WO1994027600A1 - Pharmaceutical formulations with clavulanic acid and an antimycobacterial agent - Google Patents

Pharmaceutical formulations with clavulanic acid and an antimycobacterial agent Download PDF

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Publication number
WO1994027600A1
WO1994027600A1 PCT/IB1994/000204 IB9400204W WO9427600A1 WO 1994027600 A1 WO1994027600 A1 WO 1994027600A1 IB 9400204 W IB9400204 W IB 9400204W WO 9427600 A1 WO9427600 A1 WO 9427600A1
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Prior art keywords
clavulanic acid
acceptable salt
formulation according
pharmaceutically acceptable
agent
Prior art date
Application number
PCT/IB1994/000204
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French (fr)
Inventor
James Arthur Poupard
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority to GB939311030A priority Critical patent/GB9311030D0/en
Priority to GB9311030.2 priority
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO1994027600A1 publication Critical patent/WO1994027600A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42Oxazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • A61K31/43Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems

Abstract

Pharmaceutical formulations which comprise a pharmaceutically acceptable salt of clavulanic acid such as potassium clavulanate, in combination with an antimycobacterial agent such as ethambutol, and optionally one or more other antimicrobial agents such as amoxycillin. The formulations are suitable for therapy against infection by mycobacteria.

Description

PHARMACEUTICAL FORMULATIONS WITH CLAVULANIC ACID AND AN ANTIMYCOBACTERIAL AGENT

This invention relates to pharmaceutical formulations, in particular to novel uses of formulations in connection with the treatment of infection by mycobacteria. Mycobacteria include M. tuberculosis and nontuberculosis mycobacterial species such as M.fortuitum, M.kansasii, M.marinum and M. avium complex.

The invention provides a pharmaceutical formulation which comprises a pharmaceutically acceptable salt of clavulanic acid, in combination with an antimycobacterial agent, and optionally one or more other antimicrobial agents. The formulation of the invention is suitable for use in the treatment of infection by mycobacteria in humans or animals.

The present invention also provides a method of use of a pharmaceutically acceptable salt of clavulanic acid and an antimycobacterial agent, and optionally one or more other antimicrobial agents, together in combination in the manufacture of a medicament formulation, paπicularly a formulation for the treatment of infection of humans or animals by mycobacteria.

The present invention further provides a method for the preparation of a pharmaceutical formulation as defined above, which method comprises admixing the combination of a pharmaceutically acceptable salt of clavulanic acid, and an antimycobacterial agent and optionally one or more other antimicrobial agents.

As salts of clavulanic acid are extremely hygroscopic such formulations must be prepared in dry conditions, typically at a relative humidity of 30% or less. All constituents of the formulation should be predried. Dry formulations for aqueous reconstitution may be made up with an aqueous vehicle shortly before use. The present invention further provides a pharmaceutical formulation as defined above for use as an active therapeutic substance, particularly in the treatment of infection of humans or animals by mycobacteria.

The present invention also provides the use of a pharmaceutically acceptable salt of clavulanic acid to enhance the antimycobacterial effectiveness of an antimycobacterial agent.

Further the invention provides a method for the treatment of an infection by mycobacteria in humans or animals, which comprises administering thereto, simultaneously or successively in any order, a pharmaceutically acceptable salt of clavulanic acid and an antimycobacterial agent, and optionally one or more other antimicrobial agents. Typically the clavulanic acid and antimycobacterial agent may be co-administered together, optionally also together with one or more other antimicrobial agents, e.g. as a pharmaceutical composition.

Typical mycobacteria are M. tuberculosis, M.fortuitum, M. kansasii, M. marinwn, and M. avium complex. The most pharmaceutically stable salt of clavulanic acid is the potassium salt, ie potassium clavulanate.

A suitable antimycobacterial agent is ethambutol [ that is, 2.2'-(l,2- ethanediyldiimino)di-l-butanol; d-N,N'-bis(l-hydroxymethylpropyl) ethylene diamine] or derivatives thereof such as the hydrochloride or dihydrochloride.

