SUSTAINED RELEASE FORMULATION COMPRISING OCTREOTIDE AND TWO OR MORE POLYLACTIDE-CO-GLYCOLIDE POLYMERS

Abstract

The present invention relates to sustained release formulations comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and two or more different polylactide-coglycolide polymers (PLGAs).

Claims

1. A sustained release pharmaceutical composition in form of microparticles comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and two different polylactide-co-glycolide polymers (PLGAs), wherein the PLGAs are present as polymer blend, and wherein the microparticles are of a single composition and wherein the lactide: glycolide ratios of the different PLGAs are different from each other.

2. A sustained release pharmaceutical composition in form of microparticles comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and two different polylactide-co-glycolide polymers (PLGAs), wherein the lactide: glycolide ratios of the different PLGAs are different from each other, wherein the sustained release pharmaceutical composition is a mixture of depots, which is a mixture of two microparticles of different compositions, each with one different PLGA.

3. The sustained release pharmaceutical composition according to claim 1, wherein the PLGAs have a lactide:glycolide monomer ratio of 100:0 to 40:60.

4. The sustained release pharmaceutical composition according to claim 1, wherein the PLGAs have a lactide:glycolide monomer ratio of 90:10 to 40:60.

5. The sustained release pharmaceutical composition according to claim 1, wherein the PLGAs have a lactide:glycolide monomer ratio of 85:15 to 65:35.

6. The sustained release pharmaceutical composition according to claim 1, wherein the inherent viscosity of the PLGAs is below 0.9 dl/g in chloroform.

7. The sustained release pharmaceutical composition according to claim 1, wherein the inherent viscosity of the PLGAs is below 0.8 dl/g in chloroform.

8. The sustained release pharmaceutical composition according to claim 1, wherein at least two PLGAs are linear.

9. The sustained release pharmaceutical composition according to claim 1 comprising the pamoate salt of octreotide.

10. The sustained release pharmaceutical composition according to claim 1, wherein the release of the active ingredient is three or more months.

11. The sustained release pharmaceutical composition according to claim 1, wherein the microparticles are additionally mixed, covered or coated with an anti-agglomerating agent.

12. The sustained release pharmaceutical composition according to claim 11, wherein the microparticles are coated with an anti-agglomerating agent and the anti-agglomerating agent is present in an amount of less than 2% by weight of the microparticles.

13. The sustained release pharmaceutical composition according to claim 11, wherein the anti-agglomerating agent is mannitol.

14. The sustained release pharmaceutical composition according to claim 1 sterilized by gamma irradiation.

15. A process of manufacturing microparticles according to claim 1 comprising (i) preparation of an internal organic phase comprising (ia) dissolving the two or more different PLGA polymers in a suitable organic solvent or solvent mixture; (ib) dissolving/suspending/emulsification of octreotide or a pharmaceutically-acceptable salt thereof in the polymer solution obtained in step (ia); (ii) preparation of an external aqueous phase containing stabilizers; (iii) mixing the internal organic phase with the external aqueous phase to form an emulsion; and (iv) hardening the microparticles by solvent evaporation or solvent extraction, washing the microparticles, drying the microparticles and sieving the microparticles.

16. A process of manufacturing the sustained release pharmaceutical composition according to claim 2, wherein the polylactide-co-glycolide polymers (PLGAs) are present in a mixture of depots, comprising (i) preparation of an internal organic phase comprising (ia) dissolving one PLGA polymer in an organic solvent or solvent mixture; (ib) dissolving/suspending/emulsification of octreotide or an aqueous solution of octreotide in the polymer solution obtained in step (ia); (ii) preparation of an external aqueous phase containing stabilizers; (iii) mixing the internal organic phase with the external aqueous phase to form an emulsion; (iv) hardening the microparticles by solvent evaporation or solvent extraction, washing the microparticles, drying the microparticles; and (v) mixing the obtained microparticles with the other microparticles obtained from the same process except the PLGA polymer used in that process is different, and wherein the lactide: glycolide ratios of the different PLGAs are different from each other.

17. Microparticles obtained by the process according to claim 15.

18. A sustained release pharmaceutical composition comprising microparticles according to claim 17.

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

Description

EXAMPLES

[0046] The following examples are illustrative, but do not serve to limit the scope of the invention described herein. The examples are meant only to suggest a method of practicing the present invention.

Example 1: Microparticle Preparation

[0047] An appropriate amount of the PLGA polymers is dissolved in an appropriate amount of dichloromethane to give an appropriate polymer concentration as stated in column “PLGA conc.” in Table 2. An appropriate amount of drug substance is weight into a glass beaker and the polymer solution is poured over the drug substance so that the resulting microparticles have a drug load as stated in column “drug load”.

