Mixed release profile polymeric microsphere formulations containing octreotide and methods of making and using same

Abstract

A mixed release profile polymer microsphere formulation comprising octreotide is provided. In one aspect, the microsphere formulation is characterized in that the octreotide is released in vivo in humans over a period of about 60 days. Methods of making and using the formulation are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 381,696, filed October 31, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] General structure [ka] Octreotide acetate (chemical formula C 53 H 76 N 10 O 14 S 2、 CAS number 79517-01-4) is used to treat diarrhea in people with growth hormone-producing tumors (acromegaly and gigantism) when surgery is contraindicated, pituitary tumors that secrete thyroid-stimulating hormone (thyrotropinoma), diarrhea and hot flushing episodes associated with carcinoid syndrome, and vasoactive intestinal peptide-secreting tumors.

[0003] Octreotide acetate is currently available as an immediate-release subcutaneous injection under the trade name Sandostatin® and as a 28-day sustained-release intramuscular injection under the trade name Sandostatin LAR®. Sandostatin LAR® comprises a complex formulation made by a complex manufacturing process. See U.S. Patent Nos. 5,538,739 and 5,639,480.

[0004] There is a need for formulations containing octreotide, including octreotide acetate formulations, that can be administered by long-acting (e.g., about 60 days) sustained-release injection. In particular, there is a need for mixed-release profile polymer microsphere formulations containing octreotide, in which a first formulation of polymer microspheres is characterized by supratherapeutic release of octreotide over a first period of time and a second formulation of polymer microspheres is characterized by supratherapeutic release of octreotide over a second period of time that is slower than the first period of time. Summary of the Invention

[0005] A mixed-release profile microsphere formulation comprising octreotide is provided. In one embodiment, the mixed-release profile microsphere formulation comprises (i) a first polymeric microsphere characterized by a supratherapeutic release of octreotide between about 5 days and about 40 days, and (ii) a second polymeric microsphere characterized by a supratherapeutic release of octreotide between about 20 days and about 60 days. In one embodiment, the first polymeric microsphere is further characterized by a peak release of octreotide between about 15 days and about 25 days. In one embodiment, the second polymeric microsphere is further characterized by a peak release of octreotide between about 35 days and about 50 days.

[0006] In one embodiment, the mixed release profile microsphere formulation comprises: (A)(i) mixing a first biodegradable polymer in a first polymer solvent system to form a first polymer solution; (ii) mixing octreotide in a first drug solvent system to form a first octreotide solution; (iii) mixing the first polymer solution with the first octreotide solution to form a first dispersed phase; (B)(i) mixing a second biodegradable polymer in a second polymer solvent system to form a second polymer solution; (ii) mixing octreotide in the second drug solvent system to form a second octreotide solution; (iii) mixing the second polymer solution with the second drug solvent system to form a first dispersed phase; (C) mixing (i) water and (ii) a surfactant to form a continuous phase; (D) combining the first dispersed phase with a first portion of the continuous phase in a first homogenizer to form a first microsphere formulation having a first release profile; (E) combining the second dispersed phase with a second portion of the continuous phase in a second homogenizer to form a second microsphere formulation having a second release profile; and (F) combining the first microsphere formulation with the second microsphere formulation to form a mixed release profile microsphere formulation. In one embodiment, the first homogenizer and the second homogenizer are the same.

[0007] In another aspect, a single polymer microsphere formulation is provided, the single polymer microsphere formulation comprising polymer microspheres, each polymer microsphere comprising (i) octreotide and (ii) a biodegradable polymer, each polymer microsphere comprising a drug loading of octreotide of between about 6% and about 14% by weight of the polymer microsphere, the polymer microspheres having a diameter of between about 55 μm and about 75 μm (D 50 In one embodiment, the microsphere formulation is characterized by an in vivo release duration in humans of about 60 days.

[0008] In one aspect, a single polymer microsphere formulation may be made by a method including: (A) (i) mixing a biodegradable polymer in a polymer solvent system to form a polymer solution; (ii) mixing octreotide in a drug solvent system to form an octreotide solution; and (iii) mixing the polymer solution with the octreotide solution to form a dispersed phase; (B) (i) mixing water and (ii) a surfactant to form a continuous phase; and (C) blending the dispersed phase with the continuous phase in a homogenizer.

[0009] In one aspect, a method of treating acromegaly or diarrhea is provided, which may comprise administering to a patient in need thereof by intramuscular injection a mixed release profile or single polymer microsphere formulation made according to the methods described herein.

