CA2055115A1 - A process for preparing a pharmaceutical composition - Google Patents
A process for preparing a pharmaceutical compositionInfo
- Publication number
- CA2055115A1 CA2055115A1 CA002055115A CA2055115A CA2055115A1 CA 2055115 A1 CA2055115 A1 CA 2055115A1 CA 002055115 A CA002055115 A CA 002055115A CA 2055115 A CA2055115 A CA 2055115A CA 2055115 A1 CA2055115 A1 CA 2055115A1
- Authority
- CA
- Canada
- Prior art keywords
- trp
- process according
- poly
- leu
- tyr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 239000011859 microparticle Substances 0.000 claims abstract description 19
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 18
- 238000001125 extrusion Methods 0.000 claims abstract description 17
- 239000013543 active substance Substances 0.000 claims abstract description 14
- 239000007943 implant Substances 0.000 claims abstract description 10
- 229920002988 biodegradable polymer Polymers 0.000 claims abstract description 9
- 239000004621 biodegradable polymer Substances 0.000 claims abstract description 9
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims abstract description 7
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 102000005157 Somatostatin Human genes 0.000 claims abstract description 5
- 108010056088 Somatostatin Proteins 0.000 claims abstract description 5
- 229920002253 Tannate Polymers 0.000 claims abstract description 5
- 150000001413 amino acids Chemical class 0.000 claims abstract description 5
- 229960000553 somatostatin Drugs 0.000 claims abstract description 5
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims abstract description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 102000055006 Calcitonin Human genes 0.000 claims abstract description 3
- 108060001064 Calcitonin Proteins 0.000 claims abstract description 3
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims abstract description 3
- 229960004015 calcitonin Drugs 0.000 claims abstract description 3
- 101000904177 Clupea pallasii Gonadoliberin-1 Proteins 0.000 claims abstract 3
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 claims abstract 3
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 claims abstract 3
- 239000011874 heated mixture Substances 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 19
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 claims description 8
- 230000006835 compression Effects 0.000 claims description 6
- 238000007906 compression Methods 0.000 claims description 6
- 230000002459 sustained effect Effects 0.000 claims description 6
- 238000013270 controlled release Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 230000003247 decreasing effect Effects 0.000 claims description 3
- 235000012438 extruded product Nutrition 0.000 claims description 3
- 238000007873 sieving Methods 0.000 claims description 3
- -1 GH-RH Chemical compound 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- IHEOXPWZFCUHOQ-UHFFFAOYSA-N 2,3-dimethyl-1,4-dioxocane-5,8-dione Chemical compound CC1OC(=O)CCC(=O)OC1C IHEOXPWZFCUHOQ-UHFFFAOYSA-N 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 abstract description 3
- 239000004615 ingredient Substances 0.000 abstract description 3
- 239000000843 powder Substances 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 9
- 239000000126 substance Substances 0.000 description 5
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108700012941 GNRH1 Proteins 0.000 description 3
- 238000003801 milling Methods 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- KGLGUDHEKBYBDR-UHFFFAOYSA-N 6-amino-N-[1-[[1-[[1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-2-[[2-[[2-[[2-[(2-amino-3-phenylpropanoyl)amino]-3-sulfanylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]hexanamide Chemical compound C=1NC2=CC=CC=C2C=1CC(C(N)=O)NC(=O)C(CS)NC(=O)C(C(C)C)NC(=O)C(CCCCN)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(NC(=O)C(CS)NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=C(O)C=C1 KGLGUDHEKBYBDR-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000004622 biodegradable polyester Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 108700029852 vapreotide Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- RFCVXVPWSPOMFJ-STQMWFEESA-N Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 RFCVXVPWSPOMFJ-STQMWFEESA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- 229920000229 biodegradable polyester Polymers 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
Abstract
ABSTRACT
A pharmaceutical composition is prepared in the form of microparticles or of an implant comprising a biodegradable polymer selected from poly-1,4-butylene succinate, poly-2,3-butylene succinate, poly-1,4-buty-lene fumarate and poly-2,3-butylene succinate, incorpo-rating as the active substance the pamoate, tannate, stearate or palmitate of a natural or of a synthetic peptide comprising 3 to 45 amino acids, such as LH-RH, somatostatin, GH-RH or calcitonin, or one of their synthetic analogues or homologues.
The preparation comprises dry blending the ingre-dients in the form of powders, pre-compressing and pre-heating the mixture and then extruding the pre-compressed and pre-heated mixture. The product resulting from the extrusion step can then be comminuted and finally sieved.
