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United States Patent  [ii] Patent Number: 5,607,685
Cimbollek et al.  Date of Patent: Mar. 4,1997
U.S. Patent Mar. 4,1997 Sheet 2 of 2 5,607,685
 PROTRACTED-RELEASE ADMINSTRATION FORMS CONTAINING CLINDAMYCIN PALMITATE
 Inventors: Monika Cimbollek, Mannheim;
Berthold Nies, Frankisch-Crumbach,
both of Germany
 Assignee: Merck Patent Gesellschaft Mit
Beschrankter Haftung, Darmstadt,
 Appl. No.: 385,428
 Filed: Feb. 8,1995
 Foreign Application Priority Data
Feb. 9, 1994 [DE] Germany 44 04 018.0
 Int. CI.6 A61K 31/40
 U.S. CI 424/422; 424/423; 424/424;
424/435; 514/42; 514/43; 514/964
 Field of Search 424/422, 423,
424/424, 435; 514/42, 93, 964; 536/16.4,
 References Cited
U.S. PATENT DOCUMENTS
5,202,128 4/1993 Morella et al 424/469
5,378,474 1/1995 Morella et al 424/469
Primary Examiner—Nathan M. Nutter
Attorney, Agent, or Firm—Millen, White, Zelano, & Brani
The invention relates to the use of clindamycin palmitate for the production of pharmaceutical administration forms having a protracted release of the antibiotic active compound clindamycin, and corresponding administration forms which are preferably used in the form of shaped implants.
9 Claims, 2 Drawing Sheets
FORMS CONTAINING CLINDAMYCIN
BACKGROUND OF THE INVENTION 5
The invention relates to the use of clindamycin palmitate for the production of pharmaceutical administration forms having a protracted release of the antibiotic active compound clindamycin and to corresponding administration 10 forms, in particular in the form of shaped implants.
Clindamycin is an antibiotic of generally recognized value. It exhibits particular effectiveness against Grampositive organisms such as staphylococci and streptococci and also against Gram-negative anaerobes. This antibiotic is 15 therefore used for the treatment of a wide spectrum of diseases, e.g., in the control of infections of the digestive tract, the skin and the soft tissue and also in osteomyelitis and in gynecological infections. Clindamycin has furthermore been successfully employed in prophylaxis and 20 therapy of bacterial endocarditis.
In the indications mentioned, this antibiotic is used in the form of physiologically acceptable salts such as, for example, clindamycin HQ, clindamycin phosphate ester or alternatively in the form of free clindamycin base.
Clindamycin is also known in the form of the palmitate ester. Clindamycin palmitate itself is microbiologically inactive. However, it is readily hydrolyzed by enzymes of the small intestine and the active clindamycin base is released 30 from this form. The plasma half-life of the active compound is in this case about 2 hours. As a result of this property, clindamycin palmitate has found use in the form of the HC1 salt, which is readily soluble in aqueous medium, as a rapidand short-acting antibiotic in therapy forms where the active 35 compound is administered orally. The free clindamycin palmitate ester (i.e., not in the form of the HC1 salt) is virtually insoluble in aqueous media and therefore until now remained pharmacologically unimportant.
Surprisingly, it has now been found that the hydrolysis of clindamycin palmitate to the active clindamycin can take place not only in the gastrointestinal tract, but also in other 45 sites of the body under the influence of body fluids such as serum and blood. By means of in vitro experiments, it was found that in serum or whole blood or under the influence of macrophages, the active clindamycin base was released slowly from clindamycin palmitate, over a period of days to 50 weeks, at an approximately constant rate. As a result of these findings, the basic suitability of clindamycin palmitate per se emerges as a depot antibiotic to be employed locally, for example, on operation wounds, for the prophylaxis and therapy of infections, due to the protracted release of the 55 active compound clindamycin.
Clindamycin palmitate is especially suitable for the production of pharmaceutical administration forms having a protracted release of the antibiotic active compound clindamycin. 60
BRIEF DESCRIPTION OF THE DRAWINGS
Various other objects, features and attendant advantages of the present invention will be more fully appreciated as the 65 same becomes better understood when considered in conjunction with the accompanying drawings, in which like
reference characters designate the same or similar parts throughout the several views, and wherein:
FIG. 1 shows the release of clindamycin from a Teflon nonwoven implanted in rat thigh as disclosed in Example 6; and
FIG. 2 shows the release of clindamycin and gentamicin from cardiac valve suture rings implanted in rat thigh as disclosed in Example 7.
DETAILED DESCRIPTION OF THE
The invention thus relates to the use of clindamycin palmitate for the production of pharmaceutical administration forms having a protracted release of the antibiotic active compound clindamycin.
The invention furthermore relates to pharmaceutical administration forms having a protracted release of the antibiotic active compound clindamycin, these containing clindamycin palmitate.
The invention in particular relates to pharmaceutical administration forms of this type in the form of shaped implants.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
The suitability according to the invention of clindamycin palmitate as a depot antibiotic for the production of administration forms having a protracted release of active compound results on the one hand from its low solubility in aqueous or physiological media and on the other hand from the hitherto undiscovered accessibility by metabolizing processes in body fluids, through which the active clindamycin base is released and can exhibit its antibiotic action. After an incubation time of 4 hours, hydrolysis of clindamycin palmitate to 70% and, after 24 hours, to 100% thus results, for example, from in vitro investigations in rat blood. In human serum and in horse serum, after this period 35% of the ester is cleaved to the active clindamycin base. In vivo experiments on rats which were implanted with pieces of clindamycin palmitate-impregnated nonwoven PTFE in the thigh muscle showed a constant to slightly increasing excretion of clindamycin base in the urine of the animals over a period of 14 days, while clindamycin palmitate could not be found. Additionally, clindamycin base could be detected in the muscle tissue surrounding the implant.
According to the invention, clindamycin palmitate can therefore be employed advantageously in pharmaceutical administration forms having a protracted release of the active compound clindamycin. Administration forms of this type are preferably produced in the form of shaped implants. These shaped implants are principally used in bone replacement in the treatment or reconstitution of bone defects caused by accident or disease. Furthermore, corresponding shaped implants can also be used for the replacement of other organ parts, such as, for example, as artificial cardiac valves, cardiac valve suture rings, artificial blood vessels or other surgical suture material. Shaped implants, however, can also be used only as depot implants for local release of active compound in the control or prophylaxis of infections.
The term "shaped implants" means that these implant materials have already obtained their final form or shape before they are loaded with the antibiotic. This refers, e.g., to porous bone substitutes, joint prostheses, vascular prostheses, etc. This is distinct from those methods of antibiotic