FR2668707A1 - Process for preparing a pharmaceutical composition - Google Patents

Abstract

A pharmaceutical composition is prepared in the form of microparticles or implant comprising a biodegradable polymer chosen from poly-1,4-butylene-succinate, poly-2,3-butylene-succinate, poly-1,4-. butylene fumarate and poly-2,3-butylene succinate, incorporating as active substance a pamoate, tannate, stearate or palmitate of a natural or synthetic peptide comprising from 3 to 45 amino acids, such as LH-RH , somatostatin, GH-RH or calcitonin or one of their synthetic analogs or homologues. The preparation comprises the dry mixing of the ingredients, in powder form, the precompression and the preheating of the mixture followed by the extrusion of the precompressed and preheated mixture. The product resulting from the extrusion can then be pulverized and finally sieved.

Description

Process for preparing a pharmaceutical composition The invention

  object a process for the preparation of a pharmaceutical composition in the form of microparticles or of an implant, the composition thus obtained

and its use.

  The subject of the invention is more specifically a process for the preparation of a pharmaceutical composition intended for the sustained and controlled release of a medicinal substance comprising a biodegradable polyester-type copolymer such as polysuccinate or polyfumarate, incorporating as active substance a pamoate, tannate , stearate or palmitate of a natural or synthetic peptide, more particularly a peptide comprising from 3 to 45 amino acids. Various solutions have been proposed to date for the preparation of sustained-release and controlled-release compositions of medicinal substances, using the manufacture of biodegradable implants, microencapsulation or the preparation of biodegradable porous matrices, for example in the form of microparticles of various dimensions.

  EP-A-0052510 for microencapsulation and EP-A-

  0058481 or US-A-3 976 071 for the preparation of biodegradable porous implants or matrices based on polylactide or

  co-polylactide-glycolide for the most part, or DE-A-

  3835099 8 relating to polyesters such as poly-1,4-

  butylene succinate or fumarate, poly-2,3-butylene succinate or fumarate for example These techniques all involve the prior dissolution in an organic solvent, the biodegradable polymer or copolymer used as a carrier, where appropriate to the dissolution of the drug substance itself If, in such cases, the 2-dispersion of the active substance within the biodegradable polymer mass is satisfactory, there is still the problem of traces of residual solvent which may compromise the use of such compositions as Therapeutic The choice of low-toxicity solvents or the extensive removal of traces of solvent can be sometimes complex and expensive, and can lead to a decrease in purity

unacceptable product.

  It has also been proposed to dry mix, ie without solvent, a protein substance (Bovine Serum Albumin) and a biodegradable copolymer of lactic and glycolic acid in pulverulent form, followed by the compression at the melting temperature of the mixture obtained (JD Gresser et al, Biopolymeric Controlled Release System Vol II, p 136) This technique has not proved satisfactory, especially as regards the homogeneity of the distribution of the protein substance (BSA) within of the mass and, consequently, the regularity of the

release of the active substance.

  Against all odds, it was found that one could overcome these various obstacles by starting

  of biodegradable polymers selected from poly-1,4-

  butylene-succinate, poly-2,3-butylene succinate, poly-

  1,4-butylene-fumarate and poly-2,3-butylene-fumarate and natural or synthetic peptides, such as octa-, nona- or decapeptides, more generally peptides comprising from 3 to 45 amino acids, by the implementation of the method of

  Poly (1,4-butylene) is preferably used.

  succinate. According to the invention, the natural or synthetic peptides are used in the form of salts, more precisely in the form of pamoates, tannates, stearates or palmitates, 3-pamoate being preferably used.

  that these peptide salts are insoluble in water.

  The aforementioned salts, as well as the biodegradable polyesters mentioned above are used in pulverulent form, in fact in the form of microparticles of average dimensions of less than about 500 microns. Good results have been obtained with polymer microparticles of about 180 microns. micron or less, the peptide salt can be of even smaller particle size Mixing of these materials is carried out dry in any suitable apparatus, for example a ball mill, at room temperature (approx. lower temperature, for example 5 to 100 C The proportions of the pulverulent constituents may vary widely, for example from 0.1 to 15% by weight of peptide salt, in

  function of the desired therapeutic effects.

  According to the invention, once the determined mixture duly homogenized, it is subjected to a progressive compression and simultaneously to a progressive heating before being extruded These two operations, as well as the transport of the mixture to the zone of precompression and preheating can be advantageously performed using a worm screw, appropriately sized, where appropriate with two worms acting in a combined manner The compression ratio may vary depending on many factors such as that the geometry of the apparatus or the particle size of the pulverulent mixture Plus determining to be controlled is the preheating and its evolution as and the progress of the mixture: according to the nature of the products to be treated (polyester, peptide) one s strives to maintain a temperature gradient whose maximum is of the order of 900 ° C. The initial temperature at which the powder mixture is subjected to could be 250 C, more

either less depending on the case.