A pharmaceutical composition is prepared in the form of microparticles or of an implant comprising a biodegradable polymer selected from poly-1,4-butylene succinate, poly-2,3-butylene succinate, poly-1,4-buty-lene fumarate and poly-2,3-butylene succinate, incorpo-rating as the active substance the pamoate, tannate, stearate or palmitate of a natural or of a synthetic peptide comprising 3 to 45 amino acids, such as LH-RH, somatostatin, GH-RH or calcitonin, or one of their synthetic analogues or homologues.
The preparation comprises dry blending the ingre-dients in the form of powders, pre-compressing and pre-heating the mixture and then extruding the pre-compressed and pre-heated mixture. The product resulting from the extrusion step can then be comminuted and finally sieved.
Description
z~
A P~OCE8S FOR PR~PARING A PNa~MaCXUTICA~ O~POSITIO~
The object of the invention is a process for preparing a pharmaceutical composition, in the form of microparticles or of an implant, the composition thus obtained and its use.
~ ore specifically, the object of the invention is a process for preparing a pharmaceutical composition designed lor ensuring a sustained and a controlled release of a drug, comprising a biodegradable copolymer of the polyester type, such as a polysuccinate or a polyfumarate and incorporating as the active substance, the pamoate, tannate, stearate or palmitate of a natural or of a synthetic peptide, and more particularly, of a peptide comprising 3 to 45 amino acids.
Various solutions have been proposed to this day for preparing compositions ensuring the sustained and the controlled release of drugs, which make use of biodegradable implants, microencapsulation or of bio-degradable porous matrices which are obtained for example as microparticles of various sizes. One can mention in this respect, EP-A-0052510 for micro-encapsulation, EP-A-0058481 or US-A-3976071 for the pre-paration of implants or biodegradable porous matrices based substantially on a polylactide or a co-poly-lactide-glycolide, or further DE-A-3835093.8, which is concerned with polyesters such as for example poly-1,4-butylene succinate or fumarate, and poly-2,3-butylene succinate or fumarate. All these techniques involve first dissolving the biodegradable polymer or copolymer used as support in an organic solvent, and sometimes dissolving also the drug itself. If in such cases, the dispersion of the active substance through the bulk of the biodegradable polymer is satisfactory, the problem still remains that trace amounts of solvent are retained which can jeopardize the use of such compositions in therapeutic applications. Choosing low toxicity solvents , , .. .
A P~OCE8S FOR PR~PARING A PNa~MaCXUTICA~ O~POSITIO~
The object of the invention is a process for preparing a pharmaceutical composition, in the form of microparticles or of an implant, the composition thus obtained and its use.
~ ore specifically, the object of the invention is a process for preparing a pharmaceutical composition designed lor ensuring a sustained and a controlled release of a drug, comprising a biodegradable copolymer of the polyester type, such as a polysuccinate or a polyfumarate and incorporating as the active substance, the pamoate, tannate, stearate or palmitate of a natural or of a synthetic peptide, and more particularly, of a peptide comprising 3 to 45 amino acids.
Various solutions have been proposed to this day for preparing compositions ensuring the sustained and the controlled release of drugs, which make use of biodegradable implants, microencapsulation or of bio-degradable porous matrices which are obtained for example as microparticles of various sizes. One can mention in this respect, EP-A-0052510 for micro-encapsulation, EP-A-0058481 or US-A-3976071 for the pre-paration of implants or biodegradable porous matrices based substantially on a polylactide or a co-poly-lactide-glycolide, or further DE-A-3835093.8, which is concerned with polyesters such as for example poly-1,4-butylene succinate or fumarate, and poly-2,3-butylene succinate or fumarate. All these techniques involve first dissolving the biodegradable polymer or copolymer used as support in an organic solvent, and sometimes dissolving also the drug itself. If in such cases, the dispersion of the active substance through the bulk of the biodegradable polymer is satisfactory, the problem still remains that trace amounts of solvent are retained which can jeopardize the use of such compositions in therapeutic applications. Choosing low toxicity solvents , , .. .
- 2 - ~ ~5~5 or removing thoroughly trace amounts of residual solvent can be sometimes complicated and costly, and it can further result in an unacceptable 105s of purity for the product.
It has also been proposed to dry blend - i. e. mix without using any solvent - a proteinic substance (Bovine Serum Albumine) and a biodegradable copolymer of lactic and glycolic acid used as powders, and then to proceed to the compression of the mixture at the melting temperature thereof (J. D. Gresser and col., Biopolymeric Controlled Release System Vol. II, p. 136).
This technique has not proven satisfactory, in parti-cular for achieving a homogeneous distribution of the proteinic substance (BSA) throughout the bulk of the product and accordingly, for ensuring the regularity of the release of the active substance.