[0048] E.g. for microparticles with a drug load of 20% and a polymer concentration of 20% the numbers are as the following: 3.547 g of the PLGA polymers are dissolved into 17.7 ml dichloromethane to give a 20% (w/v) polymer solution. 1.453 g of octreotide pamoate (corresponding to 1.00 g=20% octreotide free base) is weight into a glass beaker and the polymer solution is poured over the drug substance.

[0049] The suspension is homogenized with an Ultra-Turrax rotor-stator mixer with 20′000 rpm for 1 min under cooling with an ice/water mixture. This suspension is referred to as S/O suspension.

[0050] 10.00 g of Polyvinylalcohol PVA 18-88, 3.62 g KH.sub.2PO.sub.4 and 15.14 g Na.sub.2HPO.sub.4 are dissolved in 2.00 L deionized water to form a 0.5% PVA 18-88 solution buffered to pH 7.4.

[0051] The S/O suspension is mixed with the 0.5% PVA18-88 solution by pumping the S/0 suspension with the help of a flexible tube pump (Perpex, Viton tube) at a rate of 10 ml/min into a turbine and by pumping the aqueous solution with a gear pump (Ismatec MV-Z/B with pumping head P140) at a rate of 200 ml/min into the same turbine. The two solutions are mixed in the turbine at 4′500 rpm. The homogenized S/O/W emulsion is collected into a 2 L glass beaker which is prefilled with 200 ml of the buffered PVA solution.

[0052] The S/O/W emulsion is then heated up to 52° C. in 3.5 h-5 h. The temperature of 52° C. is hold for further 30 min-120 min, before the batch is cooled to room temperature again. During this process escaping dichloromethane is removed by vacuum and the batch is stirred by a 4 blade-propeller-stirrer at 250 rpm.

[0053] As a result, microparticles are formed out of the S/O/W emulsion. The microparticles are collected by filtration (5 μm). They are washed 5 times with 200 ml water and dried for 36 h at 20° C. and 0.030 mbar. The dried microparticles are sieved through 140 μm and filled under nitrogen into glass vials. Prepared in that way, the microparticles are sterilized by gamma-irradiation with a dose of 30 kGy.

[0054] The particle size of the microparticles is measured by laser light diffraction. The microparticles are resuspended in white spirit using ultra sound. Table 2 gives the diameter x.sub.90 (90% of all particles are smaller than this value) after 120 seconds of ultra sound treatment.

[0055] The assay of the microparticles (amount of active ingredient) is determined by HPLC after dissolving the microparticles with ultra sound in a 3:2 mixture of acetonitrile and methanol and further 1:1 dilution with a sodium acetate buffer (pH 4). The solution is cleared from residual particulate matter by centrifugation.