[0010] In another aspect, the use of a mixed release profile or single polymer microsphere formulation comprising polymer microspheres in the manufacture of a medicament for the treatment of acromegaly or diarrhea, wherein each polymer microsphere comprises (i) octreotide and (ii) a biodegradable polymer, each polymer microsphere comprising a drug loading of octreotide of between about 6% and about 14% by weight of the polymer microsphere, and the polymer microspheres have a diameter of between about 50 μm and about 90 μm (D 50 The use of mixed release profile or single polymer microsphere formulations with particle sizes between 100 and 150 μg is disclosed.

[0011] In another embodiment, a mixed release profile or single polymer microsphere formulation comprising polymer microspheres, each polymer microsphere comprising (i) octreotide and (ii) a biodegradable polymer, each polymer microsphere comprising a drug loading of octreotide of between about 6% and about 14% by weight of the polymer microsphere, and the polymer microspheres have a diameter of between about 50 μm and about 90 μm (D 50 ) are provided for use as pharmaceuticals for the treatment of acromegaly or diarrhea.

[0012] In another embodiment, a kit includes mixed release profile or single polymer microspheres, each mixed release profile or single polymer microsphere comprising (i) octreotide and (ii) a biodegradable polymer, each polymer microsphere comprising a drug loading of octreotide of between about 6% and about 14% by weight of the polymer microsphere, and the polymer microspheres have a diameter of between about 50 μm and about 90 μm (D 50 ) is provided. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is a schematic diagram illustrating an exemplary system and method for making a single polymer microsphere formulation encapsulating octreotide.

[0014] [Figure 2] FIG. 2 is a schematic diagram illustrating an exemplary system and method for making mixed release profile polymer microsphere formulations encapsulating octreotide in which the mixed release profile polymer microsphere formulations are mixed and injected into a vial through a single filling needle.

[0015] [Figure 3] FIG. 3 is a schematic diagram illustrating an exemplary system and method for making a mixed release profile polymer microsphere formulation encapsulating octreotide, in which the mixed release profile polymer microsphere formulation is injected into a vial via two separate suspension fills (two fill needles).

[0016] [Figure 4] FIG. 4 is a graph showing the in vitro cumulative octreotide release over time from four different formulations of octreotide-encapsulated polymer microspheres.

[0017] [Figure 5]FIG. 5 is a graph showing mixed release profile dose modeling of octreotide-loaded polymer microspheres.

[0018] [Figure 6] FIG. 6 is a graph showing the results of an in vivo pharmacokinetic study of the four formulations referred to in FIG. 4 in dogs.

[0019] [Figure 7] FIG. 7 is a graph showing the results of an in vivo pharmacokinetic study of the three single polymer microsphere formulations referred to in FIG. 4 in dogs.

[0020] [Figure 8] FIG. 8 is a graph depicting the results of an in vivo pharmacokinetic study of the single polymer microsphere formulations referred to in FIG. 4 versus the mixed release profile polymer microsphere formulations in dogs.

[0021] [Figure 9] FIG. 9 is a graph showing the amount of octreotide acetate released over time in vitro from small and large batches of octreotide acetate-loaded polymer microspheres at one month of mixed release profile polymer microsphere formulation.

[0022] [Figure 10] FIG. 10 is a graph showing the amount of octreotide acetate released over time in vitro from small and large batches of polymer microspheres encapsulating octreotide acetate at two months of mixed release profile polymer microsphere formulation. DETAILED DESCRIPTION OF THE INVENTION

[0023] A mixed-release profile microsphere formulation comprising octreotide is provided. In one embodiment, the mixed-release profile microsphere formulation comprises (i) a first polymeric microsphere characterized by a supratherapeutic release of octreotide between about 5 days and about 40 days, and (ii) a second polymeric microsphere characterized by a supratherapeutic release of octreotide between about 20 days and about 60 days. In one embodiment, the first polymeric microsphere is further characterized by a peak release of octreotide between about 15 days and about 25 days. In one embodiment, the second polymeric microsphere is further characterized by a peak release of octreotide between about 35 days and about 50 days.