Against all expectations, it was found that these various dif~iculties could be overcome according to the process of the invention, by using as starting materials biodegradable polymers selected from poly-1,4-butylene succinate, poly-2,3-butylene succinate, poly-1,4-butylene fumarate or poly-2,3-butylene fumarate and na-tural or synthetic peptides such as octa-, nona-, or decapeptides, and more generally peptides comprising 3 to 45 amino acids. Poly-1,4-butylene succinate is the preferred polym~r.
According to the invention, natural or synthetic peptides are used in the form of their salts, and more particularly as pamoates, tannates, stearates or palmi-tates, and preferably as pamoates. It should be noted at this point, that th~se peptide salts are water-insoluble.
Both the above-mentioned salts and the above-mentioned biodegradable polyesters are used as powders, and more particularly as microparticles having an ave-rage size smaller than about 500 microns. Good results were achieved with polymeric microparticles in the order - 3 - 2~ 5 of 180 microns or less, and the particle size of the peptide salt can be even smaller. The mixture of these compounds is carried out by dry blending in any appro-priate equipment, such as for example a ball mill, at room temperature (about 25C) or even at a lower tempe-rature, for example in the range from 5 to 10C. The proportions of the powdered components can vary conside-rably, depending on the therapeutic effect desired, for example from 0.1 to 15% in weight for the peptide salt.
According to the invention, once the selected mix-ture is thoroughly homogenized, it is subjected to a progressive compression and, simultaneously, to a pro-gressive heating before beiny extruded. Both operations, as well as the transfer of the mixture to the pre-compression and pre-heating zone can be advantageously carried out using an appropriately dimensioned endless screw or, if required, two co-operating endless s rews.
The compression rate can vary depending on a numerous factors such as extruder geometry or particle size of the powdered mixture. An important factor which must be controlled is the pre-heating and its evolution as the mixture moves forward; depending upon the nature of the products to be treated (polyester, peptide), one should strive at maintaining a temperature gradient with a maximum of about 90C. The initial temperature of the powdered mixture can be 25C, or it can be higher or lower, depending on circumstances.
Th~ mixture thus pre-compressed and pre-heated is then subjected to an extrusion at a temperature gene-rally comprised between approximately 90 and 100C, the upper limit of this range being function of the nature of the drug (peptide), which must not be allowed to deteriorate. The extrusion can be carried out in a wide range of pressures extending from 50 to 500 kg/cm2, the important point being that the extrusion temperature and the pression must be suited to the viscosity of the product. Appropriate pressure and temperature are - 2~ 5 clearly favourable fox ensuring the perfect homogeniza-tion of the ingredients and in particular the regular distxibution of the peptide salt throughout the bulk of the biodegradable polymer.
The extrusion per se is carried out using a die of conventional shape and size, which is located at the downstream end of the above-mentioned endless screw The cooling of the extruded product is ensured by any appropriate means, for example through a simple heat transfer to cooled sterile gas or air.
When the process of preparation is stopped after this step, a composition in accordance with the inven-tion is obtained in the form of implants. Such implants are simply collected by cutting segments of predeter-mined length as the product is pressed out from the extrusion die.
Incidently, the shape of said implant can be varied by changing the shape of the extrusion die.
In one embodiment of the invention, the extruded product appropriately cooled is subsequently comminuted at decreased temperature, preferably at a temperature below O~C, or even much lower, such as for example -30C. Cryogenic comminution, a technique which is known per se, is advantageously used for this purpose. In accordance with the process of the invention, the pro-duct thus comminuted is then subjected to a selection of microparticles based on their average size, with parti-cles smaller than 200 microns and preferably smaller or e~ual to 180 microns being retained. This selection of microparticles can be carried out for example, by sieving. The microparticles thus selected and collected are ready for use.
In accordance with the process of the invention, the above-described steps are carried out in succession without any excessive time lag in-between. The advantage of this process, is that it can be carried out on a continuous basis, with all the operations being carried .
Z~ 5 out one after the other, merely by transferring the mixture being processed.
According to the invention, a biodegradable poly-ester comprised of poly-1,4-butylene succinate is used preferably as the biodegradable polymer. Such polymers are easily prepared as described in the cited literature and they can be obtained commercially from specialized firms.
Whether they be natural or synthetic, the peptide salts incorporated into the polymer are preferably pep-tide salts comprising 3 to 45 amino acids, and more particularly salts of LH-RH (Luteinizing Hormone Releasing Hormone), somatostatin, GH-RH tGrowth Hormone - Releasing Hormone), calcitonin or of their synthetic homologues and analogues.
