Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1987-08-18
1990-01-09
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424 11, 424425, 424426, 424445, 424450, 528328, 530300, 530333, 623 11, 623 16, 623 66, A61F 1300
Patent
active
048927333
DESCRIPTION:
BRIEF SUMMARY
The present invention has for an object a non-toxic, hydrosoluble, biodegradable polypeptide which can be used in biology and for various therapeutic applications, namely to be used as a drug carrier substrate, the drugs being thereafter progressively released in the organism as the biochemical degradation of the polymer progresses.
Non-toxic biodegradable polymers have been known for several years which can be used as drug reservoir and which make it possible to progressively and controllably release the drug in the organism as the degradation of the polymer carrier occurs. General information on this kind of products is to be found in "Fundamental Aspects of Biocompatibility" by D. F. WILLIAM, CRC Press (1981). See also U.S. Pat. No. 4,093,709.
Among these polymers, synthetic polypeptides (polyaminoacids) are more particularly cited whose structure is akin to that of proteins. These polypeptides are biocompatible and their degradation products (amino-acids) are resorbed by the organism. Thus, SIDMAN et al., (J. Membr. Sci. (1980), 7 (3), 277-91) disclose a glutamic acid -.gamma.-ethyl-glutamate copolymer whose degradation rate is a function of the copolymer composition (molar ratio of esterified segments to non-esterified segments) which enables to store many products, for instance anti-cancer, anti-malarial drugs and the like. Such polymers can be used in the form of rods containing, in admixture, the desired drug or in the form of capsules containing the drug when the latter is not miscible with the polymer. However, alkyl polyglutamate and polyaspartate (straight esters of these polyacids) are degradable within a reasonable period (i.e. of a duration compatible with a pharmaceutical utilization) only when in partially hydrolyzed form (see for instance ASANO et al., J. Macromol. Sci. Chem. A21 (5) (1984), 561-582. For obtaining such partially esterified polymers, the polyglutamate or polyaspartates must be subjected to spare hydrolysis under conditions which are very difficult to reproduce. Moreover, very small differences of the extent of hydrolysis have a considerable influence on the rate of subsequent biodegradation which constitutes one further problem of using such polymers for the foregoing objectives.
Hence, despite the interest inherent to the aforementioned products, the search for a product of improved quality and, namely, with the following properties has been continued:
1. Excellent solubility in most current harmless solvents suitable for drugs, and even in water (effectively, the known polyaminoacid derivatives are generally only soluble in some special solvents (DMF, pyridine, F.sub.3 CCOOH) the use of which is inconvenient for pharmaceutical preparation).
2. Improved control of the degradation sequence. Effectively, the degradation rate of known synthetic polypeptides is tightly bound to their chemical structure, e.g. to the level of esterification. Thus, in a given case (see K. R. SIDMAN et al., PB 81-132,136 NTIS (1980), p.42), a variation of the level of esterification in the order of 10% changes the degradation rate from one to a hundred times (see also the foregoing SIDMAN reference), which raises problem of making reproducible samples.
DEFINITION OF THE INVENTION
The polymer of the invention (and its copolymers with other amino-acids) has made it possible to achieve these objectives, and still other ones which are not less important, as will be seen later. This polymer is an esterified polypeptide of formula: ##STR1## in which R is a rest of any amino-acid but, preferentially, is hydrogen (glycin), methyl (alanine) benzyl (phenylalanine), etc . . . However R can also designate amino-acid rests comporting OH, SH, NH.sub.2 functions (which correspond to other aminoacids), as well as the COOH function (which corresponds to aspartic and glutamic acids), this carboxylic group can be free, partially esterified with a lower alkyl, or totally esterified.
In the foregoing formula I, n is equal to 1 or 2, m is equal to 0 or an integer from 1 to 4, p is equal to zero 1 or 2 and x has a v
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Bichon Daniel
Borloz William
Lamy Bernard
Imperial Chemical Industries plc
Page Thurman K.
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