days, for example, 60 days, 63 days, or 70 days. 90 days or more may be 90 to 200 days, for example, 90 to 180 days, for example, 90 to 126 days, for example, 90 to 120 days, for example, 112 days, 90 to 110 days, for example, 105 days, 90 to 100 days, for example, 90 days, 91 days, or 98 days. 120 days or more may be 120 to 200 days, for example, 120 to 180 days, for example, 120 to 126 days, for example, 120 days. The sustained release period disclosed herein is given in days. However, the period can also be equivalent to the same period of weeks or months, for example, 28-30 days can be equivalent to 4-5 weeks or 1 month, 56-60 days can be equivalent to 8-9 weeks or 2 months, 84-90 days can be equivalent to 12-13 weeks or 3 months, 112-120 days can be equivalent to 17-18 weeks or 4 months, 140-150 days can be equivalent to 21-22 weeks or 5 months, 168-180 days can be equivalent to 25-26 weeks or 6 months, and 196-200 days can be equivalent to 27-28 weeks or 7 months.

[0042] In one embodiment, the pharmaceutical composition of the present invention provides sustained release of the somatostatin analog or pharma- ceutically acceptable salt thereof for 30 days or more, preferably 30-200 days, such as 30-180 days, such as 30-126 days, or in another embodiment, for about 30 days or more, preferably about 30-200 days, such as 28-200 days, such as 30-180 days, such as 30-126 days. In a more specific embodiment, the pharmaceutical composition of the present invention is a one-month sustained release formulation, preferably administered to a patient about every 30 days, such as every 24-35 days, such as every 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 days. In one embodiment of the invention, the sustained release pharmaceutical composition of the invention provides sustained release for 60 days or more, preferably 60-200 days, such as 60-180 days, e.g., 60-126 days, or in another embodiment, for about 60 days or more, preferably 56-200 days, such as 60-200 days, e.g., 60-180 days, e.g., 60-126 days. In a more specific embodiment, the pharmaceutical composition of the invention is a two-month sustained release formulation, preferably administered to a patient about every 60 days, e.g., every 54-65 days, e.g., every 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 days. In one embodiment, the sustained release pharmaceutical composition of the present invention provides sustained release for 90 days or more, preferably 90-200 days, e.g., 90-180 days, e.g., 90-126 days, or in another embodiment, for about 90 days or more, preferably 84-200 days, e.g., 90-200 days, e.g., 90-180 days, e.g., 90-126 days. In a more specific embodiment, the pharmaceutical composition of the present invention is a 3-month sustained release formulation, preferably administered to a patient about every 90 days, e.g., every 84-95 days, e.g., every 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 days. In one embodiment, the pharmaceutical composition of the present invention provides sustained release of the somatostatin analog or pharma- ceutical acceptable salt thereof for 120 days or more, preferably 120-200 days, such as 120-180 days, e.g., 120-126 days, or in another embodiment, for about 120 days or more, preferably 112-200 days, such as 120-200 days, such as 120-180 days, e.g., 120-126 days. In a more specific embodiment, the pharmaceutical composition of the present invention is a 4-month sustained release formulation, preferably administered to a patient about every 120 days, e.g., every 112-125 days, e.g., every 114-125 days, e.g., every 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 days. The pharmaceutical compositions described herein may provide sustained release as described herein above and below, but the pharmaceutical compositions are not limited to being sustained release compositions as described herein. The product features of the pharmaceutical compositions as specified herein, e.g., in claim 1 attached hereto, provide advantageous release characteristics, regardless of whether they are classified as any particular type of "sustained release".

[0043] The pharmaceutical composition of the present invention may have a low initial release (low burst) of the somatostatin analogue or its pharma- ceutically acceptable salt after administration to a patient. This may help to minimize any side effects / adverse reactions that may be associated with administration of the somatostatin analogue or its pharma- ceutically acceptable salt. The pharmaceutical composition of the present invention may be considered to be low burst if it is characterized by a release of the somatostatin analogue contained therein that meets the following criteria: less than 15%, such as less than 10%, of the somatostatin analogue, e.g., octreotide, released therein over a period of 5 hours. The release may be measured in vitro (at 37°C in 900 mL of 100 mM acetate buffer at pH 4, e.g., with stirring at 75 RPM) according to the method described in European Pharmacopoeia 10, 2.9.3. The method in which the composition is tested in an amount equivalent to 30 mg, 60 mg or 90 mg of somatostatin analogue, e.g., octreotide. The percentages in this paragraph and the following two paragraphs may be understood as being expressed on aw / w basis or on a mole / mole basis.

[0044] In one embodiment, the pharmaceutical composition of the invention releases less than 7%, such as less than 6%, 5%, 4%, 3% of the somatostatin analogue, such as octreotide, contained therein over a 5 hour period. In a more specific embodiment of the invention, the pharmaceutical composition of the invention releases less than 3% of the contained somatostatin analogue, e.g., octreotide, over a 5 hour period when measured in vitro at 37° C. in acetate buffer at pH 4.

[0045] The pharmaceutical composition according to the present invention may be a composition of dry biodegradable polymer microparticles, e.g., biodegradable polymer microspheres, ready to be suspended in a liquid vehicle prior to injection, or may be a ready-to-use liquid vehicle suspension, e.g., comprising a biodegradable polymer, e.g., biodegradable polymer microspheres. The liquid vehicle may be an aqueous (water-based) or non-aqueous vehicle. The biodegradable polymer microparticles, e.g., biodegradable polymer microspheres, contained in the liquid vehicle may be any of the biodegradable polymer microparticles, e.g., biodegradable polymer microspheres, described herein above. In one embodiment, the pharmaceutical composition of the present invention is a liquid vehicle suspension comprising biodegradable polymeric microparticles, e.g., biodegradable polymeric microspheres, or a composition of dry biodegradable polymeric microparticles, e.g., biodegradable polymeric microspheres. The liquid vehicle may be an aqueous (water-based) or non-aqueous liquid vehicle. The composition of dry biodegradable polymeric microparticles, e.g., dry biodegradable polymeric microspheres, or a liquid vehicle suspension containing biodegradable polymeric microparticles, e.g., biodegradable polymeric microspheres, can be provided, for example, in a syringe ready for injection. The composition of dry biodegradable polymer microparticles or the liquid vehicle suspension containing biodegradable polymer microparticles may contain biodegradable polymer microparticles as defined herein as the only biodegradable polymer microparticles of the composition, or may be a mixture of biodegradable polymer microparticles as defined herein with other biodegradable polymer microparticles. As stated above, preferably at least 50 w / w%, more preferably at least 80 w / w%, of the biodegradable polymer microparticles contained in such compositions of the invention are biodegradable polymer microparticles as defined herein.

[0046] As used herein, the term "aqueous liquid vehicle" or "aqueous-based liquid vehicle" refers to a pharma- ceutically acceptable liquid that is predominantly water, e.g., a pharma- ceutically acceptable liquid that contains more than 50% water, e.g., 60% or more, 70% or more, 80% or more, 90% or more, 93% or more, 95% or more, or even 97% or more water. Such percentages are (w / v) ratios. Aqueous liquid vehicles may contain pharmaceutical excipients. Such excipients may be used to ensure isotonicity and improve the wettability and non-settling properties of microparticles, e.g., microspheres. Examples of such pharmaceutical excipients include, but are not limited to, mannitol, sodium chloride, glucose, dextrose, sucrose, or glycerin, non-ionic surfactants, e.g., poloxamer, poly(oxyethylene)-sorbitan-fatty acid esters, sodium carboxymethylcellulose (CMC-Na), sorbitol, poly(vinylpyrrolidone), or aluminum monostearate, polyethylene glycols (PEG), e.g., PEG 4000. A composition of dry biodegradable polymeric microparticles, e.g., dry biodegradable polymeric microspheres, can, for example, be suspended prior to injection in an aqueous vehicle, e.g., an aqueous vehicle comprising glucose and PEG 4000, e.g., 3-7 w / w% glucose, e.g., 5 w / w% glucose, and 5-9 w / w%, e.g., 7.5 w / w% PEG 4000, or, for example, an aqueous vehicle comprising sodium carboxymethylcellulose, mannitol, and Tween 80, e.g., 1 w / w%-2 w / w% carboxymethylcellulose, 4-5 w / w% mannitol, and 0.05-0.15 w / w% Tween 80. Advantageously, the inventors have found that the somatostatin analogue release profile of a non-aqueous liquid vehicle suspension comprising biodegradable polymeric microparticles according to the present invention can be the same or substantially the same as that of a corresponding aqueous vehicle suspension (wherein all characteristics of the microparticles are the same), e.g., there is no change or substantially no change in the burst, sustained release, or release period, which means that non-aqueous and aqueous liquid vehicles can be used interchangeably as needed, e.g., due to regulatory constraints, financial considerations, or personal preference.