  4 - The mixture thus precompressed and preheated is then subjected to extrusion, at a temperature generally between 90 and 1000 C, the upper limit of this interval being dictated by the nature of the drug substance (peptide) that is appropriate The extrusion can take place at a pressure that varies greatly, from 50 to 500 kg / cm 2, the main thing being to use temperature and extrusion pressure with the viscosity of the product. understood the perfect homogenization of the ingredients, in particular the regular distribution of the peptide salt at

  within the biodegradable polymer mass.

  The actual extrusion is carried out by means of a nozzle of standard shape and dimensions, placed at the end of the end of the auger mentioned above. The cooling of the extruded product is carried out using any suitable means. , air or sterile gas cooled or by

simple heat loss.

  When the preparation process is completed at this stage, a composition according to the invention is obtained in the form of implant. Such implants are simply collected by cutting a segment of length.

  determined product leaving the extrusion nozzle.

  The shape of said implant can be

  dependent on that of the extrusion nozzle.

  According to one of the embodiments of the invention, the suitably cooled extrusion product is then sprayed at a low temperature, preferably at a temperature below 0 ° C, or even considerably lower, -300 ° C for example. cryogenic spraying, a technique known per se The product thus sprayed is then subjected to sorting of the microparticles according to their average dimensions, those of dimension less than 200 microns, preferably less than or equal to 180 microns being then retained, in accordance with This sorting of the microparticles can be, for example, carried out by sieving. The microparticles sorted and collected are

then ready for use.

  According to the method of the invention, the steps described above take place successively, without excessive dead time from one phase to another. The advantage of this method is that it can also be carried out continuously all the operations are chained one after the other by

  simple transfer of the treated mixture.

  According to the invention, as a biodegradable polymer

  Preferably, a biodegradable polyester composed of poly-1,4-butylene succinate is used. Such polymers are readily prepared in accordance with the cited literature.

  or can be obtained from the specialized trade.

  The peptide salts, natural or synthetic, thus incorporated into the polymer mass are preferably peptide salts comprising from 3 to 45 amino acids, more particularly LH-RH (Luteinizing Hormone Releasing Hormone), somatostatin salts. , GH-RH (Growth Hormone Releasing Hormone) or calcitonin, or

  their counterparts or synthetic analogues.

  In particular, they are pamoates of LH-

  RH or somatostatin or one of their counterparts or analogues selected from

I 1

  D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-OH, D-Phe-Cys-Phe-D-TrpLys-Thr-Cys-Trp-NH 2, D-Trp-D Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2, -6 D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2, D-Phe-Cs -Tyr-D-Trp-Lys-Val-C'-Trp-NH 2, y Ac Phe-Cys-PheD-Trp-Lys-Thr-Cys-Thr-NH 2, Ac Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Trp-NH 2, (pyro) Glu-His-Trp-D-Ser-Tyr-D-Leu-Arg-Pro-NHR 1, (pyro) Glu-His-Trp-SerTyr-D- Trp-Leu-Arg-Pro-NH R1, (pyro) Glu-His-Trp-Ser-Tyr-D-Trp-Leu-ArgPro-Gly-NH 2 or (pyro) Glu-His-Trp-Ser-Tyr- D-Phe-Leu-Arg-Pro-Gly-NH 2 (R 1 = lower alkyl), this enumeration not being limiting. The microparticles obtained according to the process of the invention from the abovementioned ingredients are then used, after an adequate sterilization, for the

  preparation of injectable suspensions.

  The examples below illustrate the invention of

  in more detail without limiting it.

Example 1

  g of poly-1,4-butylene-succinate (inherent viscosity ca. 0.35 in HFIP) in the form of granules of the order of 3 to 5 mm in diameter were first milled at low temperature and sieved to room temperature. obtaining microparticles of average size of 500 microns or less. To this powdery mass was added 0.445 g of D-Trp 6-LH-RH pamoate (peptide formula): 7 - (pyro) Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-ProGly Finely pulverized NH 2 This product is in the form of microparticles approximately 10 microns in size and of amorphous structure. The resulting mixture was homogenized at

  room temperature, in a mill.

  The homogenized mixture was then placed in an apparatus equipped with an endless screw coupled to a conventional extrusion nozzle.

  length of about 25 cm and a diameter of about 1.5 cm.

  It comprises a first zone used exclusively for moving the mixture, adjacent to a second reserved zone

  compression and preheating.

  Throughout its course, the mixture is increased from 25 to about 900 C, the speed of movement being adapted so that this phase is of the order of 5 min. The actual extrusion takes place at 980 ° C., the extrusion nozzle having an orifice of the order of 1.0 mm in diameter. The filaments thus obtained are then allowed to cool to room temperature, cut into small portions and finally milled at -300 ° C. After sieving, the microparticles of average size of 180 microns or less are recovered. The chemical analysis carried out on samples of extruded and ground product confirms the perfect homogeneity of the dispersion of the active substance within the polymer mass. The microparticles obtained above were subjected to gamma sterilization and

  then suspended in a suitable sterile vehicle.

  In vivo tests (assay of blood testosterone levels in male rat strains) confirm the regular release of the active substance for at least 25 days, which results in a collapse of testosterone

castration values.

