JPH11501904A - Pharmaceutical formulation comprising clavulanic acid salt, vancomycin and one or more beta-lactam antibiotics - Google Patents

Abstract

  (57) [Summary] Comprising vancomycin and one or more beta-lactam antibiotics, particularly a pharmaceutically acceptable salt of clavulanic acid, particularly potassium clavulanate, in combination with sodium amoxicillin or ticarcillin sodium Pharmaceutical prescription. The formulations of the present invention are suitable for parenteral administration in the treatment of methicillin-resistant Staphylococcus infections.

Description

The present invention relates to pharmaceutical formulations, particularly to the treatment of bacterial infections, comprising a salt of clavulanic acid, vancomycin and one or more beta-lactam antibiotics. New use of the prescribed formula. Increasing infection rates due to methicillin-resistant Staphylococcus (MRS) have become an important clinical problem worldwide. Most of these organisms are resistant to many drugs, raising important issues for antimicrobial therapy. Glycopeptides are the major therapeutics for MRS infection, and bacterial resistance to this class of compounds may be a major problem. Vancomycin is a known glycopeptide antibiotic, usually administered in the form of its hydrochloride salt. As used herein, the term "vancomycin" includes vancomycin itself and pharmaceutically acceptable derivatives thereof. The present invention provides a pharmaceutical formulation comprising a pharmaceutically acceptable salt of clavulanic acid in combination with vancomycin and one or more β-lactam antibiotics. The invention also relates to a combination of a pharmaceutically acceptable salt of clavulanic acid and vancomycin, and one or more pharmaceutically acceptable salts in the manufacture of a pharmaceutical formulation, particularly for the treatment of human or animal infection by bacteria. The use of a β-lactam antibiotic is provided. Further, the present invention relates to a method for producing the above-mentioned pharmaceutical formulation, which comprises mixing a pharmaceutically acceptable salt of clavulanic acid, and a combination of vancomycin and one or more β-lactam antibiotics. Provide a way to Clavulanic acid salts are extremely hygroscopic and such formulations must be prepared in the dry state, typically at or below 30% relative humidity. Dry formulations that are reconstituted with water may be reconstituted with an aqueous carrier immediately before use. The invention further provides the above pharmaceutical formulation, particularly for use as an active therapeutic substance in the treatment of human or animal infection by bacteria. The present invention also provides the use of a pharmaceutically acceptable salt of clavulanic acid for improving the antibacterial efficacy of a combination of vancomycin and one or more β-lactam antibiotics. Further, the present invention is a method of treating a bacterial infection in a human or animal, comprising administering a pharmaceutically acceptable salt of clavulanic acid and vancomycin, and / or one or more β-lactam antibiotics. Sequentially administered to a human or animal in the following order: Typically, clavulanic acid and vancomycin may be co-administered, optionally in combination with one or more β-lactam antibiotics, for example, as a pharmaceutical composition. The formulations and methods of the present invention are suitable for the treatment of bacterial infections in humans or animals, particularly MRS, such as infections by Staphylococcus aureus and Staphylococcus epidermis. The most pharmaceutically stable salt of clavulanic acid is the potassium salt, ie potassium clavulanate. Suitable β-lactam antibiotics that may be used in the formulations and methods of the present invention include penicillins and cephalosporins. Suitable antibiotics include, for example, those listed on page 3, lines 25-36 of GB1 587,739. Suitable β-lactam antibiotics include penicillins (amoxicillin, ampicillin, aparcillin, aspoxycillin, azidocillin, azulocillin, aztreonam, benzylpenicillin, bacampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxicillin, epicillin, flucicillin, flucicillin, flucicillin, flucixillin, flucixillin, flucicillin, flucixillin, flucixillin, flucixillin, flucixillin, flucixillin, flucixillin) , Methicillin, mezlocillin, phenoxymethylpenicillin, piperacillin, pivanpicillin, propicillin, sulbenicillin, tarampicillin, and ticarcillin); , Cefdinir, cefepime, cefetametopivo Syl, cefixime, cefminox, cefminoxime, cefmetazole, cefoniside, cefoperazone, cefotaxime, cefotetan, cefotiam, cefotiamhexetil, cefoxitin, cefpimisole, cefpyramide, cefrilom, cefpodoxime