WO2005082418A1 - Formulation retard solide comprenant de l’acetate de triporeline - Google Patents
Formulation retard solide comprenant de l’acetate de triporeline Download PDFInfo
- Publication number
- WO2005082418A1 WO2005082418A1 PCT/FR2005/000248 FR2005000248W WO2005082418A1 WO 2005082418 A1 WO2005082418 A1 WO 2005082418A1 FR 2005000248 W FR2005000248 W FR 2005000248W WO 2005082418 A1 WO2005082418 A1 WO 2005082418A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- triptorelin acetate
- formulation
- weight
- mixture
- triptorelin
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 115
- 238000009472 formulation Methods 0.000 title claims abstract description 73
- HPPONSCISKROOD-OYLNGHKZSA-N acetic acid;(2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-y Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(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=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 HPPONSCISKROOD-OYLNGHKZSA-N 0.000 title claims abstract description 60
- 229960000434 triptorelin acetate Drugs 0.000 title claims abstract description 60
- 239000007787 solid Substances 0.000 title claims abstract description 17
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 84
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims abstract description 79
- 229920001577 copolymer Polymers 0.000 claims abstract description 46
- 239000004310 lactic acid Substances 0.000 claims abstract description 39
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 39
- 229920000642 polymer Polymers 0.000 claims abstract description 39
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 25
- 238000001125 extrusion Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000007911 parenteral administration Methods 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 9
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 3
- 230000003111 delayed effect Effects 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 1
- 230000004927 fusion Effects 0.000 abstract description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 33
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=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 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 19
- 239000007943 implant Substances 0.000 description 12
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 8
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 229960004824 triptorelin Drugs 0.000 description 7
- 238000011282 treatment Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 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
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000005185 salting out Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000005056 compaction Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 2
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007580 dry-mixing Methods 0.000 description 2
- 239000002434 gonadorelin derivative Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- -1 triptorelin salt Chemical class 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Definitions
- the subject of the present invention is a solid depot formulation for parenteral administration comprising triptorelin acetate.
- Triptorelin (also known as [D-Trp 6 ] LHRH) is an analogue of the hormone LHRH.
- This decapeptide intended to treat, in particular, prostate cancer or endometriosis, is currently used as active ingredient of the drug Decapeptyl ® (also called Diphereline ® in certain countries).
- a solid retardation formulation for parenteral administration comprising a homogeneous mixture of an active principle (in particular a triptorelin salt) in the dispersed or non-dispersed state forming a continuous phase at least part of which is in direct contact with the exchange surface of the formulation and of the external biological medium, and of a biocompatible, biodegradable excipient (in particular a polymer or copolymer of lactic and / or glycolic acid or a mixture of polymers and / or copolymers of lactic and / or glycolic acid), in which the amount of active principle is at least 50% by weight relative to the total weight of the formulation, and having a release profile independent of the composition of the excipient, the molecular weight of the excipient or the active ingredient / excipient weight ratio, the release profile being essentially exclusively dependent on the quantity Total active principle present in the formulation.
- an active principle in particular a triptorelin salt
- a biocompatible, biodegradable excipient in particular a polymer or copo
- the Applicant has also discovered manufacturing conditions, according to an advantageous process, allowing some of said delay formulations to be obtained.
- a formulation according to the invention does not present such an initial isolated release peak but rather a maximum release at the start which stabilizes regularly towards the delay profile (circulating rate) necessary and sufficient.
- Continuity in the dose of triptorelin delivered represents an important advantage of this type of formulation because the circulating dose in the patient can thus be maintained at levels sufficient to obtain a therapeutic effect and the concentration of circulating triptorelin will remain, thanks to repeated injections at regular intervals and to a release profile without initial peak and without trough, greater than or equal treatment needs.