[0047] The term "non-aqueous liquid" as used herein refers to a pharma- ceutically acceptable liquid that is free or substantially free of water, e.g., a pharma- ceutically acceptable liquid that contains 0.25% (w / v) or less of water, 0.1% or less of water, 0.05% (w / v) or less of water. The non-aqueous liquid is inert or substantially inert to the biodegradable polymer microparticles contained in the compositions of the present invention, as well as to any somatostatin analogues contained therein, e.g., it does not interact or does not substantially interact with, or does not solubilize or substantially solubilize, the biodegradable polymer, e.g., PLGA, microparticles or the somatostatin analogues contained therein. The water content of non-aqueous liquids can be measured using conventional methods, for example micrometric methods as described in the European Pharmacopoeia, 10.0, Chapter 2.5.32. In one embodiment of the present invention, the viscosity of the non-aqueous liquid is 25 to 33 MPa at 20°C. The viscosity of non-aqueous liquids can be measured using conventional methods, for example, The Capillary Viscometer Method as described in the European Pharmacopoeia, Year 10.0, Chapter 2.2.9. The non-aqueous liquid may be a pharma- ceutically acceptable oil. The term "oil" as used herein refers to a substance that is in a viscous liquid state at ambient temperature (20°C to 30°C) or at slightly warmer temperatures and is hydrophobic (immiscible with water) and lipophilic (miscible with other oils). Non-limiting examples of suitable oils include vegetable oils, such as coconut oil, palm oil, palm kernel oil, sesame oil, soybean oil, almond oil, rapeseed oil, corn oil, sunflower oil, peanut oil, olive oil, castor oil, soybean oil, safflower oil, cottonseed oil, ethyl oleate, and any combination thereof.

[0048] In one embodiment of the invention, the non-aqueous liquid is a pharma- ceutically acceptable oil. Particularly suitable oils may include medium chain triglycerides (MCTs). As used herein, the term "medium chain triglyceride (MCT)" refers to a glyceride ester formed from glycerol and three medium chain fatty acids, each of which is a C6-C12 fatty acid, i.e., a carboxylic acid having an aliphatic chain of 6 to 12 carbon atoms, e.g., C6 (hexanoic acid), C8 (octanoic acid), C10 (decanoic acid), and C12 (dodecanoic acid). The three medium chain fatty acids from which the triglyceride is formed may all be the same, e.g., all three may be medium chain fatty acids having an aliphatic chain of, e.g., 8 or 10 carbon atoms, or one or all of the medium chain fatty acids may be different from the others. The aliphatic chains of the MCT may be saturated or unsaturated.

[0049] In one embodiment, the non-aqueous liquid is a pharma- ceutically acceptable oil consisting essentially of one or more medium chain triglycerides (MCTs). A pharma- ceutically acceptable oil is considered to consist essentially of one or more MCTs if it contains more than 50%, e.g., 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, e.g., 96%, 97%, 98%, 99%, 100% of one or more medium chain triglycerides, where the content of a particular MCT in the oil is measured by GC without further conversion according to the method described in Ph.Eur.2.4.22. In an even more specific embodiment, the non-aqueous liquid is an oil consisting essentially of C8 and / or C10 medium chain triglycerides, e.g. consisting essentially of C8 and C10 medium chain triglycerides, e.g. consisting of 50%-80% C8 MCT and 20%-50% C10 MCT, such as 58% C8 MCT and 41% C10 MCT as present in MIGLYOL® 812 as described below. As mentioned above, the MCT content of the oil is measured by GC without further conversion according to the method described in Ph.Eur.2.4.22. For stability reasons, if the MCTs used in the compositions of the invention are saturated, it is preferred that, for example, at least 80%, such as at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5%, such as 100%, of any MCTs used in the compositions are saturated, where the MCT content of the oil is measured by GC without further conversion according to the method described in Ph.Eur.2.4.22. Pharmaceutically acceptable MCT oils are commercially available. Non-limiting examples of commercially available MCT oils include MIGLYOL® 810, 812, 818 (SasolgermanygmbH, Witten, Germany). A particularly effective MCT oil can be MIGLYOL® 812.

[0050] The amount of liquid vehicle used in the suspension (v) may be about 1 to about 5 mL per dose, for example, about 2 to about 3 mL per dose, for example, 2.9 mL, 2.8 mL, 2.7 mL, 2.6 mL, for example, about 2 to about 2.5 mL per dose, for example, 2.5 mL, 2.4 mL. In one embodiment, the composition of dry biodegradable polymer microparticles, for example, biodegradable polymer microspheres, and the vehicle for suspension may be separately contained in a double-chamber syringe. The liquid vehicle used for the suspension may contain the biodegradable polymer microparticles at any suitable concentration, depending on the desired dose and the desired injection volume. In one embodiment, the liquid vehicle contains the biodegradable polymer microparticles at a concentration of 100 mg / mL to 500 mg / mL, for example, 100 to 400 mg / mL, for example, 200 to 400 mg / mL, for example, 230 to 350 mg / mL, 200 to 350 mg / mL, for example, 250 to 350 mg / mL, based on the total volume of the suspension. Preferably, the liquid vehicle contains the biodegradable polymer microparticles at a concentration of 100 mg / mL to 375 mg / ml, for example, 125 mg / mL to 375 mg / ml, 250 to 375 mg / ml, based on the total volume of the suspension. The injection volume of the liquid suspension may be about 1 to about 5 mL per dose, for example, about 2 to about 2.5 mL per dose, for example, 2.4 mL per dose. A liquid suspension of a composition of dry biodegradable polymer microparticles according to the invention, or a ready-to-use liquid suspension comprising biodegradable polymer microparticles according to the invention, may be administered through a needle of any suitable gauge (G), for example 16G or smaller, for example 18G, 19G, 20G, 21G, 23G, 25G, preferably 20G.

[0051] The pharmaceutical compositions according to the invention can be prepared sterile or non-sterile and then terminally sterilized, for example by irradiation, for example by X-ray or gamma irradiation. In one embodiment, the pharmaceutical compositions of the invention are sterilized by irradiation.

[0052] The pharmaceutical compositions of the present invention may be manufactured by any method known for producing the compositions of interest. Biodegradable polymeric microparticles, e.g., biodegradable polymeric microspheres, comprising a somatostatin analog or a pharma- ceutically acceptable salt thereof, can be prepared by any process known in the art, such as coacervation or phase separation, spray drying, water-in-oil (W / O) or water-in-oil-in-water (W / O / W) or solid-in-oil-in-water (S / O / W) or oil-in-water (O / W) emulsion / suspension methods followed by solvent extraction or solvent evaporation. In one embodiment of the invention, the biodegradable polymeric microparticles are formed from a biodegradable polymer comprising at least 50 w / w%, such as at least 85 w / w%, such as 100%, PLGA as defined herein, and the biodegradable polymeric microparticles, such as microspheres comprising a somatostatin analogue or a pharma- ceutically acceptable salt thereof, have the following properties: (i) preparing an organic phase comprising an organic solvent mixture or a mixture of dichloromethane and methanol in a mass ratio of 80:20 to 95:5, said biodegradable polymer in a concentration of 10 w / w% to 30 w / w%, and a somatostatin analog or a pharma- ceutically acceptable salt thereof in a concentration sufficient to achieve a pre-determined drug loading of 10 w / w% to 15 w / w%; (ii) preparing an aqueous phase containing 0.1 w / v% to 10 w / v% of a stabilizer or PVA, and 2 w / w% to 5 w / w% of a salting-out agent or sodium chloride; (iii) continuously mixing the organic phase and the aqueous phase of (i) and (ii) in a volume ratio of 1:80 to 1:250 to form an emulsion; (iv) removing the organic solvent from the emulsion of (iii) by solvent evaporation or solvent extraction; (v) drying the biodegradable polymer microparticles obtained in (iv) and sieving them through a suitable size sieve; (vi) optionally repeating (v) until the residual organic solvent is below a predetermined level; The compound is produced / obtainable by a method / process comprising: Here, w / w% and w / v% except for drug loading are based on the mass or volume of each solution.