Suitable optional other antimicrobial agents which may be included in the formulations and methods of this invention as described herein include antibiotics, e.g β-lactam antibiotics such as penicillins and cephalosporins. Suitable antibiotics include those for example listed in GB 1578739, e.g on page 3 line 25 to 36 thereof. Suitable β-lactam antibiotics include the penicillins: amoxycillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, aztreonam, benzylpenicillin, bacampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxicillin, epicillin, flucloxacillin, lenampicillin, mecillinam, methicillin, mezlocillin, phenoxy- methylpenicillin, piperacillin, pivampicillin, propicillin, sulbenicillin, talampicillin, and ticarcillin; and the cephalosporins: cefaclor, cefadroxil, cefatrizine, cefclidine, cefamandole, cefazolin, cefbuperazone, cefcanel daloxate, cefdinir, cefepime, cefetamet pivoxil, cefixime, cefminox, cefminoxime,. cefmetazole, cefonicid, cefoperazone, cefotaxime, cefotetan, cefotiam, cefotiam hexetil, cefoxitin, cefpimizole, cefpiramide, cefrirome, cefpodoxime proxetil ,cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime axetil, cefuroxime, cephacetrile, cephalexin, cephaloridine, cephalothin, cephamanadole nafate, cephapirin, cephoperazone, cefsulodin, cefuzonam, cephradine, loracarbef, DQ 2556, ME1207, S-1006, SCE-2787 and moxalactam.

Amoxycillin is a preferred β-lactam antibiotic, for example used in the form of amoxycillin trihydrate or sodium amoxycillin, for example anhydrous crystalline sodium amoxycillin in the form described in EP 0131147.

The clavulanic acid and antimycobacterial agent and other optional antimicrobial agents, as used in this invention, whether in the form of the free acids, salts, esters or derivatives thereof are preferably each in a substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, preferably at least 85% especially at least 98% pure on a weight basis.

The formulations of the invention may be in a form adapted for oral or parenteral use and may be used for the treatment of infection in humans and animals especially mammals, including in particular domesticated animals (including farm animals).

The formulations of the invention may, for example, be made up in the form of tablets, suspensions, solutions, reconstitutable powders, and sterile forms suitable for injection or infusion. Such formulations may contain conventional pharmaceutically acceptable materials, for example solid or liquid diluents, colours and preservatives, in accordance with conventional pharmaceutical practice in a manner well understood by those skilled in the art of formulating antibiotics. Normally all such ingredients are predried. Aqueous solutions are normally provided in the form of dry ingredients for reconstitution immediately prior to use. It can be particularly advantageous for the formulations of the invention to be administered to a patient by injection or infusion. That method of administration has the advantage of rapidly resulting in high blood levels of the active ingredient compounds being administered. Accordingly, in one preferred form of the formulation of the invention, the compounds are present in sterile form, including in sterile crystalline form. A further preferred form of the formulation of the invention, is one in which the formulation is in injectable or infusable form.

One injectable or infusable form of the formulation of the invention is an injectable or infusable solution, which suitably comprises an aqueous solution of a pharmaceutically acceptable salt of clavulanic acid and an antimycobacterial agent, and optionally one or more other antimicrobial agents, in a sterile pyrogen-free liquid, for example water or aqueous ethanol. Because of the water sensitivity of salts of clavulanic acid such a formulation should be provided as the dry constituents and be made up with water immediately prior to use.

A further injectable or infusable form of the formulation of the invention is an injectable or infusable suspension, in which case the salt of clavulanic acid, and antimycobacterial agent are advantageously present in finely paniculate form. The suspension may be an aqueous suspension in, for example, sterile water or sterile saline, which may additionally include a suspending agent, for example poly- vinylpyrrolidone. Alternatively, the suspension may be an oily suspension in a pharmaceutically acceptable oil suspending agent, for example arachis oil, which should be dry. Because of the water sensitivity of clavulanic acid salts such aqueous suspensions should be made up from dry constituents immediately prior to use.

A formulation according to the invention may be in unit dosage form, for example unit dosage form for parenteral administration, which will primarily include administration by injection or infusion, especially intramuscular and intravenous administration.

In the formulations and methods according to the invention, the antimycobacterial agent may be administered to the patient in an antibacterially effective amount, and the salt of clavulanic acid may be administered in an amount effective to inhibit β-lactamase enzymes.

