Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-10-13
2001-04-17
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S501000, C424S502000, C428S402210
Reexamination Certificate
active
06217893
ABSTRACT:
The invention relates first of all to a composition in the form of microcapsules or implants comprising a biodegradable polymeric or copolymeric excipient or a mixture of such excipients with an inherent viscosity of between 0.5 dl/g and 1.6 dl/g in CHCl
3
, and at least one active substance. The invention further relates to a composition in the form of microcapsules or implants comprising at least one biodegradable polymer or copolymer of high molecular weight and at least one water-soluble active substance of high specific surface area. Such compositions will be used to obtain a uniform release of the active substance over a prolonged period of up to more than three months.
These compositions, and especially the microcapsules, are mainly used in pharmacy, but can also be employed in other sectors, particularly in agrochemistry, i.e. in the plant protection sector.
BACKGROUND OF THE INVENTION
The value of administering active principles in the form of sustained release compositions has been known for a long time, whether they be conventional pharmaceutical products, for example steroids, peptides or proteins (cf., for example, U.S. Pat. No. 3,773,919 to Boswell), or products for use in plant protection. The formulations adopted can take the form of microparticles in which the active principle is incorporated in a biodegradable polymer or copolymer such as a polylactide/coglycolide copolymer (PLGA).
It has been found that, especially when a relatively constant or, in any case, uninterrupted release mode is sought—this mode being referred to for example as “monophase” in European Patent EP 58 481—PLGA-type polymers of relatively low molecular weight, i.e. of low viscosity, are required. European patents EP 21 234 (cf. Example 8.B.2. describing a copolymer of intrinsic viscosity 0.5 dl/g), EP 52 510, in which a copolymer with a viscosity of 0.38 dl/g in hexafluoroisopropanol (HFIP) is tested in vivo, and EP 26 599, which describes, by way of example, polymers with viscosities of 0.12 to 0.20 dl/g and claims polymers with a viscosity of 0.08 to 0.30 dl/g, may be mentioned in this connection. The polymers described in said patents are presented as producing constant release compositions. The compositions of Patent EP 26 599 can contain fertility control agents, for example.
It is moreover important to note in this respect that in the opposition proceedings relating to European Patent EP 58 481, which are still in progress on the date of filing of the present patent application, the Applicant limited its main claim to polymers of low viscosity (below 0.3 or 0.5 dl/g), which, according to the Applicant, are the only ones capable of permitting a release of the monophase type.
Furthermore, when a longer release period, for example of more than one month, is sought, more complex problems appear and a solution proposed by Patent EP 0 302 582, for example, consists in mixing several types of microcapsules made up of polymers of different viscosities.
BRIEF DESCRIPTION OF THE INVENTION
Now, the present Applicant has just found that certain polymers of high viscosity are suitable for the preparation of long-term sustained release compositions. It has also been found that the use of certain polymers produces compositions which have a very long-term monophase release profile without an initial period of no release (dead period). This applies particularly to polymers with an inherent viscosity preferably of at least 0.5 dl/g in CHCl
3
and more preferably of at least 0.6 or 0.7 dl/g. In principle, however, the inherent viscosity of these polymers will not exceed 1.6 dl/g in CHCl
3
and may be below 1.4 or 1.2 dl/g. Said polymers will preferably be PLGAs with a lactide/glycolide ratio varying from 40/60 to 90/10, and being preferably about 75/25.
The polymers according to the invention can be prepared by the customary methods, especially by opening of the lactide or glycolide rings. Such a process is described for example in American U.S. Pat. No. 3,773,919.
In the present invention it is also possible to use a mixture of polymers of different high viscosities, but compositions containing only one polymer or copolymer are preferred.
DETAILED DESCRIPTION OF THE INVENTION
The invention therefore relates first of all to a composition in the form of microcapsules or implants comprising a biodegradable polymeric or copolymeric excipient or a mixture of such excipients with an inherent viscosity of between 0.5 dl/g and 1.6 dl/g in CHCl
3
, and an active substance or a mixture of active substances, it being possible for these microcapsules or implants to release the active substance or mixture of active substances over a prolonged period of at least 1 month, preferably of at least 2 months and more preferably of at least 3 months.
Microcapsule is also understood to include microspheres, microparticles, nanocapsules, nanospheres or nanoparticles. Polymer will be understood as meaning a polymer, a copolymer or any mixture of these entities. Finally, active substance is understood as meaning an active substance, one of its salts, one of its precursors or any mixture of these compounds.
Salts of active substances which can be used for compositions according to the invention include especially the salts obtained from organic acids like acetic, malic, tartaric, oxalic, fumaric, citric, lactic, stearic, pamoic, methanesulphonic or p-toluenesulphonic acids, or from inorganic acids like hydrochloric, sulphuric, phosphoric or hydrobromic acids. It will be preferable to use a water-soluble product obtained by salification in the form of a cation, for example with acetic acid. However, it is possible to use an insoluble salt, for example a pamoate. Particularly, the invention relates to a composition in the form of microcapsules or implants comprising a biodegradable polymeric or copolymeric excipient or a mixture of such excipients and an active substance or a mixture of active substances, said microcapsules or said implants being able to release the active substance or the mixture of active substances over a prolonged period of time of up to three months or more with an essentially monophase release profile, said composition being characterized in that:
either, when the composition is in the form of microcapsules:
either the viscosity of said polymers or copolymers is comprised between 0.7 dl/g and 1.6 dl/g in CHCl
3
and the preparation process for said microcapsules does not comprise any stage of fusion of said microcapsules,
or the viscosity of said polymers ou copolymers is comprised between 0.5 dl/g and 1.6 dl/g in CHCl
3
and said polymers or copolymers have an hydrophilic character;
or, when the composition is in the form of implants, the viscosity of said polymers or copolymers is comprised between 0.5 dl/g and 1.6 dl/g in CHCl
3
. Preferably, the viscosity of the polymers or copolymers for the compositions according to the invention will be at least equal to 0.9 dl/g in CHCl
3
.
The polymers or copolymers which can be used for the invention can be especially polymers such as those of lactic acid, glycolic acid, citric acid or malic acid, or else other biocompatible polymers like poly-&bgr;-hydroxybutyric acid, polyorthoesters, polyorthocarbonates, poly-&agr;-cyanoacrylic acid esters, polyalkylene oxalates such as polytrimethylene or polytetramethylee oxalate, polyamino acids, etc. They can also be copolymers like PLGA, polystyrene, polymethacrylic acid, methacrylic acid/acrylic acid copolymers, polyamino acids, maleic anhydride polymers, ethyl cellulose, nitrocellulose, acetyl cellulose, etc. All these polymers or copolymers can be used by themselves or in any mixture. Generally, the PLGAs will comprise from 40 to 90% of lactide and from 10 to 60% of glycolide. It will be preferable to use D,L-PLGA and more preferable to use a D,L-PLGA produced from 70 to 80% of DL-lactide and 20 to 30% of glycolide. A PLGA synthesized from 75% of DL-lactide and 25% of glycolide will be particularly suitable for the invention.
Another particularly preferred polymer for the invention is L-PLGA obtained from L-lactide
Pellet Marc
Roume Chantal
Azpuru Carlos A.
Bierman, Muserlian and Lucas
Pharma Biotech
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