[0053] The organic solvent mixture comprises an organic solvent suitable for dissolving the biodegradable polymer and an organic solvent suitable for dissolving the somatostatin analog or a pharma- ceutically acceptable salt thereof. The organic solvent is a mixture of two or more different solvents, preferably two different solvents. Non-limiting examples of organic solvents that can be used to dissolve the biodegradable polymer include ethyl acetate, acetone, dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, or halogenated hydrocarbons such as dichloromethane (DCM), chloroform, or hexafluoroisopropanol (HFIP). Non-limiting examples of organic solvents used to dissolve the somatostatin analog or a pharma- ceutically acceptable salt thereof can be methyl-2-pyrrolidone, dimethylsulfoxide (DMSO), dimethylacetamide, ethanol, DMF, isopropanol, ethyl acetate, acetone, methanol, THF, acetonitrile, or halogenated hydrocarbons such as methylene chloride, DCM, chloroform, or HFIP. A preferred organic solvent mixture is a mixture of dichloromethane (DCM) and methanol. DCM and methanol may be mixed in a ratio of 80:20 to 95:5, for example, 85:15, 90:10. The biodegradable polymer may be dissolved in the organic solvent used to dissolve it at a concentration of 10 w / w% to 30 w / w%, for example, 11 w / w%, 12 w / w%, 13 w / w%, 14 w / w%, 25 w / w%, 16 w / w%, 17 w / w%, 18 w / w%, 19 w / w%, 20 w / w%, 21 w / w%, 22 w / w%, 23 w / w%, 24 w / w%, 25 w / w%, 26 w / w%, 27 w / w%, 28 w / w%, 29 w / w%, all w / w% based on the weight of the final solution prepared in (i) above (the organic phase) of the process above.

[0054] The somatostatin analogue or a pharma- ceutically acceptable salt thereof may be dissolved in the organic solvent used to dissolve it at a concentration appropriate to achieve a desired drug loading, i.e., 10-15 w / w%, for example 11 w / w%, 11.5 w / w%, 12 w / w%, 12.5 w / w%, 13 w / w%, 13.5 w / w%, 14 w / w%, 14.5 w / w%. As the skilled artisan will appreciate, to achieve a desired drug loading, it may be necessary to dissolve 10%-35%, such as 10%-25%, e.g., 20%-25% more somatostatin analogue or pharma- ceutically acceptable salt thereof, e.g., for a desired drug loading of 12 w / w%, it may be necessary to dissolve 13 w / w%-15 w / w% somatostatin analogue or pharma- ceutically acceptable salt thereof in the relevant organic solvent, e.g., 11 w / w%, 11.5 w / w%, 12 w / w%, 12.5 w / w%, 13 w / w%, 13.5 w / w%, 14 w / w%, 14.5 w / w%, where all w / w% are based on the mass of the final solution prepared in (i) above (the organic phase) of the process above.

[0055] The term "stabilizer" as used herein refers to an ingredient that can act as an emulsifier and stabilize the emulsion, i.e., the emulsion formed when the organic and aqueous phases of (i) and (ii) of the above process are mixed. Non-limiting examples of stabilizers include polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, dextrin, polyethylene glycol, poloxamer, poly(oxyethylene)-sorbitan-fatty acid esters, sorbitan fatty acids, lecithin, and mixtures thereof. In one embodiment, the stabilizer is polyvinyl alcohol (PVA). The aqueous phase prepared in (ii) of the above process may contain a stabiliser in a concentration of 0.1 w / v% to 10 w / v%, such as 0.5 w / v% to 5 w / v%, such as 1 w / v%, 1.5 w / v%, 2 w / v%, 2.5 w / v%, 3 w / v%, 3.5 w / v%, 4 w / v%, 4.5 w / v%, all w / v% being based on the weight of the final solution prepared in (ii) (aqueous phase) of the above process.

[0056] The term "salting agent" as used herein refers to an ingredient that attracts water molecules, thereby reducing the number of water molecules available to interact with the PLGA and / or the somatostatin analog or salt thereof. The salting agent in (ii) of the method may be a salt. Non-limiting examples of suitable salts include sodium chloride (NaCl) and potassium chloride (KCl). In one embodiment of the present invention, the salting agent in (ii) is NaCl. The aqueous phase prepared in (ii) of the above process may contain the salting-out agent in a concentration of 2 w / v% to 5 w / v%, such as 3 w / v% to 4 w / v%, such as 3.1 w / v%, 3.2 w / v%, 3.3 w / v%, 3.4 w / v%, 3.5 w / v%, 3.6 w / v%, 3.7 w / v%, 3.8 w / v%, 3.9 w / v%, all w / v% being based on the weight of the final solution prepared in (ii) (aqueous phase) of the above process. The organic and aqueous phases prepared in (i) and (ii) of the process described herein are mixed continuously in (iii), i.e., the organic and aqueous phases are simultaneously fed / pumped into a mixing device, e.g., a rotary mixer, and mixed. The organic solvent may be removed from the emulsion by solvent evaporation or solvent extraction. The microparticles may then be dried, for example by freeze drying or drying in an oven, and sieved. The drying and sieving steps may be repeated until the residual organic solvent is below a predetermined level. The predetermined level of any residual solvent may be a level that complies with the International Conference on Harmonization of Technical Requirements for Pharmaceuticals or Human Use (ICH) Q3C guidelines. For DCM, the predetermined level of residual solvent may be a level of 8000 ppm or less. For methanol, the predetermined level of residual solvent may be a level of 40,000 ppm or less, such as 3000 ppm or less, such as 500 ppm or less. Sieving is carried out using sieves having mesh sizes resulting in the particle sizes specified above and below. Preferably, the sieve is a 180 μm sieve, but smaller or larger opening sizes such as 160 μm or 200 μm or any other value in the range of 150 μm to 200 μm can be used as well. Once the biodegradable polymers, such as PLGA, microparticles, such as microspheres, are obtained, they can be suspended in a non-aqueous or aqueous liquid vehicle. The biodegradable polymers, such as PLGA, microparticles, such as microspheres, can be suspended in an aqueous or non-aqueous liquid vehicle by simple mixing.