[0024] In one embodiment, the mixed release profile microsphere formulation comprises: (A)(i) mixing a first biodegradable polymer in a first polymer solvent system to form a first polymer solution; (ii) mixing octreotide in a first drug solvent system to form a first octreotide solution; (iii) mixing the first polymer solution with the first octreotide solution to form a first dispersed phase; (B)(i) mixing a second biodegradable polymer in a second polymer solvent system to form a second polymer solution; (ii) mixing octreotide in the second drug solvent system to form a second octreotide solution; (iii) mixing the second polymer solution with the second drug solvent system to form a first dispersed phase; (C) mixing (i) water and (ii) a surfactant to form a continuous phase; (D) combining the first dispersed phase with a first portion of the continuous phase in a first homogenizer to form a first microsphere formulation having a first release profile; (E) combining the second dispersed phase with a second portion of the continuous phase in a second homogenizer to form a second microsphere formulation having a second release profile; and (F) combining the first microsphere formulation with the second microsphere formulation to form a mixed release profile microsphere formulation. In one embodiment, the first homogenizer and the second homogenizer are the same.

[0025] Octreotide The active pharmaceutical ingredient is octreotide. Octreotide may be in the form of a free base, an acid addition salt, or a complex. In one embodiment, octreotide is an acetate salt. In one embodiment, octreotide acetate is supplied by Bachem. In one embodiment, octreotide acetate is hydrophilic. In one embodiment, octreotide acetate is characterized by an aqueous solubility of >220 mg / mL.

[0026] biodegradable polymers In one aspect, the dispersed phase may comprise a biodegradable polymer such as poly(lactic-co-glycolic acid) (PLGA) or polylactic acid (PLA), although it is contemplated that other suitable biodegradable polymers may be used.

[0027] In some embodiments, the biodegradable polymer comprises PLGA. In one embodiment, the PLGA comprises a lactide:glycolide ratio of 75:25 or 85:15. In embodiments where the microsphere formulation is a mixed release profile formulation, the first PLGA may comprise a lactide:glycolide ratio of 75:25 and the second PLGA may comprise a lactide:glycolide ratio of 85:15. In one embodiment where the microsphere formulation is a mixed release profile formulation, the biodegradable polymer comprises (i) a first PLGA comprised of a lactide:glycolide ratio of 75:25 and (ii) a second PLGA comprised of a lactide:glycolide ratio of 85:15. For the avoidance of doubt, a mixed release profile formulation does not comprise a blend of PLGA; rather, a mixed release profile polymeric microsphere formulation comprises (i) first polymeric microspheres, each first polymeric microsphere comprising octreotide or a pharmaceutically acceptable salt thereof and a first PLGA having a lactide:glycolide ratio, each first polymeric microsphere comprising a drug loading of octreotide and a first particle size, and wherein the first polymeric microspheres release supratherapeutic levels for a first period of time. and (ii) second polymer microspheres, each second polymer microsphere comprising octreotide or a pharmaceutically acceptable salt thereof and a second PLGA having a lactide:glycolide ratio, each second polymer microsphere comprising a drug loading of octreotide and a second particle size, wherein the second polymer microspheres are characterized by supratherapeutic release of octreotide over a second period of time.

[0028] In one embodiment, the PLGA is acid-terminated. In one embodiment, ester-terminated PLGA is specifically excluded. In one embodiment, the PLGA has an IV of about 0.1 dL / g to about 0.4 dL / g, including about 0.1 dL / g to about 0.3 dL / g, about 0.2 dL / g to about 0.4 dL / g, about 0.19 dL / g, about 0.2 dL / g, about 0.21 dL / g, and about 0.27 dL / g, as well as any value or range between any two of these IV values.

[0029] In one embodiment, the PLGA comprises Viatel™ DLG7502A ("7502A"), a poly(D,L-lactide-co-glycolide) manufactured by Ashland with acid ends, lactide:glycolide 75:25, and an IV=0.2. In one embodiment, the PLGA comprises Viatel™ DLG8502A ("8502A"), a poly(D,L-lactide-co-glycolide) manufactured by Ashland with acid ends, lactide:glycolide 85:15, and an IV=0.19. In one embodiment, the PLGA comprises Viatel™ DLG8503A ("8503A"), a poly(D,L-lactide-co-glycolide) manufactured by Ashland with acid ends, lactide:glycolide 85:15, and an IV=0.27.

[0030] In some embodiments, the biodegradable polymer is PLA. In one embodiment, the PLA is acid-terminated. In one embodiment, the PLA has an IV between about 0.16 dL / g and about 0.24 dL / g, including about 0.21 dL / g, and any value or range between any two of these IV values.