- the subject of the invention is therefore a solid retardation formulation for parenteral administration comprising: a) triptorelin acetate, and b) one or more excipients comprising a polymer or copolymer of lactic acid and / or glycolic acid or a mixture of polymers and / or copolymers of lactic acid and / or glycolic acid, said formulation containing from 10 to 99% of triptorelin acetate by weight relative to the total weight of the formulation and being obtained by a process comprising fusion of the mixture of triptorelin acetate and of the excipient (s) during the fusion-extrusion of triptorelin acetate with the excipient (s), said formulation being such that it releases triptorelin acetate over a period of at least one week when administered parenterally to a patient.
- a formulation according to the invention once administered to a patient by the parenteral route, will release triptorelin acetate at an effective dose for a period of at least 14 days (more preferably over a period of at least 28 or 30 days, and even more preferably over a period of at least 60, 90, 120 or even 180 or 360 days).
- the solid retardation formulation will preferably comprise from 20 to 90%, more preferably from 25 to 80% and even more preferably from 30 to 70% by weight of triptorelin acetate relative to the total weight of the formulation.
- the solid retardation formulation of the invention may comprise from 35 to 55% by weight of triptorelin acetate relative to the total weight of the formulation.
- the melting of the mixture of triptorelin acetate and of the excipient (s) takes place at the same time as the extrusion of said mixture leading to the retard formulation of the invention.
- said formulation when it comprises more than 35% of triptorelin acetate by weight relative to the total weight of the formulation, said formulation will be such that it releases in less than a week (and preferably in less than 48 hours ) almost all of the triptorelin acetate it contains in 500 ml of an aqueous solution at pH 6.0 containing 0.9% by weight sodium chloride and kept stirring at a speed of 25 rpm at a temperature between 25 and 37 ° C, preferably between 30 and 37 ° C and particularly at around 30 ° C, but also such that it releases triptorelin acetate over a period of at least one week once administered parenterally to a patient, and will be further characterized in that the amount of residual water in the triptorelin salt mixture of excipients incorporated in said depot formulation will not exceed 8% by weight of water per relative to the total weight of said mixture.
- triptorelin acetate when it is not given more precision, is meant in the present application triptorelin acetate pure at more than 95% by weight, and preferably pure at more than 97 or 98% expressed by weight of triptorelin acetate. This corresponds respectively to a percentage of the order of about 80, 84 or 85% by weight of peptide.
- triptorelin acetate By almost all of the triptorelin acetate is meant more than 80% of the initial amount of triptorelin acetate, and more preferably more than 90 or even 95% of this amount.
- the amount of triptorelin acetate will be at least 55% or even 60% by weight relative to the total weight of the formulation, and more preferably at least 70% or even 75% by weight. weight relative to the total weight of the formulation.
- the amount of polymer or copolymer of lactic acid and / or glycolic acid or a mixture of polymers and / or copolymers of lactic acid and / or glycolic acid will be preferably at least 20% by weight relative to the total weight of the formulation, and more preferably at least 25% or even 30% by weight relative to the total weight of the formulation.
- the amount of triptorelin acetate will be 35 to 55% (and more preferably 35 to 50%) by weight relative to the total weight of the formulation.
- the polymer or copolymer of lactic acid and / or glycolic acid or the mixture of polymers and / or copolymers of lactic acid and / or glycolic acid will preferably be a copolymer of lactic acid and glycolic acid or a mixture of such copolymers.
- lactic acid and glycolic acid copolymers may be used for the compositions according to the invention, and in particular a PLGA 50-50 (ie a copolymer of lactic acid and glycolic acid (PLGA) ) comprising 50% of units derived from lactic acid and 50% of units derived from glycolic acid), a PLGA 75-25 (ie a copolymer of lactic acid and glycolic acid (PLGA) comprising 75 % of units derived from lactic acid and 25% of units derived from glycolic acid), a PLGA 80-20 (ie a copolymer of lactic acid and glycolic acid (PLGA) comprising 80% of units derived from lactic acid and 20% units derived from glycolic acid) or a PLGA 85-15 (ie a copolymer of lactic acid and glycolic acid (PLGA) comprising 85% units derived lactic acid and 15% units derived from glycolic acid).
