Novel composition

Abstract

A pharmaceutical composition comprising biodegradable polymer microparticles comprising a somatostatin analogue or a pharmaceutically acceptable salt thereof, in which the pharmaceutical composition preferably provides sustained release of a somatostatin analogue or a pharmaceutically acceptable salt thereof over 30 days or more.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising biodegradable polymer microparticles containing a somatostatin analogue or a pharmaceutically acceptable salt thereof, and also relates to the use of the pharmaceutical composition as a medicament. Background Art

[0002] Somatostatin analogs (e.g., octreotide, lanreotide, and pasireotide) are polypeptide drugs that can be used in various therapeutic applications, such as in the treatment of acromegaly, carcinoid syndrome associated with neuroendocrine tumors, and vasoactive intestinal peptide tumors (VIPoma tumors). These polypeptide drugs generally require long-term treatment and are generally administered parenterally, such as via injection, which can present disadvantages, particularly when repeated and frequent administration over a long period of time is required, such as daily or weekly.

[0003] In view of the shortcomings of frequent parenteral administration, pharmaceutical manufacturers have focused on developing sustained release compositions that can be used to reduce the number of long-term required administrations. Such sustained release pharmaceutical compositions are usually poly-lactic-co-glycolic acid copolymers (PLGA). However, it is challenging to formulate PLGA sustained release pharmaceutical compositions to have an acceptable somatostatin analog release profile, particularly if the required sustained release profile exceeds 1 month (30 days), such as 2 months (60 days) or more days or even 3 months (90 days) or more days. In this case, a special challenge is to avoid the initial release (outburst) of the somatostatin analog after administration to reach an unacceptable level while ensuring that it is fully and stably released throughout the sustained release period.

[0004] In order to meet the above challenges, formulators have developed sustained release pharmaceutical compositions including blends of microparticles made from different PLGAs. However, the production of such compositions can be complicated and expensive. In addition, depending on the desired sustained release period, it may be necessary to administer high doses of somatostatin analogs (and therefore require large amounts of PLGA microparticles), which can lead to problems with injectability and injectability of the formulation.

[0005] Therefore, there is still a need for a new sustained release pharmaceutical composition that can provide sustained release of somatostatin analogs, particularly over a longer period of time, such as more than 1 month, such as 2 months or more days, 3 months or more days or even more days. Such a somatostatin sustained release composition is particularly needed, and the somatostatin sustained release composition has an acceptable somatostatin release curve (such as the full release of somatostatin analogs throughout the expected sustained release period), and an acceptable burst (which can be minimized or minimized the risk of side effects / adverse reactions associated with the use of somatostatin analogs). Further, such a pharmaceutical composition is needed, which is not complicated or expensive to manufacture, convenient and easy to use, has an acceptable shelf life, is safe and well tolerated by patients, and will, for example, minimize the patient discomfort caused by repeated administration associated with long-term treatment and / or injectability and injectability issues.

[0006] It is an object of the following invention to meet one or more of the above needs.

[0007] The inventors have now surprisingly found that the pharmaceutical compositions as described herein can meet one or more of the aforementioned needs. Specifically, the inventors have found that the pharmaceutical compositions according to the present invention can release somatostatin analogs over 30 days or more, such as 60 days or more, 90 days or more, or even more days, and can have an acceptable burst. Further, the inventors have also surprisingly found that compared with currently marketed somatostatin analogs (e.g., octreotide), sustained release formulations (e.g., ), the bioavailability of the somatostatin analogs included in the pharmaceutical composition of the present invention can be unexpectedly high, which can reduce the dosage of the somatostatin analogs (and thus obtain a lower amount of PLGA microparticles) while obtaining the same effect as higher doses in other formulations. Summary of the invention

[0008] 1. A pharmaceutical composition comprising biodegradable polymer microparticles containing a somatostatin analog or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer comprises PLGA having the following items:

[0009] a molar ratio of lactide to glycolide of 80:20 to 90:10, and

[0010] · Inherent viscosity of 0.2 to 0.4 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0011] And wherein the biodegradable polymer particles have:

[0012] 10w / w% to 15w / w% drug loading,

[0013] · Dv50 from 30μm to 90μm, and

[0014] · Measured by gas adsorption, less than 0.50m 2 / g and preferably less than 0.40m 2 / g specific surface area,

[0015] And wherein, preferably, the pharmaceutical composition provides sustained release of the somatostatin analog or a pharmaceutically acceptable salt thereof within 30 days or more and more preferably within 30 to 200 days.

[0016] 2. The pharmaceutical composition according to item 1, wherein the pharmaceutical composition provides sustained release of the somatostatin analogue over 60 days or more and preferably over 60 to 200 days.

[0017] 3. The pharmaceutical composition according to item 1, wherein the pharmaceutical composition provides sustained release of the somatostatin analogue over 90 days or more and preferably over 90 to 200 days.

[0018] 4. A pharmaceutical composition according to any of the preceding items, wherein the PLGA defined in item 1 has a molar ratio of lactide to glycolide of 83:17 to 87:13 and an intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w % in chloroform at 25°C.

[0019] 5. The pharmaceutical composition according to any of the preceding items, wherein the PLGA defined in any of the preceding items comprises less than 0.5 w / w % of residual lactide and / or glycolide monomers.

[0020] 6. The pharmaceutical composition according to any of the preceding items, wherein the biodegradable polymer microparticles defined in any of the preceding items have a drug loading of 11 to 14 w / w % and preferably 11.5 to 12.5 w / w %.

[0021] 7. The pharmaceutical composition according to any one of the preceding items, wherein the biodegradable polymer microparticles defined in any one of the preceding items are biodegradable polymer microspheres.

[0022] 8. The pharmaceutical composition according to any one of the preceding items, wherein the biodegradable polymer microparticles defined in any one of the preceding items have:

[0023] · Dv50 of 50 μm to 80 μm, preferably 60 μm to 75 μm, and / or

[0024] ·Measured by gas adsorption, 0.05 to 0.3 m 2 / g specific surface area.

[0025] 9. The pharmaceutical composition according to any of the preceding items, wherein the somatostatin analogue is octreotide or a pharmaceutically acceptable salt thereof, and preferably wherein the somatostatin analogue is a pharmaceutically acceptable salt of octreotide selected from the group consisting of octreotide acetate and octreotide pamoate.

[0026] 10. The pharmaceutical composition according to any of the preceding items, wherein the biodegradable polymer defined in any of the preceding items comprises at least 50 w / w%, preferably at least 85 w / w% and more preferably 100 w / w% of PLGA defined in any of the preceding items.

[0027] 11. The pharmaceutical composition according to any of the preceding items, wherein the biodegradable polymer microparticles defined in any of the preceding items account for at least 50 w / w%, preferably at least 75 w / w% and more preferably at least 80 w / w% of the total number of all biodegradable polymer microparticles included in the pharmaceutical composition.

[0028] 12. A pharmaceutical composition according to any of the preceding claims, wherein the composition is characterized by a release of a somatostatin analogue satisfying the following criteria: the release of the somatostatin analogue comprised therein is less than 7% within 5 hours, wherein the release is measured in vitro (at 37°C in 900 mL of pH 4 100 mm acetate buffer) according to the method described in European Pharmacopoeia 10, 2.9.3, wherein the composition is tested in an amount equivalent to 30 mg of the somatostatin analogue, and wherein the somatostatin analogue is preferably octreotide,

[0029] 13. A pharmaceutical composition according to any of the preceding claims, wherein the composition is characterized by a release of a somatostatin analogue that meets the following test criteria: the release of the somatostatin analogue comprised therein is less than 3% within 5 hours, wherein the release is measured in vitro (at 37°C in 900 mL of pH 4 100 mm acetate buffer) according to the method described in European Pharmacopoeia 10, 2.9.3, wherein the composition is tested in an amount equivalent to 30 mg of the somatostatin analogue, and wherein the somatostatin analogue is preferably octreotide.

[0030] 14. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is a composition comprising a liquid suspension of biodegradable polymer microparticles or dried biodegradable polymer microparticles.

[0031] 15. The pharmaceutical composition according to item 14, wherein the pharmaceutical composition is a liquid suspension comprising biodegradable polymer microparticles, and wherein the biodegradable polymer microparticles are suspended in an aqueous carrier or a non-aqueous carrier, and preferably wherein the non-aqueous liquid carrier is a pharmaceutically acceptable oil consisting essentially of one or more medium chain triglycerides.

[0032] 16. The pharmaceutical composition according to item 15, wherein the liquid comprises microparticles at a concentration of 100 mg / mL to 500 mg / mL, particularly preferably 100 mg / mL to 375 mg / mL, and most preferably 125 mg / mL to 375 mg / mL.

[0033] 17. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition is sterilized by irradiation.

[0034] 18. A pharmaceutical composition as defined in any one of the preceding clauses for use as a medicament.

[0035] 19. A pharmaceutical composition as defined in any one of items 1 to 17 for use in the treatment of a disease, wherein the somatostatin analogue or a pharmaceutically acceptable salt thereof has a therapeutic effect, and wherein the disease is preferably selected from the group consisting of autosomal dominant polycystic kidney disease, Cushing's disease, polycystic liver disease, acromegaly, gigantism, TSH-secreting pituitary adenoma, carcinoid syndrome, vasoactive intestinal polypeptide tumors and neuroendocrine neoplasms, including neuroendocrine tumors, including gastro-entero-pancreatic neuroendocrine tumors, and preferably selected from acromegaly and gastro-entero-pancreatic neuroendocrine tumors.

[0036] 20. A pharmaceutical composition as defined in any one of items 1 to 17 for use according to item 18 or 19, wherein the composition provides a sustained release of the somatostatin analogue over 60 days or more and is to be administered once every about 60 days at a dose corresponding to a dose of 25 mg to 105 mg of octreotide, or an equivalent dose of a pharmaceutically acceptable salt of octreotide, and preferably wherein the composition provides a sustained release of octreotide or a pharmaceutically acceptable salt thereof over 84 days or more and is to be administered once every 84 days at a dose corresponding to a dose of 60 mg, 90 mg or 120 mg of octreotide, or an equivalent dose of a pharmaceutically acceptable salt of octreotide.

[0037] 21. A pharmaceutical composition as defined in any one of items 1 to 17 for use according to item 18 or 19, wherein the composition provides sustained release of the somatostatin analogue over 90 days or more and is administered once every about 90 days at a dose corresponding to a dose of 25 mg to 105 mg of octreotide, or an equivalent dose of a pharmaceutically acceptable salt of octreotide.

[0038] 22. The pharmaceutical composition for use according to any one of items 18 to 21, wherein the pharmaceutical composition is to be administered to the patient enterally, and preferably via intra-muscular or subcutaneous injection, wherein the subcutaneous injection is preferably a deep subcutaneous injection.

[0039] 23. A kit comprising:

[0040] i. A pharmaceutical composition as defined in any one of items 1 to 17,

[0041] ii. optionally a vector for reconstruction, and

[0042] iii. A vial or optionally a syringe prefilled with the pharmaceutical composition of item (i).

[0043] 24. A method for producing biodegradable polymer microparticles as defined in any preceding item, wherein the biodegradable polymer comprises at least 50 w / w%, preferably 85 ww% and most preferably 100 w / w% of PLGA as defined in any preceding item, and wherein the method comprises the following steps:

[0044] 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; a biodegradable polymer in a concentration of 10 w / w% to 30 w / w%; and a somatostatin analog or a pharmaceutically acceptable salt thereof in a concentration sufficient to obtain a predetermined drug loading of 10 w / w% to 15 w / w%,

[0045] ii. preparing an aqueous phase comprising 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),

[0046] iii. continuously mixing the organic phase and the aqueous phase of step i and step ii at a volume ratio of 1:80 to 1:250 to form an emulsion,

[0047] iv. removing the organic solvent from the emulsion of step iii by solvent evaporation or solvent extraction,

[0048] v. drying the biodegradable polymer particles obtained in step iv and sieving through a sieve of appropriate size,

[0049] vi. optionally repeating step v until any residual organic solvent is below a predetermined level,

[0050] Except for the drug loading, all w / w% and w / v% in the above process are based on the weight or volume of the respective solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 In vivo pharmacokinetic release profile of the suspension of Composition D microspheres (Example 4).

[0052] Figure 2 In vivo pharmacokinetic release profile of the suspension of Composition A microspheres (Example 5).

[0053] Figure 3 In vivo pharmacokinetic release profiles of Composition D microparticles in aqueous and non-aqueous suspensions (Example 9) by route of administration and reconstitution vehicle.

[0054] Figure 4 Mean plasma octreotide levels during the study period obtained with a single administration of Composition D microparticles (90 mg of octreotide) or with 3x30 mg (once per month) of Sandostatin LAR (Example 10B).

[0055] Figure 5 Changes in IGF1 serum levels during the study period obtained with a single administration of Composition D microparticles (90 mg of octreotide) or with 3x30 mg (once a month) of Sandostatin LAR (Example 10B). DETAILED DESCRIPTION

[0056] In a first aspect of the present invention, a pharmaceutical composition is provided. The pharmaceutical composition comprises biodegradable polymer particles containing a somatostatin analog or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer comprises PLGA having the following items:

[0057] a molar ratio of lactide to glycolide of 80:20 to 90:10, and

[0058] · Intrinsic viscosity of 0.2 to 0.4 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0059] And wherein the biodegradable polymer particles have:

[0060] 10w / w% to 15w / w% drug loading,

[0061] · Dv50 from 30μm to 90μm, and

[0062] · Measured by gas adsorption, less than 0.50m 2 / g and preferably less than 0.40m 2 / g average specific surface area.

[0063] The term "biodegradable polymer" as used herein refers to a polymer or a mixture of polymers that degrades in response to contact with body fluids, such as after being injected into a patient's body. Non-limiting examples of biodegradable polymers include polylactic acid, poloxamer, polyglycolic acid, polycaprolactone, polycarbonate, polyesteramide, polyanhydride, polyamino acid, polyethylene glycol (PEG), polyorthoester, polycyanoacrylate (and copolymer), PLGA and a mixture of any of the above, and copolymers based on two or more repeating units forming the above polymers. In the context of the present invention, preferred biodegradable polymers are mixtures of polylactic acid, polyglycolic acid, PEG, PLGA and any of the foregoing, and copolymers based on two or more repeating units forming the listed preferred polymers. For example, a biodegradable polymer may include PLGA in a mixture with any other biodegradable polymer, and may particularly include PLGA in a mixture with any biodegradable polymer listed above except PLGA.