Example 2

  In accordance with Example 1, microparticles of poly-1,4-butylene succinate (iv about 0.35) containing, at a comparable dosage, a pamoate of one of the following decapeptides were prepared: (pyro) ) Glu-His-Trp-Ser-Tyr-D-Phe-Leu-Arg-Pro-Gly-NH 2 (pyro) Glu-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro NR 1, or (pyro) Glu-His-Trp-SerTyr-D-Tyr-Leu-Arg-Pro-NHR 1 (R 1) = ethyl)

Example 3

  The procedure according to Example 1 was carried out starting from 18 g of poly-1,4-butylene succinate (about 0.35) and

  2.85 g pamoate of a somatostatin analogue -

  peptide formula: D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH 2 to obtain microparticles having the desired particle size. The chemical analysis carried out on samples of extruded and ground product confirms the perfect homogeneity of the dispersion of the active substance within the copolymer mass. In vivo tests, in addition, confirm the controlled release of the active substance (

  somatostatin) over a period of at least 7 days.

Example 4

  As in Example 3, to obtain microparticles of poly-1,4-butylene-succinate containing, at a comparable dosage, a pamoate of one of the following octapeptides: D-Phe-Cys-Phe-D- Trp-Lys-Thr-Cys-ThrOH, D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH 2, D-Trp-Cys-Phe-D-Trp-LysThr-Cys-Thr -NH 2, D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2, Ac Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 , i 1

  Ac Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH 2.

  The chemical analysis performed on samples of extruded and ground product confirms the perfect homogeneity of the dispersion of the active substance in the copolymer mass.

* * * * * * * * * * * * * * * *

  In the experiments described above, it was observed that the extruded filaments, when cut into sticks of appropriate length, could be directly used as implants, after sterilization. Such implants also provide sustained release and

controlled active substance.

he -

Claims (8)

  A process for the preparation of a pharmaceutical composition for sustained and controlled release of a medicinal substance comprising a   biodegradable polymer selected from poly-1,4-   butylene succinate, poly-2,3-butylene succinate,   poly-1,4-butylene-fumarate and poly-2,3-   butylene succinate, incorporating as active substance a pamoate, tannate, stearate or palmitate of a natural or synthetic peptide, characterized in that a) the selected biodegradable polymer and active substance are mixed dry, both in the form of microparticles of average size less than about 500 microns; b) gradually compressing and gradually heating up to about 900 C the powder mixture obtained; c) the precompressed and preheated extrusion mixture is subjected to a temperature of about 1000 C, and then the extruded product is cooled; and, where appropriate, d) the product resulting from the extrusion is sprayed at low temperature, then selected and   finally collects the microparticles obtained.   2 Method according to claim 1, characterized in that it comprises the steps a, b and c and that it leads to obtaining an implant.   12 - 3 Process according to claim 1, characterized in that it comprises the steps a, b, c and d and that it   leads to obtaining microparticles.   4 Process according to claim 3, characterized in that the microparticles of biodegradable polymer have an average size of less than or equal to 200 microns, preferably less than or equal to microns.   Process according to Claim 1, characterized in that the precompression and the preheating of the mixture are carried out simultaneously, with the aid of one or several worms.   Process according to Claim 1, characterized in that the extrusion is carried out at a pressure between 50 and 500 kg / cm 2.   Method according to one of claims 1 and 3,   characterized in that the spraying of the product resulting from the extrusion is a cryogenic spray.   8 Process according to one of claims 1 and 3   characterized in that the selection of the microparticles resulting from the spraying is sieved.   Process according to one of Claims 1 to 8,   characterized in that the active substance is a pamoate, tannate, stearate or palmitate of a natural or synthetic peptide comprising from 3 to 45 acids   amines, including LH-RH, somatostatin, GH-   HR or calcitonin or their analogues or synthetic counterparts.   13 - Process according to claim 9, characterized in that the active substance is an LH-RH pamoate, somatostatin or one of their analogues or synthetic homologues chosen from D-Phe-Cys-Phe-DTrp-Lys- Thr-Cys-Thr-OH, I-PE-D-Tp-Lys Thr-Cs-Tr IN D-Phe-CysPhe-D-Trp-Lys-Thr-Cys-Trp-NH 2, D- Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2, D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2, D-Phe-Cys- Tyr-D-Trp-Lys-ValCys-Trp-NH 2, Ac Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2, 1 Ac Phe-CysTyr-D-Trp-Lys- Val-Cys-Trp-NH 2, (pyro) Glu-His-Trp-Ser-Tyr-D-Trp-Leu-ArgPro-Gly-NH 2, (pyro) Glu-His-Trp-Ser-Tyr-D- Phe-Leu-Arg-Pro-Gly-NH 2, (pyro) Glu-His-Trp-D-Ser-Typ-D-Leu-Leu-Arg-Pro-NH R1, or (pyro) Glu-HisTrp-Ser -Tyr-D-Trp-Leu-Arg-Pro-NHR 1 (R 1 = lower alkyl).   Pharmaceutical composition obtained by the process   according to one of claims 1 to 10.