WO2011078820A1

WO2011078820A1 - Pharmaceutical formulations comprising a third generation cephalosporin and clavulanic acid

Info

Publication number: WO2011078820A1
Application number: PCT/TR2010/000240
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2009-12-25
Filing date: 2010-12-03
Publication date: 2011-06-30
Also published as: EP2515905A1; TR200909787A2

Abstract

Present invention relates to pharmaceutical compositions comprising a third generation cephalosporin selected from a group comprising cefdinir, cefixime and cefpodoxime proxetil and clavulanic acid and/or pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations thereof for use in the treatment of infections caused by resistant bacteria.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING A THIRD GENERATION CEPHALOSPORIN AND CLAVULANIC ACID

Prior Art Antibiotics are one of the most frequently used medications used in medical practice and they form an important part of drug expenses. Although when used appropriate they provide important benefits, upon random use they cause economic losses and development of resistant bacteria strains.

Antibiotics have lost their effect mainly due to antibiotic resistance that that has developed by improper and unnecessary use of the antibiotics. Microorganisms develop a resistance for the antimicrobial substances that is used to destroy them.

Resistance to antibacterial agents is an expected result however in our time development of the resistance takes place in a way that is too fast to allow development of new antibiotics. The fact that they are easy to obtain, results in development of resistance to antibiotics. When infections caused by resistant bacteria are present more toxic and expensive drugs must be used for the treatment. In some cases the illness may not be cured due to the fact that an antibiotic that is effective enough to destroy the resistant bacteria. In addition to that antibiotic resistance may spread to other bacterial infections. All of these reasons lead to longer hospitalization times and paying higher amounts of money for treatment. A lot of problems such as insufficiency of the medications and as a result of that increase in death rates, increase in defects due to sickness, increased hospitalization times, increased treatment costs arise. All over the world resistant infection cases increase due to decrease in susceptibility to beta lactam and other antibiotics. Sicknesses caused by Streptococcus Pneumonia can be given as an example to these. For these reasons it is necessary to maximize the use of antibiotics and to prevent resistance. Lately researchers try to remove the factors that cause bacterial resistance and they have proposed new combinations for this purpose.

Beta lactam antibiotics are a group of antibiotics wherein there are bacteria that can develop resistance against them. Many of the bacteria prevent the activity of the beta lactam antibiotics by producing beta lactamase enzyme.

These antibiotics can be classified in 5 groups;

1. Penicillins

2. Cephalosporins

3. Monobactams

4. Carbapenems

5. Beta-lactamase inhibitors

7-arninocephalosporanic acid forms the core of the cephalosporins. Cephalosporins are classified with different generations in respect of their antibacterial spectrum. From first generation to third generation gram (+) activity decreases and gram (-) activity increases.

Third generation cephalosporins have an extensive activity spectrum compared to first and second generation antibiotics. They have antibacterial activity on bacteria susceptible to first and second generation cephalosporins and additionally they are effective on bacteria like Serratia, Pseudomonas, Citribacter and Enterobacter which are resistant to hospital conditions.

Third generation cephalosporins are used for the treatment of commonly acquired pneumonia, urinary tract infections, endocartidis originating from streptococcus viridance, gnococ infections and infections developing in hospitals. In addition to these it is also used for pneumonia originating from hospitals, soft tissue infections, osteomyellitis, septic arthritis, acute bacterial meningitis, abdominal and gynecological infections, diabetic foot infections and sepsis incidents caused by gram negative bacteria.

Because of the resistance problems developed in many centers wide spectrum antibiotics are preferred to prophylaxis of the neutropenic patients.

Beta lactamase enzyme production which inactivates beta lactam antibiotics by hydrolyzing them is the most important resistance mechanism of the many bacteria types such as members of enterobacteriaceae. In the last few years some beta lactam antibiotics are combined with beta lactamase inhibitors to prevent enzymatic cleavage.

Application numbered GB 1508977 discloses clavulanic acid shown with Formula 1 and its derivatives (such as its salts like potassium clavulanate). Clavulanic acid and its derivatives are known as beta lactamase inhibitors that inhibit the activity of beta lactamase enzymes.

(I)

In literature there are works related to combined use of beta lactam antibiotics and beta lactamase enzymes to prevent increased antibiotic resistance.