The salt of clavulanic acid will generally be administered in an amount sufficient to inhibit the β-lactamase enzyme(s) associated with infecting bacterial and/or mycobacterial organism(s). To that end, it may suitably be administered to the patient at a daily dosage of from 0.3 to 15 mg kg, preferably from 0.7 to 10 g/kg, for example from 0.7 to 7 mg/kg, of body weight. For an adult human (of approximately 70 kg body weight), from 25 to 1000 mg, preferably from 50 to 500 mg, of the salt of clavulanic acid may be administered daily, suitably in from 1 to 6, preferably from 2 to 4, separate doses. Higher or lower dosages may, however, be used in accordance with clinical practice.

When the formulations according to the invention are presented in unit dosage form, each unit dose may suitably comprise from 12.5 to 1000 mg, preferably from 12.5 to 250 mg, of the salt of clavulanic acid. Each unit dose may, for example, be 12.5, 25, 50, 75, 100, 125, 150, 200, or 250 mg of the salt of clavulanic acid. The ratio of the amount of the salt of clavulanic acid used according to the invention : amount of any other optional antimicrobial agent present may vary within a wide range, e.g 1:1 to 1:30 by weight. In the case of amoxycillin or salts or esters thereof the said ratio may, for example, be from 1:1 to 1:12; more particularly, it may, for example, be from 1:1 to 1:7, 1:1 to 1:4 or 1:1 to 1:2, by weight. The amount of any optional other antimicrobial agent, e.g amoxycillin or salts or esters thereof in a formulation according to the invention will normally be approximately similar to the amount in which it is conventionally used per se. In the case of amoxycillin for example from 125 to 3000 mg per day, and from 125 to 3000 mg per unit dose, advantageously from about 125 to 1000 mg per unit dose, from 2 to 4 times daily may be administered. In the case of ticarcillin for example a maximum of 3.2 g six to eight hourly may be administered.

The amount of antimycobacterial agent in a formulation according to the invention will normally be approximately similar to the amount in which it is conventionally used per se. For example in the case of ethambutol up to 25 mg/kg per day may be administered.

An example of a suitable formulation for oral administration according to the invention is one comprising from 12.5 to 250 mg, preferably from 25 to 125 mg, of potassium clavulanate, in admixture or conjunction with 100 to 400 mg of ethambutol or a derivative thereof per unit dose, optionally also comprising 125 to 3000mg of amoxycillin trihydrate.

An example of a suitable formulation for parenteral administration according to this invention is one comprising from 12.5 to 250mg, preferably from 25 to 125 mg, of potassium clavulanate, in admixture or conjunction with 100 to 400 mg of ethambutol or a derivative thereof per unit dose, optionally also comprising 125 to 3000 mg of sodium amoxycillin.

The following example illustrates the synergistic antibacterial activity of a combination of a salt of clavulanic acid and the antimycobacterial agent ethambutol, together with the antimicrobial agent amoxycillin, and compares this combination with the activity of amoxycillin and a salt of clavulanic acid alone, and of ethambutol alone, against mycobacteria. Example 1.

The susceptibility of four mycobacterial species to amoxycillin plus clavulanate, and ethambutol was determined. Microdilution MIC methodology was used to test 24 M.fortuitum, M. kansasii and M. m rinum strains and BACTEC methodology was used to test 20 M. avium complex (MAC) isolates.

Five of the nine M. fortuitum, four of the ten M. kansasii and three of the five M. marinum isolates had amoxyciUin/clavulanate MIC's of < 8/4 mcg/ml. Ten of the twenty MAC isolates had amoxyciUin/clavulanate MIC results < 8/4 mcg/ml, with eight of the isolates having MIC's of < 4/2 mcg/ml. Amoxycillin alone and clavulanate alone were relatively ineffective against these isolates. When amoxyciUin/clavulanate was combined with 2 mcg/ml of ethambutol, the susceptibility of seven M. kansasii and four M. marinum isolates was increased compared to either amoxyciUin/clavulanate or ethambutol alone. The data obtained indicate that the concentrations of amoxyciUin/clavulanate alone and in combination with ethambutol required to inhibit mycobacterial growth in vitro are within the therapeutic range of amoxyciUin/clavulanate.

The data presented below in Tables 1 and 2 shows MIC (μg/ml) results for M. kansasii and M. marinum. MICs were determined in middlebrook broth with OADC (oleic acid, albumin, dextrose and catalase) enrichment inocculated with 5 x 10^ CFU/ml of the mycobacteria. After sufficient growth the MICs were determined as the lowest concentration of antibiotic(s) which inhibited growth.