[0064] The term "biodegradable polymer microparticles" as used herein refers to monolithic microparticles formed from one or more biodegradable polymers. The microparticles have an internal continuous biodegradable polymer matrix. The microparticles can be of any shape, including spherical or irregular shapes. The term encompasses microspheres and microparticles.

[0065] The biodegradable polymer used to form the biodegradable polymer-containing microparticles included in the pharmaceutical composition of the present invention includes 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 a concentration of 0.5 w / w% in chloroform at 25°C.

[0066] In embodiments, the PLGA has a molar ratio of lactide to glycolide of 82:18 to 88:12, eg, 83:17 to 87:13.

[0067] In an embodiment, the PLGA has an intrinsic viscosity of 0.2 to 0.4 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C.

[0068] In more specific embodiments, the PLGA has a molar ratio of lactide to glycolide of 83:17 to 87:13, and an intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w % in chloroform at 25°C.

[0069] The PLGA may be linear or branched, hyperbranched, comb-branched, dendritic-branched, T-shaped, star-shaped or any mixture thereof. In an embodiment of the present invention, the PLGA is linear PLGA.

[0070] The PLGA may be poly (D,L-lactide-co-glycolide).

[0071] The PLGA may include less than 5 w / w %, such as less than 3 w / w %, of residual lactide and / or glycolide monomers.

[0072] In embodiments, the PLGA comprises less than 0.5 w / w % residual lactide and / or glycolide monomers. Most preferably, the PLGA contains no residual lactide and / or glycolide monomers, ie, comprises 0% residual lactide and / or glycolide monomers.

[0073] The terminal groups of the PLGA are not limited. Examples of possible terminal groups include hydroxyl, ester (eg, stearoyl), acid (eg, carboxyl), and the like.

[0074] In an embodiment of the present invention, the terminal groups of the PLGA are acidic, and preferably carboxyl groups.

[0075] The molar ratio of lactide to glycolide in PLGA can be determined by conventional methods, such as by nuclear magnetic resonance (NMR). 1 1H NMR).

[0076] In the present invention, the intrinsic viscosity is measured at a concentration of 0.5 w / w% in chloroform at 25° C. The intrinsic viscosity can be measured using conventional methods, for example, the capillary viscometer method as described in “European Pharmacopoeia”, 10.0, Chapter 2.2.9.

[0077] As will be appreciated by those skilled in the art, the intrinsic viscosity of PLGA and the molar ratio of lactide to glycolide are average values ​​within a certain range, for example, as indicated in the PLGA manufacturer's instructions.

[0078] As described herein, any PLGA having the desired properties (e.g., molar ratio of lactide to glycolide and intrinsic viscosity) can be included in the biodegradable polymers defined herein, i.e., in the biodegradable polymers used to form the biodegradable polymer microparticles defined herein and included in the pharmaceutical compositions of the present invention.

[0079] Non-limiting examples of commercially available PLGA include Evonik's (Evonik), Evonik Corbion and Seqens

[0080] The biodegradable polymer microparticles included in the sustained release pharmaceutical composition of the present invention include a somatostatin analog or a pharmaceutically acceptable salt thereof, and the somatostatin analog or a pharmaceutically acceptable salt thereof can be loaded into the biodegradable polymer microparticles at a drug loading of 10 to 15 w / w%.

[0081] As used herein, the term "drug loading" refers to the weight ratio (expressed as a percentage) of the mass of the somatostatin analog to the combined total mass of the biodegradable polymer microparticles, that is, as shown in the following equation:

[0082] Weight ratio = m(SA) / T(BPM)

[0083] Here, m(SA) represents the weight of the somatostatin analogue, and T(BPM) represents the weight of the biodegradable polymer microparticles.

[0084] In case of using a pharmaceutically acceptable salt of a somatostatin analog, the weight ratio is calculated based on the weight of the molar amount of the free base of the somatostatin analog which is the same as the molar amount of the pharmaceutically acceptable salt of the somatostatin analog included in the biodegradable polymer microparticles.

[0085] The drug loading can be measured using conventional methods, such as using high performance liquid chromatography (HPLC), for example, an appropriate weight (e.g., 20 mg) of biodegradable polymer microparticles can be weighed, dissolved in dimethylsufoxide (DMSO) and the sample can be analyzed by, for example, the method set forth in the European Pharmacopoeia, such as the method set forth in the Octreotide General Monograph for Octreotide.

[0086] In an embodiment of the present invention, the biodegradable polymer microparticles included in the pharmaceutical composition of the present invention have a drug loading of 11 w / w% to 14 w / w%, such as 11 w / w% to 13 w / w%, 11.5 w / w% to 13 w / w%, 12 w / w% to 13 w / w%. In a more specific embodiment, the biodegradable polymer microparticles have a drug loading of 11.5% to 13%, such as 12 w / w% to 13 w / w%, and in an even more specific embodiment, have a drug loading of 11.5 w / w% to 12.5 w / w%, such as 12 w / w% to 12.5 w / w%.

[0087] As used herein, the term "biodegradable polymer microparticles" refers to non-spherical irregularly shaped monolithic microparticles formed from one or more biodegradable polymers. The microparticles have an internal continuous biodegradable polymer, for example, a PLGA matrix.

[0088] The term "biodegradable polymer microspheres" as used herein refers to spherical or substantially spherical regular shaped monolithic microparticles formed from one or more biodegradable polymers. The microspheres have an internal continuous biodegradable polymer, for example, PLGA matrix.

[0089] Biodegradable polymer microparticles can be prepared, for example, by dry processes such as extrusion and grinding, while biodegradable polymer microspheres can be prepared, for example, by wet processes such as emulsification and precipitation.

[0090] In a particular embodiment of the present invention, the biodegradable polymer microparticles are biodegradable polymer microspheres.

[0091] The biodegradable polymer microparticles, e.g., biodegradable polymer microspheres, included in the pharmaceutical composition of the present invention may have a median particle size (i.e., Dv50) of 30 to 90 μm, e.g., 30 to 80 μm, 40 to 90 μm, 40 to 80 μm, 50 to 90 μm, 60 to 80 μm, e.g., 60 to 70 μm, 60 to 65 μm.

[0092] The biodegradable polymer microparticles may additionally have one or more of the following particle size values:

[0093] a Dv90 of 70 to 200 μm and preferably 100 to 150 μm, for example 100 to 140 μm, 100 to 130 μm, 100 to 125 μm,

[0094] • Dv10 of 5 to 50 μm and preferably 20 to 40 μm, for example 20 to 30 μm, 20 to 25 μm.

[0095] In a specific embodiment, the biodegradable polymer microparticles included in the composition of the present invention have a Dv of 60 μm to 80 μm, such as 60 μm to 75 μm, such as 60 μm to 70 μm, such as 62 μm to 65 μm. 50 , Dv of 80 μm to 200 μm and preferably 100 μm to 150 μm, for example 100 μm to 140 μm, 100 μm to 130 μm, 100 μm to 125 μm 90 , and Dv10 of 5 μm to 50 μm and preferably 20 μm to 40 μm, for example 20 μm to 30 μm, 20 μm to 25 μm.

[0096] Dvx refers to the volume of the biodegradable polymer microparticle sample having X% below the indicated diameter value, e.g., Dv 50 90 μm means that 50% of the volume of the biodegradable polymer microparticle sample has a diameter below 90 μm, for example, a diameter of 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm. For example, DvX, such as Dv50, is determined by wet laser diffraction as described in European Pharmacopoeia V.10.8, Chapter 2.9.31. For example, DvX can be determined 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 hydraulic medium volume (MV) dispersion unit. The biodegradable polymer microparticles can be suspended in an aqueous based medium including a surfactant, such as polysorbate 80 (0.1%) (at room temperature, such as 20-25° C.), and the sample can then be dispersed in purified water in a hydrodynamic MV dispersion unit (stirring speed 2000 rpm) until a fuzziness between 10% and 20% is reached, after which the sample is subjected to ultrasound for 3 minutes (hydraulic MV dispersion unit setting medium (50%)), and then the sample is analyzed using a Malvern particle size analyzer 3000. The calculation results are based on Mie theory (the refractive index of real particles is 1.52, and the refractive index of virtual particles is 0.001). A general analysis model can be used.

[0097] In an embodiment, the biodegradable polymer microparticles have a Dv50 of 50 μm to 80 μm, more specifically 60 μm to 80 μm.

[0098] The biodegradable polymer microparticles defined herein and included in the pharmaceutical composition of the present invention may have a microstructure of less than 0.5 μm. 2 / g, for example 0.49m 2 / g, 0.48m 2 / g, 0.47m 2 / g, 0.46m 2 / g, 0.45m 2 / g or less, such as 0.44m 2 / g, 0.43m 2 / g, 0.42m 2 / g, 0.41m 2 / g, 0.4m 2 / g, for example, less than 0.4m 2 / g, for example 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, for example 0.29m 2 / g, 0.28m 2 / g, 0.27m 2 / g, 0.26m 2 / g, 0.25m 2 The specific surface area can be, for example, 0.05 to less than 0.5 m 2 / g, for example 0.05 to 0.45 m 2 / g, 0.05 to 0.4 m 2 / g or less, 0.05 to 0.35m 2 / g or less, 0.05 to 0.3m 2 / g or less, 0.05 to 0.25m 2 / g or less, wherein the specific surface area is determined by gas (e.g., nitrogen or krypton gas) adsorption, for example using the N2-BET or Kr-BET adsorption method described in Chapter 10.8, 2.9.26 of the European Pharmacopoeia, for example as described in Example 3.

[0099] Specific surface area refers to the total surface area per unit mass of the biodegradable polymer microparticles as defined herein and included in the composition of the present invention. The specific surface area value may be an average value calculated for multiple batches of biodegradable polymer microparticles, e.g., 2, 3, 4, 5, or 6 batches. In an embodiment, the specific surface area is determined by nitrogen adsorption using the Brunauer-Emmett-Teller (N2-BET) theory, e.g., as described in Example 3.

[0100] In an embodiment, the biodegradable polymer microparticles defined herein have a microstructure of 0.05 to 0.3 m 2 / g and more specifically 0.1 to 0.28 m 2 / g specific surface area.

[0101] In a more specific embodiment, the biodegradable polymer microparticles included in the composition of the present invention have a Dv50 of 50 μm to 80 μm, such as 60 μm to 75 μm, such as 60 μm to 70 μm, such as 62 μm to 65 μm, and a Dv50 of 0.05 to 0.3 μm. 2 / g, for example 0.1 to 0.28 m 2 / g, 0.1 to 0.25m 2 / g, 0.20 to 0.21 m 2 / g, for example 0.15m 2 / g, 0.2m 2 / g, 0.21m 2 / g, 0.206m 2 / g, 0.25m 2 The average specific surface area of ​​​​the ...

[0102] In an even more specific embodiment, the biodegradable polymer microparticles comprised in the composition of the present invention have a Dv50 of 60 to 80 μm, for example 60 to 75 μm, for example 60 to 70 μm, for example 62 to 65 μm, a Dv90 of 80 to 200 μm and preferably 100 to 150 μm, for example 100 to 140 μm, 100 to 130 μm, 100 to 125 μm, and a Dv10 of 5 to 50 μm and preferably 20 to 40 μm, for example 20 to 30 μm, 20 to 25 μm, and a Dv10 of 0.05 to 0.3 μm. 2 / g, for example 0.1 to 0.28 m 2The average specific surface area of ​​??g is 200 Å, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, determined using the N2-BET or Kr-BET adsorption method as described in Example 3.

[0103] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention have:

[0104] PLGA having a molar ratio of lactide to glycolide of 83:17 to 87:13,

[0105] · Intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0106] · Dv50 of 60 μm to 75 μm, for example 60 μm to 70 μm, for example 62 μm to 65 μm,

[0107] 0.05 to 0.3 m 2 / g, for example 0.1 to 0.28 m 2 / g, 0.1 to 0.25m 2 / g, 0.20 to 0.21 m 2 / g, for example 0.15m 2 / g, 0.2m 2 / g, 0.21m 2 / g, 0.206m 2 / g,0.25m 2 An average specific surface area of ​​100 g / g, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, as determined using the N2-BET or Kr-BET adsorption method described in Example 3, and

[0108] • A drug loading of 11.5% to 13%, such as 11.5 w / w% to 12.5 w / w%, such as 12 w / w% to 12.5 w / w%.

[0109] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention have:

[0110] PLGA having a molar ratio of lactide to glycolide of 83:17 to 87:13,

[0111] · Intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0112] · Dv50 of 60 μm to 75 μm, for example 60 μm to 70 μm, for example 62 μm to 65 μm,

[0113] · Dv90 of 100 μm to 150 μm, for example 100 μm to 140 μm, 100 μm to 130 μm, 100 μm to 125 μm,

[0114] · Dv10 of 20 μm to 40 μm, for example 20 μm to 30 μm, 20 μm to 25 μm,

[0115] 0.05 to 0.3 m 2 / g, for example 0.1 to 0.28 m 2 / g, 0.1 to 0.25m 2 / g, 0.20 to 0.21 m 2 / g, for example 0.15m 2 / g, 0.2m 2 / g, 0.21m 2 / g, 0.206m 2 / g,0.25m 2 An average specific surface area of ​​100 Å / g, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, as determined using the N2-BET or Kr-BET adsorption method described in Example 3, and

[0116] • A drug loading of 11.5% to 13%, such as 11.5 w / w% to 12.5 w / w%, such as 12 w / w% to 12.5 w / w%.

[0117] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention include a biodegradable polymer and a somatostatin analog, preferably octreotide or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer is composed of PLGA having:

[0118] a molar ratio of lactide to glycolide of 83:17 to 87:13,

[0119] · Intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0120] The biodegradable polymer particles have:

[0121] · Dv50 of 60μm to 75μm,

[0122] 0.05 to 0.3 m 2 The average specific surface area of ​​??g, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, using the N2-BET or Kr-BET adsorption method as described in Example 3, and

[0123] 11.5% to 13% drug loading.