- PLGA 50-50 ie a copolymer of lactic acid and glycolic acid (
- PLGAs comprising from 50% to 85% of units derived from lactic acid and from 15% to 50% of units derived from glycolic acid, in particular PLGA comprising from 70% to 85% of units derived from lactic acid and from 15% to 30% of units derived from glycolic acid, and in particular a PLGA comprising approximately 75% of units derived from lactic acid and approximately 25% units derived from glycolic acid (ie a PLGA approximately 75-25).
- Said PLGAs will have a more or less short chain depending on the duration of release of the active ingredient sought.
- polymers of pure lactic acid (PLA) in particular for the forms intended to obtain a release over a period greater than 3 months.
- Said polymers or copolymers will preferably be used in a purified form or free of the residual monomer fraction.
- Polymers or copolymers of this type are for example described in US Pat. No. 4,728,721.
- the polymer or copolymer of lactic acid and / or glycolic acid or the mixture of polymers and / or copolymers of lactic acid and / or glycolic acid will comprise a PLGA
- the latter will preferably have a molecular mass d '' at least 60,000 g / mol, more preferably at least 75,000 or even 90,000 or 95,000 g / mol (and in particular approximately 100,000 g / mol).
- the polymer or copolymer of lactic acid and / or glycolic acid or the mixture of polymers and / or copolymers of lactic acid and / or glycolic acid will comprise a PLA
- the latter will preferably have a molecular weight between 15,000 or 20,000 and 30,000 or 40,000 g / mol (in particular approximately 25,000 g / mol)
- the delay formulations according to the invention allow the use of a wide variety of polymers with in particular favorable results before or after radiosterilization despite the change in molecular weight which therefore allow for example an aseptic or gamma-irradiated preparation.
- PLGA low molecular weight polymer
- This small percentage will preferably be between 0 and 5%, more preferably between 0 and 2% and more preferably between 0 and 1%.
- the mixture of triptorelin acetate with the polymeric excipient (s) or copolymers will be dried beforehand so that its water content does not exceed 8% by weight (preferably 4 or 5% and very particularly 2%).
- the preferred manufacturing process according to the invention comprises dry mixing of said triptorelin salt in proportions which can range up to more than 50% with the said polymer or copolymer excipients. Said mixture is then compacted and dry granulated at a temperature less than or equal to 25 ° C. The mixture is then dried so as to have a residual humidity which does not exceed 8% and preferably less than 4 or 5% or even approximately equal to 2%. Said mixture will then be brought to its melting temperature directly and rapidly during the extrusion process.
- the mixture of triptorelin acetate with the polymer or copolymer of a lactic acid and / or glycolic acid or the mixture of polymers and / or copolymers of lactic acid and / or glycolic acid will then be in the state molten.
- Said mixture is thus fed into an extrusion screw according to a process such that the liquefaction-melting time of the mixture and transit to the extrusion nozzle is reduced and less than 30 minutes and preferably less than 15 minutes.
- the mixture is operated without pretreatment using aqueous or organic solvents and / or without lyophilization of the mixtures and without separate preheating for compression before extrusion, which allows to control if necessary the low state of hydration of said mixture and to extradite at temperatures which may be higher than 100 ° C. without degradation of the active principle, over short heating times, less than 15 minutes, preferably between 5 and 10 minutes.
- the solid powder mixture of triptorelin acetate and polymer (s) or copolymer (s) of lactic acid and / or glycolic acid may be melted at a temperature sufficient to obtain a non-solid state of the two constituents and then be mixed then extruded or molded before the temperature drops and the arrangement returns to the solid state.
- triptorelin acetate should preferably be shaped at temperatures between 110 and 160 ° C, and more preferably between 125 ° C and 150 ° C or even between 137 and 145 ° C, for example at about 143 ° C.
- This temperature could of course be adapted according to the polymer or copolymer used; it will for example be approximately 10 ° C lower in the case of a PLGA approximately 50:50 or approximately 10 ° C higher for a PLGA 75-25 of higher viscosity.
- this will preferably be less than or equal to 4 or 5% (more preferably less than or equal to about 2%) by weight of water relative to the total weight.