[0057] In a further aspect of the invention there is provided a pharmaceutical composition of the invention for use as a medicament. The medicament may be for use in the long-term treatment of a disease, for example long-term maintenance therapy. In another aspect of the invention there is provided a pharmaceutical composition of the invention for use in the prevention and / or treatment of disease. The pharmaceutical composition of the present invention may be for use in the prevention and / or treatment of any disease for which a somatostatin analogue or a pharma- ceutical acceptable salt thereof provides a therapeutic effect. Such diseases include, for example, the following: (I) Autosomal dominant polycystic kidney disease (ADPKD) and polycystic kidney disease (PLD) (II) Gigantism (III) Cushing's disease (IV) Acromegaly, for example in patients whose condition has been inadequately controlled by surgery or radiation therapy, who are unsuitable for or unwilling to undergo surgery or radiation therapy, or who have been irradiated to the point where radiation therapy is effective, where treatment may reduce, control, normalize, and / or maintain blood levels of GH and / or IGF-1 for an extended period of time (long-term maintenance therapy). (V) TSH-secreting pituitary adenomas (which may be benign), for example in patients whose secretion does not normalize after surgery and / or radiation therapy, in patients who are unsuitable or unwilling to undergo surgery or radiation therapy, or in patients who have been irradiated to the point where radiation therapy is effective. (VI) Vasoactive intestinal peptide tumors (VIPomas), for example, where the watery diarrhea associated with this disease (which may be severe) can be treated, treatment can be before or after surgery, or in patients who are unsuitable or unwilling to undergo surgery or radiation therapy, or in patients who have been irradiated until radiation therapy is effective. (VII) Neuroendocrine neoplasms (NEN), e.g. neuroendocrine tumors (NETs), which may be advanced, e.g. gastroenteropancreatic neuroendocrine tumors GEP-NETs, ​​e.g. midgut or advanced NETs of unknown primary origin (non-midgut sites of origin have been excluded), treatment may be pre- or post-operative, or in patients unsuitable or unwilling to undergo surgery or radiotherapy, radioligand therapy, or even radiotherapy, radioligand therapy. (VIII) Carcinoid syndrome associated with neuroendocrine tumors such as functional gastric tumors; enteropancreatic endocrine tumors, for example, where treatment can suppress or inhibit diarrhea (which can be severe) and / or flushing episodes associated with this disease, treatment can be before or after surgery, or in patients who are not suitable or reluctant to undergo surgery or radiotherapy, radioligand therapy, or even radiotherapy, radioligand therapy. (IX) Prevention of complications after pancreatic surgery (X) Emergency management of patients with cirrhosis to stop bleeding and protect them from rebleeding due to gastroesophageal varices; Examples include:

[0058] In one embodiment, the pharmaceutical composition of the invention is for use in the prevention and / or treatment of a disease for which a somatostatin analogue or a pharma- ceutically acceptable salt thereof provides a therapeutic effect, the disease preferably comprising autosomal dominant polycystic kidney disease, Cushing's disease, polycystic kidney disease, acromegaly, gigantism, TSH-secreting pituitary adenomas, carcinoid syndrome, vasoactive intestinal peptide tumors, neuroendocrine neoplasms (neuroendocrine tumors, including gastroenteropancreatic neuroendocrine tumors). In more specific embodiments, the disease is selected from the group consisting of acromegaly and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In another aspect of the invention there is provided the use of a pharmaceutical composition of the invention for use in the manufacture of a medicament for use in the treatment of a disease, preferably a disease in which a somatostatin analogue or a pharma- ceutically acceptable salt thereof provides a therapeutic effect, such as acromegaly and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In another aspect of the invention, there is provided a use of a pharmaceutical composition of the invention for use in a method of treating a disease, the method comprising the step of administering a composition of the invention to a patient in need thereof, preferably a disease for which a somatostatin analogue or a pharma- ceutically acceptable salt thereof provides a therapeutic effect, such as acromegaly and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Of course, this means that the present invention also provides a method of treating any of the medical indications specified herein comprising administering a composition of the present invention to a patient in need thereof.

[0059] The pharmaceutical compositions of the present invention may be administered to a patient parenterally, for example via injection or via surgical implantation. In one embodiment, the pharmaceutical composition of the present invention is administered to the patient parenterally. In a more specific embodiment, the composition of the present invention is administered to the patient via intramuscular or subcutaneous injection. The subcutaneous injection may be deep subcutaneous. Preferably, the composition of the present invention is administered to the patient via intramuscular injection.

[0060] The pharmaceutical composition of the present invention can be administered as frequently as necessary, for example, depending on the sustained release period of the composition. The composition can be administered, for example, monthly (about every 30 days, e.g., 28-30 days), bimonthly (about every 60 days, e.g., 56-60 days), trimonthly (about every 90 days, e.g., 84-90 days), or quadrennial (about every 120 days, e.g., 112-120 days), or any period between any of the aforementioned values. In one embodiment, the pharmaceutical composition of the invention provides sustained release of a somatostatin analog or a pharma- ceutically acceptable salt thereof for 30 days or more and is administered once a month, e.g., about every 30 days, e.g., every 20-35 days, e.g., on the 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, or 34th day. In one embodiment, the pharmaceutical composition of the invention provides sustained release of a somatostatin analog or a pharma- ceutically acceptable salt thereof for 60 days or more, and is a sustained release pharmaceutical composition administered once every two months, e.g., about every 60 days, e.g., every 50-65 days, e.g., on the 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, or 64th day. In one embodiment, the pharmaceutical composition of the invention is a sustained release pharmaceutical composition providing sustained release of the somatostatin analogue or a pharma- ceutical acceptable salt thereof for 84 days or more, e.g., 84 days, and is administered once every three months, e.g., once every 84-90 days, e.g., once every 84 days. In a more specific embodiment, the pharmaceutical composition of the present invention is a three-month sustained release pharmaceutical composition providing sustained release of the somatostatin analog or a pharma- ceutically acceptable salt thereof for 84 days or more, e.g., 84 days, and administered once every three months, e.g., every 84 days. In another embodiment, the pharmaceutical composition of the present invention provides sustained release of a somatostatin analog or a pharma- ceutically acceptable salt thereof for 90 days or more and is a sustained release pharmaceutical composition administered once every three months, e.g., about every 90 days, e.g., every 80-95 days, e.g., on the 81st, 82nd, 83rd, 84th, 85th, 86th, 87th, 88th, 89th, 98th, 91st, 92nd, 93rd, and 94th days. In yet another embodiment, the pharmaceutical composition of the present invention provides sustained release of a somatostatin analog or a pharma- ceutically acceptable salt thereof for 120 days or more, and is a sustained release pharmaceutical composition administered once every four months, e.g., about every 120 days, e.g., every 110-125 days, e.g., on days 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, or 124.

[0061] The pharmaceutical compositions of the present invention may be administered in any effective dosage. The term "effective dose" as used herein refers to a dose that results in sustained release (i.e., release of an effective amount of a somatostatin analog or a pharma- ceutically acceptable salt thereof over a predetermined sustained release period, e.g., 30 days or more, 60 days or more, 90 days or more, or 120 days or more). It is understood that the exact dose will depend on several factors, including the particular somatostatin analog in question, the condition being treated, the predetermined sustained release period, e.g., 30 days or more, 60 days or more, 90 days or more, or 120 days or more. The effective dose will also depend on the characteristics of the particular patient and / or the patient's response to the treatment. For example, it is well within the skill of one in the art to determine an effective dose that balances both efficacy and side effects / adverse reactions. Where the somatostatin analogue is octreotide or a pharma- ceutically acceptable salt thereof, a particularly effective dose of a pharmaceutical composition of the invention may be a dose corresponding to a dose of 10mg to 240mg, such as 10mg to 180mg, for example 20mg to 180mg, 25mg to 120mg, 30mg to 120mg, 25mg to 90mg, or 30mg to 90mg, for example 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, or 90mg of octreotide or an equivalent dose of the compound, or a pharma- ceutically acceptable salt thereof. Such doses may be particularly effective in treating acromegaly and / or GEP-NETs in patients. The compositions of the present invention, as specified above and in more detail below, may release the somatostatin analog or a pharma- ceutically acceptable salt thereof for 30 days or more, so that a single administration of the compositions of the present invention may be sufficient to achieve a therapeutically effective plasma level over that extended period. This, in turn, means that each dosage indication provided herein is also an indication of a suitable unit dose that may be contained, for example, in a pre-filled syringe.

[0062] For a pharma- ceutically acceptable salt of a somatostatin analog, e.g., octreotide acetate, the equivalent dose is calculated as the mass of the pharma- ceutically acceptable salt of the somatostatin analog provided in the same molar amount as the molar amount of the free base, e.g., octreotide, provided in the doses specified herein, i.e., equivalence of doses of the free base drug and its salt is determined based on the molar amounts which are the same. In one embodiment of the present invention, the pharmaceutical composition of the present invention provides sustained release of the somatostatin analog octreotide for 30 days or more and is administered approximately every 30 days (e.g., one month) at a dose corresponding to a dose of 10-180 mg, e.g., 25 mg-120 mg, 25 mg-105 mg, e.g., 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of octreotide, or an equivalent dose of a pharma- ceutically acceptable salt thereof. A particularly effective dose may be 25 mg-105 mg, or an equivalent dose of a pharma-ceutically acceptable salt thereof. Preferably, administration is for the treatment of acromegaly and / or GEP-NET in a patient.