TABLE-US-00002 TABLE 2 Examples 1-1 to 1-82: octreotide pamoate microparticles prepared by one PLGA (reference examples), blends of two PLGAs and micropaticle mixtures prepared by microparticles batches with one PLGA only. Particle Drag PLGA Pro- size Ex. Load conc. cess x.sub.90 Assay Batch (%) (%) A B C D E F G Info (μm) (%) Microparticles with one PLGA in the matrix (Reference Examples) 1-1 20 20 100 7 46.7 18.6 1-2 20 20 100 7 44.1 18.5 1-3 20 20 100 4 85.7 16.9 1-4 20 20 100 7 73.0 18.6 1-5 20 20 100 4/38 58.2 9.0 1-6 20 20 100 7 18.4 18.4 1-7 20 20 100 4 62.3 14.7 1-8 20 20 100 4 85.4 15.7 1-9 20 20 100 7 80.2 17.2 MICROPARTICLE MIXTURES: Powder mixtures of microparticles with one PLGA in the matrix 1-10 20 20 30 70 7 18.5 1-11 20 20 10 90 7 18.5 1-12 20 20 50 50 4/7  16.7 1-13 20 20 50 50 4 15.8 POLYMER BLENDS: Microparticles with two PLGA polymers in the matrix 1-14 20 20 10 90 7 47.0 18.4 1-15 25 20 10 90 7 56.4 25.4 1-16 20 20 30 70 7 46.4 19.5 1-17 20 20 50 50 7 44.3 20.4 1-18 20 20 10 90 7 44.6 19.3 1-19 20 20 20 80 7 45.2 20.9 1-20 20 20 20 80 4 75.4 14.2 1-21 20 20 10 90 7 67.6 15.5 1-22 20 20 10 90 4 69.4 13.4 1-23 20 25 10 90 4 84.8 14.3 1-24 10 20 20 80 4 63.7 7.0 1-25 15 20 20 80 4 64.7 10.3 1-26 20 20 20 80 4 75.5 14.1 1-27 20 20 20 80 5 67.8 14.2 1-28 25 20 20 80 4 74.6 11.8 1-29 30 20 20 80 4 89.4 10.5 1-30 20 20 30 70 4 59.4 11.5 1-31 20 20 50 50 7 46.3 16.4 1-32 20 20 40 60 7 42.6 18.1 1-33 20 20 30 70 7 51.9 18.9 1-34 20 25 30 70 7/38 72.6 19.0 1-35 20 20 30 70 .sup. 7/1:25 53.7 18.9 1-36 20 20 30 70 7/38 49.3 18.5 1-37 20 20 30 70  7/GP 59.6 18.6 1-38 20 20 30 70 7/38 52.3 17.9 1-39 15 20 30 70 7 36.2 14.4 1-40 22½ 20 30 70 7/38 55.0 19.6 1-41 25 20 30 70 7/38 61.3 21.5 1-42 25 25 30 70 7/38/1:25 75.1 22.5 1-43 20 20 20 80 7 43.4 17.8 1-44 20 20 10 90 7 40.0 18.1 1-45 20 20 50 50 7 61.3 18.9 1-46 20 20 50 50 4 85.9 13.4 1-47 20 25 30 70 4 95.6 17.7 1-48 20 20 30 70 7 59.7 18.6 1-49 20 25 20 80 4 100.5 17.6 1-50 20 20 20 80 4 75.4 15.8 1-51 20 25 10 90 4 105.9 16.9 1-52 20 20 50 50 7 49.5 17.7 1-53 15 20 50 50 7 58.9 13.0 1-54 20 20 50 50 4 58.7 12.1 1-55 20 20 20 80 4 64.0 13.5 1-56 20 20 10 90 4 73.4 14.6 1-57 20 20 50 50 4/38 69.5 12.1 1-58 20 20 90 10 7/38 49.1 16.6 1-59 20 20 70 30 7/38 53.5 18.0 1-60 20 20 50 50 7 37.7 18.3 1-61 20 20 30 70 7/38 52.1 17.1 1-62 20 20 70 30 7 62.8 16.3 1-63 20 20 50 50 7 47.8 16.1 1-64 20 20 30 70 7 50.2 18.1 1-65 20 20 90 10 7/38 50.2 18.9 1-66 20 20 80 20 7 47.2 17.7 1-67 20 20 70 30 7/38 60.2 17.7 1-68 20 20 50 50 7 58.6 18.6 1-69 20 20 50 50 7/38 65.6 18.3 1-70 20 20 50 50 4 67.4 15.2 1-71 20 20 30 70 4 56.7 11.7 1-72 20 20 20 80 4 77.4 13.2 1-73 20 20 10 90 4 66.5 14.3 1-74 20 20 90 10 7 75.2 18.7 1-75 20 20 70 30 7 88.2 17.1 1-76 20 20 50 50 7 65.1 18.2 1-77 20 20 50 50 4 88.3 16.0 1-78 20 20 30 70 4 75.3 16.0 1-79 20 20 20 80 4 81.9 15.9 1-80 20 20 10 90 4 83.7 16.5 POLYMER BLENDS: Microparticles with three PLGA polymers in the matrix 1-81 20 20 15 70 15 7 43.4 19.4 1-82 20 20 15 70 15 7 38.2 18.6 A: star-PLG-D-glucose 50:50 ester 0.3 dL/g (%) B: PLGA 65:35 ester 0.6 dL/g (%) C: PLGA 75:25 ester 0.4 dL/g (%) D: PLGA 75:25 ester 0.6 dL/g (%) E: PLGA 85:15 ester 0.4 dL/g (%) F: PLGA 85:15 ester 0.6 dL/g (%) G: PLA 100:0 acid 0.2 dL/g (%)

Process Info=Further Process Information:

7: 66 mM PBS pH 7.4

[0056] 5: 69 mM Citrate-phosphate buffer pH 5.0
4: 69 mM Citrate-phosphate buffer pH 4.0
38: Turbine speed 3800 rpm instead of 4500 rpm
1:25: Flowrate ratio SO/W=1:25 instead of 1:20
GP: Gear pump instead of peristaltic pump

Example 2: Vehicle Compositions A to G

[0057] CMC-Na, Mannitol and Pluronic F68 in an amount as given in Table 3 are dissolved in about 15 ml hot deionized water of a temperature of about 90° C. under strong stirring with a magnetic stirrer. The resulting clear solution is cooled to 20° C. and filled up with deionized water to 20.0 ml.