More particularly, the products are chosen amongst the pamoates of LH-RH, somatostatin or of synthetic homologues and analogues thereof, such as D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-OH, D-Phe-C~s-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2, D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-~H2, D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2, AcPhe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, AcPhe-~ys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2, tpyro)Glu-His-Trp-D-Ser-Tyr-D-Leu-Arg-Pro-NHRl, tpyro)Glu-His-Trp-Ser~Tyr-D-Trp-Leu-Arg-Pro-NHRl, tpyro)Glu-~is-Trp-ser-Tyr-D-Trp-Leu-Arg-pro-Gly-NH2~ and tpyro)Glu-His-Trp-Ser-Tyr-D~Phe-Leu~Arg-Pro-Gly-NH2, where R1 = lower alkyl, this list not being limitative.
The microparticles obtained in accordance with the process of the invention from the above-mentioned ingre-dients are then used, after an appropriate steriliza-tion, for preparing injectable suspensions.
The following Ex~mples illustrate the invention in more details, without however being limitative thereof.
2~!5 ~ample 1 20 g of poly-1,4-butylene succinate, tinherent vis-cosity of about 0.35 in HFIP) obtained as granules with a diameter ranging approximately from 3 to 5 mm were first milled at a decreased temperature and sieved to obtain microparticles with an average si~e of 500 mi-crons or less.
To this powdered composition, 0.445 g of finely comminuted D-Trp6-LH-RH pamoate were added, the peptide having the following formula : ~
(pyro)Glu-His-Trp-Ser~Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2.
This product consists of microparticles of about 10 microns and its structure is amorphous. The resulting mixture was homogenized at room temperature, using a mill.
The resulting homogenized mixture was then placed inside an apparatus eguipped with an endless screw co-operating with a conventional extrusion die. The endless screw can have a length of about 2~ cm and a diameter of about 1.5 cm. It comprises a first zone which functions simply to move the mixture and which is adjacent to a second zone, designed for the compression and the pre-heating.
As it moves forward, the mixture is heated from 25 to about 90C, the rate of progression being selected so that this phase lasts about 5 min. The extrusion per S8 takes place at 98C, through an extrusion die with an orifice having a diameter of about 1.0 mm.
The filaments thus obtained are allowed to cool to room temperature, then they are cut into small segments and finally milled at -30C. After sieving, those micro-particles having an average diameter of 180 microns or less are collected.
The chemical analysis carried out on samples of the product after extrusion and milling confirms the perfect homogeneity of the dispersion of the active substance throughout the bulk of the polymer.
Z~ 5 The microparticles obtained above were subjected to a sterilization by gamma rays and then they were sus-pended in an appropriate sterile vehicle.
The in vivo tests (determination of the blood testosterone level in strains of male rats) confirm that the release of the active substance remains sustained for at least 25 days, as can be inferred from the collapse of the testosterone level to values observed on castratad animals.
3xampl~ 2 The operations of Example 1 were repeated to obtain microparticles of poly 1,4-butylene succinate ~i. v. of about 0.35) containing comparable amounts of the pamoate of one of the following decapeptides :
(pyro)Glu-His-Trp-Ser-Tyr-D-Phe-Leu-Arg-Pro-Gly-NH2, (pyro)Glu-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro-NR1, or (pyro)Glu-His-Trp-Ser-Tyr-D-Tyr-Leu-Arg-Pro-NR1, where R1 = ethyl.
Example 3 The operations of Example 1 were repeated, using as starting material 18 g of poly-1,4-butylene succinate (i. v. of about 0.35) and 2.85 g of the pamoate of an analogue of somatostatin, having the following peptide formula :
D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 for the preparation of microparticl~s having the desired particle size.
The chemical analysis carried out on samples of the product after extrusion and milling, confirms the perfect homogeneity of the dispersion of the active substance throughout the bulk of the polymer.
In ViYo tests further confirm, that the release of the active substance (an analogue of somatostatin) re-mains sustained over a period of at least 7 days.
- 8 - ~ S
~xample 4 The operations of Example 3 were repeated, for obtaining micropartisles of poly-1,4-butylene succinate with compaxable levels of the pamoate of one o~ the following octapeptides :
D-Phe-C~s-Phe-D-Trp-Lys-Thr-Cys-Thr-OH, D-Phe-Cl~s-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2, D-Trp-C~s Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, D-Phe-Cys-Tyr-D-Tr}?-Lys-Val-Cys-Thr-NH2, AcPhe-Cys-Phe-D-Trp-Lys-Thr ~ s-Thr-NH2, AcPhe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2.
The chemical analysis carried out on samples of the product after extrusion and milling, confirms the per-fect homogeneity of the dispersion of the active sub-stance throughout the bulk of the copolymer.
* * * * * * * * * * * *
During the experimentation described above, it was found that the extruded filaments, once cut into rods of an appropriate l~ngth, can be used directly as implants, after sterilization. Such implants also Dnsure ~ -a sustained and a controlled release of the active substance.