[0031] In one embodiment, the PLA comprises Resomer® R202H (“202H”), a poly(D,L-lactide) from Evonik with an IV=0.21 at the acid ends.

[0032] dispersed phase In one embodiment, the dispersed phase comprises a polymer solvent system. In one embodiment, the polymer solvent system comprises dichloromethane (DCM). In one embodiment, the dispersed phase comprises a drug solvent system. In one embodiment, the drug solvent system comprises methanol (MeOH) and / or acetic acid (AcOH). In one embodiment, the polymer is dissolved in the polymer solvent system and the octreotide is dissolved in the drug solvent system, and the two solutions are mixed before contacting the continuous phase. In one embodiment, the ratio of AcOH to octreotide can be 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, or about 1:1. In one embodiment, the dispersed phase can comprise an antioxidant. In one embodiment, the antioxidant can comprise butylated hydroxytoluene. The methods described herein do not involve precipitating the dispersed phase by contacting the dispersed phase with anhydrous diethyl ether and / or anhydrous n-heptane.

[0033] Continuous Phase The dispersed phase may be miscible with an aqueous continuous phase comprising water and, optionally, a buffer, a surfactant, or both. Specifically excluded are continuous phases comprising organic ions selected from the group consisting of trifluoromethyl p-toluate, 2-naphthalenesulfonate, 2,3-naphthalenedicarboxylate, 2-naphthoate, and salicylsalicylate.

[0034] In one embodiment, a buffer may be added to the continuous phase to maintain the pH of the solution at about 7.0 to about 8.0. In one embodiment, the buffer may be a phosphate buffer or a carbonate buffer. In one embodiment, the buffer may be a phosphate or carbonate buffer solution and may be used to create and maintain a pH level of the system at about 7.4.

[0035] The surfactant component may be present in the continuous phase in an amount of about 0.35% to about 1.0% by weight in water. In one embodiment, the surfactant component comprises polyvinyl alcohol ("PVA") at a concentration of 0.35% by weight in water. In one embodiment, the surfactant component comprises polyvinyl alcohol ("PVA") at a concentration of 1% by weight in water.

[0036] In some embodiments, the flow rate of the dispersed phase to the homogenizer may be about 10 mL / min to about 30 mL / min, including about 20 mL / min and about 25 mL / min. In some embodiments, the flow rate of the continuous phase to the homogenizer may be about 2 L / min. Thus, in one embodiment, the ratio of continuous phase to dispersed phase may be about 66:1 to about 200:1, including about 100:1 and about 80:1. Larger batches may require higher flow rates. For example, in some embodiments, the flow rate may be doubled.

[0037] The continuous phase may be provided at room temperature or at a temperature above or below room temperature, hi some embodiments, the continuous phase may be provided at about 40°C, about 37°C, about 35°C, about 30°C, about 25°C, about 20°C, about 15°C, about 10°C, about 5°C, about 0°C, and any value or range between any two of these temperature values.

[0038] Homogenizer For the sake of brevity, and because the method is equally applicable to either, the term "homogenizer" contemplates a system or apparatus capable of homogenizing a dispersed phase and a continuous phase, emulsifying a dispersed phase and a continuous phase, or both, which systems and apparatus are known in the art. For example, in one embodiment, the homogenizer is an in-line Silverson homogenizer (commercially available from Silverson Machines, Waterside, UK), used, for example, as described in U.S. Pat. No. 5,945,126, or a Levitronix® BPS-i100 integrated pump system, used, for example, as described in U.S. Pat. No. 11,167,256, each of which is incorporated herein by reference in its entirety. In one embodiment, the homogenizer is a membrane emulsifier or a static mixer. In one embodiment, the homogenizer operates at an impeller agitation speed of about 1,000 to about 4,000 revolutions per minute (RPM), including about 2,000 RPM, about 2,250 RPM, about 2,500 RPM, and any value or range between any two of these RPM values.

[0039] Drug Loading The drug loading of each polymeric microsphere, expressed as a percentage, in terms of drug to polymer ratio, can be from about 6% to about 14% by weight, including about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, and about 13% by weight, as well as any value or range between any two of these drug loading amounts.

[0040] particle size In one embodiment, the polymer microspheres have a diameter of about 55 μm (D 50 ) ~ approx. 75 μm (D 50 ) and approximately 60 μm (D 50 ) ~ approx. 75 μm (D 50 ) and approximately 60 μm (D 50 ), approximately 65 μm (D 50 ), approximately 70 μm (D 50 ), approximately 75 μm (D 50 ), and any value or range between any two of these particle sizes. 50 ) particle size.