[0124] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention include a biodegradable polymer and a somatostatin analog, preferably octreotide or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer is composed of PLGA having:

[0125] a molar ratio of lactide to glycolide of 83:17 to 87:13,

[0126] · Intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0127] The biodegradable polymer particles have:

[0128] · Dv50 of 60μm to 70μm,

[0129] 0.1 to 0.28 m 2 The average specific surface area of ​​??g, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, using the N2-BET or Kr-BET adsorption method as described in Example 3, and

[0130] · 11.5 w / w% to 12.5 w / w% drug loading.

[0131] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention include a biodegradable polymer and a somatostatin analog, preferably octreotide or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer is composed of PLGA having:

[0132] a molar ratio of lactide to glycolide of 83:17 to 87:13,

[0133] · Intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0134] The biodegradable polymer particles have:

[0135] · Dv50 of 62μm to 65μm,

[0136] 0.1 to 0.25 m 2 / g, for example 0.15m 2 / g, 0.2m 2 / g, 0.20m 2 / g, 0.206m 2 / g, 0.21m 2 / g, 0.25m 2An average specific surface area of ​​1000 g / g, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, as determined using the N2-BET or Kr-BET adsorption method described in Example 3, and

[0137] · 12 w / w% to 12.5 w / w% drug loading.

[0138] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention include a biodegradable polymer and a somatostatin analog, preferably octreotide or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer is composed of PLGA having:

[0139] a molar ratio of lactide to glycolide of 83:17 to 87:13,

[0140] · Intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0141] The biodegradable polymer particles have:

[0142] · Dv50 of 60μm to 75μm,

[0143] 100μm to 150μm Dv90,

[0144] · Dv10 from 20μm to 40μm,

[0145] 0.05 to 0.3 m 2 An average specific surface area of ​​100 g / g, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, using the N2-BET or Kr-BET adsorption method as described in Example 3, and

[0146] 11.5% to 13% drug loading.

[0147] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention include a biodegradable polymer and a somatostatin analog, preferably octreotide or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer is composed of PLGA having:

[0148] a molar ratio of lactide to glycolide of 83:17 to 87:13,

[0149] · Intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0150] The biodegradable polymer particles have:

[0151] · Dv50 of 60μm to 70μm,

[0152] 100μm to 140μm Dv90,

[0153] 20μm to 30μm Dv10,

[0154] 0.1 to 0.28 m 2 The average specific surface area of ​​??g, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, using the N2-BET or Kr-BET adsorption method as described in Example 3, and

[0155] · 11.5 w / w% to 12.5 w / w% drug loading.

[0156] In another embodiment, the biodegradable polymer microparticles included in the composition of the present invention include a biodegradable polymer and a somatostatin analog, preferably octreotide or a pharmaceutically acceptable salt thereof, wherein the biodegradable polymer is composed of PLGA having:

[0157] a molar ratio of lactide to glycolide of 83:17 to 87:13,

[0158] · Intrinsic viscosity of 0.25 to 0.35 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C,

[0159] The biodegradable polymer particles have:

[0160] · Dv50 of 62μm to 65μm,

[0161] · Dv90 of 100 μm to 130 μm, for example 100 μm to 125 μm,

[0162] 20μm to 25μm Dv10,

[0163] 0.1 to 0.25 m 2 / g, for example 0.15m 2 / g, 0.2m 2 / g, 0.20m 2 / g, 0.206m 2 / g, 0.21m 2 / g, 0.25m 2 An average specific surface area of ​​1000 g / g, wherein the specific surface area is measured by gas (e.g., nitrogen or krypton) adsorption, for example, as determined using the N2-BET or Kr-BET adsorption method described in Example 3, and

[0164] · 12 w / w% to 12.5 w / w% drug loading.

[0165] The somatostatin analog or a pharmaceutically acceptable salt thereof is included in the biodegradable polymer microparticles, such as biodegradable polymer microspheres, included in the pharmaceutical composition of the present invention. The somatostatin analog or a pharmaceutically acceptable salt thereof can be dispersed, for example, uniformly dispersed in the matrix of the internally continuous biodegradable polymer (e.g., PLGA), biodegradable polymer microparticles (e.g., biodegradable polymer microspheres).

[0166] As used herein, the term "somatostatin analogue" refers to any pharmacologically active synthetic (rather than naturally occurring) compound that is intended to pharmacologically mimic somatostatin by binding to one or more of the five somatostatin receptor subtypes. A somatostatin analogue may be considered to be pharmaceutically active if it binds to at least one somatostatin receptor subtype, for example, if it binds to at least one of the five somatostatin receptor subtypes in the nM or μM range, for example, if the IC50 (nM) for one or more of the five somatostatin subtypes 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. 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.

[0167] IC50 (nM) can be determined by known methods, for example, by measuring 125 Binding of an I-labeled somatostatin analog to a cloned subtype receptor of interest is measured, for example, by measuring binding in CHO-K1 (Chinese Hamster Ovary) cells transfected with the receptor of interest (eg, subtype 2).

[0168] As used herein, the term "somatostatin" refers to any naturally occurring somatostatin, such as somatostatin-14 or somatostatin-28.

[0169] Non-limiting examples of somatostatin analogs include octreotide, lanreotide, pasireotide, and vapreotide.

[0170] Any pharmaceutically acceptable salt of somatostatin analogs can be included in the biodegradable polymer microparticles included in the pharmaceutical composition of the present invention, such as biodegradable polymer microspheres. Acceptable salts can be acid addition salts using, for example, inorganic acids, polymeric acids or organic acids, such as 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 (pamoic (embonic) acid). The acid addition salt can be a monovalent salt or a divalent salt. The salt can be water-soluble or water-insoluble.

[0171] In a specific embodiment, the somatostatin analog included in the biodegradable polymer PLGA microparticles (eg, biodegradable polymer microspheres) in the pharmaceutical composition of the present invention is octreotide or a pharmaceutically acceptable salt thereof.

[0172] Preferred pharmaceutically acceptable salts may be acetate or pamoate.

[0173] In a more specific embodiment, the somatostatin analog is octreotide and / or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of octreotide acetate, octreotide pamoate, and a combination thereof. Preferably, the pharmaceutically acceptable salt thereof is octreotide acetate.

[0174] The advantage of the sustained release pharmaceutical composition of the present invention is that only biodegradable polymer microparticles as defined herein and formed from PLGA as defined herein are required in the composition to obtain a composition having one or more of the following:

[0175] Desired sustained release, e.g., 30 days or more, e.g., 60 days or more, 90 days or more, or 120 days or more,

[0176] Lower initial release (burst), and

[0177] - Surprisingly high bioavailability of somatostatin analogs or pharmaceutically acceptable salts thereof after administration to patients.

[0178] Thus, the biodegradable polymer used to form the biodegradable polymer microparticles comprised in the pharmaceutical composition of the present invention may comprise only or may comprise essentially only PLGA as defined herein.

[0179] In an 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 a concentration of 0.5 w / w % in chloroform at 25°C.

[0180] 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.

[0181] The expression "at least 50%" as used above and below, and in particular in the first two and last paragraphs, may in certain embodiments refer to 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%, for example at least 95 w / w%, such as 96 w / w% or more, 97 w / w% or more, 98 w / w% or more, 99 w / w% or more, for example 100 w / w%.

[0182] In the above embodiment having a biodegradable polymer comprising less than 100% PLGA as defined herein, the remainder to 100% is preferably any one or more of the biodegradable polymers listed in the above paragraph defining the term "biodegradable polymer" (except PLGA as defined herein).

[0183] The biodegradable polymer microparticles described herein may be the only biodegradable polymer microparticles included in the composition of the present invention, or they may account for at least 50w / w%, for example, at least 60w / w%, at least 70w / w%, at least 80w / w%, at least 90w / w%, at least 95w / w%, at least 99w / w%, at least 99.9w / w% of the total number of any biodegradable polymer microparticles included in the composition. Preferably, the biodegradable polymer microparticles described herein account for at least 80w / w%, at least 85w / w%, for example, at least 90w / w%, at least 95w / w%, at least 99w / w%, at least 99.9w / w%. Most preferably, the biodegradable polymer microparticles described herein are the only biodegradable polymer microparticles included in the composition of the present invention.

[0184] If the biodegradable polymer microparticles account for less than 100 w / w% of the biodegradable polymer microparticles included in the pharmaceutical composition of the present invention, the remaining % of the biodegradable microparticles are "other" biodegradable microparticles of those biodegradable microparticles defined herein. The other biodegradable microparticles may also include PLGA. The PLGA may be the same as or different from the PLGA defined herein. The other biodegradable microparticles may also include somatostatin analogs or pharmaceutically acceptable salts thereof. Preferably, the other biodegradable polymer microparticles are formed by biodegradable polymers including PLGA as defined herein, and preferably, they include somatostatin analogs or pharmaceutically acceptable salts thereof as defined herein. More preferably, the other biodegradable polymer microparticles are formed by biodegradable polymers including at least 50 w / w of PLGA as defined herein, and preferably, they include somatostatin analogs or pharmaceutically acceptable salts thereof as defined herein. Other biodegradable polymer microparticles may be different from the biodegradable polymer microparticles defined herein because they have different drug loading, Dv50 or specific surface area. The further biodegradable polymer microparticles may differ in only one of these properties / characteristics.

[0185] The compositions according to the invention may additionally comprise one or more other pharmaceutical excipients, for example pharmaceutical excipients usually included in the formulation type in question, such as diluents, surfactants, stabilizers, release modifiers, preservatives, antioxidants, buffers and anti-caking agents, etc.

[0186] Non-limiting examples of other pharmaceutical excipients include: polyvinyl alcohol; polyvinyl pyrrolidone; sodium carboxymethyl cellulose (CMC-Na); dextrin; polyethylene glycol; suitable surfactants such as poloxamer (also known as poly(oxyethylene-block-oxypropylene)), poly(oxyethylene)-sorbitan-fatty acid esters, known and traded under the name commercially available (e.g., Tween 20, Tween 40, Tween 60, Tween 80, Tween 65, Tween 85, Tween 21, Tween 61, Tween 81); sorbitan fatty acid esters, such as those known by the type and trade name SPAN; lecithin; inorganic salts, such as zinc carbonate, magnesium hydroxide, magnesium carbonate; or protamine (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); and gelatin, such as porcine or fish gelatin. Suitable anti-caking agents include, for example, mannitol, glucose, dextrose, sucrose, sodium chloride or a water-soluble polymer, such as polyvinyl alcohol, polyvinyl pyrrolidone or polyethylene glycol.

[0187] The pharmaceutical composition of the present invention can provide sustained release of the somatostatin analog or a pharmaceutically acceptable salt thereof included in the biodegradable polymer microparticles included therein.

[0188] As used herein, the term "sustained release" refers to the sustained release of a certain amount of somatostatin analogs or pharmaceutically acceptable salts thereof over a predetermined 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 to a patient by IM injection. The amount of somatostatin analogs released can be an effective amount. For example, in an embodiment, 30 mg of somatostatin analogs, preferably octreotide or a pharmaceutically acceptable salt thereof, can be administered to a patient by IM injection, and it is confirmed that the plasma level of somatostatin analogs, particularly octreotide, does not drop to a level below 0.5 ng / mL for at least 30 days, thereby confirming sustained release.

[0189] In another embodiment where the somatostatin analog is octreotide or a pharmaceutically acceptable salt thereof, sustained release can be confirmed by administering an amount of the composition of the present invention corresponding to a dose of 90 mg of octreotide to a patient (e.g., a patient in need thereof, e.g., a patient with acromegaly or GEP-NET) by IM injection and confirming that the plasma level of octreotide does not drop below a level of 0.5 ng / mL within the 21st to 84th day after administration on day 0.

[0190] In this test, and in other tests described above and below, a larger number of patients (e.g., 5, 10, 15, 20, 50, or 100 patients) may be tested and the results then averaged to improve the quality and precision of the results obtained.

[0191] In the context of the present invention, an effective amount may be an amount that results in a patient having a therapeutically effective plasma level of a somatostatin analog (eg, octreotide) and may depend on the patient's existing plasma levels.

[0192] An effective amount may be an amount that results in a plasma level of somatostatin analogue of 0.1 ng / mL, such as 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 ng / mL or more.

[0193] In the case of a somatostatin analog (e.g., lanreotide, octreotide, pasireotide or vapreotide), the therapeutically effective plasma level can be, for example, 0.3 ng / mL to 12 ng / mL or more, such as 2 ng / mL, 2.5 ng / mL, 3 ng / mL, 3.5 ng / mL, 4 ng / mL, 4.5 ng / mL, 5 ng / mL, 5.5 ng / mL, 6 ng / mL, 6.5 ng / mL, 7 ng / mL, 7.5 ng / mL, 8 ng / mL, 8.5 ng / mL, 9 ng / mL, 9.5 ng / mL, 10 ng / mL or more.

[0194] In the case of octreotide, the therapeutically effective plasma level can be, for example, 0.3 ng / mL to 1 ng / mL or higher, such as 0.3 ng / mL to 3 ng / mL, such as 0.4 ng / mL, 0.5 ng / mL, 0.6 ng / mL, 0.7 ng / mL, 0.8 ng / mL, 0.9 ng / mL, 1.5 ng / mL, 1.8 ng / mL, 2 ng / mL, 2.5 ng / mL, 3 ng / mL. A particularly effective plasma level can be 1 ng / mL.

[0195] What constitutes a therapeutically effective plasma level of a somatostatin analog may depend on characteristics of the patient, for example, how well the patient responds to the somatostatin analog in question.

[0196] The term "therapeutic effect or therapeutic effectiveness" as used herein refers not only to the complete cure of a disease, but also to the alleviation or improvement of a disease or any symptom associated therewith (e.g., improvement in quality of life) or the slowing down of disease progression or the stabilization of a disease. The therapeutic effect of a patient can be monitored by any method known to a person of ordinary skill in the clinical art of treating the disease in question.