In Tables 1 and 2, clav. = clavulanate alone, amx. = amoxyciUin alone, etham. = ethambutol alone, clav/amx = clavulanate + amoxycillin, clav/amx/etham = clavulanate + amoxycillin + ethambutol.

Table 1: Mycobacterium Kansasii.

Isolate clav. amx. clav/amx etham. clav/amx clav/amx /etham. /etham.

258A 64 >256 8/4 16 <0.25/ <0.25/ 0.125/1 0.125/2

475A 64 >256 8/4 16 <0.25/ <0.25/ 0.125/1 0.125/2

506A >128 >256 64/32 16 16/8/1 8/4/2

626A 32 >256 16/8 16 <0.25/ <0.25/ 0.125/1 0.125/2

640A 32 256 8/4 16 <0.25/0.1 <0.25/ 25/1 0.125/2

1220 A 32 64 8/4 8 <0.25/ <0.25/ 0.125/1 0.125/2

1609 A 128 >256 32/16 8 <0.25/ <0.24/ 0.125/1 0.125/2

1610A 32 >256 32/16 16 4/2/1 2/1/2

1722A 64 >256 16/8 8 2/1/1 2/1/2

1870A 64 >256 16/8 16 <0.25/ <0.25/ 0.125/1 0.125/2

Table 2: Mycobacterium Marinum.

Isolate clav. amx. clav/amx etham. clav/amx clav/amx /etham /etham

1508A 64 256 16/8 8 <0.25/ <0.25/ 0.125/1 0.125/2

2084A 32 >256 8/4 4 <0.25/ <0.25/ 0.125/1 0.125/2

2162A 32 >256 8/4 4 <0.25/ <0.25/ 0.125/1 0.125/2

4935A 32 128 8/4 4 <0.25/ <0.25/ 0.125/1 0.125/2

4939A 32 >256 16/8 8 2/1/1 1/0.5/2

Claims

Claims:
1. A pharmaceutical formulation comprising a pharmaceutically acceptable salt of clavulanic acid, in combination with an antimycobacterial agent, and optionally with one or more other antimicrobial agents.
2. A formulation according to claim 1 wherein the pharmaceutically acceptable salt of clavulanic acid is potassium clavulanate.
3. A formulation according to claim 1 wherein the antimycobacterial agent is ethambutol.
4. A formulation according to claim 1 wherein an additional antimicrobial agent is present which is a β-lactam antibiotic.
5. A formulation according to claim 4 wherein the β-lactam antibiotic is amoxycillin, present as the free acid, or as a pharmaceuticaly acceptable salt or ester thereof.
6. A formulation according to claim 4 wherein the ratio pharmaceutically acceptable salt of clavulanic acid : β-lactam antibiotic is in the range 1:1 to 1:30.
7. A formulation according to claim 1 in unit dosage form comprising 12.5 to 1000 mg of a pharmaceutically acceptable salt of clavulanic and 100 to 400 mg of ethambutol or a derivative thereof.
8. A formulation according to claim 7 additionally comprising 125 to 3000 mg of amoxycillin or a derivative thereof.
9. A formulation according to claim 1 for parenteral administration.
10. A formulation according to claim 1 for oral administration.
11. A formulation according to claim 1 for use in the treatment of infection by mycobacteria in humans or animals.
12. A method of use of a pharmaceutically acceptable salt of clavulanic acid, and an antimycobacterial agent, and optionally one or more other antimicrobial agents, together in combination in the manufacture of a medicament formulation.
13. A method according to claim 11 comprising admixing the combination pharmaceutically acceptable salt of clavulanic acid, an antimycobacterial agent, and optionally one or more other antimicrobial agents.
14. A pharmaceutical formulation according to claim 1 for use as an active therapeutic substance^.
15. The use of a pharmaceutically acceptable salt of clavulanic acid to enhance the antimycobacterial activity of an antimycobacterial agent.
16. A method for the treatment of an infection by mycobacteria in humans or animals, which comprises administering thereto, simultaneously or successively in any order, a pharmaceutically acceptable salt of clavulanic acid and an antimycobacterial agent and optionally one or more other antimicrobial agents.
PCT/IB1994/000204 1993-05-28 1994-05-16 Pharmaceutical formulations with clavulanic acid and an antimycobacterial agent WO1994027600A1 (en)

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GB939311030A GB9311030D0 (en) 1993-05-28 1993-05-28 Pharmaceutical formulations
GB9311030.2 1993-05-28