It has also been proposed to dry blend - i. e. mix without using any solvent - a proteinic substance (Bovine Serum Albumine) and a biodegradable copolymer of lactic and glycolic acid used as powders, and then to proceed to the compression of the mixture at the melting temperature thereof (J. D. Gresser and col., Biopolymeric Controlled Release System Vol. II, p. 136).
This technique has not proven satisfactory, in parti-cular for achieving a homogeneous distribution of the proteinic substance (BSA) throughout the bulk of the product and accordingly, for ensuring the regularity of the release of the active substance.
Against all expectations, it was found that these various dif~iculties could be overcome according to the process of the invention, by using as starting materials biodegradable polymers selected from poly-1,4-butylene succinate, poly-2,3-butylene succinate, poly-1,4-butylene fumarate or poly-2,3-butylene fumarate and na-tural or synthetic peptides such as octa-, nona-, or decapeptides, and more generally peptides comprising 3 to 45 amino acids. Poly-1,4-butylene succinate is the preferred polym~r.
According to the invention, natural or synthetic peptides are used in the form of their salts, and more particularly as pamoates, tannates, stearates or palmi-tates, and preferably as pamoates. It should be noted at this point, that th~se peptide salts are water-insoluble.
Both the above-mentioned salts and the above-mentioned biodegradable polyesters are used as powders, and more particularly as microparticles having an ave-rage size smaller than about 500 microns. Good results were achieved with polymeric microparticles in the order - 3 - 2~ 5 of 180 microns or less, and the particle size of the peptide salt can be even smaller. The mixture of these compounds is carried out by dry blending in any appro-priate equipment, such as for example a ball mill, at room temperature (about 25C) or even at a lower tempe-rature, for example in the range from 5 to 10C. The proportions of the powdered components can vary conside-rably, depending on the therapeutic effect desired, for example from 0.1 to 15% in weight for the peptide salt.
According to the invention, once the selected mix-ture is thoroughly homogenized, it is subjected to a progressive compression and, simultaneously, to a pro-gressive heating before beiny extruded. Both operations, as well as the transfer of the mixture to the pre-compression and pre-heating zone can be advantageously carried out using an appropriately dimensioned endless screw or, if required, two co-operating endless s rews.
The compression rate can vary depending on a numerous factors such as extruder geometry or particle size of the powdered mixture. An important factor which must be controlled is the pre-heating and its evolution as the mixture moves forward; depending upon the nature of the products to be treated (polyester, peptide), one should strive at maintaining a temperature gradient with a maximum of about 90C. The initial temperature of the powdered mixture can be 25C, or it can be higher or lower, depending on circumstances.
Th~ mixture thus pre-compressed and pre-heated is then subjected to an extrusion at a temperature gene-rally comprised between approximately 90 and 100C, the upper limit of this range being function of the nature of the drug (peptide), which must not be allowed to deteriorate. The extrusion can be carried out in a wide range of pressures extending from 50 to 500 kg/cm2, the important point being that the extrusion temperature and the pression must be suited to the viscosity of the product. Appropriate pressure and temperature are - 2~ 5 clearly favourable fox ensuring the perfect homogeniza-tion of the ingredients and in particular the regular distxibution of the peptide salt throughout the bulk of the biodegradable polymer.
The extrusion per se is carried out using a die of conventional shape and size, which is located at the downstream end of the above-mentioned endless screw The cooling of the extruded product is ensured by any appropriate means, for example through a simple heat transfer to cooled sterile gas or air.
When the process of preparation is stopped after this step, a composition in accordance with the inven-tion is obtained in the form of implants. Such implants are simply collected by cutting segments of predeter-mined length as the product is pressed out from the extrusion die.
Incidently, the shape of said implant can be varied by changing the shape of the extrusion die.
In one embodiment of the invention, the extruded product appropriately cooled is subsequently comminuted at decreased temperature, preferably at a temperature below O~C, or even much lower, such as for example -30C. Cryogenic comminution, a technique which is known per se, is advantageously used for this purpose. In accordance with the process of the invention, the pro-duct thus comminuted is then subjected to a selection of microparticles based on their average size, with parti-cles smaller than 200 microns and preferably smaller or e~ual to 180 microns being retained. This selection of microparticles can be carried out for example, by sieving. The microparticles thus selected and collected are ready for use.
In accordance with the process of the invention, the above-described steps are carried out in succession without any excessive time lag in-between. The advantage of this process, is that it can be carried out on a continuous basis, with all the operations being carried .
Z~ 5 out one after the other, merely by transferring the mixture being processed.