[0197] In some embodiments of the present invention, an effective amount of a composition of the present invention may be an amount of a somatostatin analog, such as an amount of plasma levels of octreotide, that results in a reduction in serum levels of insulin-like growth factor 1 (IGF1) in a patient (e.g., a patient with acromegaly). Administration of an effective amount (e.g., a composition of the present invention comprising octreotide or a pharmaceutically acceptable salt thereof) may result in a reduction in serum IGF1 levels. There are no particular limitations on the reduction that can be achieved. In some embodiments, the reduction may be up to 50%, for example up to 40% or up to 30% from the baseline (IGF1 level in a patient before administration of the pharmaceutical composition of the present invention), and may be reduced by at least 1%, typically at least 15%, and particularly at least 20%. For these assays, serum IGF1 levels may be measured using a validated IDS-iSYS method or a validated LC-MS / MS method, such as the method described in Example 10B herein.

[0198] In some embodiments of the invention, an effective amount of a composition of the invention can be an amount of a somatostatin analog, such as an amount of plasma levels of octreotide, that results in a decrease in serum levels of growth hormone (GH) in a patient (e.g., a patient with acromegaly). In some embodiments, administration of an effective amount (e.g., a composition of the invention comprising octreotide or a pharmaceutically acceptable salt thereof) can result in a decrease in serum levels of GH, for example, to a value of 3 μg / L or less, such as a value of 2.5 μg / L or less, such as a value of 2 μg / L or less, such as a value of 1.5 μg / L or less, or such as a value of 1 μg / L or less, with the minimum decrease being the level of detection. For these assays, serum human growth hormone (GH) levels can be determined using the IDS-iSYS multidisciplinary automation system described in more detail below.

[0199] In a preferred embodiment, the effective amount of the composition of the present invention may be a plasma level of a somatostatin analogue, such as octreotide, that results in a reduction in serum levels of IGF1 and / or GH in acromegaly patients. The reduction may be as described above.

[0200] In some embodiments of the invention, an effective amount of a composition of the invention may be an amount of a somatostatin analog, such as octreotide, that results in a reduction in serum levels of chromogranin A (CgA) in a patient (e.g., a patient with GEP-NET). There are no particular limitations on the reduction that can be achieved. Serum levels of CgA may be determined using the TRACE analysis of the manufacturer BRAHMS using the B·R·A·H·M·S CgA II KRYPTOR assay kit (reference number 839.050).

[0201] For example, sustained release of an effective amount of a somatostatin analog substantially within a predetermined release period may refer to release within a predetermined release period minus a lag period (e.g., the period after injection before an effective amount is released), for example, the lag period may be 21 days or less, 18 days or less, 15 days or less, such as 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 lag period is 5 days, then after administration of the first dose of the composition of the invention on day 0, the patient's plasma level of the somatostatin analog will be within the therapeutically effective range from day 5 to the end of the sustained release period. Typically, the lag period will only occur in patients who do not have a therapeutically effective plasma level of the somatostatin analog and are administering the composition of the invention for the first time, for example, the patient in need of treatment has not been pre-treated with a somatostatin analog.

[0202] The term "patient" as used herein refers to a human or animal subject. In an embodiment of the present invention, the patient is a human. The human can be an adult or a child. Before applying the composition of the present invention, the patient may have been pretreated (previous treatment) with a somatostatin analog or a pharmaceutically acceptable salt thereof, and may have a therapeutically effective plasma level of the somatostatin analog (e.g., octreotide or lanreotide) (e.g., the patient may switch from a type of somatostatin analog treatment to a treatment with the composition of the present invention, or may have been pretreated to ensure that the somatostatin analog is well supported by the patient). After the last application of any pretreatment, the therapeutically effective plasma level of the somatostatin analog may exist for several weeks. The patient may also be pretreated to avoid any lag period after the first application of the composition of the present invention.

[0203] The pharmaceutical composition of the present invention preferably provides a sustained release of the somatostatin analog or a pharmaceutically acceptable salt thereof over 30 days or more, for example, over 40 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, for example, over 200 days.

[0204] 30 days or more may refer to 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 (e.g., 56 days), 30 to 50 days (e.g., 49 days, 42 days), 30 to 40 days (e.g., 35 days, 30 days).

[0205] 60 days or more may refer to 60 to 200 days, such as 60 to 180 days, 60 to 126 days, such as 60 to 120 days, 60 to 90 days, 60 to 80 days (e.g., 77 days, 84 days), 60 to 70 days (e.g., 60 days, 63 days, 70 days).

[0206] 90 days or more may refer to 90 to 200 days, for example 90 to 180 days, for example 90 to 126 days, for example 90 to 120 days (e.g., 112 days), 90 to 110 days (e.g., 105 days), 90 to 100 days (e.g., 90 days, 91 days, 98 days).

[0207] 120 days or more may refer to 120 to 200 days, such as 120 to 180 days, such as 120 to 126 days (eg, 120 days).

[0208] The sustained release period disclosed herein is in days. However, this time period can also be equivalent to the same period in weeks or months, for example, 28-30 days can be equivalent to 4 to 5 weeks or 1 month, 56-60 days can be equivalent to 8 to 9 weeks or 2 months, 84-90 days can be equivalent to 12 to 13 weeks or 3 months, 112-120 days can be equivalent to 17 to 18 weeks or 4 months, 140-150 days can be equivalent to 21 to 22 weeks or 5 months, 168-180 days can be equivalent to 25 to 26 weeks or 6 months, and 196-200 days can be equivalent to 27 to 28 weeks or 7 months, etc.

[0209] In an embodiment, the pharmaceutical composition of the present invention provides a sustained release of a somatostatin analog or a pharmaceutically acceptable salt thereof within 30 days or more, preferably within 30 to 200 days, for example, within 30 to 180 days, for example, within 30 to 126 days, or in other embodiments, within about 30 days or more, preferably within about 30 to 200 days, for example, within 28 to 200 days, for example, within 30 to 180 days, for example, within 30 to 126 days. In a more specific embodiment, the pharmaceutical composition of the present invention is a 1-month sustained release formulation, preferably administered to a patient once every 30 days, for example, every 24-35 days (e.g., 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days).

[0210] In an embodiment of the invention, the sustained release pharmaceutical composition of the invention provides sustained release within 60 days or more, preferably within 60 to 200 days, for example, within 60 to 180 days, for example, within 60 to 126 days, or in other embodiments, within about 60 days or more, preferably within 56 to 200 days, for example, within 60 to 200 days, for example, within 60 to 180 days, for example, within 60 to 126 days. In a more specific embodiment, the pharmaceutical composition of the invention is a 2-month sustained release formulation, preferably administered once every 60 days, for example, every 54-65 days (e.g., 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days) to the patient.

[0211] In an embodiment, the sustained release pharmaceutical composition of the present invention provides sustained release within 90 days or more, preferably within 90 to 200 days, for example, within 90 to 180 days, for example, within 90 to 126 days, or in other embodiments, within about 90 days or more, preferably within 84 to 200 days, for example, within 90 to 200 days, for example, within 90 to 180 days, for example, within 90 to 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 once every 90 days, for example, every 84-95 days (e.g., 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days, 94 days).

[0212] In an embodiment, the pharmaceutical composition of the present invention provides a sustained release of a somatostatin analog or a pharmaceutically acceptable salt thereof within 120 days or more, preferably within 120 to 200 days, for example, within 120 to 180 days, for example, within 120 to 126 days, or in other embodiments, within about 120 days or more, preferably within 112 to 200 days, for example, within 120 to 200 days, for example, within 120 to 180 days, for example, within 120 to 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 once about every 120 days, for example, every 112-125 days, for example, every 114-125 days (e.g., 112 days, 113 days, 114 days, 115 days, 116 days, 117 days, 118 days, 119 days, 120 days, 121 days, 122 days, 123 days, 124 days).

[0213] Although the pharmaceutical compositions described herein can provide sustained release as described above and below, the pharmaceutical compositions are not limited to sustained release compositions as described herein. The product features of the pharmaceutical compositions as specified herein (e.g., in appended claim 1) produce favorable release features, regardless of whether these features are classified as any particular type of "sustained release".

[0214] A low initial release (low burst) of a somatostatin analogue or a pharmaceutically acceptable salt thereof may be exhibited after administration of the pharmaceutical composition of the present invention to a patient. This may be used to minimize any side effects / adverse reactions that may be associated with the administration of the somatostatin analogue or a pharmaceutically acceptable salt thereof. A pharmaceutical composition of the present invention may be considered to have a low burst if it is characterized by the release of a somatostatin analogue (included therein) that meets the following criteria: less than 15%, for example less than 10%, of the somatostatin analogue, for example octreotide, included in the pharmaceutical composition is released within 5 hours. Wherein the release is measured in vitro (at 37°C in 900 mL of pH 4 100 mM acetate buffer, for example, stirred at 75 RPM) according to the method described in European Pharmacopoeia 10, 2.9.3, and wherein the composition is tested in an amount equivalent to 30 mg, 60 mg or 90 mg of a somatostatin analogue (e.g., octreotide). Percentage indications in this paragraph and the next two paragraphs may be understood to be expressed on a w / w basis, or alternatively on a mol / mol basis.

[0215] In an 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, comprised therein within 5 hours.

[0216] In a more specific embodiment of the invention, the pharmaceutical composition of the invention releases less than 3% of the somatostatin analogue, such as octreotide, comprised therein within 5 hours, as measured in vitro in acetate buffer at pH 4 at 37°C.

[0217] The pharmaceutical composition according to the present invention may be a composition of dry biodegradable polymer microparticles, such as biodegradable polymer microspheres, ready to be suspended in a liquid carrier prior to injection, or it may be, for example, a liquid carrier suspension comprising biodegradable polymers, such as biodegradable polymer microspheres. The liquid carrier may be an aqueous (water-based) or non-aqueous carrier. The biodegradable polymer microparticles, such as biodegradable polymer microspheres, contained in the liquid carrier may be any biodegradable polymer microparticles, such as biodegradable polymer microspheres, as described above.

[0218] In an embodiment, the pharmaceutical composition of the present invention is a liquid carrier suspension comprising biodegradable polymer microparticles, such as biodegradable polymer microspheres, or a composition of dried biodegradable polymer microparticles, such as biodegradable polymer microspheres. The liquid carrier can be an aqueous (water-based) or non-aqueous carrier.

[0219] The composition of dried biodegradable polymer microparticles, such as dried biodegradable polymer microspheres, or a suspension of biodegradable polymer microparticles, such as biodegradable polymer microspheres, in a liquid carrier may be provided, for example, in a syringe ready for injection.

[0220] The composition of the dried biodegradable polymer particles or the liquid carrier suspension comprising the biodegradable polymer particles may comprise the biodegradable polymer particles defined herein as the only biodegradable polymer particles of the composition, or may be a mixture of the biodegradable polymer particles defined herein and other biodegradable polymer particles. As previously stated, preferably at least 50 w / w%, more preferably at least 80 w / w% of the biodegradable polymer particles included in such a composition of the present invention are biodegradable polymer particles as defined herein.

[0221] The term aqueous liquid carrier or water-based liquid carrier used herein refers to a pharmaceutically acceptable liquid that is primarily water, for example, a pharmaceutically acceptable liquid that includes more than 50% water, for example 60% or more, 70% or more, 80% or more, 90% or more, 93% or more, 95% or more, or even 97% or more of water. These percentage notations are (w / v) percentages.

[0222] Water-based (aqueous) liquid carriers can include pharmaceutical excipients. The excipient can be used to ensure isotonicity and improve wettability and non-sedimentation properties of microparticles (e.g., microspheres). The example of this pharmaceutical excipient includes but is not limited to mannitol, sodium chloride, glucose, dextrose, sucrose or glycerol, nonionic surfactants (e.g., poloxamer, poly (ethylene oxide)-sorbitol-fatty acid esters), sodium carboxymethylcellulose (CMC-Na), sorbitol, poly (vinyl pyrrolidone) or aluminum monostearate, polyethylene glycol (PEG) (e.g., PEG 4000).

[0223] The composition of dried biodegradable polymer microparticles, such as dried biodegradable polymer microspheres, can be suspended in a water-based carrier, for example, before injection, for example, in a water-based carrier comprising glucose and PEG 4000, for example, 3 to 7 w / w% glucose (e.g., 5 w / w% glucose) and 5 to 9 w / w% (e.g., 7.5 w / w%) PEG4000, or, for example, in a water-based carrier comprising sodium carboxymethylcellulose, mannitol and Tween 80 (e.g., 1 w / w% to 2 w / w% carboxymethylcellulose, 4 to 5 w / w% mannitol and 0.05 to 0.15 w / w% Tween 80).

[0224] Advantageously, the inventors have discovered that the release profile of a somatostatin analog from a non-aqueous liquid carrier suspension comprising biodegradable polymer microparticles according to the present invention can be the same or substantially the same as the release profile of a somatostatin analog from a corresponding (all characteristics of the same microparticles) aqueous-based carrier suspension, e.g., with no or no substantial change in the burst, lag or release period, which means that non-aqueous and aqueous liquid carriers can be used interchangeably as desired, e.g., due to regulatory restrictions, financial considerations or personal preference.

[0225] The term "non-aqueous liquid" as used herein refers to a pharmaceutically acceptable liquid that is free of water or substantially free of water, for example, a pharmaceutically acceptable liquid comprising 0.25% (w / v) or less water, 0.1% or less water, 0.05% (w / v) or less water. The non-aqueous liquid is inert or substantially inert with respect to the biodegradable polymer microparticles included in the composition of the present invention and with respect to any somatostatin analogs included therein, for example, it does not or substantially does not interact with the biodegradable polymer (e.g., PLGA), microparticles or somatostatin analogs included therein, or dissolves or substantially dissolves the biodegradable polymer (e.g., PLGA), microparticles or somatostatin analogs included therein.

[0226] The water content of non-aqueous liquids can be determined by conventional methods, for example, the microassay method described in European Pharmacopoeia 10.0, Chapter 2.5.32.

[0227] In an embodiment of the present invention, the viscosity of the non-aqueous liquid at 20°C is 25 to 33 mPa.

[0228] The viscosity of non-aqueous liquids can be measured by conventional methods, for example, the capillary viscometer method described in Chapter 2.2.9 of the European Pharmacopoeia 10.0.

[0229] The non-aqueous liquid can be a pharmaceutically acceptable oil. The term oil as used herein refers to a substance that is in a viscous liquid state at ambient temperature (20°C-30°C) or at a slightly higher temperature, and is both hydrophobic (incompatible with water) and lipophilic (compatible 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.