proxetixefifixifixetififixifixifixefifixifixifixefifixifixefixefifixefixifixefixifixefixetif Xenon, cefuroxime axetil, cefuroxime, cephacetrile, cephalexin, cephaloridine, cephalotin, cephamanadole naphate, cephapirin, cefoperazone, cefsulodin, cefzonam, cefradine, loracarbef, DQ2556, ME1207, S-1007, SCE-lactam ). Amoxicillin and ticarcillin are preferred β-lactam antibiotics, for example, amoxicillin used in the form of amoxicillin sodium, such as spray-dried amoxicillin sodium or anhydrous crystalline amoxicillin sodium as described in EP0131147, and sodium salts The form of ticarcillin is preferred. The clavulanic acid and vancomycin and β-lactam antibiotics used in the present invention, whether in the form of their free acids, salts, esters or derivatives, are each preferably in substantially pure form, for example, by weight. At least 60%, more suitably at least 75%, preferably at least 85%, especially at least 98%. The formulations of the present invention may be in a form adapted for parenteral administration, i.e., usually administered vancomycin, and administered to humans and animals, especially domesticated animals, including agricultural animals. Animal) may be in a form adapted for parenteral administration in a manner that can be used to treat infections. The formulations of the present invention may be, for example, in tablets, suspensions, solutions, reconstitutable powders, and sterile forms suitable for injection or infusion. Such formulations may be prepared according to conventional pharmaceutical practices in a manner well understood by those skilled in the art of antibiotic formulation, including conventional pharmaceutically acceptable substances, such as solid or liquid diluents, coloring agents and the like. Preservatives may be included. Usually, such ingredients are pre-dried. Typically, aqueous solutions are provided in the form of a dry composition, which is reconstituted just prior to use. It may be particularly advantageous to administer the formulation of the invention to a patient by injection or infusion. Such an administration method has the advantage that the blood level of the administered active ingredient is rapidly increased. Thus, in one preferred form of the formulation of the invention, the compound is in a sterile form, including a sterile crystalline form. A further preferred form of the formulation according to the invention is that in which the formulation is injectable or infusible. One injectable or infusible form of the formulations of the present invention is an injectable or infusible solution, suitably a sterile pyrogen-free liquid, such as a pharmaceutically acceptable salt of clavulanic acid in water or aqueous ethanol. And an aqueous solution of vancomycin and, optionally, one or more other antimicrobial agents. Due to the water sensitivity of the salt of clavulanic acid, such a formulation should be provided as a dry composition and be reconstituted with water immediately before use. A further injectable or infusible form of the formulations of the present invention is an injectable or infusible suspension, advantageously where the salt of clavulanic acid and vancomycin are present in particulate form. The suspension may be an aqueous suspension, for example, an aqueous suspension in sterile water or sterile saline, which may additionally contain a suspending agent (eg, polyvinylpyrrolidone). Alternatively, the suspension may be an oily suspension in a pharmaceutically acceptable oily suspension to be dried (eg, peanut oil). Due to the water sensitivity of the salts of clavulanic acid, such aqueous suspensions should be prepared from the dry composition immediately before use. The formulations of the present invention may be in a unit dosage form, for example, a parenteral dosage unit, which will be administered primarily by injection or infusion, in particular by intramuscular and intravenous administration. The formulation may comprise a mixture of vancomycin and the β-lactam antibiotic / clavulanic acid present in separate dosage forms administered together or sequentially. For example, these components and suitable excipients (as would be apparent to those skilled in the art) may be provided in separate vials to provide a solution or suspension for injection or infusion. In the formulations and methods of the present invention, an antibacterial effective amount of vancomycin can be administered to the patient, and an amount of clavulanic acid salt effective to inhibit the β-lactamase enzyme can be administered. Generally, a salt of clavulanic acid, particularly potassium clavulanate, is administered in an amount sufficient to inhibit the β-lactamase enzyme associated