- it will be comprised 1.5 and 2.5% by weight of water relative to the total weight, and any preferably between 1.8 and 2.2% by weight of water relative to the total weight (for example approximately 2% by weight of water relative to the total weight).
- the invention therefore therefore also relates more generally to formulations of triptorelin acetate comprising a polymer excipient (in particular a PLGA) or a mixture of polymer excipients, said formulations being capable of releasing, at an effective dose in the treatment of prostate cancer and over a period of at least one month, triptorelin acetate in the body of the patients to which they are administered, said formulations containing from 1 to 2 mg (and in particular approximately 1.5 mg mg) triptorelin acetate per month of release at an effective dose of triptorelin acetate.
- a polymer excipient in particular a PLGA
- a mixture of polymer excipients said formulations being capable of releasing, at an effective dose in the treatment of prostate cancer and over a period of at least one month, triptorelin acetate in the body of the patients to which they are administered, said formulations containing from 1 to 2 mg (and in particular approximately 1.5 mg mg) triptorelin acetate per month of release at an effective dose of
- monthly formulations could contain of the order of 1.5 mg of active principle such as triptorelin acetate
- compositions intended for 4 months of salting out could contain of the order of 1 , 5 mg / month of active principle (or approximately 6 mg)
- compositions intended for a treatment duration of 6 months could contain of the order of 1.5 to 2 mg / month (or approximately 9 to 12 mg).
- this hot arrangement can give the desired shape directly thanks to the mixing of the screw and the diameter of the extrusion nozzle. It will also be possible to carry out a control of the solid form and in particular of its diameter thanks to a drawing machine regulating the diameter of the extradate.
- the drawing machine can act at room temperature at the outlet of the extruder.
- the extradate may also pass through a thermostatically controlled chamber at a high temperature, equal to or lower than the extrusion temperature to allow greater drawing and in particular the obtaining of very small diameters (for example less than 0.1 mm or else less than 0.05 mm).
- This continuous extradate can then be cut to size (exchange surface) offering the desired release profile, for example by cryogenic grinding.
- the desired dose can be obtained and injected in the form of one or more pellets or in the form of microgranulated and calibrated powder.
- this manufacturing process can also be applied to forms with low loads of active principle, less than 20% in particular between 0.5 and 10% or with high loads, greater at 50% and in particular between 60 and 80%.
- It may thus be one or more solid forms of length which may be greater than 1 cm or less than 0.1 mm, depending on the case and injected either as an implant or as a suspension.
- extrusion nozzle with several channels allowing in parallel the exit of several extrudates of the same screw.
- extrusion wires of small diameter can be cut mechanically to regular lengths (for example 0.05 mm) or even cold-cryo-crushed (liquid nitrogen) according to fracture points to obtain scattered forms.
- solutions can be prepared in organic solvents miscible with water (for example in acetic acid) or in supercritical fluids (for example in CO 2 in the supercritical state). These mixtures in solution will then be dried or lyophilized and then treated by extrusion or directly nebulized, possibly under pressure.
- the preferred process comprises dry mixing of the triptorelin salt with the said polymer or copolymer excipient (s) before compacting and granulating at dry
- satisfactory alternative methods will consist in omitting the compaction or in carrying out this compaction by means of a first extrusion before using the mixture obtained for an extrusion under the temperature conditions described above.
- the solid retardation formulation will be in the form of a microimplant, ie a small diameter cylinder (less than 1.5, 1, 0.8, 0.6, 0.5, 0 , 25 or even 0.1 mm) and a few mm in length, said length preferably being between 5 and 50 mm (more preferably between 10 and 30 or 40 mm).
- the cylinder will have a length / diameter ratio at least equal to 10, and more preferably at least equal to 12, or even at least equal to 15 or 20.
- the microimplant according to the invention may have, for example, a diameter of 0.8 to 0.9 mm and comprise 70% by weight of triptorelin salt and 30% by weight of PLGA about 75-25.
- the microimplant according to the invention will have a weight proportional to the desired release time, ie approximately 4.6 to 5.6 mg for a release time of approximately 1 month or approximately 13.7 to 16, 7 mg for a release period of approximately 3 months.