[0230] In an embodiment of the present invention, the non-aqueous liquid is a pharmaceutically acceptable oil. Particularly suitable oils may include medium chain triglycerides (MCT).

[0231] The term medium-chain triglyceride (MCT) as used herein refers to a glyceride formed by glycerol and three medium-chain fatty acids, each of which is a C6 to C12 fatty acid, i.e., a carboxylic acid with a fatty chain of 6 to 12 carbon atoms, such as C6 (caproic acid), C8 (octanoic acid), C10 (decanoic acid), C12 (dodecanoic acid). The three medium-chain fatty acids forming the triglyceride can all be the same, for example, all three can be medium-chain fatty acids with a fatty chain of, for example, 8 or 10 carbon atoms, or one or all of the medium-chain fatty acids can be different from the other medium-chain fatty acids. The fatty chain of MCT can be saturated or unsaturated.

[0232] In an embodiment, the non-aqueous liquid is a pharmaceutically acceptable oil consisting essentially of one or more medium chain triglycerides (MCTs).

[0233] A pharmaceutically acceptable oil is considered to consist essentially of one or more MCTs if it comprises 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, wherein the content of a particular MCT in the oil is determined by GC according to the method described in Ph. Eur. 2.4.22 without further conversion.

[0234] In even more specific embodiments, the non-aqueous liquid is an oil consisting essentially of C8 and / or C10 medium chain triglycerides, e.g., an oil consisting essentially of C8 and C10 medium chain triglycerides, e.g., consisting of 50% to 80% C8 MCT and 20% to 50% C10 MCT, such as those mentioned below in 58% of C8 MCT and 41% of C10 MCT present in 812. As mentioned above, the content of MCT in the oil was determined by GC according to the method described in European Pharmacopoeia 2.4.22 without further conversion.

[0235] For stability reasons, it is preferred that the MCT used in the composition of the invention is saturated, e.g. at least 80%, e.g. at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5%, e.g. 100% of any MCT used in the composition is saturated. Wherein the MCT content of the oil is measured by GC according to the method described in Ph. Eur. 2.4.22 without further conversion.

[0236] Pharmaceutically acceptable MCT oils are commercially available. Non-limiting examples of commercial MCT oils include 810, 812, 818 (Sasol Deutschland GmbH, Witten, Germany).

[0237] Particularly effective MCT oils can be 812.

[0238] The amount of the liquid carrier for the suspension (v) can be about 1 to about 5 mL per dose, such as about 2 to about 3 mL per dose (e.g., 2.9 mL, 2.8 mL, 2.7 mL, 2.6 mL), such as about 2 to about 2.5 mL per dose (e.g., 2.5 mL, 2.4 mL). In an embodiment, the composition of the dried biodegradable polymer microparticles, such as biodegradable polymer microspheres, and the carrier for the suspension can be separately contained in a double-chamber syringe.

[0239] The liquid carrier for suspension can include any appropriate concentration of biodegradable polymer microparticles, depending on the desired dose and the desired injection volume. In an embodiment, the liquid carrier includes a concentration of 100 mg / mL to 500 mg / mL, such as 100 to 400 mg / mL, such as 200 to 400 mg / mL, such as 230 to 350 mg / mL, 200 to 350 mg / mL, such as 250 to 350 mg / mL of biodegradable polymer microparticles, based on the total volume of the suspension. Preferably, the liquid carrier includes a concentration of 100 mg / mL to 375 mg / mL, such as 125 mg / mL to 375 mg / mL, 250 mg / mL to 375 mg / mL of biodegradable polymer microparticles, based on the total volume of the suspension. The injection volume of the liquid suspension can 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.

[0240] The liquid suspension of the dried biodegradable polymer microparticle composition according to the present invention, or the ready-to-use liquid suspension comprising the biodegradable polymer microparticles according to the present invention can be administered via a needle of appropriate gauge (G), e.g. 16G or smaller (e.g. 18G, 19G, 20G, 21G, 23G, 25G), preferably 20G.

[0241] The pharmaceutical composition according to the invention can be manufactured aseptically or non-aseptically and then terminally sterilized, for example by irradiation (eg by X-ray or gamma irradiation).In an embodiment, the pharmaceutical composition of the invention is sterilized by irradiation.

[0242] The pharmaceutical compositions of the present invention may be manufactured by any known method for manufacturing such compositions.

[0243] Biodegradable polymer microparticles, such as biodegradable polymer microspheres, comprising a somatostatin analog or a pharmaceutically acceptable salt thereof can be manufactured by any process known in the art, for example, by coacervation or phase separation, spray drying, water-in-oil (W / O / W) or water-in-oil-in-water (W / O / W) or solids-in-oil-in-water (S / O / W) or oil-in-water (Oil-in-water O / W) emulsion / suspension methods, followed by solvent extraction or solvent evaporation.

[0244] In an embodiment of the present invention, the biodegradable polymer microparticles are formed of a biodegradable polymer comprising at least 50 w / w % (e.g., at least 85 w / w %, e.g., 100% PLGA as defined herein), and the biodegradable polymer microparticles (e.g., microspheres comprising a somatostatin analogue or a pharmaceutically acceptable salt thereof) are manufactured / obtainable by a method / process comprising the following steps:

[0245] 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; a biodegradable polymer in a concentration of 10 w / w% to 30 w / w%; and a somatostatin analog or a pharmaceutically acceptable salt thereof in a concentration sufficient to obtain a predetermined drug loading (i.e., 10 w / w% to 15 w / w%),

[0246] ii. preparing an aqueous phase comprising 0.1 w / v% to 10 w / v%, for example 0.5 w / v% to 5 w / v%, for example 1 w / v% of a hydrophilic stabilizer (preferably PVA) and 2 w / w% to 5 w / w% of a salting-out agent (preferably sodium chloride),

[0247] iii. continuously mixing the organic phase and the aqueous phase of steps i and ii to form an emulsion in a volume ratio of 1:80 to 1:250,

[0248] iv. removing the organic solvent from the emulsion of step iii by solvent evaporation or solvent extraction,

[0249] v. drying the biodegradable polymer particles obtained in step iv and sieving through a sieve of appropriate size,

[0250] vi. Optionally repeating step v until any residual organic solvent is below a predetermined level, for example, DCM is below a level of 8000 ppm and preferably below a level of 7500 ppm.

[0251] Except for the drug loading, all w / w% and w / v% in the above process are based on the weight or volume of the respective solution.

[0252] 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 pharmaceutically acceptable salt thereof. The organic solvent is a mixture of 2 or more different solvents, preferably 2 different solvents.

[0253] 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).

[0254] Non-limiting examples of organic solvents for dissolving the somatostatin analog or a pharmaceutically acceptable salt thereof can be methyl-2-pyrrolidone, dimethyl sulfoxide (DMSO), dimethylacetamide, ethanol, DMF, isopropanol, ethyl acetate, acetone, methanol, THF, acetonitrile or halogenated hydrocarbons such as methyl chloride, DCM, chloroform or HFIP.

[0255] A preferred organic solvent mixture is a mixture of dichloromethane (DCM) and methanol. DCM and methanol can be mixed in a ratio of 80:20 to 95:5, such as 85:15, 90:10.

[0256] The biodegradable polymer can be dissolved in the organic solvent used to dissolve it at a concentration of 10 w / w%-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%. Wherein all w / w% are based on the weight of the final solution prepared in step i (organic phase) of the above method.

[0257] The somatostatin analog or its pharmaceutically acceptable salt can be dissolved in the organic solvent used to dissolve it, and the concentration of the somatostatin analog or its pharmaceutically acceptable salt is sufficient to achieve a predetermined drug loading amount, i.e., 10-15w / w% (i.e., 11w / w%, 11.5w / w%, 12w / w%, 12.5w / w%, 13w / w%, 13.5w / w%, 14w / w%, 14.5w / w%). As will be appreciated by those skilled in the art, in order to achieve the desired drug loading, it may be necessary to dissolve 10% to 35%, such as 10% to 25%, such as 20% to 25% of the somatostatin analog or its pharmaceutically acceptable salt, for example, for a desired drug loading of 12 w / w%, it may be necessary to dissolve 13 w / w% to 15 w / w%, such as 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% of the somatostatin analog or its pharmaceutically acceptable salt in the relevant organic solvent, wherein all w / w% are based on the weight of the final solution prepared in step i (organic phase) of the above method.

[0258] The term "stabilizer" as used herein refers to an ingredient that can act as an emulsifier and stabilize the emulsion (ie, the emulsion formed when the organic phase and the aqueous phase of steps i and ii in the above process are mixed).

[0259] Non-limiting examples of stabilizers include polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, dextrin, polyethylene glycol, poloxamer, poly(oxyethylene)-sorbitan-fatty acid esters, sorbitan fatty acid, lecithin, and mixtures thereof. In an embodiment, the stabilizer is polyvinyl alcohol (PVA).

[0260] The aqueous phase prepared in step ii of the above method may include a stabilizer 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%, wherein all w / v% are based on the weight of the final solution prepared in step ii (aqueous phase) of the above method.

[0261] As used herein, the term "salting-out agent" refers to a component that attracts water molecules, thereby reducing the number of water molecules that interact with PLGA and / or somatostatin analogs or salts thereof.

[0262] The salting-out agent in step ii of the method can be a salt. Non-limiting examples of suitable salts include sodium chloride (NaCl), potassium chloride (KCl). In an embodiment of the present invention, the salting-out agent in step ii is NaCl.

[0263] The aqueous phase prepared in step ii of the above method may include a salting-out agent at a concentration of 2 w / v% to 5 w / v%, such as 3 w / v% to 4 w / v% (e.g., 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%). Wherein all w / v% are based on the weight of the final solution prepared in step ii (aqueous phase) of the above method.

[0264] In step iii the organic phase and the aqueous phase prepared in steps i and ii of the process described herein are mixed continuously, ie the organic phase and the aqueous phase are simultaneously fed / pumped into a mixing device (eg a rotary mixer) and mixed therein.

[0265] 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 any residual organic solvent is below a predetermined level.

[0266] The predetermined level of any residual solvent may be a level that complies with the International Council for Harmonization of Technical Requirements for Pharmaceuticals or Human Use ICHQ3C guidelines. In the case of DCM, the predetermined level of residual solvent may be 8000 ppm or less. In the case of methanol, the predetermined level of residual solvent may be 40,000 ppm or less, such as 3000 ppm or less, such as 500 ppm or less.

[0267] Sieving is performed using a sieve having a mesh size of the particle size specified above and below. Preferably, the sieve is a 180 μm sieve, although smaller or larger opening sizes may also be used, such as 160 μm or 200 μm or any other value in the range of 150 μm to 200 μm.

[0268] Once the biodegradable polymer (e.g., PLGA) microparticles (e.g., microspheres) are obtained, they can be suspended in a non-aqueous or aqueous liquid carrier. The biodegradable polymer (e.g., PLGA) microparticles (e.g., microspheres) can be suspended in an aqueous or non-aqueous liquid carrier via simple mixing.

[0269] In another aspect of the present invention, a pharmaceutical composition of the present invention for use as a medicament is provided. The medicament can be used for long-term therapy of a disease, such as long-term maintenance therapy.

[0270] In another aspect of the present invention, a pharmaceutical composition of the present invention for preventing and / or treating a disease is provided.

[0271] The pharmaceutical composition of the present invention can be used to prevent and / or treat any disease for which somatostatin analogs or pharmaceutically acceptable salts thereof have a therapeutic effect. Such diseases include, for example:

[0272] I. Autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD),

[0273] II. Gigantism

[0274] III. Cushing's disease,

[0275] IV. Acromegaly (where treatment can reduce, control, normalize and / or maintain blood levels of GH and / or IGF-1 over a long period of time (long-term maintenance therapy), e.g., in patients whose disease is not adequately controlled by surgery or radiation therapy, in patients who are unsuitable or unwilling to undergo surgery or radiation therapy, or in patients who are irradiated until radiation therapy is effective,

[0276] V. TSH-secreting pituitary adenomas (can be benign), for example, patients whose secretion does not return to normal after surgery and / or radiation therapy, patients who are not suitable for or unwilling to undergo surgery or radiation therapy, or patients who receive irradiation until radiation therapy is effective.

[0277] VI. VIPoma, for example, in the context of treating the watery diarrhea (which can be severe) associated with this disease, treatment can be done before or after surgery, or in patients who are unsuitable or unwilling to undergo surgery or radiation therapy, or in patients who are irradiated until radiation therapy is effective,

[0278] VII. Neuroendocrine neoplasms (NEN), e.g., neuroendocrine tumours (NET) (can be advanced), e.g., gastro-entero-pancreatic neuroendocrine tumours GEP-NET, e.g., advanced NET of the midgut or NET of unknown primary, where non-midgut sites of origin have been excluded, treatment can be before or after surgery, or in patients who are not suitable for or are unwilling to undergo surgery or radiation therapy, radioligand therapy or concomitant radiation therapy, radioligand therapy,

[0279] VIII. Carcinoid syndrome associated with neuroendocrine tumors, such as functional gastro-entero-pancreatic endocrine tumors, for example, where treatment can suppress or inhibit the diarrhea (which can be severe) and / or flushing episodes associated with such diseases, treatment may be given pre- or post-operatively, or in patients who are unsuitable for or unwilling to undergo surgery or radiation therapy, radioligand therapy, or concomitant radioligand therapy,

[0280] IX. Prevention of complications after pancreatic surgery

[0281] X. Emergency management of hemostasis and prevention of rebleeding due to gastroesophageal varices in patients with cirrhosis.

[0282] In an embodiment, the pharmaceutical composition of the present invention is used to prevent and / or treat a disease for which a somatostatin analogue or a pharmaceutically acceptable salt thereof has a therapeutic effect, and wherein the disease is preferably selected from the group consisting of autosomal dominant polycystic kidney disease, Cushing's disease, polycystic liver disease, acromegaly, gigantism, TSH-secreting pituitary adenoma, carcinoid syndrome, vasoactive intestinal peptide tumors, neuroendocrine tumors, including neuroendocrine tumors, including gastro-entero-pancreatic neuroendocrine tumors.

[0283] In a more specific embodiment, the disease is selected from the group consisting of acromegaly and gastro-entero-pancreatic neuroendocrine tumors (GEP-NET).