with infectious bacteria and / or bacterial organisms. To this end, a dose of 0.3 to 15 mg / kg body weight / day, preferably 0.7 to 10 mg, for example 0.7 to 7 mg / day (based on the original clavulanic acid), is suitably administered to the patient. May be administered. For a human adult (body weight of about 70 kg), 25 to 1000 mg, preferably 50 to 500 mg of a salt of clavulanic acid may be administered daily, suitably 1 to 6 times, preferably 2 to 4 times. Good. However, higher or lower doses may be used depending on clinical practice. Where the formulations of the present invention are provided in a single dosage form, suitably each dosage form may comprise 12.5 to 1000 mg, preferably 12.5 to 250 mg, of the salt of clavulanic acid. . Each dosage form may be, for example, 12.5, 25, 50, 75, 100, 125, 150, 200 or 250 mg of a salt of clavulanic acid. The ratio by weight of the salt of clavulanic acid to the β-lactam antibiotic present used according to the invention may vary widely, for example from 1: 1 to 1:30 by weight. In the case of amoxicillin, the ratio may be, for example, 1: 1 to 1:12 by weight; more particularly, for example, 1: 1 to 1: 7, 1: 1 to 1: 4, or 1: 1 to 1: 2. It may be. For example, the amount of a β-lactam antibiotic, such as amoxicillin or ticarcillin, as the respective sodium salt in the formulations of the present invention is usually about the same as that used per se. In the case of amoxicillin, for example, 125 to 3000 mg per day, 125 to 3000 mg per dose, advantageously about 125 to 1000 mg per dose, may be administered 2 to 4 times a day. In the case of ticarcillin, for example, a maximum of 5 g may be administered in 8 hours, or 7 g in 20 hours. These weights are given on the basis of the original free acid. The amount of vancomycin (eg, hydrochloride) in the formulations of the present invention will usually be about the same as that conventionally used per se. For example, in the case of an adult, the dose may be up to 2000 mg daily, typically in several divided doses by intravenous infusion for 60 minutes. Up to 40 mg may be administered by slow 60 minute intravenous infusion in several divided doses. These weights are given on the basis of the original free acid. An example of a formulation suitable for parenteral administration according to the invention is a formulation comprising 12.5 to 250 mg, preferably 25 to 125 mg, of potassium clavulanate mixed or conjugated with 100 to 500 mg of vancomycin per serving. (May contain 125-3000 mg of amoxicillin sodium or ticarcillin sodium). The following examples illustrate the invention. In these examples, the abbreviation AMX is used for amoxicillin and CA is used for clavulanic acid used in the form of a potassium salt. Example 1 Improved Efficacy of Amoxicillin / Clavulanate in Combination with Vancomycin against Experimental Staphylococcal Endocarditis in Rats Animals were injected intravenously into S. aureus E164 (MRSA) Endocarditis was caused by internal infection. Treatment (subcutaneous injection) was started 8 or 24 hours after infection and continued for 4 days. Growth was harvested at the time of death 96 hours after infection or earlier if it died. Amoxicillin / clavulanate (200/20 mg / growth) + vancomycin (80 mg / kg) administered 8 hours post-infection was given by any of the drugs administered alone (5.9 ± 2.5 and 6 respectively). Compared to (.3 ± 2.5 log ₁₀ cfu / each growth), the number of bacteria was significantly reduced (3.4 ± 2.4 log ₁₀ cfu; p <0.01). Reducing the content of either amoxicillin / clavulanic acid (100/20 mg / kg) or vancomycin (40 mg / kg) did not abolish the efficacy of the antibiotic combination. When treatment was delayed to 24 hours post-infection, bacterial counts for amoxicillin / clavulanate (100/20 mg / kg) or vancomycin (80 mg / kg) were not significantly different compared to untreated controls ( p> 0.05). In contrast, the combination treatment (amoxicillin / clavulanate 100/20 mg / kg + vancomycin 80 mg / kg) caused a significant (2.5-3 log) decrease in viable bacterial count (p <0.05). Example 2: Synergistic activity of vancomycin and ticarcillin / clavulanate on MRS FICs were examined in a checkerboard test for ticarcillin / clavulanate and vancomycin on 19 strains of MRS. A synergistic effect was shown against 6 of the 14 MRSA strains and 5 of the 5 methicillin resistant Staphylococcus epidermis (MRSE) strains. An additive effect was observed for all other strains. The bactericidal activity of these agents alone and in combination was assayed by viable count and flow cytometry (FC). Vancomycin at 0.25 mcg / ml (1/4 of MIC) was ineffective, and 8/2 mcg / ml ticarcillin / clavulanate was essentially