- release profile according to the invention for producing microimplants of only 15.2 to 18.5 mg for a release time of approximately 4 months or else microimplants of 18.2 to 22.2 mg. for a release period of around 6 months or even even smaller microimplants corresponding to average monthly doses of triptorelin less than 2 mg.
- the microimplant according to the invention may have, for example, a diameter of 0.8 to 0 , 9 mm and comprise approximately 36% by weight of triptorelin salt and about 64% by weight of PLGA about 85-15.
- a microimplant may in particular contain approximately 2.16 mg of triptorelin acetate and approximately 3.84 mg of PLGA approximately 85-15.
- a person skilled in the art can of course choose to use other polymers or copolymers of lactic acid and / or glycolic acid or else a mixture of polymers and / or copolymers of lactic acid and / or glycolic acid. , or to have other proportions of triptorelin salt and PLGA; in this case, he will adapt the molecular weight of the PLGA and the weight of the microimplants to obtain the desired effect.
- the invention therefore also relates to a method of treatment of a patient in need of regular administration of an LHRH analog, said method consisting in the injection and implantation in this patient of a solid retardation formulation according to the invention.
- the invention is either at the monthly doses usually used for said LHRH analog, or at lower doses made possible by the formulation and its administration profile.
- the attending doctor or veterinarian may use injection devices such as those described in PCT application WO 98/24504 or standard size syringes for carrying out the administration.
- approximately refers to an interval around the value considered.
- approximately X means a range of X minus 10% of X to X plus 10% of X, and preferably a range of X minus 5% of X to X plus 5% of X
- approximately Y ° C refers to an interval of Y minus 10 ° C to Y plus 10 ° C, and preferably an interval of Y minus 5 ° C to Y plus 5 ° C.
- the polymer or copolymer on the one hand and the triptorelin acetate on the other hand are weighed then their powders are mixed using a Turbula T2C L S4586 apparatus (rotation speed 42 rpm) and transformed (by compression or compaction) in granules whose size does not exceed 1.4 or 1.5 mm (control ensured by sieving).
- the water content present in the granules is determined on a sample and then adjusted to the desired level by drying under vacuum at room temperature.
- the dried granules are then subjected to a fusion-extrusion process at a speed of 10 revolutions / min (Scamex 8/12 mm extradeuse (Scamia)) while the temperature during this process is maintained at the desired temperature (for the case particularly implants comprising at least 50% triptorelin acetate).
- Two devices are used to carry out the fusion-extrusion; their characteristics are collated in the table below.
- the extradate is cut manually into implants which are then ⁇ -irradiated (25 kGy). The implants are then ready to be loaded into injection devices.
- a 7.5 mg implant measuring 0.85 mm in diameter and approximately 25 mm in length and comprising 50% by weight of triptorelin acetate (purity> 98.5%) and 50% by weight of PLGA 85:15 (Boehringer Ingelheim; viscosity index IN in hexafluoroisopropanol: 1.2 dl / g ⁇ IN ⁇ 1.6 dl / g), is carried out according to the general procedure described above.
- An implant of 16.2 mg, measuring 0.85 mm in diameter and approximately 20 mm in length and comprising 56% by weight of triptorelin acetate (purity> 98.5%) and 50% by weight of PLGA 75:25 (viscosity index IN in hexafluoroisopropanol: IN 0.95 dl / g), is carried out according to the general procedure described above. During fusion-extrusion, the temperature is maintained at 144-147 ° C.
- An implant of 9.1 mg, measuring 0.85 mm in diameter and approximately 22 mm in length and comprising 65% by weight of triptorelin acetate (purity> 97.5%) and 35% by weight of PLGA 75:25 (viscosity index IN in hexafluoroisopropanol: IN 0.95 dl / g), is carried out according to the general procedure described above. During fusion-extrusion, the temperature is maintained at 144-147 ° C.