[0284] In another aspect of the present invention, there is provided the use of the pharmaceutical composition of the present invention in the preparation of a medicament for treating the following diseases, preferably diseases for which somatostatin analogs or pharmaceutically acceptable salts thereof have a therapeutic effect, such as acromegaly and gastro-entero-pancreatic neuroendocrine tumors (GEP-NET).

[0285] In another aspect of the present invention, there is provided the use of the pharmaceutical composition of the present invention for use in a method for treating a disease, wherein the method comprises the step of administering the composition of the present invention to a patient in need thereof and preferably a patient with a disease in which a somatostatin analogue or a pharmaceutically acceptable salt thereof has a therapeutic effect, such as acromegaly and gastro-entero-pancreatic neuroendocrine tumor (GEP-NET).

[0286] Of course, this means that the present invention also provides a method of treating any of the medical indications specified herein comprising the step of administering to a patient in need thereof a composition of the present invention.

[0287] The pharmaceutical compositions of the present invention may be administered to a patient parenterally, for example via injection or via surgical implantation.

[0288] In an embodiment, the pharmaceutical composition of the present invention is administered to a patient parenterally. In a more specific embodiment, the composition of the present invention is administered to a patient via intramuscular or subcutaneous injection. Subcutaneous injection can be a deep subcutaneous injection. Preferably, the composition of the present invention is administered to a patient via intramuscular injection.

[0289] Pharmaceutical composition of the present invention can be used frequently as required, for example, depending on the sustained release cycle of the composition. The composition can be used, for example, every month (about every 30 days, for example 28 to 30 days), every 2 months (about every 60 days, for example 56 to 60 days), every 3 months (about 90 days, for example 84 to 90 days) or every 4 months (about 120 days, for example 112 to 120 days) or any time period between these values.

[0290] In an embodiment, the pharmaceutical composition of the present invention is a pharmaceutical composition that provides sustained release of a somatostatin analog or a pharmaceutically acceptable salt thereof over 30 days or more and is administered once a month, for example, about every 30 days, for example, every 20-35 days (e.g., 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days).

[0291] In an embodiment, the pharmaceutical composition of the present invention is a pharmaceutical composition that provides sustained release of a somatostatin analog or a pharmaceutically acceptable salt thereof over 60 days or more and is administered once a month, for example, about every 60 days, for example, every 50-65 days (e.g., 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days).

[0292] In an embodiment, the pharmaceutical composition of the present invention is a sustained release pharmaceutical composition that provides sustained release of a somatostatin analog or a pharmaceutically acceptable salt thereof over 84 days or more (e.g., 84 days) and is administered once every 3 months, e.g., every 84 to 90 days (e.g., every 84 days).

[0293] In a more specific embodiment, the pharmaceutical composition of the present invention is a 3-month sustained-release pharmaceutical composition, which provides sustained release of a somatostatin analog or a pharmaceutically acceptable salt thereof for 84 days or more (e.g., 84 days), and is administered once every 3 months, for example, once every 84 days.

[0294] In another embodiment, the pharmaceutical composition of the present invention is a sustained release pharmaceutical composition that provides sustained release of a somatostatin analog or a pharmaceutically acceptable salt thereof over 90 days or more and is administered once every 3 months, for example, about every 90 days, for example, every 80-95 days (e.g., 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 98 days, 91 days, 92 days, 93 days, 94 days).

[0295] In another embodiment, the pharmaceutical composition of the present invention is a sustained release pharmaceutical composition that provides sustained release of a somatostatin analog or a pharmaceutically acceptable salt thereof over 120 days or more and is administered once every 4 months, for example, about every 120 days, for example, every 110-125 days (e.g., 111 days, 112 days, 113 days, 114 days, 115 days, 116 days, 117 days, 118 days, 119 days, 120 days, 121 days, 122 days, 123 days, 124 days).

[0296] The pharmaceutical compositions of the present invention may be administered at any effective dose.

[0297] The term "effective dose" as used herein refers to a dose that results in sustained release (i.e., releasing an effective amount of a somatostatin analog or a pharmaceutically acceptable salt thereof over a predetermined sustained release period, such as 30 or more days, 60 or more days, 90 or more days, or 120 or more days). It will be appreciated that the exact dose will depend on many factors, including the specific somatostatin analog in question, the condition to be treated, the predetermined sustained release period (e.g., 30 or more days, 60 or more days, 90 or more days, or 120 or more days). The effective dose may also depend on specific patient characteristics and / or their response to treatment. Determining an effective dose (e.g., balancing efficacy and side effects / adverse reactions) is well within the purview of the technician.

[0298] If the somatostatin analogue is octreotide or a pharmaceutically acceptable salt thereof, a particularly effective dose of the pharmaceutical composition of the present invention may be a dose corresponding to a dose of 10 mg to 240 mg, e.g. 10 mg to 180 mg, e.g. 20 mg to 180 mg, 25 mg to 120 mg, 30 mg to 120 mg, 25 mg to 90 mg, or 30 mg to 90 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 or 90 mg) of octreotide, or an equivalent dose of a pharmaceutically acceptable salt of octreotide.

[0299] These doses may be particularly effective in treating patients with acromegaly and / or GEP-NET.

[0300] Since the compositions of the present invention can release the somatostatin analog or its pharmaceutically acceptable salt over 30 days or more, as described in more detail above and below, a single administration of the compositions of the present invention can be sufficient to achieve therapeutically effective plasma levels over such a long period of time. This in turn means that each dosage indication provided herein is also an indication of a suitable unit dose, which unit dose can, for example, be contained in a prefilled syringe.

[0301] For a pharmaceutically acceptable salt of a somatostatin analog, e.g., octreotide acetate, an equivalent dose is calculated based on the weight of the pharmaceutically 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 dose specified herein. That is, the equivalency of doses of the free base drug and its salt is determined on the basis of the same molar amounts.

[0302] In an embodiment of the invention, the pharmaceutical composition of the invention provides sustained release of the somatostatin analog octreotide over 30 days or more, and is administered approximately every 30 days (e.g., 1 month) at a dose corresponding to a dose of 10 to 180 mg, e.g., 25 mg to 120 mg, 25 mg to 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 a pharmaceutically acceptable salt thereof in an equivalent dose. A particularly effective dose may be a dose of 25 mg to 105 mg or a pharmaceutically acceptable salt thereof in an equivalent dose. Preferably, the administration is used to treat acromegaly and / or GEP-NET in a patient.

[0303] In an embodiment of the invention, the pharmaceutical composition of the invention provides sustained release of the somatostatin analog octreotide over 60 days or more, and is administered approximately every 60 days (e.g., 2 months) at a dose corresponding to a dose of 10 to 180 mg, e.g., 25 mg to 120 mg, 25 mg to 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 105 mg) of octreotide or a pharmaceutically acceptable salt thereof in an equivalent dose. A particularly effective dose may be a dose of 25 mg to 105 mg or a pharmaceutically acceptable salt thereof in an equivalent dose. Preferably, the administration is used to treat acromegaly and / or GEP-NET in a patient.

[0304] In an embodiment of the invention, the pharmaceutical composition of the invention provides a sustained release of the somatostatin analog octreotide or a pharmaceutically acceptable salt thereof for 84 days or more, and is administered once every 84 days (i.e., about 3 months) at a dose corresponding to a dose of 10 to 180 mg, for example 25 mg to 120 mg, 25 mg to 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 a pharmaceutically acceptable salt thereof in an equivalent dose. In this embodiment, a particularly effective dose may be a dose of 25 mg to 105 mg (e.g., 60 mg, 90 mg or 120 mg) or a pharmaceutically acceptable salt thereof in an equivalent dose. Preferably, according to this embodiment, administration is used to treat acromegaly and / or GEP-NET in a patient.

[0305] In another embodiment of the invention, the pharmaceutical composition of the invention provides sustained release of the somatostatin analog octreotide over 90 days or more and is administered approximately every 90 days (e.g., 3 months) at a dose corresponding to a dose of 10 to 180 mg, e.g., 25 mg to 120 mg, 25 mg to 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 or 105 mg) of octreotide or a pharmaceutically acceptable salt thereof in an equivalent dose. A particularly effective dose may be a dose of 25 mg to 105 mg or a pharmaceutically acceptable salt thereof in an equivalent dose. Preferably, the administration is used to treat acromegaly and / or GEP-NET in a patient.

[0306] In another embodiment of the invention, the pharmaceutical composition of the invention provides sustained release of the somatostatin analog octreotide over 120 days or more and is administered approximately every 120 days (e.g., 4 months) at a dose corresponding to a dose of 10 to 180 mg, e.g., 25 mg to 120 mg, 25 mg to 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 or 105 mg) of octreotide or a pharmaceutically acceptable salt thereof in an equivalent dose. A particularly effective dose may be a dose of 25 mg to 105 mg or a pharmaceutically acceptable salt thereof in an equivalent dose. Preferably, the administration is used to treat acromegaly and / or GEP-NET in a patient.

[0307] Administration of the pharmaceutical composition of the present invention (particularly wherein the somatostatin analog included in the biodegradable polymer microparticles is octreotide or a pharmaceutically acceptable salt thereof) can result in suppression / reduction of serum growth hormone (GH) levels and / or serum insulin-like growth factor (IGF1) levels in patients (e.g., patients with acromegaly).

[0308] Said suppression / reduction of serum GH levels may result in a GH serum level of 3 μg / L or less, such as 2.5 μg / L or less, such as 2 μg / L or less, such as 1.5 μg / L or less, such as less than 1 μg / L or less.

[0309] Serum growth hormone (GH) levels can be determined using the IDS-iSYS multidisciplinary automated system. The analysis is based on chemiluminescence technology. The sample is incubated with a biotinylated monoclonal anti-GH antibody and streptavidin-labeled magnetic particles. The magnetic particles are "captured" using a magnet and a washing step is performed. An acridine-labeled anti-GH monoclonal antibody is added and a second washing step is performed after a further incubation step. After the addition of the triggering reagent, the light emitted by the acridine label is proportional to the concentration of GH in the original sample.

[0310] Serum IGF1 levels can be reduced by up to 50% from baseline (the patient's IGF1 level before administration of the pharmaceutical composition of the invention), for example up to 40%, up to 30%, up to 20%. IGF1 levels can be measured using a validated IDS-iSYS method or a validated LC-MS / MS method, such as the method set forth in Example 10B herein.

[0311] The reduction of IGF1 and / or GH serum levels can be within the predetermined release period or substantially beyond the release period, such as outside the predetermined release period, such as 84 days or more, such as 90 days or more, minus the lag period. For example, the lag period can be 7 days or less.

[0312] When administered at corresponding doses (e.g., 3x30 mg Sandostatin LAR per month), administration of the composition of the present invention can result in a suppression / reduction of GH and / or IGF1 (e.g., within 84 days) comparable to that of currently marketed sustained release formulations (e.g., )The effects after application are comparable.

[0313] As mentioned above, compared with the sustained-release preparations currently on the market (e.g. ), the bioavailability of the somatostatin analogs (e.g., octreotide) included in the compositions of the present invention can be surprisingly high. This can reduce the dosage of the somatostatin analogs while achieving the same efficacy as other formulations (e.g., ) has the same effect as higher doses (which can be given in multiple injections).

[0314] In the composition of the present invention, the bioavailability of the somatostatin analog (e.g., octreotide) can be compared to that of The bioavailability of other formulations is higher, for example, 20%, 50%, 60%, 70%, 80%, 90%, 100% or more (e.g., 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3 or more times) and thus a lower dose of somatostatin analog (e.g., octreotide) can be administered to treat the disease.

[0315] In another aspect of the present invention, a kit is provided, the kit comprising:

[0316] i. the pharmaceutical composition of the present invention,

[0317] ii. optionally a liquid carrier for suspension, and

[0318] iii. A vial or optionally a syringe prefilled with the pharmaceutical composition of item (i).

[0319] The pharmaceutical composition of the invention of item i, whether in the form of dry biodegradable microparticles or in the form of a suspension in a liquid carrier, can be included in the vial or prefilled syringe of item iii without the liquid carrier used for the suspension of item ii. The liquid carrier of item ii can be provided in a separate compartment of the vial or syringe together with the pharmaceutical composition of the invention of item i, which is in the form of dry biodegradable microparticles and is also provided in a separate compartment of the vial or syringe. The pharmaceutical composition of the invention of item i (e.g., a composition of dry biodegradable polymer microparticles) can be suspended in the suspension of item ii, e.g., a water (aqueous) carrier containing a pharmaceutical excipient, by simple mixing before injection into a patient.

[0320] Alternatively, the pharmaceutical composition of the present invention, for example, the composition of dried biodegradable polymer microparticles according to item i, may be separated from the suspension according to item ii in a dual chamber pre-filled syringe.

[0321] In another alternative, the pharmaceutical composition can be a liquid suspension comprising biodegradable polymer microparticles ready for injection, for example, a suspension comprising biodegradable polymer microparticles in a non-aqueous carrier (e.g., MCT oil). The liquid suspension can be provided in a vial or a pre-filled syringe.

[0322] Unless explicitly stated otherwise, any embodiment disclosed herein may be combined with any other embodiment disclosed herein.

[0323] As used in the present disclosure and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Thus, for example, reference to "a material" or "the material" includes two or more materials. The words "comprise", "comprises" and "comprising" should be interpreted as inclusive, not exclusive. Similarly, the terms "include", "including" and "or" should all be interpreted as inclusive, unless the context clearly prohibits such an interpretation. However, the compositions disclosed herein may lack any element that is not specifically disclosed. Therefore, the disclosure of embodiments using the term "comprising" includes the disclosure of embodiments consisting of the components identified by "consisting mainly of" and "consisting of". Similarly, the methods disclosed herein may lack any steps that are not specifically disclosed herein. Therefore, the disclosure of embodiments using the term "comprising" includes the disclosure of embodiments consisting of the components identified by "consisting mainly of" and "consisting of".

[0324] The term "and / or" used in the context of "X and / or Y" should be interpreted as "X" or "Y" or "X and Y." The terms "example" and "such as" as used herein, especially when followed by a list of terms, are exemplary and illustrative only and should not be considered exclusive or comprehensive.

[0325] Unless otherwise indicated, all percentages and ppm values ​​expressed herein are expressed by weight based on the total weight of the composition.

