Octreotide Depot Formulation with Constantly High Exposure Levels

Abstract

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

Claims

1. A depot formulation in form of microparticles comprising as active ingredient octreotide, or a pharmaceutically acceptable salt thereof, incorporated into a biodegradable polymer matrix consisting of a blend and of two different linear polylactide-co-glycolide polymers (PLGAs) each having a molar lactide:glycolide (L:G) ratio of 75:25 and wherein said two polymers have different viscosities, wherein one of the PLGAs has an ester and the other an acid end group, wherein said polymers have inherent viscosities between 0.1 dl/g and 0.8 dl/g in CHCl.sub.3 at 25° C. at a concentration of 0.1%, where the active ingredient which is used to prepare the depot formulation is in the form of an amorphous powder.

2. The depot pharmaceutical formulation of claim 1, wherein the amorphous powder of the active ingredient has a has a particle size of 0.1 microns to 15 microns (99%>0.1 microns, 99%<15 microns).

3. The depot pharmaceutical formulation of claim 1, wherein said polymers have inherent viscosities between 0.1 dl/g and 0.5 dl/g in CHCl.sub.3.

4. The depot pharmaceutical formulation according to claim 1 wherein the active ingredient is octreotide pamoate.

5. The depot pharmaceutical formulation composition according to claim 1 wherein the microparticles have a diameter between 10 μm and 90 μm.

6. The depot pharmaceutical formulation according to claim 1 wherein the microparticles are covered or coated with an anti-agglomerating agent.

7. The depot pharmaceutical formulation according to claim 1 in the form of microparticles comprising octreotide pamoate and blend of 30% linear polymer PLGA 75:25 acid 0.2 dL/g (%) and 70% linear polymer PLGA 75:25 ester 0.4 dL/g (%), with a drug load of 20%, with a PLGA concentration of 20% and a X.sub.90 particle size of 60 micrometers.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The FIGURE shows examples 1-1, 1-2 and 1-3 (formulation variants C, B, A and in comparison). Octreotide serum conc. over time after 12 mg/kg dosage i.m. into rabbits. Mean and SD of 4 animals.

EXPERIMENTAL PART

[0045] 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

[0046] 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”.

[0047] 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 with a free peptide content of 68.8% (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.

[0048] 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.

[0049] 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.

[0050] The S/O suspension is mixed with the 0.5% PVA18-88 solution by pumping the S/O 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 as described in Table 2. 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.

[0051] The S/O/W emulsion is then heated up to 45° C. in 5 h. The temperature of 45° C. is hold for further 2 h 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.

[0052] 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.

[0053] 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 x90 (90% of all particles are smaller than this value) after 120 seconds of ultra sound treatment.

[0054] The assay of the microparticles 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-00001 TABLE 2 Examples 1-1: octreotide pamoate microparticles prepared by blend of two linear PLGAs (75:25). Comparative examples 1-2 and 1-3: octreotide pamoate microparticles prepared by blend of two or three linear PLGAs. Particle Drug PLGA Turbine size Ex. Load conc. speed x.sub.90 Assay Batch (%) (%) A B C D (rpm) □(□m) (%) 1-1 20 20 30 70 — 2800 60 18.4 Var C 1-2 20 20 33 — 34 33 3800 68.4 19.6 Var B 1-3 20 20 — — 50 50 4500 58.6 18.6 Var A A: PLGA 65:35 ester 0.6 dL/g (%) B: PLGA 75:25 acid 0.2 dL/g (%) C: PLGA 75:25 ester 0.4 dL/g (%) D: PLGA 85:15 ester 0.6 dL/g (%)

EXAMPLE 2

Vehicle Compositions A to G

[0055] 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-00002 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 0.04 0.04 0.04 0.04 0.04 0.04 0.04 F68

EXAMPLE 3

Microparticle Suspension

[0056] 180 mg of microparticles of example 1-1, 1-2 or 1-3 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

[0057] 180 mg of microparticles of example 1-1, 1-2 or 1-3 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)

[0058] Microparticles containing octreotide are suspended in 1 ml of a suitable aqueous vehicle and the resulting suspension is injected intramusculary (i.m.) into male New Zealand White rabbits in a dose of 12 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 by radioimmunoassay (RIA).

TABLE-US-00003 TABLE 4 Plasma Levels Example 1-1 Subject No. Mean or Time [days] 473 474 476 480 Range‡ SD 0 0.000 0.000 0.000 0.000 0.000 0.000 0.021 56.026 41.316 52.099 48.148 49.397 6.274 0.042 40.769 50.921 37.531 30.494 39.929 8.491 0.083 16.154 25.658 15.185 11.889 17.222 5.913 0.167 4.590 5.408 4.654 2.617 4.317 1.193 0.25 2.103 1.987 1.383 1.006 1.620 0.517 1 0.763 0.597 0.503 0.517 0.595 0.119 2 0.579 0.694 0.513 0.476 0.566 0.096 6 1.769 2.105 1.556 1.802 1.808 0.226 9 2.218 2.895 2.099 1.864 2.269 0.442 16 2.744 2.750 2.198 2.136 2.457 0.336 23 2.436 3.118 2.185 2.049 2.447 0.475 30 2.192 2.579 1.741 2.173 2.171 0.342 37 2.564 3.526 2.049 2.605 2.686 0.614 44 1.731 3.053 1.667 2.420 2.218 0.653 51 2.589 2.355 1.259 2.914 2.279 0.718 58 2.128 1.842 1.104 2.975 2.012 0.773 65 1.206 1.684 0.712 2.333 1.484 0.691 72 0.631 1.056 0.613 1.358 0.915 0.360 79 0.218 0.600 0.389 0.837 0.511 0.268 86 0.111 0.219 0.143 0.425 0.225 0.141 93 0.000 0.105 0.000 0.231 0.084 0.110 100 0.000 0.000 0.000 0.111 0.028 0.056