- Implants according to Example 4 were administered by the intramuscular route on the one hand to Beagles dogs (weight about 12 kg) in a muscle of the hind paw and on the other hand to humans.
- a plasma assay revealed that the level of triptorelin remained constantly above 0.1 ng / ml over a period of more than 80 days while the level of testosterone measured was constantly below the level of castration (0.24 ng / 1) between the 21st and the 113th day after the administration of the implant; in humans, the level of triptorelin remained constantly above 0.03 ng / ml over a period of more than 112 days while the level of testosterone measured was constantly below the level of castration (0.50 ng / 1) between 15 th and 105 th day after the administration of the implant.
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- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
Description
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05717551A EP1722820A1 (fr) | 2004-02-05 | 2005-02-04 | Formulation retard solide comprenant de l'acetate de triptoreline |
MXPA06008617A MXPA06008617A (es) | 2004-02-05 | 2005-02-04 | Formulacion solida de accion prolongada que comprende acetato de triptorelina. |
CN2005800035442A CN1913924B (zh) | 2004-02-05 | 2005-02-04 | 包括醋酸曲普瑞林的固体缓释制剂 |
CA002554870A CA2554870A1 (fr) | 2004-02-05 | 2005-02-04 | Formulation retard solide comprenant de l'acetate de triporeline |
JP2006551883A JP2007520533A (ja) | 2004-02-05 | 2005-02-04 | トリプトレリンアセテートを含有してなる持続性の固体組成物 |
BRPI0507326-0A BRPI0507326A (pt) | 2004-02-05 | 2005-02-04 | formulação sólida de ação retardada para administração parenteral |
IL176786A IL176786A0 (en) | 2004-02-05 | 2006-07-11 | Long-acting solid formulation comprising triptorelin acetate |
HK07108741.8A HK1101127A1 (en) | 2004-02-05 | 2007-08-13 | Long-acting solid formulation comprising triptorelin acetate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0401109 | 2004-02-05 | ||
FR0401109A FR2865938B1 (fr) | 2004-02-05 | 2004-02-05 | Formulation retard solide comprenant de l'acetate de triptoreline |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005082418A1 true WO2005082418A1 (fr) | 2005-09-09 |
Family
ID=34778533
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2005/000248 WO2005082418A1 (fr) | 2004-02-05 | 2005-02-04 | Formulation retard solide comprenant de l’acetate de triporeline |
Country Status (14)
Country | Link |
---|---|
US (1) | US20070031500A1 (fr) |
EP (1) | EP1722820A1 (fr) |
JP (1) | JP2007520533A (fr) |
CN (1) | CN1913924B (fr) |
AR (1) | AR047797A1 (fr) |
BR (1) | BRPI0507326A (fr) |
CA (1) | CA2554870A1 (fr) |
FR (1) | FR2865938B1 (fr) |
HK (1) | HK1101127A1 (fr) |
IL (1) | IL176786A0 (fr) |
MX (1) | MXPA06008617A (fr) |
RU (1) | RU2399384C2 (fr) |
TW (1) | TWI399224B (fr) |
WO (1) | WO2005082418A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2246063A1 (fr) * | 2009-04-29 | 2010-11-03 | Ipsen Pharma S.A.S. | Formulations à libération prolongée contenant des analogues de GnRH |
Families Citing this family (8)
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CA2540838C (fr) | 2003-10-03 | 2014-12-16 | Thorn Bioscience, Llc | Processus de synchronisation de l'ovulation pour la reproduction reglee sans detection des chaleurs |
CA2688478C (fr) * | 2007-06-06 | 2015-10-27 | Debio Recherche Pharmaceutique S.A. | Composition pharmaceutique a liberation lente, faite de microparticules |