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EP19940918998 EP0675716A1 (en) 1993-05-28 1994-05-16 Pharmaceutical formulations with clavulanic acid and an antimycobacterial agent

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1044680A1 (en) * 1999-04-13 2000-10-18 Beecham Pharmaceuticals (Pte) Limited Novel method of treatment using a high dosage regimen of amoxycillin and potassium clavulanate
US6294199B1 (en) 1999-04-13 2001-09-25 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising administering amoxycillin
US6726908B2 (en) 1995-09-07 2004-04-27 Smithkline Beecham P.L.C. Pharmaceutical formulation
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
US6783773B1 (en) 1999-04-13 2004-08-31 Beecham Pharmaceuticals (Pte) Limited Composition comprising amoxicillin and potassium clavulanate
US7011849B2 (en) 2000-10-12 2006-03-14 Beecham Pharmaceuticals (Pte) Limited Second release phase formulation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
C. BHATTACHARYA ET AL.: "Comparison of sensitivity of Mycobacterium spp. to combinations of clavulanic acid & penicillins with certain antitubercular agents", INDIAN J. MED. RES., vol. 88, August 1988 (1988-08-01), pages 118 - 123 *
J. NADLER ET AL.: "Amoxicillin-Clavulanic acid for treating drug-resistant Mycobacterium tuberculosis", CHEST, vol. 99, no. 4, 1991, pages 1025 - 1026 *
M. CASAL ET AL.: "In vitro activity of antimicrobial agents aginst mycobacteria", DRUGS EXP. CLIN. RES., vol. 14, no. 12, 1988, pages 741 - 745 *
Y. ZHANG ET AL.: "Beta-lactamase inhibitors and the inducibility of the beta-lactamase of Mycobacterium tuberculosis", AM. REV. RESPIR. DIS., vol. 145, no. 3, 1992, pages 657 - 660 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6726908B2 (en) 1995-09-07 2004-04-27 Smithkline Beecham P.L.C. Pharmaceutical formulation
EP1044680A1 (en) * 1999-04-13 2000-10-18 Beecham Pharmaceuticals (Pte) Limited Novel method of treatment using a high dosage regimen of amoxycillin and potassium clavulanate
WO2000061116A3 (en) * 1999-04-13 2001-02-01 Beecham Pharm Pte Ltd Pharmaceutical formulation comprising amoxycillin and clavulanate
US6294199B1 (en) 1999-04-13 2001-09-25 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising administering amoxycillin
JP2002541187A (en) * 1999-04-13 2002-12-03 ビーチャム・ファーマシューティカルズ・(プライベイト)・リミテッド New treatments
EP1269997A1 (en) * 1999-04-13 2003-01-02 Beecham Pharmaceuticals (Pte) Limited Unit dosage comprising amoxicillin and clavulanate
EP1269996A1 (en) * 1999-04-13 2003-01-02 Beecham Pharmaceuticals (Pte) Limited Unit dosage comprising amoxycillin and clavulanate
WO2000061116A2 (en) * 1999-04-13 2000-10-19 Beecham Pharmaceuticals (Pte) Limited Pharmaceutical formulation comprising amoxycillin and clavulanate
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
AP1806A (en) * 1999-04-13 2007-12-14 Beecham Pharm Pte Ltd The use of a high dosage regimen of amoxycillin and potasslum chavulate for the treatment of bacterial infections
US6783773B1 (en) 1999-04-13 2004-08-31 Beecham Pharmaceuticals (Pte) Limited Composition comprising amoxicillin and potassium clavulanate
US6878386B1 (en) 1999-04-13 2005-04-12 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate
US7250176B1 (en) 1999-04-13 2007-07-31 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection
US7217430B2 (en) 1999-04-13 2007-05-15 Beecham Pharmaceuticals (Pte) Limited Compositions and methods of treatment comprising amoxicillin and potassium clavulanate with xanthan
JP4880125B2 (en) * 1999-04-13 2012-02-22 ビーチャム・ファーマシューティカルズ・(プライベイト)・リミテッドBEECHAM PHARMACEUTICALS (Pte) LIMITED New treatments
US7011849B2 (en) 2000-10-12 2006-03-14 Beecham Pharmaceuticals (Pte) Limited Second release phase formulation
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form

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GB9311030D0 (en) 1993-07-14
EP0675716A1 (en) 1995-10-11

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