Especially penicillin compositions comprising beta lactamase inhibitors such as sulbactam, tazobactam, clavulanic acid and penicillin derivatives such as ampicillin, amoxycillin, ticarcillin, piperacillin are prepared to incorporate bacteria producing beta lactamase within their activity domain. Although antibiotics present in this group are effective against many bacteria that produce beta-lactamase they are not resistant to type I beta lactamase. They are not effective against bacterias having this type of beta-lactamase enzyme such as Enterobacter, Citrobacter, Serratia and P. Aeruginosa. There are different kinds of said combinations such as Amoxycillin-clavulanic acid, ampicillin-sulbactam, ticarcillin- clavulanic acid, piperacillin-tazobactam. Amoxycillin-clavulanic acid is a combination that is orally used.

Patent application numbered GB2005538 describes formulations comprising amoxycillin trihydrate and potassium clavulanate. Patent applications numbered W095/28927 and EP 1269996 disclose use of amoxycillin and potassium clavulanate in combined form for treatment of bacterial infection and tablet formulations for this combination respectively. WO97/09042 describes tablet formulations comprising amoxycillin and clavulanic acid in an amount in the ratio of 12:1 to 20:1 preferably in 14:1. However, the most important disadvantage of the penicillin antibiotics is the serious allergic reactions they cause. Penicillin allergy is very common and 3-10 people out of 100 people are allergic to penicillin. Although this sensitivity to penicillin is mostly displayed with very mild reactions, death rate due to penicillin allergy is relatively high.

Treatments having low side effects, wide spectrum and higher efficacy are required for treatment of bacterial resistant infections. Infections caused by resistant bacteria leads to serious therapeutic problems.

Inventors have surprisingly found that use of third generation cephalosporin and clavulanic acid or its pharmaceutically acceptable derivatives as a beta lactamase inhibitor shown a synergic effect in treatment of patients having resistance to beta lactam antibiotics and that it provides an effective and safe therapeutical benefit compared to the other medications. The term "beta lactamase inhibitor" mentioned in this invention comprises clavulanic acid and/or its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts and free base form, all esters, polymorphs, crystal forms and amorphous forms; the term "third generation cephalosporin antibiotic" comprises cefdinir, cefixime and/or cefpodoxime proxetil and/or their solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts and their free base form, all esters, polymorphs, crystal forms and amorphous forms.

In one aspect present invention provides a treatment method comprising use of a third generation cephalosporin and clavulanic acid that shows synergic effect.

In another aspect present invention provides use of formulations comprising a combination of a third generation cephalosporin and clavulanic acid that shows synergic effect for treatment of infections caused by resistant bacteria.

In another aspect present invention discloses combination medicament wherein active agents are prepared in a single pharmaceutical composition.

Detailed description of the invention

Synergic pharmaceutical composition of the present invention comprises; a) A third generation cephalosporin antibiotic;

b) Clavulanic acid and

c) At least one pharmaceutically acceptable excipient.

Said third generation cephalosporin antibiotic is selected from a group comprising cefdinir, cefixime and/or cefpodoxime proxetil. Said clavulanic acid is in the form of an alkali metal salt, preferably in the form of its potassium salt (i.e. potassium clavulanate).

According to invention treatments comprise application of effective amounts of a third generation cephalosporin and clavulanic acid and in this context activity of the combination against the bacterial infections is synergic.

Present invention provides use of a third generation cephalosporin and clavulanic acid ratio within the range of 1 :0.01 to 1 :10 for manufacture of a medicament that will be used orally and that is for treatment of infections caused by resistant bacteria.

In formulations of the present invention third generation cephalosporin is present in an amount 5-50% and clavulanic acid is present in an amount 1 to 30 %.

Pharmaceutical formulations of the present invention are suitable for oral or peroral application and can be present as solid or liquid dosage forms.

In formulations of the present invention third generation cephalosporin amount in unit dose is in the range of 50 to 1000 mg; clavulanic acid amount in unit dose is in the range of 20 to 300 mg.

Pharmaceutical formulations that will be applied orally can be in the form of tablets, dispersible tablets, effervescent tablets, chewable tablets, coated tablets, dispersible granules, dispersible powders, capsules, emulsions, suspensions, solutions.

Formulations of the present invention can be in the form of powders or granules stored in small packages and are used by dispersing in water prior to use.

Said pharmaceutical composition may comprise an active combination of the two compounds or each one of the active agents can be in different parts of the pharmaceutical composition, such as one may be in the inside of a tablet and the other may be in the coating of the tablet.

Pharmaceutical formulation prepared according to the present invention may comprise one or more conventionally used pharmaceutically acceptable excipients, such as at least one binder, at least one disintegrant, at least one glidant, at least one lubricant, at least one humectant, at least one sweetener, at least one flavoring agent and/or basic coating.