According to the invention, a biodegradable poly-ester comprised of poly-1,4-butylene succinate is used preferably as the biodegradable polymer. Such polymers are easily prepared as described in the cited literature and they can be obtained commercially from specialized firms.
Whether they be natural or synthetic, the peptide salts incorporated into the polymer are preferably pep-tide salts comprising 3 to 45 amino acids, and more particularly salts of LH-RH (Luteinizing Hormone Releasing Hormone), somatostatin, GH-RH tGrowth Hormone - Releasing Hormone), calcitonin or of their synthetic homologues and analogues.
More particularly, the products are chosen amongst the pamoates of LH-RH, somatostatin or of synthetic homologues and analogues thereof, such as D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-OH, D-Phe-C~s-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2, D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-~H2, D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2, AcPhe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, AcPhe-~ys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2, tpyro)Glu-His-Trp-D-Ser-Tyr-D-Leu-Arg-Pro-NHRl, tpyro)Glu-His-Trp-Ser~Tyr-D-Trp-Leu-Arg-Pro-NHRl, tpyro)Glu-~is-Trp-ser-Tyr-D-Trp-Leu-Arg-pro-Gly-NH2~ and tpyro)Glu-His-Trp-Ser-Tyr-D~Phe-Leu~Arg-Pro-Gly-NH2, where R1 = lower alkyl, this list not being limitative.
The microparticles obtained in accordance with the process of the invention from the above-mentioned ingre-dients are then used, after an appropriate steriliza-tion, for preparing injectable suspensions.
The following Ex~mples illustrate the invention in more details, without however being limitative thereof.
2~!5 ~ample 1 20 g of poly-1,4-butylene succinate, tinherent vis-cosity of about 0.35 in HFIP) obtained as granules with a diameter ranging approximately from 3 to 5 mm were first milled at a decreased temperature and sieved to obtain microparticles with an average si~e of 500 mi-crons or less.
To this powdered composition, 0.445 g of finely comminuted D-Trp6-LH-RH pamoate were added, the peptide having the following formula : ~
(pyro)Glu-His-Trp-Ser~Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2.
This product consists of microparticles of about 10 microns and its structure is amorphous. The resulting mixture was homogenized at room temperature, using a mill.
The resulting homogenized mixture was then placed inside an apparatus eguipped with an endless screw co-operating with a conventional extrusion die. The endless screw can have a length of about 2~ cm and a diameter of about 1.5 cm. It comprises a first zone which functions simply to move the mixture and which is adjacent to a second zone, designed for the compression and the pre-heating.
As it moves forward, the mixture is heated from 25 to about 90C, the rate of progression being selected so that this phase lasts about 5 min. The extrusion per S8 takes place at 98C, through an extrusion die with an orifice having a diameter of about 1.0 mm.
The filaments thus obtained are allowed to cool to room temperature, then they are cut into small segments and finally milled at -30C. After sieving, those micro-particles having an average diameter of 180 microns or less are collected.
The chemical analysis carried out on samples of the product after extrusion and milling confirms the perfect homogeneity of the dispersion of the active substance throughout the bulk of the polymer.
Z~ 5 The microparticles obtained above were subjected to a sterilization by gamma rays and then they were sus-pended in an appropriate sterile vehicle.
The in vivo tests (determination of the blood testosterone level in strains of male rats) confirm that the release of the active substance remains sustained for at least 25 days, as can be inferred from the collapse of the testosterone level to values observed on castratad animals.
3xampl~ 2 The operations of Example 1 were repeated to obtain microparticles of poly 1,4-butylene succinate ~i. v. of about 0.35) containing comparable amounts of the pamoate of one of the following decapeptides :
(pyro)Glu-His-Trp-Ser-Tyr-D-Phe-Leu-Arg-Pro-Gly-NH2, (pyro)Glu-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro-NR1, or (pyro)Glu-His-Trp-Ser-Tyr-D-Tyr-Leu-Arg-Pro-NR1, where R1 = ethyl.
Example 3 The operations of Example 1 were repeated, using as starting material 18 g of poly-1,4-butylene succinate (i. v. of about 0.35) and 2.85 g of the pamoate of an analogue of somatostatin, having the following peptide formula :
D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 for the preparation of microparticl~s having the desired particle size.
The chemical analysis carried out on samples of the product after extrusion and milling, confirms the perfect homogeneity of the dispersion of the active substance throughout the bulk of the polymer.
In ViYo tests further confirm, that the release of the active substance (an analogue of somatostatin) re-mains sustained over a period of at least 7 days.