[0063] In one embodiment of the present invention, the pharmaceutical composition of the present invention provides sustained release of the somatostatin analog octreotide for 60 days or more and is administered once about every 60 days (e.g., 2 months) at a dose corresponding to a dose of 10-180 mg, e.g., 25 mg-120 mg, 25 mg-105 mg, e.g., 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg of octreotide, or an equivalent dose of a pharma- ceutically acceptable salt thereof. A particularly effective dose may be 25 mg-105 mg, or an equivalent dose of a pharma-ceutically acceptable salt thereof. Preferably, the administration is for the treatment of acromegaly and / or GEP-NET in a patient. In one embodiment of the present invention, the pharmaceutical composition of the present invention provides sustained release of the somatostatin analog octreotide or a pharma- ceutically acceptable salt thereof for more than 84 days, for example, for 84 days. And is administered once every 84 days (i.e., about 3 months). The corresponding dose of octreotide is 10-180 mg, for example, 25 mg-120 mg, 25 mg-105 mg, for example, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, or an equivalent dose of a pharma- ceutically acceptable salt thereof. Particularly effective doses in this embodiment may be 25 mg-105 mg, for example, 60 mg, 90 mg, or 120 mg, or an equivalent dose of a pharma- ceutically acceptable salt thereof. Preferably, according to this embodiment, the administration is for the treatment of acromegaly and / or GEP-NETs in a patient. In another embodiment of the invention, the pharmaceutical composition of the invention provides sustained release of the somatostatin analog octreotide for 90 days or more and is administered once about every 90 days (e.g., 3 months) at a dose corresponding to a dose of 10-180 mg, e.g., 25 mg-120 mg, 25 mg-105 mg, e.g., 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg of octreotide, or an equivalent dose of a pharma- ceutically acceptable salt thereof. A particularly effective dose may be 25 mg-105 mg, or an equivalent dose of a pharma-ceutically acceptable salt thereof. Preferably, the administration is for the treatment of acromegaly and / or GEP-NET in a patient. In yet another embodiment of the invention, the pharmaceutical composition of the invention provides sustained release of the somatostatin analog octreotide for 120 days or more and is administered once about every 120 days (e.g., 4 months) at a dose corresponding to a dose of 10-180 mg, e.g., 25 mg-120 mg, 25 mg-105 mg, e.g., 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg of octreotide, or an equivalent dose of a pharma- ceutically acceptable salt thereof. A particularly effective dose may be 25 mg-105 mg, or an equivalent dose of a pharma-ceutically acceptable salt thereof. Preferably, the administration is for the treatment of acromegaly and / or GEP-NET in a patient.

[0064] Administration of the pharmaceutical compositions of the present invention, particularly those in which the somatostatin analogue contained within the biodegradable polymer microparticles is octreotide or a pharma- ceutically acceptable salt thereof, may suppress / reduce serum growth hormone (GH) levels and / or serum insulin-like growth factor (IGF1) levels in patients, e.g., patients suffering from acromegaly. Said serum GH levels are suppressed / reduced such that GH serum levels are below 3 μg / L, such as below 2.5 μg / L, such as below 2 μg / L, such as below 1.5 μg / L, such as below 1 μg / L. Serum human growth hormone (GH) levels can be determined using the IDS-iSYS Multi-Discipline Automated System. The assay is based on chemiluminescence technology. Samples are incubated with biotinylated monoclonal anti-GH antibodies and streptavidin-labeled magnetic particles. The magnetic particles are "captured" using a magnet and a washing step is performed. Acridinium-labeled anti-GH monoclonal antibodies are added and a further incubation step is followed by a second washing step. A trigger reagent is added and the resulting light emitted by the acridinium label is directly proportional to the concentration of GH in the original sample. The reduction in serum IGF1 levels can be up to 50%, e.g., up to 40%, up to 30%, up to 20% from baseline (IGF1 levels in the patient prior to administration of the pharmaceutical composition of the invention). IGF1 levels can be measured using a validated IDS-iSYS method or a validated LC-MS / MS method, such as the method described in Example 10B herein. The reduction in IGF1 and / or GH serum levels may be seen over or substantially over the predetermined release period, for example over the predetermined release period, e.g., 84 days or more, e.g., 90 days or more minus the sustained release period. The sustained release period may be, for example, 7 days or less.

[0065] Administration of the compositions of the present invention may result in a degree of GH and / or IGF1 suppression / reduction over, for example, 84 days, comparable to that seen following administration of currently commercially available sustained release formulations, such as Sandostatin® LAR®, when administered at a corresponding dosage, for example 3 x 30 mg Sandostatin LAR monthly, compared to a composition of the present invention administered as a single dose in an amount equivalent to 90 mg of octreotide. As noted above, the bioavailability of somatostatin analogs, such as octreotide, contained within the compositions of the present invention can be surprisingly high compared to currently available sustained release formulations, such as Sandostatin® LAR®, which may allow for reduced doses of somatostatin analogs to be administered while achieving the same effect as higher doses (possibly administered in multiple injections) of other formulations, such as Sandostatin® LAR®. The bioavailability of the somatostatin analog, e.g., octreotide, in the compositions of the invention may be higher than other formulations, such as Sandostatin (registered trademark) LAR (registered trademark), e.g., 20%, 50%, 60%, 70%, 80%, 90%, 100% higher or more, e.g., 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3 times or more higher, and therefore more bioavailable, allowing the condition to be treated by administering a lower dose of the somatostatin analog, e.g., octreotide.

[0066] In another aspect of the invention, (i) a pharmaceutical composition of the present invention; (ii) optionally, a vehicle for reconstitution; and (iii) a vial or syringe, optionally pre-filled with the pharmaceutical composition of (i); A kit is provided comprising: The pharmaceutical composition of the present invention (i) in the form of either dry biodegradable microparticles or suspension in liquid vehicle can be contained in the vial or pre-filled syringe (iii) without the liquid vehicle for suspension (ii).The liquid vehicle (ii) can be provided in a separate vial or compartment of a syringe together with the pharmaceutical composition of the present invention (i) in the form of dry biodegradable microparticles and provided in a separate vial or compartment of the syringe.The pharmaceutical composition of the present invention (i), for example, a composition of dry biodegradable polymer microparticles, can be suspended in the suspension vehicle (ii), for example, a water (aqueous) vehicle containing pharmaceutical excipients, by simple mixing before injection into a patient. Alternatively, the pharmaceutical composition of the present invention, for example the composition of dry biodegradable polymeric microparticles of item i, can be separated from the vehicle for suspension according to (ii) above in a dual-chamber pre-filled syringe. In another alternative, the pharmaceutical composition may be a liquid suspension of biodegradable polymer microparticles ready for injection, such as a suspension of biodegradable polymer microparticles in a non-aqueous vehicle, such as MCT oil, which may be provided in a vial or a pre-filled syringe. Any embodiment disclosed herein may be combined with any other embodiment disclosed herein, unless expressly stated otherwise. As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a material" or "the material" includes two or more materials. The terms "comprises" and "comprising" should be interpreted inclusively rather than exclusively. Similarly, the terms "include" and "or" should be interpreted as all-inclusive unless such interpretation is clearly prohibited by context. However, the compositions disclosed herein may be free of any element not specifically disclosed. Thus, disclosure of an embodiment using the term "comprising" includes disclosure of embodiments "consisting essentially of" and "consisting of" the specified components. Similarly, the methods disclosed herein may be free of any step not specifically disclosed herein. Thus, disclosure of an embodiment using the term "comprising" includes disclosure of embodiments "consisting essentially of" and "consisting of" the specific steps. The term "and / or" used in the context of "X and / or Y" should be interpreted as "X" or "Y" or "X and Y." As used herein, the terms "examples" and "such as," particularly when followed by a list of terms, are merely exemplary and illustrative and should not be considered as exclusive or inclusive. All percentages and ppm values ​​expressed herein are by weight based on the total weight of the composition, unless otherwise indicated. The terms "about" and "approximately" as used herein are understood to refer to numbers within a numerical range, e.g., within -10% to +10% of the referenced number, preferably within -5% to +5% of the referenced number, more preferably within -1% to +1% of the referenced number, and most preferably within -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers, whole numbers or fractions within that range. Furthermore, such numerical ranges should be interpreted as providing support for claims directed to any number or subset of numbers within that range. For example, a disclosure of 1 to 10 should be interpreted as supporting ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc. Although the present invention has been illustrated and described with reference to exemplary embodiments and examples, it would be apparent to those skilled in the art that various modifications and improvements can be made therein without departing from the scope and spirit of the present invention. Therefore, the present invention should not be limited by the exemplary embodiments and examples. We now present a series of non-limiting examples which serve to illustrate the invention. EXAMPLES

