Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Chemical aftertreatment – e.g. – acylation – methylation – etc.
Patent
1985-02-28
1987-06-23
Welsh, Maurice J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Chemical aftertreatment, e.g., acylation, methylation, etc.
528328, 5283291, 5262381, 604890, 424484, B07K 700, C08H 100, C08G 6910
Patent
active
046753818
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is a new biodegradable esterified polypeptide in which drugs can be incorporated, the drugs then being gradually released in proportion to the biochemical degradation of the polymer.
Non-toxic biodegradable polymers have been known for several years which can act as a reservoir of drugs and which allow for the controlled gradual release of the latter into the organism at the time of the degradation of the carrier polymer. General information on products of this type can be found in the work: "Fundamental Aspects of Biocompatibility" by D. F. WILLIAMS. CRC Press (1981). See also U.S. Pat. No. 4,093,709.
Of these polymers, those which are referred to in particular are synthetic polypeptides (polyamino acids), the structure of which is related to that of proteins. These polypeptides are biocompatible and the products of their degradation (amino acids) can be reabsorbed by the organism. Thus SIDMAN et al (J. Membr. Sci (1980), 7(3), 277-91) disclosed a copolymer of glutamic acid and of ethyl .gamma.-glutamate, of which the rate of degradation is a function of the composition of the copolymer (molar proportions of the esterified segments as a ratio of the non-esterified segments) and which can store numerous medicinal products, more particularly steroids, peptides, and anti-malaria, anti-cancer and other products. Polymers of this type can be used in the form of sticks containing, mixed therewith, the desired drug, or in the form of capsules enclosing the drug if the latter cannot be mixed with the polymer.
In spite of the interest attached to the above product, there is still a search for a product with improved qualities which has the following properties in particular: drugs (in fact known derivatives of polyaminoacids are not generally soluble in certain specific solvents (DMF, pyridine, F.sub.3 CCOOH), the use of which is not suitable for pharmaceutical products). cannot in fact be generally mixed with conventional biocompatible plasticizers (polyalkylene glycols) and are consequently not thermoplastic. degradation of known synthetic polypeptides is linked in a manner which is difficult to reproduce to their chemical structure, more particularly to the rate of esterification. Thus in a given case (see SIDMAN K. R. et al., Publication PB 81-132136 NTIS (1980) p. 42) a variation in the rate of esterification of the order of 10% causes the rate of degradation to increase from 1 to a hundredfold (see also the reference: SIDMAN mentioned above).
The polymer of the invention allows these improvements to be put into effect. It is an esterified polypeptide with the formula: ##STR1## in which R.sup.1 and R.sup.2 are alkyl groups or hydrogen and R a substituted or non-substituted aliphatic or aromatic residue, or R.sup.2 is hydrogen and an alkyl and R.sup.1 and R linked to one another are substituted or non-substitued methylene or methenyl groups, n being equal to 1 or 2 and x being such that the molecular weight is at least 5000 D.
As can be seen from formula 1, the polymer of the invention is a polyaspartate or polyglutamate esterified by a derivative of acyloxymethanol (HO--CR.sup.1 R.sup.2 --OOCR) in which R is either any organic residue, or is linked to R.sup.1 so as to form a cycle. The use of the word "any" means that the nature and the structure of the R group is not critical and, for instance, there has been no case in which if R is part of the conventional compound with an RCOO-group the corresponding constituent of the invention could not be obtained. However, it is preferred to use compounds in which R is a substituted or non-substituted aliphatic or aromatic group, the substitutes being chosen from amongst the biocompatible organic groups. From amongst the preferred R groups, are the groups methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, phenyl, benzyl and other similar groups. Of course, other groups are possible, but it is clear that the inventor has not been able to consider them all during the limited period of time available to him.
When R and R.sup.1 ar
REFERENCES:
patent: 3230274 (1966-01-01), Garber et al.
patent: 3371069 (1968-02-01), Miyamae et al.
patent: 4351337 (1982-09-01), Sidman
Williams, "Review Biodegradation of Surgical Polymers", J. of Material Science 17 (1982) pp. 1233-1246.
Yoshida et al., "In Vivo Controlled Release . . . Tablets" CA#223180s, vol. 96 1982.
Dickinson et al., Biodegradation of a Poly-(.alpha.Amino Acid) Hydrogel", J. Biomed. Mater. Res. vol. 15, 1981, pp. 591-603.
Wood, Biodegradable Drug Delivery Systems" Inter. J. Pharmaceutics 7, 1980, pp. 1-18.
Battelle (Memorial Institute)
Draper Garnette D.
Welsh Maurice J.
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