Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1998-04-17
2000-09-19
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424489, 424497, 424486, 424461, 424468, 424426, 424490, A61F 200
Patent
active
06120787&
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE96/01091 filed Sep. 3, 1996.
TECHNICAL FIELD
The present invention is within the field of sustained release particles for parenteral administration of biologically active substances, especially drugs. More specifically it relates to a new preparation method for such particles containing a biologically active substance as well as to new sustained release particles obtainable thereby.
BACKGROUND OF THE INVENTION
Many drugs have to be administered by injection since they are either degraded or absorbed inefficiently when given for instance orally or nasally or by the rectal route. A drug formulation intended for parenteral use has to meet a number of requirements in order to be approved by the regulatory authorities for use in humans. Thus, it has to be biocompatible and biodegradable and all substances used and their degradation products should be non toxic. In addition thereto, particulate drugs intended for injection have to be small enough to pass through the injection needle, which preferably means that they should be smaller than 200 .mu.m. The drug should not be degraded to any large extent in the formulation during production or storage thereof or after administration and should be released in a biologically active form with reproducible kinetics.
One class of polymers which fulfils the requirements as to biocompatibility and biodegradation to harmless end products are the linear polyesters based on lactic acid, glycolic acid and mixtures thereof. In the text below said polymers will also be referred to as PLGA. PLGA is degraded by ester hydrolysis to lactic acid and glycolic acid and has been shown to display excellent biocompatiblity. The innocous nature of PLGA is furthermore exemplified by the approval of several parenteral sustained release formulations based on these polymers by regulatory authorities, like the US Food and Drug Administration.
Parenterally administrable sustained release products on the market today based on PLGA include Decapeptyl.TM. (Ibsen Biotech), Prostap SR.upsilon. (Lederle), Decapeptyl.RTM. Depot (Ferring) och Zoladex.RTM. (Zeneca). The drugs of these formulations are all peptides. In other words they consist of amino acids condensed to a polymer with a relatively low degree of polymerisation and they do not have any well defined three-dimensional structure. This in turn generally permits the use of rather harsh conditions during preparations of said products. For example extrusion and subsequent size reduction can be used, which techniques should not be permissible in connection with proteins since they generally do not withstand such harsh conditions.
Consequently there is also a need for sustained release formulations for proteins. Proteins are similar to peptides in that they also consist of amino acids, but the molecules are larger and most proteins are dependant on a well defined three-dimensional structure as to many of their properties, including biological activities and immunogenicity. Their three-dimensional structures can relatively easily be destroyed, for example by high temperatures, surface induced denaturation and, in many cases exposure to organic solvents. Thus, a very serious drawback in connection with the use of PLGA, which is an excellent material per se, for sustained release of proteins is the requirement to utilize organic solvents to dissolve said PLGA, with the associated risk of compromising the stability of the protein.
Despite large efforts aiming at a modification of the PLGA technology in order to avoid this inherent problem with protein instability during the preparation process the progress in this field has been very slow and as yet no protein products have appeared on the market based on PLGA technology. The main reason therefore probably is that the three-dimensional structures of most proteins are too sensitive to withstand the preparation procedures used and/or being stored in a PLGA-matrix.
The most commonly used technique at present for entrapping water soluble substances such as proteins
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Fyhr Peter
Gustafsson Nils-Ove
Jonsson Monica
Laakso Timo
Benston, Jr. William E.
Biogram AB
Page Thurman K.
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