[0326] As used herein, it is understood that "about" and "approximately" refer to numbers in a range of numbers, such as a range of -10% to +10% of a reference number, preferably in a range of -5% to +5% of a reference number, more preferably in a range of -1% to +1% of a reference number, and most preferably in a range of -0.1% to +0.1% of a reference number. All numerical ranges herein are understood to include all integers within the range, including integers or fractions. In addition, these numerical ranges should be interpreted as supporting claims for any number or subset within the range. For example, the disclosure of 1 to 10 should be interpreted as supporting ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0327] Although the present invention has been illustrated and described with reference to illustrative embodiments and practice modes, it will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the scope and spirit of the present invention. Therefore, the present invention is not limited to the illustrative embodiments and practice modes.

[0328] The following is a series of non-limiting examples used to illustrate the present invention.

[0329] Example

[0330] Example 1 Preparation of microspheres

[0331] The microspheres listed in Table I (compositions A, B, C, and D) were prepared using the following method.

[0332] 1. An appropriate amount of dichloromethane and methanol were mixed in a glass container to obtain a solution with an appropriate concentration of methanol as described in Table I ("Methanol Concentration" column). An appropriate amount of PLGA polymer was then dissolved in the solution to obtain a polymer concentration as described in Table I ("PLGA Concentration" column). Then, an appropriate amount of octreotide acetate was weighed and added to the solution under magnetic stirring (the amount of octreotide acetate added was equivalent to the theoretical drug loading of the microspheres formed later, as described in Table I ("Theoretical Drug Loading" column)). The resulting solution is referred to as the "organic solution".

[0333] 2. Dissolve an appropriate amount of PVA 4-88 in an appropriate amount of deionized water to form a 1% PVA 4-88 solution. Then, dissolve an appropriate amount of NaCl in the 1% PVA 4-88 solution to obtain a solution having a NaCl concentration as described in Table I ("NaCl concentration" column). The resulting solution is referred to as an "aqueous solution".

[0334] 3. The organic solution was mixed with the aqueous solution by pumping the organic solution into the rotor-stator apparatus at a rate of 5 mL / min using a hose pump and the aqueous solution was pumped into the same rotor-stator apparatus 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 resulting microsphere suspension of the O / W emulsion was collected in a glass beaker.

[0335] 4. Collect the microspheres by filtration (5um) and then wash several times with an appropriate amount of 10% methanol aqueous solution (to remove octreotide acetate and / or PVA on their surface). Then, dry the microspheres under vacuum at 30°C overnight (16h). The dried microspheres are passed through a 180um sieve and added to a glass vial under nitrogen. The microspheres are then sterilized by X-ray irradiation at a dose of 25kGy.

[0336] 5. Drug loading was quantified via liquid chromatography (quantitative). The drug loading is shown in Table I in the column entitled "Actual Drug Loading".

[0337] Example 2 In vitro characteristics of the outbreak

[0338] For each composition listed in Table I (A, B, C and D), the percentage dissolution after 5 h was determined in 900 mL of pH 4 acetate buffer at 37° C. using a USP2 paddle apparatus. After introduction of a composition amount of the dissolution medium equivalent to 30, 60 or 90 mg of the drug substance, paddle rotation was started at a speed of 75 rpm. After 5 h, the dissolution medium was sampled, filtered and the dissolved drug in the filtrate was quantified using an appropriate HPLC method. The results are shown in Table I.

[0339] Example 3 Determination of specific surface area and particle size

[0340] The specific surface areas of microspheres of compositions A, B, C and D were determined by measuring the adsorption isotherms of nitrogen at 77 K on more than 0.3 g of appropriately degassed samples and then applying the Bruno, Emmett and Taylor models over the 0.05 to 0.2 relative pressure range of the isotherms, which includes at least 7 data points.

[0341] The specific surface area (SSA) was measured by nitrogen adsorption multi-point BET surface area (using Micromeritics TriStar II 3020 volumetric method). About 350 mg of each sample was added to the sample tube and then placed under vacuum at 20°C for 1 hour. After adjustment, the net mass of each sample was re-recorded and analyzed using these values. During the analysis, the sample tube was surrounded by an isothermal jacket and equipped with a filling rod. The BET surface area was measured using the following parameters:

[0342] Adsorption analysis: N2

[0343] Analysis bath temperature: 77.300K

[0344] Warm free space: Measured Cold free space: Measured Equilibrium interval: 5s

[0345] Low pressure dose: None

[0346] Automatic degassing: No

[0347] Relative pressure tolerance: 5%

[0348] Minimum equilibration delay when P / PO>0.995: 600 seconds

[0349] Recorded P / P0 range: 0.05-0.99 (0.012 intervals 88 points)

[0350] The specific surface area results are shown in Table 1.

[0351] The particle size distribution was determined using a Malvern Particle Sizer 3000 wet laser diffractometer. Each sample was resuspended in an aqueous solution of sodium carboxymethylcellulose (1.5% w / w) and polysorbate 80 (0.1%) and then diluted / dispersed in purified water in a hydrodynamic MV dispersion unit (stirring at 2000 rpm) until a stable laser obscuration of 10% to 20% was achieved. The samples were then sonicated for 3 min (MV dispersion unit setting medium (50%)), and the volume-weighted particle size distribution was calculated using the following parameters by Mie theory: the refractive index of the dispersant was 1.33; the refractive index of the real particles was 1.52; the refractive index of the virtual particles was 0.001.

[0352]

[0353] Example 4 In vivo pharmacokinetic characteristics of composition D (in rats)

[0354] The microspheres of composition D were suspended in a physiologically acceptable lipophilic carrier to obtain a drug suspension concentration of 4.8 mg / mL. The resulting suspension was subcutaneously injected into 6 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 prescribed time period, plasma samples were collected and analyzed for octreotide concentration. The results are shown in Table II and Figure 1 Shown in.

[0355]

[0356] Table II

[0357] Example 5: In vivo pharmacokinetic characteristics of composition A (in rats)

[0358] The microspheres of composition A were suspended in a physiologically acceptable lipophilic carrier to obtain a drug suspension concentration of 4.8 mg / mL. The resulting suspension was subcutaneously injected into 6 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 time periods, plasma samples were collected and analyzed for octreotide concentrations. The results are shown in Tables III and Figure 2 Shown in.

[0359]

[0360] Table III

[0361] Example 6a: Sustained release composition for injection (single dose)

[0362] Composition D microspheres (corresponding to an amount of 30 mg of octreotide) were aseptically filled into a two-chamber syringe (TCS), which consisted of a compartment containing microparticles and a compartment containing 2.4 mL of an aqueous vehicle for suspending microparticles. The aqueous vehicle was an aqueous solution of 4.25% mannitol, 0.1% Tween and 1.5% sodium carboxymethylcellulose.

[0363] The microparticles and aqueous vehicle are mixed prior to injection.

[0364] The composition can provide a 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 can be 1 month, 2 months, 3 months or 4 months, depending on the characteristics of the patient and their response to treatment.

[0365] Example 6b: Sustained release composition for injection (single dose)

[0366] Composition D microspheres (amount corresponding to 30 mg of octreotide) were aseptically filled into a two-chamber syringe (TCS) consisting of one compartment containing microparticles and one compartment containing 2.4 mL of an aqueous vehicle for suspending microparticles. The non-aqueous vehicle was MCT oil ( 812).

[0367] The microparticles and non-aqueous vehicle are mixed prior to injection.

[0368] The composition can provide a 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 can be 1 month, 2 months, 3 months or 4 months, depending on the characteristics of the patient and their response to treatment.

[0369] Example 7a: Sustained release composition for injection (single dose)

[0370] Composition D microspheres (corresponding to an amount of 60 mg of octreotide) were aseptically filled into a two-chamber syringe (TCS) consisting of a compartment containing microparticles and a compartment containing 2.4 mL of an aqueous vehicle for suspending the microparticles. The aqueous vehicle was an aqueous solution of 4.25% mannitol, 0.1% Tween and 1.5% sodium carboxymethylcellulose.

[0371] The microparticles and aqueous vehicle are mixed prior to injection.

[0372] The composition can provide a 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 can be 1 month, 2 months, 3 months or 4 months, depending on the characteristics of the patient and their response to treatment.

[0373] Example 7b: Sustained release composition for injection (single dose)

[0374] Composition D microspheres (amount corresponding to 60 mg of octreotide) were aseptically filled into a two-chamber syringe (TCS) consisting of one compartment containing microparticles and one compartment containing 2.4 mL of an aqueous vehicle for suspending microparticles. The non-aqueous vehicle was MCT oil ( 812).

[0375] The microparticles and non-aqueous vehicle are mixed prior to injection.

[0376] The composition can provide a 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 can be 1 month, 2 months, 3 months or 4 months, depending on the characteristics of the patient and their response to treatment.

[0377] Example 8a: Sustained release composition for injection (single dose)

[0378] Composition D microspheres (corresponding to an amount of 90 mg of octreotide) were aseptically filled into a two-chamber syringe (TCS) consisting of a compartment containing microparticles and a compartment containing 2.4 mL of an aqueous vehicle for suspending the microparticles. The aqueous vehicle was an aqueous solution of 4.25% mannitol, 0.1% Tween and 1.5% sodium carboxymethylcellulose.

[0379] The microparticles and aqueous vehicle are mixed prior to injection.

[0380] The composition can provide a 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 can be 1 month, 2 months, 3 months or 4 months, depending on the characteristics of the patient and their response to treatment.

[0381] Example 8b: Sustained release composition for injection (single dose)

[0382] Composition D microspheres (amount corresponding to 90 mg of octreotide) were aseptically filled into a two-chamber syringe (TCS) consisting of one compartment containing microparticles and one compartment containing 2.4 mL of an aqueous vehicle for suspending microparticles. The non-aqueous vehicle was MCT oil ( 812).

[0383] The microparticles and non-aqueous vehicle are mixed prior to injection.

[0384] The composition can provide a 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 can be 1 month, 2 months, 3 months or 4 months, depending on the characteristics of the patient and their response to treatment.

[0385] Example 9: Effect of administration route and carrier

[0386] The composition D microspheres were suspended in a physiologically acceptable aqueous or non-aqueous carrier to obtain a drug suspension concentration of 4.8 mg / mL. The resulting suspension was injected subcutaneously or intramuscularly into 6 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 prescribed time period, plasma samples were collected and analyzed for octreotide concentrations within 28 days. The results are shown in Table 1. Figure 3 As shown, no significant differences were observed.

[0387] Example 10A: Bioavailability

[0388] A) Sandostatin immediate release (Sandostatin IR) was administered to 15 healthy subjects via subcutaneous injection at a dose equivalent to 0.2 mg octreotide. After administration, the plasma concentration of octreotide was determined during the study. The AUC for each subject was calculated. 最后 (up to approximately 24 hours) and normalized by dose.

[0389] Subsequently (at least one week later), the same 15 subjects were administered an intramuscular injection of MCT oil equivalent to 30 mg of octreotide ( 812) suspension of composition D microspheres. After administration, the plasma concentration of octreotide was determined during the study period. The AUC for each subject was calculated 最后 (up to 84 to 112 days) and were normalized by dose.

[0390] Then, the two AUCs normalized by dose value were 最后 An internal comparison was performed. The objective was to determine the relative bioavailability of Composition D microspheres compared to Sandostatin IR within the same subject.

[0391] For each subject, the following ratios were determined:

[0392]

[0393] Among them, the composition D microparticle AUC 最后The area under the curve corresponding to the period from day 0, the first administration of microparticles of composition D, to the last day of quantifiable (quantitative) plasma octreotide concentration, where Sandostatin IR AUC 最后 The area under the curve corresponds to the time from the administration of Sandostatin IR to the last quantifiable plasma octreotide concentration (which corresponds to the dose approximately 24 h later).

[0394] The average of the determined ratios is then calculated.

[0395] B) A control arm of 15 healthy subjects received a dose of Sandostatin IR equivalent to 0.2 mg octreotide via subcutaneous injection. After administration, plasma concentrations of octreotide were determined during the study. The AUC for each subject was calculated. 最后 (up to approximately 24 hours) and normalized by dose.

[0396] Subsequently (at least 1 week later), the same 15 control subjects were given 30 mg of long-acting Sandostatin (Sandostatin) via intramuscular injection. ), repeated every 4 weeks for 12 weeks (3×30 mg doses, cumulative dose of 90 mg during the study). Plasma octreotide concentrations were used to calculate the AUC for each subject during the study (up to 21 days for one subject who withdrew consent or up to 70 to 84 days). 最后 , and were normalized according to the cumulative dose of Sandostatin LAR administered during the study, ie, divided by 30 mg or 90 mg.

[0397] 2 AUCs normalized by dose value 最后 A separate internal comparison was then performed in control subjects. The objective was to determine the relative bioavailability of Sandostatin LAR compared to Sandostatin IR in the same subjects.

[0398] Using the data generated from the above studies, the relative bioavailability of Composition D microparticles can be compared to the relative bioavailability of Sandostatin LAR:

[0399] For each subject, the following ratios were determined:

[0400]

[0401] Among them, Sandostatin LAR AUC 最后 corresponds to the area under the curve from day 0 of the first administration of Sandostatin LAR to the last day of quantifiable plasma octreotide concentrations, and where Sandostatin IR AUC 最后 The area under the curve corresponds to the period from the administration of Sandostatin IR to the last quantifiable plasma octreotide concentration measured (which corresponds to the dose approximately 24 h later).

[0402] The average of the determined ratios is then calculated.

[0403] The average ratio calculated in A) above is then compared to the average calculated in B) above.

[0404] The results are shown in Table IV and indicate that the bioavailability of the microparticles of Composition D is approximately twice that of Sandostatin LAR in humans.

[0405]

[0406] Table IV

[0407] All treatments were well tolerated, and there were no significant differences in the pattern or severity of adverse events.

[0408] Example 10B: Changes in Bioavailability and Serum IGF1

[0409] A) The IGF1 levels of 7 healthy volunteers were determined. After the IGF1 measurement, Sandostatin immediate release (Sandostatin IR) equivalent to 0.2 mg of octreotide was administered to the same 7 healthy subjects via subcutaneous injection.

[0410] I. Determine the plasma concentration of octreotide during the study and calculate the AUC of octreotide plasma concentration for each subject 最后 (up to approximately 24 h) and were normalized by dose.