[0067] Preparation of microspheres The following method was used to prepare the microspheres listed in Table I (Compositions A, B, C, and D). Appropriate amounts of dichloromethane and methanol were mixed in a glass container to obtain a methanol-containing solution of the appropriate concentration as listed in Table I (column "Methanol Concentration"). An appropriate amount of PLGA polymer was then dissolved in this solution to obtain the polymer concentration as listed in Table I (column "PLGA Concentration"). An appropriate amount of octreotide acetate was then weighed and added to this solution under magnetic stirring (octreotide acetate was added in an amount equal to the theoretical drug loading for the microspheres subsequently formed, as listed in Table I (column "Theoretical Drug Loading"). The resulting solution is referred to as "organic solution". An appropriate amount of PVA 4-88 was dissolved in an appropriate amount of deionized water to form a 1% PVA 4-88 solution. An appropriate amount of NaCl was then dissolved in the 1% PVA 4-88 solution to obtain a solution having a concentration of NaCl as set forth in Table I (column "NaCl Concentration"). The resulting solution is referred to as the "Aqueous Solution." The organic solution was mixed with the aqueous solution by pumping the organic solution into the rotor-stator device at a rate of 5 mL / min using a flexible tube pump, and the aqueous solution was pumped into the same rotor-stator device at a rate of 650 mL / min using a peristaltic pump. The two solutions were mixed in the rotor-stator chamber at a speed of 5000 rpm. The microsphere suspension obtained by O / W emulsion dispersion was collected in a glass beaker. The microspheres were collected by filtration (5 μm) and washed several times with an appropriate amount of 10% aqueous methanol solution (to remove octreotide acetate and / or PVA on their surface). After this, the microspheres were dried overnight (16 hours) at 30° C. under vacuum. The dried microspheres were sieved through a 180 μm sieve and added into a glass vial. The microspheres were then sterilized by X-ray irradiation at a dose of 25 kGy. Drug loading was quantified by liquid chromatography and is shown in Table I in the column entitled "Drug Loading Actual." EXAMPLES

[0068] In vitro characterization The dissolution rate after 5 hours for each of the compositions listed in Table I (A, B, C and D) was determined using a USP2 paddle apparatus in 900 mL of pH 4 acetate buffer at 37°C. An amount of the composition corresponding to 30, 60 or 90 mg of drug substance was introduced into the dissolution medium and then paddle rotation was started at a speed of 75 rpm. After 5 hours, the dissolution medium was sampled and filtered and the drug dissolved in the filtrate was quantified using an appropriate high performance liquid chromatography method. The results are shown in Table I. EXAMPLES

[0069] Determination of specific surface area and particle size The specific surface areas of the microspheres of compositions A, B, C and D were determined by measuring the nitrogen adsorption isotherms at 77 K on properly degassed samples of more than 0.3 g and applying the Brunauer, Emmett and Teller model in the relative pressure range of 0.05 to 0.2 of the isotherm (this range includes at least seven data points). Specific surface area (SSA) was measured using multi-point BET surface area by nitrogen adsorption (volumetric technique using a Micromeritics TriStar II 3020). Approximately 350 mg of each sample was added to a sample tube and then placed under vacuum at 20° C. for 1 hour. After conditioning, the net mass of each sample was re-recorded and this value was used for the analysis. During the analysis, the sample tube was surrounded by an isothermal jacket and contained a filler rod. The BET surface area was calculated using the following parameters: Analysis adsorption: N2 Analysis bath temperature: 77.300K Temperature free space: measurement Cold free space: measurement Equilibration interval: 5 seconds Hypobaric administration: No Automatic degassing: No Relative pressure tolerance: 5% Minimum equilibrium release at P / Po>0.995: 600 seconds Recorded P / P0 range: 0.05-0.99 (88 points at 0.012 intervals) The specific surface area was measured using the following method. The results are shown in Table I.

[0070] Particle size distributions were measured by wet laser diffraction using a Malvern mastersizer 3000. Each sample was resuspended in an aqueous solution of sodium carboxymethylcellulose (1.5% w / w) and polysorbate 80 (0.1%), then diluted / dispersed in purified water in a hydroMV dispersion unit (stirring at 2000 rpm) until a stable laser obscuration of 10%-20% was reached. Samples were then subjected to 3 min of ultrasonication (MV dispersion unit setting medium (50%)). Volume-weighted particle size distributions were calculated by Mie theory with the following parameters: dispersant refractive index 1.33; real particle refractive index 1.52; imaginary particle refractive index 0.001.

[0071] [Table 1] *Comparative composition Table 1 EXAMPLES

[0072] In vivo pharmacokinetic profile of Composition D (rats) The microspheres of Composition D were suspended in a physiologically acceptable lipophilic vehicle to obtain a drug suspension concentration of 4.8 mg / mL. The resulting suspension was injected subcutaneously into six male Sprague Dawley rats weighing 200-250 g (5-6 weeks old) on the day of treatment in an amount equivalent to a single dose of 24 mg / kg of octreotide. After the designated times, plasma samples were taken and analyzed for octreotide concentration. The results are shown in Table II and Figure 1.

[0073] [Table 2] EXAMPLES

[0074] In vivo pharmacokinetic profile of Composition A (rats) The microspheres of Composition A were suspended in a physiologically acceptable lipophilic vehicle to obtain a drug suspension concentration of 4.8 mg / mL. The resulting suspension was injected subcutaneously into six male Sprague Dawley rats weighing 200-250 g (5-6 weeks old) on the day of treatment in an amount equivalent to a single dose of 24 mg / kg of octreotide. After the designated times, plasma samples were taken and analyzed for octreotide concentration. The results are shown in Table III and Figure 2.

[0075] [Table 3] EXAMPLES

[0076] Example 6a: Injectable sustained release composition (single dose) The microspheres of Composition D (equivalent to 30 mg of octreotide) are aseptically loaded into a two-chamber syringe (TCS) consisting of one compartment containing the microparticles and one compartment containing 2.4 mL of an aqueous vehicle for the suspension of the microparticles. The aqueous vehicle is 4.25% mannitol, 0.1% tween and 1.5% sodium carboxymethylcellulose in water. The microparticles and the aqueous vehicle are mixed immediately prior to injection. The composition may provide sustained release of octreotide for 1 month (30 days), 2 months (60 days), 3 months (90 days), or 4 months (120 days). The sustained release period may be 1, 2, 3, or 4 months, depending on the patient's characteristics and the patient's response to treatment.

[0077] Example 6b: Injectable sustained release composition (single dose) The microspheres of Composition D (equivalent to 30 mg of octreotide) are aseptically loaded into a two-chamber syringe (TCS) consisting of one compartment containing the microparticles and one compartment containing 2.4 mL of a non-aqueous liquid for suspension of the microparticles. The non-aqueous vehicle is MCT oil (MIGLYOL® 812). The microparticles and the non-aqueous vehicle are mixed immediately prior to injection. The composition may provide sustained release of octreotide for 1 month (30 days), 2 months (60 days), 3 months (90 days), or 4 months (120 days). The sustained release period may be 1, 2, 3, or 4 months, depending on the patient's characteristics and the patient's response to treatment. EXAMPLES

[0078] Example 7a: Injectable sustained release composition (single dose) The microspheres of Composition D (equivalent to 60 mg of octreotide) are aseptically loaded into a two-chamber syringe (TCS) consisting of one compartment containing the microparticles and one compartment containing 2.4 mL of an aqueous vehicle for the suspension of the microparticles. The aqueous vehicle is 4.25% mannitol, 0.1% tween and 1.5% sodium carboxymethylcellulose in water. The microparticles and the aqueous vehicle are mixed immediately prior to injection. The composition may provide sustained release of octreotide for 1 month (30 days), 2 months (60 days), 3 months (90 days), or 4 months (120 days). The sustained release period may be 1, 2, 3, or 4 months, depending on the patient's characteristics and the patient's response to treatment.

