Drug – bio-affecting and body treating compositions – Fermentate of unknown chemical structure – Processes of making – purifying or recovering
Patent
1997-07-28
1998-12-29
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Fermentate of unknown chemical structure
Processes of making, purifying or recovering
530344, A61K 3812, C07K 512
Patent
active
058537201
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
International Patent Classification:
C 07 K 9/10; C 07 K 3/20; C 07 K 3/24; C 07 K 3/28
This application is a 371 of PCT1SI 96/00003, which is now published as WO96/24615 on Aug. 15, 1996.
The present invention relates to a new process for the purification of vancomycin hydrochloride, which combines the preparative chromatography on a silica gel column containing an alkaline water-methanol mobile phase and the precipitation with ethanol from a salt-water-ethanolic solution, whereby improved chromatographic purity of the product is achieved, making it available both for peroral and parenteral administration.
Vancomycin is a tricyclic amphoteric glycopepitide antibiotic in a salt (hydrochloride) form having the empirical formula C.sub.66 H.sub.75 Cl.sub.2 N.sub.9 O.sub.24.HCl and the molecular weight of 1.486. The preparation of vancomycin by fermentation of the microorganisms Amycolatopis orientalis (previously Nocardia orientalis) is described in more detail in U.S. Pat. No. 3,067,099 (filed in 1955) and in WO 91/08,300 (filed in 1990). Lyophilized vancomycin hydrochloride has an off-white colour and with water it forms a clear solution having a pH between 2.5 and 4.5.
Vancomycin hydrochloride is particularly used for the initial treatment of serious or severe infections caused by staphylococci resistant against .beta.-lactam antibiotics as well as in patients who are penicillin-sensitive or do not respond to penicillins and cephalosporines.
Vancomycin hydrochloride is commercially available in oral (solution and capsules/pulvules) and parenteral (sterile intravenous solution in vials) forms.
Oral use of vancomycin hydrochloride is only allowed in treating staphylococcal enterocolitis where the parenteral form is not effective. For all other types of indications only parenteral use is relevant.
Vancomycin hydrochloride alone or in combination with other aminoglycosides is also useful in treating staphylococcal, streptococcal, enterococcal or diphtherial endocarditis.
To reduce the possibility of side effects a high chromatographic purity of antibiotics is very important in some kinds of their usage, which cannot be achieved by hitherto existing purification processes. By the process according to the present invention the impurity portion in the sample has been reduced for one third.
TECHNICAL PROBLEM
In the preparation of vancomycin consisting of a multistage process involving fermentation, isolation and various means of purification, sometimes a product with a more distinctive colour and with an unpleasant odour is obtained and also the yield and purity are reduced, which cannot be improved even if the process is repeated several times.
Since vancomycin represents a very interesting and valuable product, a constant need for new processes for effective isolation and purification thereof exists. By the use of the most hitherto known processes and also by a multiple repetition of the processes, the portion of several kinds of impurities cannot be reduced so as to obtain vancomycin with an improved purity grade.
Therefore it is the aim of present invention to prepare vancomycin hydrochloride useful both for peroral and parenteral administration of at least an equal or better quality as found in other commercially available products.
PRIOR ART
From patent and other literature a number of methods for the preparation of glycopeptide antibiotics from the fermentation medium as well as for the purification of fermentation products are known, which include precipitation processes using NaOH (EP 323,150, U.S. Pat. No. 5,037,652, JP 5,244,964), formation of phosphates (EP 145,484) or complexes with peptides (U.S. Pat. No. 4,667,024) or imidazole (U.S. Pat. No. 4,868,285) as well as processes for adsorption onto different polymer resins (U.S. Pat. No. 4,440,753, U.S. Pat. No. 4,845,194, U.S. Pat. No. 4,874,843, U.S. Pat. No. 5,149,784, WO 91/08,300, U.S. Pat. No. 5,258,495 or WO 93/21,207).
U.S. Pat. No. 4,868,285 cites the precipitation of vancomycin hydrochloride with ethanol following the dis
REFERENCES:
patent: 5235037 (1993-08-01), Krishnan
Subramanian, G. et al.: Displacement Chromatography of biomolecules. J. of Chromatography, vol. 439, pp. 341-351, 1988.
Pflaum Zlatko
Turkalj Robert
Aulakm Charanjit S.
LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.
Rotman Alan L.
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