[0411] After the above procedure (at least 1 week later), an aqueous suspension of Composition D microspheres equivalent to 90 mg of octreotide was administered to the same 7 subjects via intramuscular injection.

[0412] II. Serum IGF1 concentrations were determined multiple times during the study and the percentage change in serum IGF was recorded.

[0413] III. Determine the plasma concentration of octreotide during the study period (3 months (84 days)) and calculate the AUC of octreotide plasma concentration for each subject 84d , and normalized by dose.

[0414] I and III AUC normalized to dose values ​​were compared internally, respectively. The objective was to determine the relative bioavailability of Composition D microspheres compared to Sandostatin IR within the same subject.

[0415] For each subject, the following ratios were determined:

[0416]

[0417] Among them, the composition D microparticle AUC 84dcorresponds to the area under the curve from day 0 when the first administration of the microparticles of composition D was performed to day 84 when the concentration could be measured, and wherein Sandostatin IR AUC 最后 The area under the curve corresponds to the period from administration of Sandostatin IR to the last quantifiable concentration (which corresponds to the dose after approximately 24 h).

[0418] The average of the determined ratios is then calculated.

[0419] B) IGF1 levels were measured in 14* healthy volunteer subjects (control group). After IGF1 measurement, a dose of Sandostatin IR equivalent to 0.2 mg octreotide was administered to the same 14* healthy subjects via subcutaneous injection.

[0420] IV. Determine the plasma concentration of octreotide during the study and calculate the AUC for each subject 最后 (up to approximately 24 h) and were normalized by dose.

[0421] Subsequently (at least 1 week later), the same 14 control subjects were given 30 mg of long-acting Sandostatin (Sandostatin) via intramuscular injection. ), repeated every 4 weeks for 12 weeks (3×30 mg dose, cumulative dose of 90 mg during the 84-day study period).

[0422] V. Determine serum IGF1 concentrations multiple times during the study and record the % change in serum IGF

[0423] VI. Determine the plasma concentration of octreotide during the study period and calculate the AUC of octreotide plasma concentration for each subject during the study period 84d , and normalized by the cumulative dose of 90 mg of Sandostatin LAR administered during the 84-day study period.

[0424] Dose-normalized IV and VI AUCs were then compared within the control subjects. The objective was to determine the relative bioavailability of Sandostatin LAR compared to Sandostatin IR in the same subjects.

[0425] For each subject, the following ratios were determined:

[0426]

[0427] Among them, Sandostatin LAR AUC 84d corresponds to the area under the curve from day 0 to day 84 from the first administration of Sandostatin LAR, and wherein Sandostatin IR AUC 最后 The area under the curve corresponds to the period from administration of Sandostatin IR to the last quantifiable concentration (which corresponds to the dose after approximately 24 h).

[0428] The average of the determined ratios is then calculated.

[0429] Using the data generated from the above studies, the relative bioavailability of Composition D microparticles can be compared to the relative bioavailability of Sandostatin LAR: the average ratio calculated in A) above is compared to the average ratio calculated in B) above.

[0430] Mean plasma octreotide levels Figure 4 The average bioavailability results are shown in Table V and show that the bioavailability of Composition D microparticles is approximately twice the bioavailability of Sandostatin LAR in humans.

[0431]

[0432] Table V

[0433] *Excluding subjects who withdrew consent before the second administration of Sandostatin LAR

[0434] The safety profile of Composition D microparticles (90 mg octreotide) was consistent with that of Sandostatin LAR, and there were no new safety signals.

[0435] The average results for IGF1 are shown in Figure 5 It can be seen that administration of Composition D microparticles equivalent to a single 90 mg octreotide dose resulted in a suppression of IGF1 over 84 days that was comparable to that of 3x30 mg Sandostatin LAR per month.

[0436] 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 determination of IGF-1 in human serum samples. Samples (using a sample volume of 100 μL serum) were processed by protein precipitation followed by phospholipid removal using Waters Ostro plates (more information on sample processing is given in Table VI). Separation between metabolites and interfering endogenous compounds was achieved by UHPLC using Waters XSelect CSH C18 (100×2.1 mm, 2.5 μm) at 40°C with 0.1% formic acid in water as mobile phase A and acetonitrile:DMSO (90:10, v / v) as mobile phase B, running at an initial flow rate gradient of 0.4 mL / min (more information on timing, flow rate and gradient is given in Table VII).

[0437] Detection was performed in positive ion mode using a triple quadruple 6500 mass spectrometer equipped with a turbo ion spray source.

[0438] Quantification is based on multiple reaction monitoring (MRM) of the following transitions:

[0439] m / z 1093.6–1196.8 for IGF-1

[0440] m / z 1106.9–1211.3 for IGF-1N15

[0441] In the range of 2.00 to 1000 ng / mL of IGF-1 in human serum, a weighting factor of 1 / x was used. 2 A linear calibration curve was obtained for . Other general method descriptions are provided in Table VIII

[0442]

[0443] Table VI

[0444]

[0445] Table VII

[0446] 3.0 General Instructions

[0447] - Refer to the appropriate PRA standard operating procedures for handling deviations from these assay instructions.

[0448] -Insulin-like growth factor 1 (IGF-1) is a hormone with a molecular structure similar to insulin, which plays an important role in the growth of children and has anabolic effects in adults. IGF-1 is composed of 70 amino acids in a single chain with three intramolecular disulfide bridges. The molecular weight of IGF-1 is 7649Da.

[0449] - Depending on age, sex and disease state, IGF-I levels in serum can range between 15 ng / ml and 765 ng / ml. Before preparing a validation pool, sera must be screened and the lowest level sera used.

[0450] - Minimum screening sera were used to prepare QC B, QC C and QC D.

[0451] -Since IGF-1 is an endogenous compound, rabbit plasma was used as a surrogate matrix for the preparation of calibration curves and minimum validation levels -For the determination or detection of IGF-1 and its internal standard, the mass spectrometer was used in high mass mode.

[0452] - For determination or detection of IGF-1 and its internal standard, 7-fold charged ions [M+7] were used.

[0453] -DMSO in the mobile phase enhances the formation of charged ions 7-fold. If tuning is necessary, add the correct mobile phase to optimize all parameters.

[0454] The chromatographic behavior of IGF-1 on analytical columns is very sensitive to small changes in mobile phase composition and column batches. A small change in mobile phase composition (1%) can cause a retention shift of 0.5 to 1 minute. As a result, the switching time of the switch valve is prolonged.

[0455] Table VIII

Claims

1. A pharmaceutical composition comprising biodegradable polymer particles containing a somatostatin analog or a pharmaceutically acceptable salt thereof, wherein: The biodegradable polymer includes PLGA having the following: a molar ratio of lactide to glycolide of 80:20 to 90:10, and · Intrinsic viscosity of 0.2 to 0.4 dl / g measured at a concentration of 0.5 w / w% in chloroform at 25°C, And wherein the biodegradable polymer particles have: 10w / w% to 15w / w% drug loading, · Dv50 from 30μm to 90μm, and · Measured by gas adsorption, less than 0.50m 2 / g and preferably less than 0.40m 2 / g specific surface area, And wherein, preferably, the pharmaceutical composition provides sustained release of the somatostatin analog or a pharmaceutically acceptable salt thereof within 30 days or more and more preferably within 30 to 200 days, or within 60 days or more and preferably within 60 to 200 days, or within 90 days or more and preferably within 90 to 200 days.

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

3. A pharmaceutical composition according to any one of the preceding claims, wherein A PLGA as defined in any one of the preceding claims comprising less than 0.5 w / w % residual lactide and / or glycolide monomers.

4. A pharmaceutical composition according to any one of the preceding claims, wherein The biodegradable polymer microparticles as defined in any one of the preceding claims have a drug loading of 11 to 14 w / w % and preferably 11.5 to 12.5 w / w %.

5. A pharmaceutical composition according to any one of the preceding claims, wherein The biodegradable polymer microparticles as defined in any one of the preceding claims are biodegradable polymer microspheres.

6. A pharmaceutical composition according to any one of the preceding claims, wherein The biodegradable polymer microparticles as defined in any one of the preceding claims have: · Dv50 of 50 μm to 80 μm, preferably 60 μm to 75 μm, and / or ·Measured by gas adsorption, 0.05 to 0.3 m 2 / g specific surface area.

7. A pharmaceutical composition according to any one of the preceding claims, wherein The somatostatin analogue is octreotide or a pharmaceutically acceptable salt thereof, and preferably wherein, The somatostatin analog is a pharmaceutically acceptable salt of octreotide selected from the group consisting of octreotide acetate and octreotide pamoate.

8. A pharmaceutical composition according to any one of the preceding claims, wherein The biodegradable polymer as defined in any one of the preceding claims comprises at least 50 w / w %, preferably at least 85 w / w % and more preferably 100 w / w % of PLGA as defined in any one of the preceding claims.

9. A pharmaceutical composition according to any one of the preceding claims, wherein The biodegradable polymer microparticles as defined in any one of the preceding claims constitute at least 50 w / w %, preferably at least 75 w / w % and more preferably at least 80 w / w % of the total number of all biodegradable polymer microparticles comprised in the pharmaceutical composition.

10. A pharmaceutical composition according to any one of the preceding claims, wherein The composition is characterized by a release of the somatostatin analogue that meets the following criteria: the release of the somatostatin analogue included therein is less than 7% within 5 hours, wherein the release is measured in vitro (at 37°C in 900 mL of pH 4 100 mm acetate buffer) according to the method described in European Pharmacopoeia 10, 2.9.3, wherein the composition is tested in an amount equivalent to 30 mg of the somatostatin analogue, and wherein the somatostatin analogue is preferably octreotide, Wherein, the composition is characterized in that the release of the somatostatin analogue meets the following test criteria: the release of the somatostatin analogue included therein is less than 3% within 5 hours, wherein the release is measured in vitro (at 37°C, in 900mL of pH4 100mm acetate buffer) according to the method described in European Pharmacopoeia 10, 2.9.3, wherein the composition is tested in an amount equivalent to 30mg of the somatostatin analogue, and wherein the somatostatin analogue is preferably octreotide.

11. A pharmaceutical composition according to any one of the preceding claims, wherein The pharmaceutical composition is a composition comprising a liquid suspension of biodegradable polymer microparticles or dried biodegradable polymer microparticles. Wherein, the pharmaceutical composition is preferably a liquid suspension comprising biodegradable polymer microparticles, and wherein the biodegradable polymer microparticles are suspended in an aqueous carrier or a non-aqueous carrier, and preferably wherein the non-aqueous liquid carrier is a pharmaceutically acceptable oil substantially consisting of one or more medium chain triglycerides, wherein the liquid more preferably comprises microparticles at a concentration of 100 mg / mL to 500 mg / mL, particularly preferably 100 mg / mL to 375 mg / mL and most preferably 125 mg / mL to 375 mg / mL.

12. A pharmaceutical composition according to any one of the preceding claims, wherein The pharmaceutical composition is sterilized by irradiation.

13. The pharmaceutical composition according to any one of the preceding claims for use as a medicament.

14. The pharmaceutical composition according to any one of claims 1 to 12, for use in treating a disease, wherein: Somatostatin analogs or pharmaceutically acceptable salts thereof have therapeutic effects, and wherein the disease is preferably selected from the group consisting of autosomal dominant polycystic kidney disease, Cushing's disease, polycystic liver disease, acromegaly, gigantism, TSH-secreting pituitary adenoma, carcinoid syndrome, vasoactive intestinal peptide tumors and neuroendocrine neoplasms, the neuroendocrine neoplasms include neuroendocrine tumors, the neuroendocrine tumors include gastro-entero-pancreatic neuroendocrine tumors, and the disease is preferably selected from acromegaly and gastro-entero-pancreatic neuroendocrine tumors.

15. The pharmaceutical composition according to any one of claims 1 to 12 for use according to claim 13 or 14, wherein The composition provides sustained release of the somatostatin analogue over 60 days or more and is administered once every about 60 days at a dose corresponding to a dose of 25 mg to 105 mg of octreotide, or an equivalent dose of a pharmaceutically acceptable salt of octreotide, or wherein, The composition provides sustained release of the somatostatin analog over 90 days or more and is administered once every about 90 days at a dose corresponding to a dose of 25 mg to 105 mg of octreotide, or an equivalent dose of a pharmaceutically acceptable salt of octreotide.

16. The pharmaceutical composition according to claim 15 for use according to claim 13 or 14, wherein The composition provides sustained release of octreotide or a pharmaceutically acceptable salt thereof for 84 days or more and is administered once every 84 days at a dose corresponding to 60 mg, 90 mg or 120 mg of octreotide, or an equivalent dose of a pharmaceutically acceptable salt of octreotide.

17. The pharmaceutical composition for use according to any one of claims 13 to 16, wherein The pharmaceutical composition will be administered to the patient parenterally, and preferably via intramuscular or subcutaneous injection, wherein the subcutaneous injection is preferably deep subcutaneous injection.

18. A kit, comprising: i. A pharmaceutical composition according to any one of claims 1 to 12, ii. optionally a vector for reconstruction, and iii. A vial or optionally a syringe prefilled with the pharmaceutical composition of item (i).

19. A method for producing biodegradable polymer microparticles according to any one of the preceding claims, wherein: The biodegradable polymer comprises at least 50 w / w%, preferably 85 ww% and most preferably 100 w / w% of PLGA as defined in any one of the preceding claims, and wherein the method comprises the steps of: i. preparing an organic phase, the organic phase comprising: an organic solvent mixture, preferably a mixture of dichloromethane and methanol in a weight ratio of 80:20 to 95:5; a biodegradable polymer in a concentration of 10 w / w% to 30 w / w%; and a somatostatin analog or a pharmaceutically acceptable salt thereof in a concentration sufficient to obtain a predetermined drug loading of 10 w / w% to 15 w / w%, ii. preparing an aqueous phase comprising 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 step i and step ii at a volume ratio of 1:80 to 1:250 to form an emulsion, iv. removing the organic solvent from the emulsion of step iii by solvent evaporation or solvent extraction, v. drying the biodegradable polymer particles obtained in step iv and sieving through a sieve of appropriate size, vi. optionally repeating step v until any residual organic solvent is below a predetermined level, Except for the drug loading, all w / w% and w / v% in the above process are based on the weight or volume of the respective solution.

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