[0079] Example 7b: Injectable sustained release composition (single dose) The microspheres of Composition D (equivalent to 60 mg of octreotide) are aseptically loaded into a two-chamber syringe (TCS) consisting of one compartment containing the microparticles and one compartment containing 2.4 mL of a non-aqueous liquid for suspension of the microparticles. The non-aqueous vehicle is MCT oil (MIGLYOL® 812). The microparticles and the non-aqueous vehicle are mixed immediately prior to injection. The composition may provide sustained release of octreotide for 1 month (30 days), 2 months (60 days), 3 months (90 days), or 4 months (120 days). The sustained release period may be 1, 2, 3, or 4 months, depending on the patient's characteristics and the patient's response to treatment. EXAMPLES

[0080] Example 8a: Injectable sustained release composition (single dose) The microspheres of Composition D (equivalent to 90 mg of octreotide) are aseptically loaded into a two-chamber syringe (TCS) consisting of one compartment containing the microparticles and one compartment containing 2.4 mL of an aqueous vehicle for the suspension of the microparticles. The aqueous vehicle is 4.25% mannitol, 0.1% tween and 1.5% sodium carboxymethylcellulose in water. The microparticles and the aqueous vehicle are mixed immediately prior to injection. The composition may provide sustained release of octreotide for 1 month (30 days), 2 months (60 days), 3 months (90 days), or 4 months (120 days). The sustained release period may be 1, 2, 3, or 4 months, depending on the patient's characteristics and the patient's response to treatment.

[0081] Example 8b: Injectable sustained release composition (single dose) The microspheres of Composition D (equivalent to 90 mg of octreotide) are aseptically loaded into a two-chamber syringe (TCS) consisting of one compartment containing the microparticles and one compartment containing 2.4 mL of a non-aqueous liquid for suspension of the microparticles. The non-aqueous vehicle is MCT oil (MIGLYOL® 812). The microparticles and the non-aqueous vehicle are mixed immediately prior to injection. The composition may provide sustained release of octreotide for 1 month (30 days), 2 months (60 days), 3 months (90 days), or 4 months (120 days). The sustained release period may be 1, 2, 3, or 4 months, depending on the patient's characteristics and the patient's response to treatment. EXAMPLES

[0082] Effect of route of administration and vehicle Composition D microspheres were suspended in a physiologically acceptable aqueous or non-aqueous vehicle to obtain a drug suspension concentration of 4.8 mg / mL. The resulting suspension was injected subcutaneously or intramuscularly into six male Sprague Dawley rats weighing 200-250 g (5-6 weeks old) on the day of treatment in an amount equivalent to a single dose of 24 mg / kg octreotide. After the prescribed period, plasma samples were collected and analyzed for octreotide concentrations over a 28 day period. The results are shown in Figure 3, and no significant differences were observed. EXAMPLES

[0083] Example 10A: Bioavailability A) Sandostatin immediate release (Sandostatin IR) was administered by subcutaneous injection to 15 healthy subjects in an amount equivalent to 0.2 mg of octreotide. After administration, octreotide plasma concentrations were measured over the study period. AUClast (up to approximately 24 hours) was calculated for each subject and normalized by dose. Subsequently (at least one week later), the same 15 subjects were administered a suspension of Composition D microspheres in MCT oil (MIGLYOL® 812) via intramuscular injection in an amount equivalent to 30 mg of octreotide. After administration, octreotide plasma concentrations were measured over the study period. AUClast (from 84 to 112 days) was calculated for each subject and normalized by dose. Then, the 2 AUClast normalized by dose value was compared within individuals.The purpose was to determine the relative bioavailability of the composition of D-microspheres compared to Sandostatin IR within the same subject. For each subject, the following ratios were determined:

[0084]

number

[0085]

number

[0086] [Table 4] All treatments were well tolerated, and there were no significant differences in the pattern or severity of adverse events.

[0087] Example 10B: Bioavailability and Changes in Serum IGF1 A) IGF1 levels were measured in seven healthy volunteer subjects. After IGF1 measurements, Sandostatin immediate release (Sandostatin IR) was administered by subcutaneous injection in an amount equivalent to 0.2 mg of octreotide to the same seven healthy subjects. I. Octreotide plasma concentrations were determined over the study period and the AUClast for octreotide plasma levels (up to approximately 24 hours) was calculated for each subject and normalized by dose. Subsequent to the above (at least one week later), the same seven subjects received an aqueous suspension of Composition D microspheres, equivalent to 90 mg of octreotide, via intramuscular injection. II. Serum IGF1 concentrations were measured at several times over the study period and the % change in serum IGF was recorded. III. Octreotide plasma concentrations were determined over the study period (3 months (84 days)) and the AUC84d for octreotide plasma levels was calculated for each subject and normalized by dose. The AUC of I and III normalized by dose value was compared within individuals. The purpose was to determine the relative bioavailability of the composition of D microspheres compared to Sandostatin IR within the same subject. For each subject, the following ratios were determined:

[0088]

number

[0089]

number

[0090] [Table 5] Table V *Subjects who withdraw consent before the second dose of Sandostatin LAR will be excluded. The safety profile of Composition D microparticles (90 mg octreotide) was consistent with Sandostatin LAR, with no new safety signals. The average IGF1 results are shown in Figure 5. As can be seen, administration of Composition D microparticles in an amount equivalent to a single 90 mg dose of octreotide results in a degree of IGF1 suppression over an 84 day period comparable to that seen following administration of 3x 30 mg of Sandostatin LAR per month. In the above example (10B), IGF1 serum levels were measured using a validated LC-MS / MS method using rabbit plasma as a surrogate matrix. The IGF-1 assay allows for the quantitative measurement of IGF-1 in human serum samples. Sample processing (using a sample volume of 100 μL of serum) is performed by protein precipitation followed by phospholipid removal using Ostro plates from Waters Corp (further information on sample processing is shown in Table VI). Separation of metabolites and interfering endogenous compounds is achieved by UHPLC using XSelect CSH C18 (100×2.1 mM, 2.5 μm) from Waters Corp. at 40° C., 0.1% formic acid in water as mobile phase A and acetonitrile:DMSO (90:10, v / v) as mobile phase B, running a gradient with an initial flow rate of 0.4 mL / min (further information on timing and flow rate and gradient is shown in Table VII). A triple quadrupole 6500 mass spectrometer equipped with a turbo ion spray source is used for detection in positive ion mode. Quantification is based on multiple reaction monitoring (MRM) of the following transitions: IGF-1 m / z 1093.6-1196.8. IGF-1 N15 m / z 1106.9-1211.3. A linear calibration curve with a weighting factor of 1 / x2 is used over the range of 2.00 to 1000 ng / mL of IGF-1 in human serum. Further general method indications are provided in Table VIII.

[0091] [Table 6] Table VI

[0092] [Table 7] 3.0 General Directions (Table VIII) Please refer to the appropriate PRA standard operating procedures to address deviations from these assay instructions. Insulin-like growth factor 1 (IGF-1) is a hormone similar in molecular structure to insulin, which plays an important role in childhood growth, and has anabolic effects in adults. It consists of a single chain of 70 amino acids with three intramolecular disulfide bridges. The molecular weight of IGF-1 is 7649 Da. IGF-I levels in serum may range from 15 to 765 ng / ml depending on age, sex and disease state. When preparing the validation pool, sera should be screened and the lowest should be used. The lowest screened serum is used for preparation of QC B, QC C and QC D. Since IGF-1 is an endogenous compound, rabbit plasma is used as a surrogate matrix for preparation of the calibration curve and the minimum validation levels. For the determination or detection of IGF-1 and its internal standard, the mass spectrometer is used in high mass mode. For the determination or detection of IGF-1 and its internal standard, a seven times charged ion [M+7] is used. DMSO in the mobile phase promotes the formation of 7-fold charged ions. If adjustments are required, use the correct mobile phase and optimize all parameters. The chromatographic behavior of IGF-1 on an analytical column is sensitive to small variations in mobile phase composition and column batches. Small changes (1%) in mobile phase composition can result in retention shifts of 0.5 to 1 min. This results in longer switching times for the switching valve.