[0041] Sustained release In one embodiment, the microsphere formulations are characterized by having an in vivo release duration in humans of about 60 days, i.e., octreotide plasma levels are maintained within the therapeutic range for about 60 days after injection. In one embodiment, the microsphere formulation comprises a mixed release profile formulation. In one embodiment, the mixed release profile formulation comprises (i) a first polymeric microsphere characterized by a supratherapeutic release of octreotide between about 5 days and about 40 days, and (ii) a second polymeric microsphere characterized by a supratherapeutic release of octreotide between about 20 days and about 60 days. In one embodiment, the first polymeric microsphere is further characterized by a peak release of octreotide between about 15 days and about 25 days. In one embodiment, the second polymeric microsphere is further characterized by a peak release of octreotide between about 35 days and about 50 days. In one embodiment, the microsphere formulation is characterized by having an in vivo release duration such that plasma levels of octreotide are below the therapeutic range before three months after injection.

[0042] Therapeutic Benefits In one aspect, a method of treating acromegaly or diarrhea is provided, which may comprise administering to a patient in need thereof by intramuscular or subcutaneous injection a single polymer microsphere formulation or a mixed release profile polymer microsphere formulation made according to the methods described herein.

[0043] In another aspect, there is provided use of a single polymer microsphere formulation or a mixed release profile polymer microsphere formulation in the manufacture of a medicament for the treatment of acromegaly or diarrhea, wherein each polymer microsphere comprises (i) octreotide and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug loading of octreotide of about 6% to about 14% by weight of the polymer microsphere, and wherein the polymer microspheres have a diameter of about 55 μm to about 75 μm (D 50 The use of single polymer microsphere formulations or mixed release profile polymer microsphere formulations having particle sizes between 100 and 150 μg / ml is disclosed.

[0044] In another embodiment, a single polymer microsphere formulation or a mixed release profile polymer microsphere formulation comprising polymer microspheres, each polymer microsphere comprising (i) octreotide and (ii) a biodegradable polymer, each polymer microsphere comprising a drug loading of octreotide of about 6% to about 14% by weight of the polymer microsphere, and the polymer microspheres have a diameter of about 55 μm to about 75 μm (D 50 ) are provided for use as pharmaceuticals for the treatment of acromegaly or diarrhea.

[0045] In another embodiment, a kit includes a single polymeric microsphere formulation or a mixed release profile polymeric microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising (i) octreotide and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of octreotide of about 6% to about 14% by weight of the polymeric microsphere, and the polymeric microspheres have a diameter of about 55 μm to about 75 μm (D 50 ) is provided. [Example]

[0046] Example 1 - General Preparation of a Single Polymer Microsphere Formulation Containing Octreotide Acetate Microsphere-Forming Phase. Referring to Figure 1, a dispersed phase ("DP") 110 is formed by dissolving a polymer matrix (such as a PLGA or PLA polymer) in a polymer solvent system (such as DCM), dissolving octreotide acetate in a drug solvent system (such as MeOH / AcOH), and mixing the two solutions. The DP 110 is filtered and pumped into a homogenizer 130 at a specified flow rate. A continuous phase ("CP") 120, comprising water, a surfactant, and optionally a buffer, is also pumped into the homogenizer 130 at a specified flow rate. The speed of the homogenizer 130 is generally kept constant to achieve the desired polymer microsphere size distribution. An exemplary continuous "upstream" microsphere-forming phase is described in U.S. Patent No. 5,945,126, incorporated herein by reference in its entirety.

[0047] Microsphere Processing Phase. Formed or forming microspheres exit the homogenizer 130 and enter the solvent removal vessel ("SRV") 140. Water may be added to the SRV 140 during microsphere formation to minimize solvent levels in the aqueous medium. See, for example, U.S. Patent No. 9,017,715, incorporated herein by reference in its entirety. After the DP 110 is discharged, the CP 120 and water flow rates are stopped, and a wash step begins. Solvent removal is achieved using a water wash and a hollow fiber filter (e.g., commercially available from Cytiva as HFF) 150. Microspheres are "essentially free" of organic solvents if they meet the criteria set forth in the "ICH Harmonized Guideline, Impurities: Guideline for Residual Solvents Q3C(R8), Current Step 4 version dated April 22, 2021," incorporated herein by reference in its entirety. A representative "downstream" microsphere processing phase is described in US Pat. No. 6,270,802, which is incorporated herein by reference in its entirety.