- 8 - ~ S
~xample 4 The operations of Example 3 were repeated, for obtaining micropartisles of poly-1,4-butylene succinate with compaxable levels of the pamoate of one o~ the following octapeptides :
D-Phe-C~s-Phe-D-Trp-Lys-Thr-Cys-Thr-OH, D-Phe-Cl~s-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2, D-Trp-C~s Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, D-Phe-Cys-Tyr-D-Tr}?-Lys-Val-Cys-Thr-NH2, AcPhe-Cys-Phe-D-Trp-Lys-Thr ~ s-Thr-NH2, AcPhe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2.
The chemical analysis carried out on samples of the product after extrusion and milling, confirms the per-fect homogeneity of the dispersion of the active sub-stance throughout the bulk of the copolymer.
* * * * * * * * * * * *
During the experimentation described above, it was found that the extruded filaments, once cut into rods of an appropriate l~ngth, can be used directly as implants, after sterilization. Such implants also Dnsure ~ -a sustained and a controlled release of the active substance.
Claims (11)
1. A process for preparing a pharmaceutical composi-tion designed for the sustained and the controlled release of a drug, including a biodegradable polymer selected from poly-1,4-butylene succinate, poly-2,3-bu-tylene succinate, poly-1,4-butylene fumarate and poly-
2,3-butylene succinate, and incorporating as the active substance the pamoate, tannate, stearate or palmitate of a natural or of a synthetic peptide, characterized in that :
a) the biodegradable polymer and the active sub-stance selected are dry blended, both as micropar-ticles having an average size smaller than about 500 microns;
b) the powdered mixture is compressed progressi-vely and heated progressively to about 90°C;
c) the pre-compressed and pre-heated mixture is subjected to an extrusion at a temperature com-prised between about 90 and 100°C, and the extru-ded product is cooled; and when required :
d) the product resulting from the extrusion is comminuted at a decreased temperature, and finally the microparticles obtained are selected and col-lected.
2. A process according to Claim 1, characterized in that it includes the steps a, b and c, and in that it leads to the obtention of an implant.
a) the biodegradable polymer and the active sub-stance selected are dry blended, both as micropar-ticles having an average size smaller than about 500 microns;
b) the powdered mixture is compressed progressi-vely and heated progressively to about 90°C;
c) the pre-compressed and pre-heated mixture is subjected to an extrusion at a temperature com-prised between about 90 and 100°C, and the extru-ded product is cooled; and when required :
d) the product resulting from the extrusion is comminuted at a decreased temperature, and finally the microparticles obtained are selected and col-lected.
2. A process according to Claim 1, characterized in that it includes the steps a, b and c, and in that it leads to the obtention of an implant.
3. A process according to Claim 1, characterized in that it includes the steps a, b, c and d and in that it leads to the obtention of microparticles.
4. A process according to Claim 3, characterized in that the microparticles of the biodegradable polymer have an average size smaller or equal to 200 microns, and preferably smaller or equal to 180 microns.
5. A process according to Claim 1, characterized in that the pre-compression and the pre-heating of the mixture are carried out simultaneously, through the use of one or more endless screws.
6. A process according to Claim 1, characterized in that the extrusion is carried out at a pressure compri-sed between 50 and 500 kg/cm2.
7. A process according to one of Claims 1 and 3, characterized in that the comminution of the product resulting from the extrusion is a cryogenic comminution.
8. A process according to one of Claims 1 and 3, characterized in that the selection of the micro-particles resulting from the comminution, is carried out by sieving.
9. A process according to one of Claims 1 to 8, characterized in that the active substance is the pamoate, tannate, stearate or palmitate of a natural or of a synthetic peptide comprising 3 to 45 amino acids, and in particular of LH-RH, somatostatin, GH-RH, calci-tonin or of their synthetic analogues or homologues.
10. A process according to Claim 9, characterized in that the active substance is the pamoate of LH-RH, of somatostatin or of one of their synthetic analogues or homologues selected from , , , , , , , (pyro)Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2, (pyro)Glu-His-Trp-Ser-Tyr-D-Phe-Leu-Arg-Pro-Gly-NH2, (pyro)Glu-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHR1, or (pyro)Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-NHR1, where R1 = lower alkyl.