TABLE-US-00003 TABLE 3 Suitable vehicles for the microparticles (Amounts given in g) A B C D E F G CMC-Na 0 0 0.05 0.14 0.28 0.35 0.40 Mannitol 0 1.04 0.99 0.90 0.76 0.74 0.68 Pluronic F68 0.04 0.04 0.04 0.04 0.04 0.04 0.04

Example 3: Microparticle Suspension

[0058] 170 mg of microparticles of example 1-33 are suspended in 1.0 ml of a vehicle of composition D (Table 3) in a 6 R vials. The suspensions are homogenized by shaking for about 30 seconds by hand. The reconstituted suspension may be injected without any issues using a 20 Gauge needle.

Example 4: Lyophilisation of the Microparticles

[0059] 170 mg of microparticles of example 1-33 are reconstituted in 1 ml of the vehicle composition F (Table 3), homogenized by stirring for 1 to 12 hours and then freeze-dried in a lyophilisator. Reconstitution of the lyophilized microparticles with 1 ml pure water (aqua ad injectabilia) resulted in fast and good wetting of the microparticles that may be injected without any issues using a 20 Gauge needle.

Example 5: Release Profile In Vivo (Rabbits)

[0060] Microparticles containing octreotide are suspended in 1 ml of a suitable aqueous vehicle, preferably in vehicle D, and the resulting suspension is injected intramuscularly (i.m.) into male New Zealand White bastard rabbits in a dose of 4 mg/kg. For each dosage form (test group) 4 animals are used. After defined time periods (indicated in the table 4) plasma samples are taken and analyzed for octreotide concentration.

TABLE-US-00004 TABLE 4 Plasma levels (dose corrected values); concentration in ng/ml Ex. Time after Administration (days) Batch 0.021 0.042 0.083 0.167 0.250 1 2 3 5 8 12 1-10 9.653 9.245 4.201 1.159 0.402 0.000 0.000 0.205 0.888 1.216 0.954 1-33* 22.735 16.333 6.359 1.621 0.575 0.017 0.085 0.318 1.081 1.249 1.088 1-68 3.622 4.099 2.748 0.939 0.440 0.028 0.000 0.085 0.377 0.690 0.575 1-44 5.675 4.460 1.799 0.522 0.175 0.000 0.000 0.103 0.695 0.918 0.785 1-33 21.071 19.719 9.704 2.852 1.121 0.155 0.334 0.858 2.240 2.868 3.093 1-40 1.047 1.032 0.856 0.350 0.182 0.000 0.000 0.188 1.252 1.374 1.169 1-48 0.662 0.645 0.494 0.248 0.123 0.000 0.000 0.108 0.751 0.992 0.901 1-67 0.952 0.928 0.672 0.232 0.094 0.000 0.000 0.096 0.448 0.609 0.519 1-82 31.669 31.171 22.023 9.302 3.985 0.411 0.417 0.425 0.209 0.219 0.247 1-22 3.973 15.301 17.168 13.803 10.187 0.944 0.270 0.283 0.946 1.684 0.527 1-26 3.799 13.875 17.515 14.105 11.060 0.697 0.164 0.271 0.535 1.491 1.505 Ex. Time after Administration (days) Batch 19 27 33 40 47 54 61 68 75 82 89 98 1-10 0.911 0.513 0.343 0.222 0.600 0.706 0.578 0.705 0.622 0.623 0.219 0.054 1-33* 0.867 0.477 0.227 0.127 0.545 0.579 0.843 1.169 0.439 0.146 0.019 0.000 1-68 0.509 0.435 0.494 0.408 0.317 0.243 0.152 0.165 0.424 0.621 0.765 0.640 1-44 0.626 0.367 0.244 0.106 0.060 0.233 0.648 1.023 1.046 0.505 0.155 0.000 1-33 2.254 1.957 0.779 0.366 0.340 1.461 3.024 3.358 2.405 0.928 0.391 0.125 1-40 0.948 0.690 0.299 0.164 0.528 1.585 1.225 0.714 0.505 0.284 0.070 0.000 1-48 0.557 0.498 0.387 0.254 0.114 0.171 0.846 1.058 1.935 0.693 0.359 0.180 1-67 0.482 0.440 0.378 0.253 0.175 0.106 0.096 0.152 0.446 0.534 0.542 0.462 1-82 0.286 0.275 0.137 0.135 0.147 0.254 0.350 0.570 0.442 0.320 0.162 0.039 1-22 0.631 1.077 0.510 0.362 0.189 0.129 0.227 0.140 0.281 0.227 0.141 0.073 1-26 0.494 0.468 0.354 0.262 0.286 0.213 0.530 0.424 0.311 0.148 0.115 0.108 *Dose = 12 mg/kg