Process for implanting a medicament depot

• US 4,853,225 A
• Filed: 12/05/1986
• Issued: 08/01/1989
• Est. Priority Date: 12/05/1985
• Status: Expired due to Fees

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Stille, Wolfgang, Rothe, Johannes, Wahlig, Helmut, Dingeldein, Elvira
• Primary Examiner(s): Page, Thurman K.
• Application Number:
  US06/938,200
• Time in Patent Office: 970 Days
• Field of Search: 424/423, 424/424, 424/425, 424/426, 424/422, 623/11, 623/16
• US Class Current: 424/423
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2300/434 of enzymes
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides

Abstract

The invention relates to an implantable medicament depot comprising physiologically acceptable excipients and at least one delayed release active compound which is a chemotherapeutic of the gyrase inhibitor type.

The depot can be used for combating infections.

Claims

1. A method of combating an infection in a patient in whom the infection already exits, comprising implanting in the patient an implantable medicament depot consisting essentially of a physiologically acceptable excipient which achieves delayed release of an active agent and an infection-treating effective amount of at least one chemotherapeutic gyrase inhibitor as the active agent for delayed release.

2. A method of claim 1, wherein the gyrase inhibitor is a compound of the formula ##STR2## wherein X is N or CR⁶,

Y is N or CR⁸,

Z is N or CH,

R¹ is alkyl, alkenyl, hydroxyalky, Hal-alkyl, NR⁹ R¹⁰, OR¹¹, cycloalkyl, Ar or Ar-alkyl,

R³ is H or alkyl,

R⁵ is H, Hal, alkyl or alkoxy,

R⁶ is H, Hal, alkyl, alkoxy or NO₂,

R⁷ is alkyl, Hal, NR⁹ R¹⁰, a 5- or 6-membered N-containing aromatic or aliphatic heterocycle, such as heterocycle containing an additional hetero O, N or S atom, or either of said heterocycles which is substituted, or

R⁶ and R⁷ together form methylenedioxy,

R⁸ is H, Hal, alkyl or alkoxy or

R⁸ and R¹ together form --O--CH₂ --CHalkyl or --CH₂ CH₂ --CHalkyl,

R⁹, R¹⁰ and R¹¹ are each H or alkyl,

Ar is phenyl or substituted phenyl,

Hal is F, Cl, Br or I, and

the alkyl, cycloalkyl, alkenyl and alkoxy groups in each case contain up to 6 C atoms.

3. A method of claim 2 wherein

Y is N or CR⁸,

Z is N or CH,

R¹ is alkyl, Hal-alkyl, NH-alkyl, O-alkyl, cycloalkyl or Hal-phenyl,

R³ is H,

R⁵ is H,

R⁶ is H or Hal,

R⁷ is alkyl, Hal or a 5- or 6-membered N-containing aromatic or aliphatic heterocycle which optionally can contain a further N atom, each optionally substituted by one or two alkyl, amino or alkylaminoalkyl groups, or

R⁶ and R⁷ together are methylenedioxy,

R⁸ is H, Hal or alkyl, or

R⁸ and R¹ together are --O--CH₂ --CHalkyl or --CH₂ CH₂ --CHalkyl and

Hal is F or Cl and

the alkyl groups in each case contain 1-3 C atoms.

4. The method of claim 2 wherein

Y is N or CR⁸,

Z is N or CH,

R¹ is alkyl, 2-fluoroethyl, methylamino, methoxy, cyclopropyl or p-fluorophenyl,

R³ and R⁵ are each H,

R⁶ is H or F,

R⁷ is methyl, Cl, pyrrl, pyrrolidino, 3,4-dimethylpyrrolidino, 3-aminopyrrolidino, 3-amino-4-methylpyrrolidino, 3-ethylaminomethyl-pyrrolidino, pyridyl, piperidyl, piperazino or 3- or 4-methylpiperazino, or

R⁶ and R⁷ together are methylenedioxy and

R⁸ is H, methyl or F, or

R⁸ and R¹ together are --OCH₂ --CH(CH₃)--or --CH₂ CH₂ --CH(CH₃)--and

the alkyl groups in each case contain 1-3 C atoms.

5. A method of claim 2 wherein

Y is N or CR⁸

Z is N or CH,

R¹ is ethyl or cyclopropyl,

R³ and R⁵ are each H,

R⁶ is F,

R⁷ is piperazino or 3- or 4-methylpiperazino, and

R⁸ is H, or

R⁸ and R¹ together are --O--CH₂ --CH(CH₃).

6. A method of claim 1 wherein the gyrase inhibitor is ciprofloxacin, ofloxacin, amifloxacin, cinoxacin, difloxacin (A-56619), enoxacin, flumequin, irloxacin, miloxacin, malidixic acid, norfloxacin, oxolic acid, pefloxacin, pipemidic acid, piromidic acid, rosoxacin, A-56620, A-57132, A-60969, A-656619, A-656620, AM-833, AT-3295, AT-3765, CI-934, E-3432, E-3499, EN-272, NY-198, OPC-7594, Ro-23-6240, S-25930, S-25932, T-14097, 79286-76-3, 80-107118, or 1-ethyl-2-phenyl-4-pyridone-5-carboxylic acid.

7. A method of claim 1 wherein the amount of active agent is 0.01 to 10%.

8. A method of claim 1 which is an implant.

9. A method of claim 1 wherein said depot is a bone cement or bone filler.

10. A method of claim 1 wherein the excipient comprises a polyacrylate or a polymethacrylate.

11. A method of claim 1 wherein the excipient is tricalcium phosphate.

12. A method of claim 1 wherein the excipient is collagen.

13. A method of claim 1 wherein the excipient is a polysaccharide or fibrin.