Claims

1. A pharmaceutical composition comprising biodegradable polymer microparticles containing a somatostatin analog or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer used to form the biodegradable polymer microparticles is The molar ratio of lactide to glycoside is 80:20 to 90:10; The intrinsic viscosity measured at 25°C in chloroform at a concentration of 0.5 w / w% is 0.2 to 0.4 dl / g. Including PLGA, and The biodegradable polymer fine particles The drug load is 10-15 w / w%; Dv50 is 30 μm to 90 μm; and, The specific surface area measured by gas adsorption is 0.50 m². ２ Less than 0.40 m / g, or 0.40 m ２ Less than / g; pharmaceutical composition.

2. The pharmaceutical composition according to Claim 1, wherein the somatostatin analog or a pharmaceutically acceptable salt thereof is released over a sustained period of 30 days or more, or 30 to 200 days, or 60 days or more, or 60 to 200 days, or 90 days or more, or 90 to 200 days.

3. The pharmaceutical composition according to claim 1, wherein the molar ratio of lactide to glycolide of the PLGA is 83:17 to 87:13, and the intrinsic viscosity measured at 25°C at a concentration of 0.5 w / w% in chloroform is 0.25 to 0.35 dl / g.

4. The pharmaceutical composition according to claim 1, wherein the PLGA comprises less than 0.5 w / w% residual lactide and / or glycolide monomer.

5. The pharmaceutical composition according to claim 1, wherein the drug load of the biodegradable polymer fine particles is 11 to 14 w / w%, or 11.5 to 12.5 w / w%.

6. The pharmaceutical composition according to claim 1, wherein the biodegradable polymer fine particles are biodegradable polymer microspheres.

7. The biodegradable polymer fine particles, Dv50 is 50 μm to 80 μm, or 60 μm to 75 μm, and / or The specific surface area measured by gas adsorption is 0.05 to 0.3 m². ２ / g is The pharmaceutical composition according to claim 1.

8. The pharmaceutical composition according to claim 1, wherein the somatostatin analog is octreotide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of octreotide selected from the group consisting of octreotide acetate and octreotide pamoate.

9. The pharmaceutical composition according to claim 1, wherein the biodegradable polymer used to form the biodegradable polymer fine particles comprises at least 50 w / w%, at least 85 w / w%, or 100 w / w% of the PLGA.

10. The pharmaceutical composition according to claim 1, wherein the biodegradable polymer microparticles constitute at least 50 w / w%, at least 75 w / w%, or at least 80 w / w% of the total amount of all biodegradable polymer microparticles contained in the pharmaceutical composition.

11. The following criteria: Release less than 7% of the somatostatin analog or octreotide over a period of 5 hours; Release is measured in vitro (in 900 mL of 100 mM acetate buffer at pH 4, at 37°C) by the method described in European Pharmacopoeia 10, 2.9.3; The pharmaceutical composition is tested in an amount equivalent to 30 mg of the somatostatin analog or octreotide; Characterized by the release of the somatostatin analog or octreotide that satisfies the following conditions, The following criteria: Release less than 3% of the somatostatin analog or octreotide over a period of 5 hours; Release is measured in vitro (in 900 mL of 100 mM acetate buffer at pH 4, at 37°C) by the method described in European Pharmacopoeia 10, 2.9.3; The pharmaceutical composition is tested in an amount equivalent to 30 mg of the somatostatin analog or octreotide; The pharmaceutical composition according to claim 1, characterized by the release of the somatostatin analog or octreotide that satisfies the following conditions.

12. The pharmaceutical composition according to claim 1, which is a liquid suspension containing the biodegradable polymer fine particles or a composition containing the dried biodegradable polymer fine particles.

13. The pharmaceutical composition according to claim 1, comprising a liquid suspension containing biodegradable polymer microparticles, wherein the biodegradable polymer microparticles are suspended in an aqueous vehicle or a non-aqueous vehicle, and the non-aqueous vehicle is a pharmaceutically acceptable oil essentially consisting of one or more medium-chain triglycerides.

14. The pharmaceutical composition according to claim 13, wherein the liquid suspension comprises biodegradable polymer fine particles in a concentration of 100 mg / mL to 500 mg / mL, 100 mg / mL to 375 mg / mL, or 125 mg / mL to 375 mg / mL.

15. The pharmaceutical composition according to claim 1, which is sterilized by irradiation.

16. A pharmaceutical composition according to claim 1 for use as a pharmaceutical.

17. The pharmaceutical composition according to claim 1, for use in the treatment of a disease in which the somatostatin analog or a pharmaceutically acceptable salt thereof has a therapeutic effect.

18. The pharmaceutical composition according to claim 1 for use in claim 17, wherein the disease is selected from the group consisting of neuroendocrine neoplasms including autosomal dominant polycystic kidney disease, Cushing's disease, polycystic liver disease, acromegaly, gigantism, TSH-secreting pituitary adenoma, carcinoid syndrome, vasoactive intestinal peptide neoplasm, and neuroendocrine neoplasms including gastrointestinal and pancreatic neuroendocrine neoplasms, or selected from acromegaly and gastrointestinal and pancreatic neuroendocrine neoplasms.

19. The somatostatin analog is released over a period of 60 days or more, and administered once every 60 days at a dose equivalent to 25 mg to 105 mg of octreotide or an equivalent dose of a pharmaceutically acceptable salt thereof, or The somatostatin analog is released over a period of 90 days or more, and administered once every 90 days at a dose equivalent to 25 mg to 105 mg of octreotide or an equivalent dose of a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to claim 1 for use in claim 16 or 17.

20. Octreotide or a pharmaceutically acceptable salt thereof is released over a period of 84 days or more, and administered once every 84 days at a dose equivalent to 60 mg, 90 mg, or 120 mg of octreotide or an equivalent dose of a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to claim 1 for use in claim 16 or 17.

21. The pharmaceutical composition according to claim 1 for use in claim 16 or 17, which is administered to a patient parenterally by intramuscular injection, subcutaneous injection, or deep subcutaneous injection.

22. below: (i) The pharmaceutical composition according to any one of claims 1 to 15; (ii) In some cases, a vehicle for reconstruction; and, (iii) The pharmaceutical composition of (i) above, optionally in a pre-filled vial or syringe; A kit that includes this.

23. A method for producing biodegradable polymer microparticles according to any one of claims 1 to 15, wherein the biodegradable polymer used to form the biodegradable polymer microparticles contains at least 50 w / w%, 85 w / w%, or 100 w / w% of the PLGA according to any one of claims 1 to 15, and wherein the method is as follows: (i) preparing an organic phase comprising an organic solvent mixture or a mixture of dichloromethane and methanol in a mass ratio of 80:20 to 95:5, the biodegradable polymer at a concentration of 10 w / w% to 30 w / w%, and the somatostatin analog or a pharmaceutically acceptable salt thereof at a concentration sufficient to achieve a predetermined drug load of 10 w / w% to 15 w / w%; (ii) Prepare an aqueous phase containing 0.1 w / v% to 10 w / v% of a stabilizer or PVA, and 2 w / w% to 5 w / w% of a salting-out agent or sodium chloride; (iii) Continuously mixing the organic phase and aqueous phase of (i) and (iii) in a volume ratio of 1:80 to 1:250 to form an emulsion; (iv) Removing the organic solvent from the emulsion of (iii) by solvent evaporation or solvent extraction; (v) Dry the biodegradable polymer fine particles obtained in (iv) above and sift them through a sieve of an appropriate size; (vi) In some cases, repeat (v) until the residual organic solvent falls below a predetermined level; This method includes, where, except for drug loading, w / w% and w / v% are based on the mass or volume of each solution.

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