11. A pharmaceutical composition obtained by means of a process according to any one of Claims 1 to 10.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH3616/90-6 | 1990-11-14 | ||
CH3616/90A CH681425A5 (en) | 1990-11-14 | 1990-11-14 |
Publications (1)
Publication Number | Publication Date |
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CA2055115A1 true CA2055115A1 (en) | 1992-05-15 |
Family
ID=4259807
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002055115A Abandoned CA2055115A1 (en) | 1990-11-14 | 1991-11-07 | A process for preparing a pharmaceutical composition |
Country Status (12)
Country | Link |
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JP (1) | JPH04288021A (en) |
AT (1) | AT397198B (en) |
BE (1) | BE1004923A5 (en) |
CA (1) | CA2055115A1 (en) |
CH (1) | CH681425A5 (en) |
DE (1) | DE4136930A1 (en) |
ES (1) | ES2049617B1 (en) |
FR (1) | FR2668707B1 (en) |
GB (1) | GB2249725B (en) |
IT (1) | IT1252870B (en) |
NL (1) | NL9101877A (en) |
SE (1) | SE506448C2 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CH683149A5 (en) * | 1991-07-22 | 1994-01-31 | Debio Rech Pharma Sa | Process for the preparation of microspheres of a biodegradable polymeric material. |
US5456917A (en) * | 1993-04-12 | 1995-10-10 | Cambridge Scientific, Inc. | Method for making a bioerodible material for the sustained release of a medicament and the material made from the method |
US5945128A (en) * | 1996-09-04 | 1999-08-31 | Romano Deghenghi | Process to manufacture implants containing bioactive peptides |
WO2004096178A1 (en) * | 2003-05-02 | 2004-11-11 | The University Of Nottingham | Nano and microparticle drug delivery systems comprising polyesters containing aliphatic dicarboxylate residues and residues of aliphatic polyols |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
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US3978203A (en) * | 1974-07-12 | 1976-08-31 | Dynatech Corporation | Sustained release of pharmaceuticals from polyester matrices |
US4481353A (en) * | 1983-10-07 | 1984-11-06 | The Children's Medical Center Corporation | Bioresorbable polyesters and polyester composites |
US4962091A (en) * | 1986-05-23 | 1990-10-09 | Syntex (U.S.A.) Inc. | Controlled release of macromolecular polypeptides |
GB2209937B (en) * | 1987-09-21 | 1991-07-03 | Depiopharm S A | Water insoluble polypeptides |
CH672887A5 (en) * | 1987-10-14 | 1990-01-15 | Debiopharm Sa | |
CH679207A5 (en) * | 1989-07-28 | 1992-01-15 | Debiopharm Sa | |
IT1243390B (en) * | 1990-11-22 | 1994-06-10 | Vectorpharma Int | PHARMACEUTICAL COMPOSITIONS IN THE FORM OF PARTICLES SUITABLE FOR THE CONTROLLED RELEASE OF PHARMACOLOGICALLY ACTIVE SUBSTANCES AND PROCEDURE FOR THEIR PREPARATION. |
-
1990
- 1990-11-14 CH CH3616/90A patent/CH681425A5/fr not_active IP Right Cessation
-
1991
- 1991-10-31 BE BE9101009A patent/BE1004923A5/en not_active IP Right Cessation
- 1991-11-01 GB GB9123241A patent/GB2249725B/en not_active Expired - Fee Related
- 1991-11-04 FR FR9113563A patent/FR2668707B1/en not_active Expired - Fee Related
- 1991-11-07 CA CA002055115A patent/CA2055115A1/en not_active Abandoned
- 1991-11-08 IT ITBS910119A patent/IT1252870B/en active IP Right Grant
- 1991-11-11 DE DE4136930A patent/DE4136930A1/en not_active Ceased
- 1991-11-11 NL NL9101877A patent/NL9101877A/en active Search and Examination
- 1991-11-12 AT AT0223591A patent/AT397198B/en not_active IP Right Cessation
- 1991-11-13 JP JP91297358A patent/JPH04288021A/en active Pending
- 1991-11-13 SE SE9103348A patent/SE506448C2/en not_active IP Right Cessation
- 1991-11-13 ES ES09102518A patent/ES2049617B1/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
CH681425A5 (en) | 1993-03-31 |
ES2049617B1 (en) | 1997-03-16 |
GB9123241D0 (en) | 1991-12-18 |
ITBS910119A1 (en) | 1993-05-08 |
SE9103348L (en) | 1992-05-15 |
SE506448C2 (en) | 1997-12-15 |
JPH04288021A (en) | 1992-10-13 |
AT397198B (en) | 1994-02-25 |
GB2249725A (en) | 1992-05-20 |
FR2668707B1 (en) | 1995-05-24 |
ITBS910119A0 (en) | 1991-11-08 |
NL9101877A (en) | 1992-06-01 |
BE1004923A5 (en) | 1993-02-23 |
SE9103348D0 (en) | 1991-11-13 |
DE4136930A1 (en) | 1992-08-20 |
FR2668707A1 (en) | 1992-05-07 |
ES2049617A1 (en) | 1994-04-16 |
ATA223591A (en) | 1993-07-15 |
GB2249725B (en) | 1994-08-10 |
IT1252870B (en) | 1995-06-28 |
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