[0048] The washed microspheres are collected and lyophilized in a freeze dryer (Virtis) to remove any moisture. The resulting microspheres are a free-flowing, off-white bulk powder.

[0049] Example 2 - General Preparation of Mixed Release Profile Polymeric Microsphere Formulations Containing Octreotide Acetate Microsphere Formation Phase. Referring to Figures 2 and 3, a first DP 210 is formed by dissolving a first polymer matrix (such as a PLGA or PLA polymer) in a first polymer solvent system (such as DCM), dissolving octreotide acetate in a first drug solvent system (such as MeOH / AcOH), and mixing the two solutions. A second DP 310 is formed by dissolving a second polymer matrix (such as a PLGA or PLA polymer) in a second polymer solvent system (such as DCM), dissolving octreotide acetate in a second drug solvent system (such as MeOH / AcOH), and mixing the two solutions. Each of the first DP 210 and the second DP 310 is filtered using a 0.2 μm sterile PTFE or PVDF membrane filter (such as EMFLON, available from Pall or Sartorious AG), and each is pumped through homogenizer 230 / 330 at a specified flow rate. CP220 / 320, which contains water, surfactants, and optionally buffers, is also pumped at a specified flow rate through homogenizers 230 and 330. The speed of homogenizers 230 and 330 is generally kept constant to achieve the desired polymer microsphere size distribution.

[0050] Microsphere Processing Phase. Formed or forming microspheres exit homogenizers 230 and 330 and enter solvent removal vessels ("SRVs") 240 and 340, respectively. Water may be added to SRVs 240 and 340 during microsphere formation to minimize solvent levels in the aqueous medium. After DPs 210 and 310 are drained, the flow of CPs 220 and 320 and water is stopped, and a wash step begins. Solvent removal is achieved using water washes and hollow fiber filters (e.g., commercially available from Cytiva as HFF) (not shown).

[0051] Example 3 - Preparation of polymeric microspheres loaded with octreotide acetate Groups 1, 2, and 4 (single polymer microsphere formulations) were prepared according to the general procedure described in Example 1 and shown in Figure 1, and Group 3 (mixed release profile polymer microsphere formulation) was prepared according to the general procedure described in Example 2 and shown in Figures 2 and 3 (which are identical prior to vial filling). Specific processing parameters and physical properties of the microspheres are detailed in Table 1. [Table 1]

[0052] FIG. 4 is a graph showing the amount of octreotide acetate released over time in vitro from groups 1 to 4 of polymer microspheres in which octreotide acetate was encapsulated.

[0053] Example 4 - Pharmacokinetic study of groups 1-4 in dogs The pharmacokinetic profile of octreotide acetate after intramuscular administration of a time-release octreotide acetate formulation in dogs was studied. Two male and two female dogs per group were dosed as follows: Octreotide per vial: Single polymer microsphere formulation 110mg octreotide / vial Mixed release profile polymer microsphere formulation 220 mg octreotide / vial Dose Levels: Single polymer microsphere formulation 1 mg / kg with 10 mg / mL octreotide concentration Mixed release profile polymer microsphere formulation 2 mg / kg with 10 mg / mL octreotide concentration Dosage: Single polymer microsphere formulation 0.1mL / kg Mixed release profile polymer microsphere formulation 0.2mL / kg Blood samples: Pre-dose, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 6 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 168 hours, and every 7 days.

[0054] Figure 5 is a graph showing mixed release profile dose modeling. Group 3 alone is a mixed release profile formulation. Conceptually, the mixed release profile formulation includes (i) a first polymeric microsphere characterized by supratherapeutic octreotide acetate release between about 5 days and about 40 days with a peak release between about 15 days and about 25 days (month 1, as shown in Table 1 and Figure 5), and (ii) a second polymeric microsphere characterized by supratherapeutic octreotide acetate release between about 20 days and about 60 days with a peak release between about 35 days and about 50 days (month 2, as shown in Table 1 and Figure 5).

[0055] Figure 6 is a logarithmic scale graph showing the measured mean blood concentrations (ng / mL) of octreotide acetate as a function of time for Groups 1-4 over approximately 70 days. Figure 7 shows the results for three single polymer microsphere formulations 1, 2, and 4 over 140 days. Figure 8 shows the results for the single polymer microsphere formulation of Group 2 versus the mixed release profile polymer microsphere formulation of Group 3 over 140 days.