CN104906556A (zh) | 2009-04-23 | 2015-09-16 | Jbs联合动物健康二有限公司 | 用于同步授精时间的方法和组合物 |
CN102048699B (zh) * | 2009-11-03 | 2012-11-07 | 长春金赛药业有限责任公司 | 一种注射用醋酸曲普瑞林的缓释微球的制备方法 |
WO2013083605A1 (fr) * | 2011-12-05 | 2013-06-13 | Ferring Bv | Composition pharmaceutique de triptoréline |
CN104994865A (zh) | 2012-11-28 | 2015-10-21 | 杰碧斯联合动物健康第二有限责任公司 | 用于同步小母猪的授精时间的方法 |
CN105267153B (zh) * | 2015-11-27 | 2018-05-11 | 上海苏豪逸明制药有限公司 | 一种曲普瑞林缓释微粒及其制备方法 |
CN105878174B (zh) * | 2016-04-26 | 2021-06-29 | 广州帝奇医药技术有限公司 | 一种固体分散体及其制备方法与应用 |
Citations (9)
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FR2650182A1 (fr) | 1989-07-28 | 1991-02-01 | Debiopharm Sa | Procede de preparation d'une composition pharmaceutique sous forme de microparticules |
GB2246514A (en) | 1990-08-01 | 1992-02-05 | Scras | Sustained release particles preparation |
US5569467A (en) * | 1993-05-15 | 1996-10-29 | Societe De Conseils De Recherches Et D'applications (S.C.R.A.S.) | Process for the preparation of microballs and microballs thus obtained |
FR2747919A1 (fr) * | 1996-04-29 | 1997-10-31 | Henkel Kgaa | Utilisation d'esters de copolymeres pour la production de microspheres pour la liberation retardee de principes actifs |
US5945128A (en) | 1996-09-04 | 1999-08-31 | Romano Deghenghi | Process to manufacture implants containing bioactive peptides |
WO2002058672A2 (fr) * | 2001-01-26 | 2002-08-01 | Debio Recherche Pharmaceutique S.A. | Microparticules de polymere biodegradable encapsulant une substance biologiquement active et formulations pharmaceutiques a liberation prolongee contenant lesdites particules |
US20020111603A1 (en) * | 1996-12-02 | 2002-08-15 | Societe De Conseils De Recherches Et D'application | Device for local administration of solid or semi-solid formulations and delayed-release formulations for proposal parental administration and preparation process |
WO2003022297A1 (fr) | 2001-09-11 | 2003-03-20 | Astrazeneca Ab | Implant biodegradable comprenant un polymere de polylactide et un analogue de la gonadoreline |
US6620422B1 (en) | 1998-12-10 | 2003-09-16 | Mediolanum Farmaceutici S.P.A. | Compositions containing a peptide and polylactic-glycolic acid suitable for preparing subcutaneous implants with an extended release period |
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GB9016885D0 (en) * | 1990-08-01 | 1990-09-12 | Scras | Sustained release pharmaceutical compositions |
DE4223169C1 (de) * | 1992-07-10 | 1993-11-25 | Ferring Arzneimittel Gmbh | Verfahren zur Mikroverkapselung wasserlöslicher Wirkstoffe |
FR2756493B1 (fr) * | 1996-12-02 | 2001-04-13 | Delab | Dispositif d'administration locale de formulations solides ou semi-solides |
-
2004
- 2004-02-05 FR FR0401109A patent/FR2865938B1/fr not_active Expired - Fee Related
-
2005
- 2005-01-27 TW TW094102537A patent/TWI399224B/zh not_active IP Right Cessation
- 2005-02-04 MX MXPA06008617A patent/MXPA06008617A/es active IP Right Grant
- 2005-02-04 CN CN2005800035442A patent/CN1913924B/zh not_active Expired - Fee Related
- 2005-02-04 EP EP05717551A patent/EP1722820A1/fr not_active Withdrawn
- 2005-02-04 CA CA002554870A patent/CA2554870A1/fr not_active Abandoned
- 2005-02-04 AR ARP050100422A patent/AR047797A1/es not_active Application Discontinuation
- 2005-02-04 WO PCT/FR2005/000248 patent/WO2005082418A1/fr active Application Filing
