Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Separation or purification
Patent
1997-07-28
1998-12-29
Rotman, Alan L.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Separation or purification
424124, C07K 512, A61K 3812
Patent
active
058543902
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
International Patent Classification: C 07 K 9/10; C 07 K 3/20
This application is a 371 of PCT/SI96/00002, which is now published as WO96/24614 on Aug. 15, 1995.
The present invention relates to a new process for the purification of crude vancomycin hydrochloride by the use of preparative HPLC (a method of reverse phase displacement chromatography), whereby the chromatographic purity of the product is improved.
Vancomycin is a tricyclic amphoteric glycopeptide 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 g/mol. The preparation of vancomycin by the fermentation of microorganisms Amycolatopsis orientalis (previously Nocardia onentalis) is described in more detail in U.S. Pat. No. 3,067,099. 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 Gram-negative 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.
However, it has been achieved by the new process according to the present invention, which is more acceptable also from the ecological point of view due to the use of non-toxic solvents.
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.
Since vancomycin represents a very interesting and valuable product, a constant need for new processes for effective isolation 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 the aim of present invention is to prepare vancomycin hydrochloride of a new quality class having a considerably greater chromatographic purity than any commercialy available products, which is shown by its whiter colour, and also to obtain a high yield by using an ecologically irreproachable process.
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 the fermentation products are known, which include precipitation processes using NaOH (EP 323,150, U.S. Pat. No. 5,037,652, JP 5,244,964) or ethanol (U.S. Pat. No. 4,868,285), 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), 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) as well as salting out and precipitation (U.S. Pat. No. 5,235,037).
In these patents chromatography is only used for preparative purposes in U.S. Pat. No. 4,667,024 (affinity) and in a part of the process in WO 91/08,300 (ion exchange).
Rev
REFERENCES:
patent: 5043423 (1991-08-01), Viscomi et al.
Subramanian, G. et al.: Displacement Chromatography of Biomolecules. J. of Chromatography vol. 439, pp. 341-351, 1988.
Bastarda Andrej
Grahek Rok
Aulakh Charanjit S.
LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.
Rotman Alan L.
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