Said binder can be selected from but not limited with a group comprising potato/whet/corn starch, microcrystalline cellulose such as avicel, filtrak, heweten or pharmacel products, hydroxyl propyl cellulose, hyroxyethylcellulose, hydroxypropylmethyl cellulose, hypromellose and polyvinylpyrolidone, for example povidone K30 (BASF)

Said disintegrant can be selected from but not limited with a group comprising corn starch, sodium starch glycolate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, crosslinked PVP such as products known as Crospovidone, Kollidon XL and Polyplasdone, alginic acid, sodium alginate and guar gum.

Said glidant can be selected from but not limited with a group comprising silica, colloidal silicon dioxide for example colloidal silica anhydrous such as Aerosil 200, magnesium trisilicate, powdered cellulose, starch and talk. Humectants can be selected from but not limited with a group comprising molecular sieves, silica gel (e.g. syloid) or crystalline sodium/potassium/calcium alumina silicates.

Said lubricant can be selected from but not limited with a group comprising magnesium, aluminium or calcium stearate, PEG 4000-8000 and/or talc.

Said sweetener can be selected from but not limited with a group comprising sodium chloride, aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, maltose.

Depending on the properties expected from the formulation one or more of these excipients can be used. Said excipients can be used for more than one purpose.

According to the inventions tablet formulations can be shaped with conventional tableting techniques. Tablet can be in one of the conventional forms such as round, spherical, block or rectangle.

Pharmaceutical formulations according to present invention can be manufactured in the form of water dispersible tablets or granules or in the form of effervescent tablets or granules.

Especially effervescent products disperse quickly and release the active agents into the liquid medium in a fast and homogeneous way. Effervescent formulations according to the present invention comprise effective amounts of a third generation cephalosporin, effective amounts of clavulanic acid and an organic base and in addition to that an effective effervescent couple. Effervescent composition comprises a mixture of components that give off C0₂ gas upon contact with water. Effervescent components of this sort are especially an alkali or alkali earth metal carbonate or hydrogen carbonate especially sodium hydrogen carbonate and an acid or an acidic salt that is capable to give off C0₂ gas upon contact with water. Acid can be anhydrous organic or inorganic pharmaceutically acceptable acid in powder form, preferably citric acid, monosodium citrate or preferably a mixture thereof. As the alkali component preferably sodium hydrogen carbonate is used.

According to present invention pharmaceutical effervescent formulation may further comprise other pharmaceutically acceptable excipients such as viscosity agents, fillers, humectants, lubricants, diluents, binders, glidants, anti-foaming agents, wetting agents, effervescent mixtures, sweeteners and taste regulators. Pharmaceutical formulation especially effervescent tablet and granule or water dispersible tablet and granule disperse in water that is at room temperature in around 1 minute.

Pharmaceutical formulation especially effervescent tablet and granules or dispersible tablet and granules are dispersed in water, fruit juice or aqueous drinks of other sorts and applied orally. In formulations applied orally clavulanic acid is usually found in a pharmaceutically acceptable salt form especially in the form of potassium clavulanate which is its most stable salt form. However, potassium clavulanate has an extremely hygroscopic nature therefore it is very difficult to formulate this compound. Therefore in formulations of the present invention potassium clavulanate is preferably used with a humidity absorbing agent wherein ratio of potassium clavulanate to humidity absorbing agent is preferably 1 :1. Humidity absorbing agent has a large surface area and small pore size, this way it protects its humidity absorbing activity and keeps the active agent free of humidity and this gives the active agents free flowing property.

One or more of these compounds that can be used to absorb humidity can be selected from the group comprising silica, colloidal silica for example colloidal silica anhydrous or Aerosil 200, magnesium trisilicate, powdered cellulose, Cabosil, magnesium oxide, calcium silicate, Syloid, starch, talc. In present invention preferably Syloid is used.

Dosage form known as "dry syrup" is provided as a powder that is dispersed in predetermined amounts of water prior to use to provide multiple doses. A desired amount of the dispersion is taken by the patient orally. Dry syrups containing multiple doses is preferably used for pediatric patients. Pediatric dosage formulations can be preferably in the form of sweet and flavored syrup. Due to the fact that clavulanate is sensitive to water, syrup formulation is stored in an opaque package in dry powder or granule form and is required to be dispersed in water prior to use.

In suspension formulations in addition to the third generation cephalosporin and clavulanic acid excipients such as suspending agents, fillers, thinners, various sweeteners and stabilizers, edible drying agents etc. can be found. Appropriate excipients comprise xanthan gum (for suspension), colloidal silica (filler), succinic acid (stabilizer), aspartame (sweetener), hydroxypropyl methyl cellulose (for suspension) and silicon dioxide (drying agent and potassium clavulanate thinner). Flavoring agent can be orange, banana, strawberry and preferably lemon.