[0056] Example 5 - Scaling up of octreotide acetate-loaded polymer microspheres A one-month formulation of the Group 3 blend was prepared according to the general procedure described in Example 1 and illustrated in Figure 1. A larger (250 g) batch was prepared in the same manner. Specific processing parameters and physical properties of the microspheres are detailed in Table 2. [Table 2]

[0057] FIG. 9 is a graph showing the amount of octreotide acetate released over time in vitro from small and large batches of octreotide acetate-encapsulated polymeric microspheres at one month.

[0058] A two-month formulation of the Group 3 blend was prepared according to the general procedure described in Example 1 and illustrated in Figure 1. A larger (250 g) batch was prepared in the same manner. Specific processing parameters and physical properties of the microspheres are detailed in Table 3. [Table 3]

[0059] FIG. 10 is a graph showing the amount of octreotide acetate released over time in vitro from small and large batches of octreotide acetate-loaded polymeric microspheres at two months.

[0060] During use, the microspheres may be suspended in a diluent for administration (injection). The diluent may generally contain a thickener, a tonicity agent, and a wetting agent. The thickener may include sodium carboxymethylcellulose (CMC-Na) or other suitable compounds. In one embodiment, the polymer microspheres do not contain cellulose-derived materials. An appropriate viscosity grade and concentration of CMC-Na may be selected so that the viscosity of the diluent is 3 cps or greater. Generally, a viscosity of about 10 cps is appropriate. However, a higher viscosity diluent may be preferred for larger microspheres to minimize settling of the microspheres in suspension.

[0061] A uniform microsphere suspension without particle settling results in a consistent delivered dose during drug administration by injection. To achieve a diluent isotonicity of approximately 290 milliosmoles (mOsm), which more closely matches biological systems, solutes such as mannitol, sodium chloride, or any other acceptable salt may be used. The diluent may also contain a buffer salt to maintain the pH of the composition. Typically, the pH is maintained near a physiologically appropriate pH (about pH 7 to about pH 8) by adjusting the buffer content as needed.

[0062] The embodiments disclosed herein are not intended to be exhaustive or limiting. Those skilled in the art will recognize that other embodiments or modifications of the embodiments of the present invention may be made without departing from the spirit or scope of the invention. The embodiments of the present disclosure, as generally described herein and illustrated in the figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are contemplated herein.

[0063] Unless otherwise stated, "a," "an," "the," "one or more of," and "at least one" are used interchangeably. The singular forms "a," "an," and "the" include their plural forms. The recitation of numerical ranges by endpoints includes all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). The terms "comprising" and "including" are intended to be equivalent and open-ended. The phrase "consisting essentially of" means that the composition or method may include additional ingredients and / or steps, but only if the additional ingredients and / or steps do not materially alter the basic and novel characteristics of the claimed composition or method. The phrase "selected from the group consisting of" means including mixtures of the recited group.

[0064] Reference to the term "each" does not mean "each and every without exception." For example, when referring to a microsphere formulation comprising polymeric microspheres, and saying that "each polymeric microsphere" has a particular octreotide acetate content, it is intended that if there are 10 polymeric microspheres and two or more of the polymeric microspheres have the particular octreotide acetate content, then a subset of the two or more polymeric microspheres satisfies the restriction.

[0065] The term "about" in conjunction with a number is merely shorthand and is intended to include ±10% of the number. This is true whether "about" is modifying an individual number or a number at either end or both ends of a range of numbers. In other words, "about 10" means 9 to 11. Similarly, "about 10 to about 20" contemplates 9 to 22 and 11 to 18. In the absence of the term "about," the exact number is intended. In other words, "10" means 10.