bacteriostatic. However, 0.25 mcg / ml vancomycin combined with 2/2 mcg / L ticarcillin / clavulanate was rapidly bactericidal and viable counts were reduced by 3 log ₁₀ after 8 hours (24 hours). Almost no regrowth during the exposure period). FC analysis supported the viable count results. These data indicate that ticarcillin / clavulanate and vancomycin are very effective in combating MRS in vitro. Example 3 Synergistic Activity of Vancomycin and Amoxicillin / Clavulanate on MRSE Methicillin-resistant Staphylococcus epidermis 100710 was cultured overnight at 37 ° C. in 9 ml of Difco Mueller (MH) broth. At time zero, 20 ml of starting medium was inoculated into 20 ml of MH broth, previously warmed in a 100 ml conical flask (10 ^-3 dilution). Addition of the antibiotic concentration to the measured concentration gave the following results: MIC (1 / 0.5 mcg / ml) AMX / CA is essentially bacteriostatic in the first 8 hours and up to 24 hours The increase in proliferation was 2 log ₁₀ . MIC (4.00 mcg / ml) vancomycin was rapidly bactericidal. A 4 log ₁₀ decrease in cell viability was observed at 6 hours, with no regrowth at 24 hours. AMX / CA and vancomycin, both １ ／ of the MIC, did not affect cell viability, and the treated cells had a similar growth pattern as the untreated control. AMX / CA at MIC (1 / 0.5 mcg / ml) and vancomycin at 1/4 (1.00 mcg / ml) MIC were rapidly bactericidal. A 4 log ₁₀ decrease in cell viability was recorded in the first 4 hours, and no subsequent growth of strain MRSE100710 was observed at 24 hours. The combination of 0.25 mcg / ml AMX / CA and 1.00 mcg / ml vancomycin is rapidly bactericidal, with a 2.5 log ₁₀ reduction in viability observed over 8 hours and up to 24 hours Showed no regrowth. These results indicate that sub-MIC levels of AMX / CA and vancomycin combinations act to produce a synergistic effect in the eradication of MRSE in vitro. Example 4: Efficacy of amoxicillin / clavulanate co-administered with vancomycin against experimental endocarditis in rats caused by methicillin-resistant Staphylococcus aureus Male CD weighing about 120-150 g For rats (Charles River), endocarditis was induced by a known protocol (Heraief et al. (1982) Natural history of aortic valve endo carditis in rats. Infect. Immunol. 37; 127-131). Rats were infected through the tail vein with about 6 log ₁₀ cfu of S. aureus. The selected strain has AMX / CA sensitivity of 8/4 mcg / ml and 16/8 mcg / ml, and S. aureus P8 + (AMX / CA MIC 8/4 mcg / ml) is heterologous. It is a resistant clinical isolate and a strong penicillinase producing strain. S. aureus E164 and 468 are typical AMX / CA resistant clinical isolates and have MIC values of 16/8 mcg / ml. AMX / CA and vancomycin were administered to infected rats by subcutaneous injection into groups of rats. Dosing commenced 8, 12, or 24 hours post-infection and was performed 3 or 4 times daily for 3 or 4 days. An additional group of rats received phosphate buffered saline and served as controls. Animals were weighed daily and animals were assayed for signs of endocarditis at least five times a day. The results show that for S. aureus P8 +, a good response was obtained with vancomycin monotherapy, but not with AMX / CA co-administration. However, compared to animals receiving vancomycin plus AMX / CA (100%), the survival rate of animals receiving vancomycin was slightly lower (85%). For S. aureus E164 with an AMX / CA MIC value of 16/8 mcg / ml, when AMX / CA 200/20 mg / kg was administered in combination with vancomycin 40 or 80 mg / kg, AMX / CA alone or vancomycin A significant decrease in bacterial counts (p = 0.01) was observed compared to the case alone. S. aureus 468 also showed improved activity when using a combination of AMX / CA and vancomycin. The results show that the increased activity determined by low average bacterial counts in the arterial growth, improved sterilization of the growth, and improved survival compared to each agent alone against the S. aureus strain. Shows that it is achieved by AMX / CA when co-administered with vancomycin. Example 5: Vancomycin against methicillin-resistant Staphylococcus aureus V12181 and ticarcillin / clavulanate synergistic activity alone or mixed AMX / CA and vancomycin about 10 ⁵ cfu / ml in MH broth 20ml containing (MRSA V12181 overnight culture). Cultures were incubated at 37 ° C. in a shaking incubator and samples were taken at appropriate times for viable cell counts. The following MRSA and MRSE strains were also examined by this method: MRSA strains; 3/02302, S1187, 100710, 57811, 59356. In this experiment, a synergistic effect between ticarcillin / clavulanate in vitro, defined as having a FIC of ≦ 0.5 for 14 