Formulations in the powder and granule form can be prepared by conventional techniques such as mixing of the powdered or granule formulations and filled into a suitable package.

Said formulations can be prepared by methods present in prior art such as by using wet granulation, dry granulation or dry blending techniques. An example to a process for preparation of tablet or granules is given below; a) Preparation of a granulate comprising a third generation cephalosporin by blending the third generation cephalosporin and/or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients, granulation of the mixture, drying formed granules and sieving them,

b) Preparing the final mixture by mixing clavulanic acid and/or a salt thereof with pharmaceutically acceptable excipients and additional agents and addition of the granulate obtained in step (a),

c) Optionally; compressing the formed mixture in the form of tablets or prepared in the form of capsules or sachets. For the preparation of effervescent tablet or granules the process described above can be used. In addition to said process, effervescent couple is added to the mixture. Effervescent acid base couple can be optionally added in (a) and/or (b) steps of the abovementioned process.

In effervescent formulations according to present invention in addition to the process mentioned above, preferably effervescent couple is granulated with the third generation cephalosporin, dried and potassium clavulanate: syloid mixture and other excipients are added to the obtained granules and mixed. Mixture prepared with this method may be compressed as tablets or may be filled into sachets or capsules.

Capsule formulations according to invention can be prepared by dry blending of active agent and excipients and then filling the formed mixture into capsules regardless of size, color and property.

Examples given below are for demonstration purposes. These examples do not limit the scope of the invention and are evaluated according to the description given above.

EXAMPLES

1. Suspension formulation

Formulation given below is for suspension formulations comprising 125 mg cefixime and 31.25 mg potassium clavulanate per 5 ml of suspension.

(*) sufficient amount

Formulation is prepared according to the amounts given in the table above and filled into bottles 2. Capsule Formulation

A capsule formulation comprising 300 mg cefdinir and 125 mg** clavulanic acid is prepared according to the amounts given in the table given below.

Content % Weight Cefdinir 41.8

Potassium clavulanate:Syloid (1:1) 41.4

Lubricant 0.59

Dispersing agent 15.9

At least one excipients 0.29

Total weight 100

** In the formulation 296.912 mg potassium clavulanate:syloid mixture which is equivalent to 125 mg clavulanic acid is used.

Claims

1. A synergic combination for use in treatment of bacterial infections characterized in that said composition comprises therapeutically effective amount of third generation cephalosporin and clavulanic acid and/or pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms thereof.

2. A formulation according to claim 1, wherein third generation cephalosporin is selected from a group comprising cefdinir, cefixime and/or cefpodoxime proxetil.

3. A formulation according to claim 1 wherein clavulanic acid is in the form of potassium clavulanate.

4. A formulation according to claim 3 wherein potassium clavulanate is used together with a humidity absorbing agent, preferably with syloid.

5. A formulation according to claim 4 wherein potassium clavulanate: syloid ratio is preferably 1:1.

6. A pharmaceutical composition according to claiml wherein ratio of third generation cephalosporin:clavulanate is in the range of 1 :0.01 to 1:10.

7. A pharmaceutical composition according to claim 1 wherein amount of third generation cephalosporin is 5-50%, amount of clavulanic acid is 1-30% by weight.

8. A pharmaceutical composition according to claim 1 wherein amount of third generation cephalosporin in single dose is in the range of 50-100 mg, amount of clavulanic acid in single dose is in the range of 20-300 mg.

9. A pharmaceutical formulation according to claim 1 wherein said formulation is suitable for peroral or parenteral application.

10. A pharmaceutical formulation according to claim 9 wherein said composition is suitable for oral use.

11. A pharmaceutical formulation according to claim 9 wherein said composition is in tablet form.

12. A pharmaceutical formulation according to claim 9 wherein said composition is in capsule form.

13. A pharmaceutical formulation according to claim 9 wherein said composition is in suspension form.

14. A pharmaceutical formulation according to claim 9 wherein said composition is in effervescent granule form.

15. A formulation according to any of the preceding claims wherein said formulation comprises disintegrants, binders, lubricants, humidity absorbers, sweeteners and in addition to that at least one excipient.

16. A medication according to claim 1 for use in treatment of infections caused by beta lactam resistant bacteria.

17. Infectious diseases according to claim 16 wherein said diseases are upper respiratory tract infections (acute otitis media, acute sinusitis, acute streptococci tonsilopharangitis), urinary tract infections, gonore, commonly acquired pneumonia and infections of skin and soft tissue.