Claims

1. A mixed-release profile polymer microsphere formulation, (A) A first polymer microsphere, wherein each first polymer microsphere is (i) Octreotide or a pharmaceutically acceptable salt thereof, (ii) A first biodegradable polymer comprising poly(D,L-lactide-co-glycolide) having a lactide:glycolide ratio of approximately 75:25, Includes, Each first polymer microsphere contains a drug load of octreotide between approximately 7% and 10% by weight of the first polymer microsphere. The first polymer microspheres are approximately 50 μm to approximately 90 μm (D ５０ ) has a particle size of, The first polymer microsphere is characterized by the release of octreotide at therapeutic levels for a period of approximately 5 to 40 days. The first polymer microsphere, (B) A second polymer microsphere, wherein each second polymer microsphere is (i) Octreotide and (ii) A second biodegradable polymer comprising poly(D,L-lactide-co-glycolide) having a lactide:glycolide ratio of approximately 85:15, Includes, Each second polymer microsphere contains a drug load of octreotide between approximately 10% and 14% by weight of the second polymer microsphere. The second polymer microspheres are approximately 50 μm to approximately 90 μm (D ５０ ) has a particle size of, The second polymer microsphere is characterized by the release of octreotide at therapeutic levels for approximately 20 to 60 days. The second polymer microsphere, A mixed-release profile polymer microsphere formulation containing the above.

2. The mixed-release profile polymer microsphere formulation according to claim 1, wherein the octreotide comprises octreotide acetate.

3. The mixed-release profile polymer microsphere formulation according to claim 1, wherein the first and second biodegradable polymers are acid-terminated.

4. The mixed-release profile polymer microsphere formulation according to claim 1, wherein the first biodegradable polymer has an intrinsic viscosity between approximately 0.1 dL / g and 0.3 dL / g.

5. The mixed-release profile polymer microsphere formulation according to claim 1, wherein the second biodegradable polymer has an intrinsic viscosity between approximately 0.2 dL / g and 0.4 dL / g.

6. The mixed-release profile polymer microsphere formulation according to claim 1, further characterized in that at least 75% of the total octreotide is released over a period of about 60 days after injection into the subject, but less than about 20% of the total octreotide is released within about 24 hours of injection into the subject.

7. The mixed-release profile polymer microsphere formulation according to claim 1, further characterized in that the first polymer microsphere exhibits peak release of octreotide between approximately 15 and 25 days, and the second polymer microsphere exhibits peak release of octreotide between approximately 35 and 50 days.

8. A pharmaceutical composition comprising a mixed-release profile polymer microsphere formulation according to any one of claims 1 to 7.

9. A method for producing a mixed-release profile microsphere formulation according to any one of claims 1 to 7, (A) (i) Mix a first biodegradable polymer containing poly(D,L-lactide-co-glycolide) having a comonomer ratio of about 75:25 in a first polymer solvent system to form a first polymer solution. (ii) Mixing octreotide or a pharmaceutically acceptable salt thereof in a first drug solvent system to form a first octreotide solution, (iii) Mix the first polymer solution with the first octreotide solution to form a first dispersed phase. (B) (i) Mix a second biodegradable polymer containing poly(D,L-lactide-co-glycolide) having a comonomer ratio of approximately 85:15 in a second polymer solvent system to form a second polymer solution. (ii) Mixing octreotide or a pharmaceutically acceptable salt thereof in a second drug solvent system to form a second octreotide solution. (iii) Mix the second polymer solution with the second octreotide solution to form a second dispersed phase. (C) (i) Water and, (ii) Surfactants and Mixing them to form a continuous phase, (D) Mixing the first dispersed phase with the first portion of the continuous phase in a first homogenizer to form a first polymer microsphere formulation having a first release profile. (E) Mixing the second dispersed phase with the second portion of the continuous phase in a second homogenizer to form a second polymer microsphere formulation having a second release profile, and (F) Mixing the first polymer microsphere formulation with the second polymer microsphere formulation to form the mixed-release profile microsphere formulation. A method that includes this.

10. The method according to claim 9, wherein the first polymer solvent system and the second polymer solvent system are each dichloromethane.

11. The method according to claim 9, wherein the first drug solvent system and the second drug solvent system are each a mixture of methanol and acetic acid.

12. (i) The first biodegradable polymer and the second biodegradable polymer are acid-terminated, (ii) The first biodegradable polymer has an intrinsic viscosity between approximately 0.1 dL / g and 0.3 dL / g, (iii) The second biodegradable polymer has an intrinsic viscosity between approximately 0.2 dL / g and 0.4 dL / g. The method according to claim 9.

13. Use of the mixed-release profile polymer microsphere formulation according to claim 1 in the manufacture of a pharmaceutical product for the treatment of acromegaly or diarrhea.

14. A mixed-release profile polymer microsphere formulation according to claim 1, for use as a pharmaceutical for the treatment of acromegaly or diarrhea.

15. A kit comprising the mixed-release profile polymer microsphere formulation described in claim 1.

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