strains in 14 MRSA and 5 strains in 5 MRSE It was observed. Concentrations of ticarcillin / clavulanate and vancomycin, which are not inherently bactericidal to MRSA, are rapidly bactericidal even at 1/4 of the MIC when combined, and regrowth is seen up to 24 hours. Did not. Example 6: Effect of prolonged dosing schedule of amoxicillin / clavulanate co-administered with vancomycin on experimental endocarditis in rats caused by methicillin-resistant Staphylococcus aureus co-administered with vancomycin The effect of an extended amoxicillin / clavulanate dosing schedule (6 days) was investigated using an experimental model of bacterial endocarditis in rats. After surgery, animals were infected intravenously with S. aureus 468. Subcutaneous treatment was initiated 12 hours post-infection and the dose in rats was chosen to approach the peak serum concentration measured in humans following parenteral treatment of severe infection. Treatment was continued three times daily for three or six days, and if death died at 96 or 168 hours, or earlier, aortic valve growth was collected at the time of death and bacterial counts were made. . Extension of the treatment period from 3 to 6 days was significantly (p <0.01) effective, as indicated by a low average bacterial count in the aortic growth, a high percentage of sterilized growth and increased survival. Improved. These data underscore the importance of the length of the administration period in obtaining better therapeutic effects with amoxicillin / clavulanate co-administered with vancomycin.

────────────────────────────────────────────────── ─── Continuation of front page    (72) Inventor Bryant, Joanna             UK, RH 3.7A             Lee, Sally, Betchworth, Blockham             Park, SmithKline Beecham Hu             Armaturicals (72) Inventor Woodnut, Gary             UK, RH 3.7A             Lee, Sally, Betchworth, Blockham             Park, SmithKline Beecham Hu             Armaturicals (72) Inventor Pearson, Stuart             UK, RH 3.7A             Lee, Sally, Betchworth, Blockham             Park, SmithKline Beecham Hu             Armaturicals (72) Inventor Simpson, Yane             UK, RH 3.7A             Lee, Sally, Betchworth, Blockham             Park, SmithKline Beecham Hu             Armaturicals (72) Moore, Roland             UK, RH 3.7A             Lee, Sally, Betchworth, Blockham             Park, SmithKline Beecham Hu             Armaturicals

Claims (1)

[Claims]   1. Combination with vancomycin and one or more beta-lactam antibiotics A pharmaceutical formulation comprising a combined pharmaceutically acceptable salt of clavulanic acid.   2. The manufacture of a formulation for the treatment of human or animal infection by bacteria, A combined pharmaceutically acceptable salt of clavulanic acid and vancomycin, and Use of one or more β-lactam antibiotics that may be used.   3. A pharmaceutically acceptable salt of clavulanic acid, and vancomycin and one or more Or a combination of more β-lactam antibiotics. The method for producing a pharmaceutical formulation according to claim 1.   4. Use as active therapeutic substance in the treatment of human or animal infections by bacteria The pharmaceutical formulation of claim 1, wherein   5. Set of vancomycin and one or more β-lactam antibiotics Pharmaceutically acceptable salts of clavulanic acid to enhance the antibacterial efficacy of the combination Use of.   6. A method of treating a bacterial infection in a human or animal, comprising pharmaceutically acceptable Of clavulanic acid and vancomycin, and one or more that may be administered. Or more β-lactam antibiotics simultaneously or sequentially in any order A method comprising administering to a human or animal.   7. Clavulanate is present as potassium clavulanate and is a β-lactam Amoxicillin or ticarcillin, which is the active substance, is present in the formulation The method according to any one of claims 1, 2 and 4, characterized in that it is used in law. Prescription.   8. Clavulanate is present as potassium clavulanate and is a β-lactam Amoxicillin or ticarcillin, which is the active substance, is present in the formulation 7. The method according to claim 3, wherein the method is used in a law. The method described.   9. Vancomycin and β-lactam antibiotic / clavulanate combination Wherein the combination is in separate dosage forms administered together or sequentially. A formulation according to claim 1 or claim 7.   10.1 Mix or contain 100 to 500 mg of vancomycin per serving Comprising 12.5 to 250 mg of potassium clavulanate, 125 to 3000 mg of amoxicillin sodium or ticarcillin 2. The formulation for parenteral administration comprising thorium. Prescription.