- 2005-02-04 BR BRPI0507326-0A patent/BRPI0507326A/pt not_active IP Right Cessation
- 2005-02-04 RU RU2006131705/15A patent/RU2399384C2/ru not_active IP Right Cessation
- 2005-02-04 JP JP2006551883A patent/JP2007520533A/ja active Pending
-
2006
- 2006-07-11 IL IL176786A patent/IL176786A0/en unknown
- 2006-08-07 US US11/499,777 patent/US20070031500A1/en not_active Abandoned
-
2007
- 2007-08-13 HK HK07108741.8A patent/HK1101127A1/xx not_active IP Right Cessation
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2650182A1 (fr) | 1989-07-28 | 1991-02-01 | Debiopharm Sa | Procede de preparation d'une composition pharmaceutique sous forme de microparticules |
GB2246514A (en) | 1990-08-01 | 1992-02-05 | Scras | Sustained release particles preparation |
US5569467A (en) * | 1993-05-15 | 1996-10-29 | Societe De Conseils De Recherches Et D'applications (S.C.R.A.S.) | Process for the preparation of microballs and microballs thus obtained |
FR2747919A1 (fr) * | 1996-04-29 | 1997-10-31 | Henkel Kgaa | Utilisation d'esters de copolymeres pour la production de microspheres pour la liberation retardee de principes actifs |
US5945128A (en) | 1996-09-04 | 1999-08-31 | Romano Deghenghi | Process to manufacture implants containing bioactive peptides |
US20020111603A1 (en) * | 1996-12-02 | 2002-08-15 | Societe De Conseils De Recherches Et D'application | Device for local administration of solid or semi-solid formulations and delayed-release formulations for proposal parental administration and preparation process |
US6620422B1 (en) | 1998-12-10 | 2003-09-16 | Mediolanum Farmaceutici S.P.A. | Compositions containing a peptide and polylactic-glycolic acid suitable for preparing subcutaneous implants with an extended release period |
WO2002058672A2 (fr) * | 2001-01-26 | 2002-08-01 | Debio Recherche Pharmaceutique S.A. | Microparticules de polymere biodegradable encapsulant une substance biologiquement active et formulations pharmaceutiques a liberation prolongee contenant lesdites particules |
WO2003022297A1 (fr) | 2001-09-11 | 2003-03-20 | Astrazeneca Ab | Implant biodegradable comprenant un polymere de polylactide et un analogue de la gonadoreline |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2246063A1 (fr) * | 2009-04-29 | 2010-11-03 | Ipsen Pharma S.A.S. | Formulations à libération prolongée contenant des analogues de GnRH |
WO2010125475A3 (fr) * | 2009-04-29 | 2011-06-23 | Ipsen Pharma S.A.S. | Formulations à libération prolongée |
CN102413835A (zh) * | 2009-04-29 | 2012-04-11 | 益普生制药股份有限公司 | 包含GnRH类似物的缓释制剂 |
CN102413835B (zh) * | 2009-04-29 | 2014-03-05 | 益普生制药股份有限公司 | 包含GnRH类似物的缓释制剂 |
US8962559B2 (en) | 2009-04-29 | 2015-02-24 | Ipsen Pharma S.A.S. | Sustained release formulations comprising GNRH analogues |
Also Published As
Publication number | Publication date |
---|---|
JP2007520533A (ja) | 2007-07-26 |
FR2865938B1 (fr) | 2006-06-02 |
TWI399224B (zh) | 2013-06-21 |
CN1913924B (zh) | 2011-11-09 |
US20070031500A1 (en) | 2007-02-08 |
EP1722820A1 (fr) | 2006-11-22 |
AR047797A1 (es) | 2006-02-22 |
RU2399384C2 (ru) | 2010-09-20 |
MXPA06008617A (es) | 2006-08-28 |
CN1913924A (zh) | 2007-02-14 |
RU2006131705A (ru) | 2008-03-10 |
IL176786A0 (en) | 2006-10-31 |
HK1101127A1 (en) | 2007-10-12 |
BRPI0507326A (pt) | 2007-07-03 |
CA2554870A1 (fr) | 2005-09-09 |
FR2865938A1 (fr) | 2005-08-12 |
TW200528143A (en) | 2005-09-01 |
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