WO2011093829A1

WO2011093829A1 - Effervescent formulations comprising cefixime and clavulanic acid as active agents

Info

Publication number: WO2011093829A1
Application number: PCT/TR2011/000033
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2010-01-29
Filing date: 2011-01-28
Publication date: 2011-08-04
Also published as: EP2528586A1; TR201000687A1; WO2011093822A1

Abstract

Present invention relates to effervescent formulations comprising cefixime 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 suitable for oral use in treatment of infectious diseases caused by resistant bacteria. Furthermore, since these active agents are given to the patients freshly right after dispersing in water, they have higher shelf life with respect to the suspension forms and they have higher bioavailability. Use of effervescent formulations is much easier for especially geriatric and pediatric patients which experience swallowing difficulties with respect to the capsule and tablet forms.

Description

EFFERVESCENT FORMULATIONS COMPRISING CEFIXIME AND CLAVULANIC

ACID AS ACTIVE AGENTS

Present invention relates to effervescent formulations comprising cefixime 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 suitable for oral use in treatment of infectious diseases caused by resistant bacteria

Prior Art

Antibiotics are one of the most frequently used medications used in medical practice and they form an important part of drug expenses. However in the last years the problem of resistant bacteria has become threatening. Due to use of high doses of antibiotics, the resistance problem has arisen and this became a problem for the humanity.

In order to overcome this problem, researchers try to remove the factors that cause the antibiotic resistance and for this purpose recommend use of different combinations.

In the last few years, some beta lactam antibiotics are combined with beta lactamase inhibitors to prevent enzymatic cleavage.

As an example to these formulations combined 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. For example, patent applications numbered W095/28927 and EP1269996 respectively disclose use of amoxicillin and potassium clavulanate in combined form for treatment of bacterial infection and tablet formulations for this combination. WO97/09042 describes tablet formulations comprising amoxycillin and clavulanic acid in an amount in the ratio of 12:1 to 20: 1 preferably in the ratio of 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. As another problem, medications comprising combinations of beta-lactam and beta-lactamase are in capsule, tablet or suspension forms. When orally applied dosage forms are taken into consideration it is seen that bioavailability of the solution forms are higher than the other forms.

In addition to that dosage forms present in the state of the art cause difficulty for pediatric and geriatric patients since they are difficult to swallow and they have an unpleasant taste. Due to this reason these patients skip dose times and this affects the efficiency of the treatment.

Description of the invention

Cefixime shown with Formula (I) is a third generation cephalosporin antibiotic which is disclosed for the first time in the European patent numbered EP0030630 (Bl) and is indicated for use in treatment of infections caused by gram positive and gram negative bacteria.

(I)

In state of the art, medications comprising cefixime as the active agent are found in forms of suspensions and tablets. Bioavailability of cefixime tablets are in the range of 40-50%. Suspension forms provide 25-50% more bioavailability compared to the bioavailability of the tablet forms.

However, cefixime suspensions present in the state of the art are in the form of powder that is to be constituted with water prior to use. The powder, once constituted, is unstable therefore is has to be consumed in 14 days. In addition to that, although cefixime is soluble in some of the organic solvents, it is very poorly soluble in water therefore solution forms of this compound were not developed. Clavulanic acid is a beta- lactamase inhibitor shown with Formula (II):

(Π)

Clavulanic acid and its derivatives (such as its salts like potassium clavulanate) are known as beta lactamase inhibitors that inhibit the activity of beta lactamase enzymes that is produced by the bacteria (e.g. GB 1508977).

Additionally, at present state of the art, in the formulations applied orally clavulanic acid is usually found in a pharmaceutically acceptable salt form especially in the form of potassium clavulanate. However, potassium clavulanate has an extremely hygroscopic nature therefore it is very difficult to formulate this compound. Therefore during its manufacture and use it should be kept away from water and mediums containing water otherwise degradation of the compound may take place. Dry powder suspension formulations present in the state of the art can stay stable for at most 5 days after dispersed in water. Water sensitive nature of clavulanic acid leads to restrictions in the formulations comprising this molecule

Studies for development of solution formulations comprising clavulanic acid or a derivative thereof together with cefixime have failed due to the fact that clavulanic acid is unstable in water and cefixime has low solubility in water.

Therefore, for formulations comprising cefixime and clavulanic acid as active agent new approaches that can provide;

Higher bioavailability compared to conventional dosage forms,

Preparation of each dose right before intake

High shelf life

High stability

Single and accurate dosing

Medication suitable for pediatric and geriatric use are necessary. Effervescent granule or tablet formulations prepared according to present invention, comprising cefixime and clavulanic acid, have surprisingly formed a clear solution in water.

Said solution is prepared by constitution with water right before oral use, this way possibility of degradation is kept at a minimum level. Likewise, since these formulations are prepared right before use they do not require addition of anti-microbial agent, and this makes them safe to use for pediatric and non-pediatric patients.

Both cefixime and clavulanic acid have neutral taste, therefore formulations of the present invention can be sweetened upon request and this way solutions having pleasant taste can be obtained. The term clavulanic acid used in the present invention relates to clavulanic acid and/or its pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations thereof. The term cefixime used in the present invention relates to cefixime and/or its pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations thereof.

Clavulanic acid used in the formulation according to present invention is in the form of an alkali metal salt, preferably in the form of potassium clavulanate.

Detailed descriptipn of the invention

First aspect of the invention is related to a pharmaceutical formulation comprising therapeutically effective amount of cefixime and clavulanic acid.

Said invention is related to effervescent formulations that can easily form clear solutions in water in order to eliminate the technical disadvantages, such as low solubility and stability, arising from cefixime and clavulanic acid.

Formulations can be produced in the form of water dispersible effervescent granules and effervescent tablets.

Effervescent forms are more advantageous compared to the conventional forms due to the fact that they disperse more rapidly. Effervescent forms disperse rapidly and they simultaneously release the active agents into the aqueous medium. The time interval between addition of the formulation into water or dispersion of the formulation and intake of the formulation is relatively short. The fact that the formulations are consumed in a short time prevents degradation of the active agents with water and also makes these formulations suitable for pediatric use since addition of antimicrobial agents is no longer necessary.

An aspect of the invention is to prepare effervescent tablet or granule that can be applied orally in the form of aqueous dispersion or solution.

Formulation disperse in aqueous medium in a rapid way and it can be applied orally or with a spoon or dropper if need be. Formulations of this sort are more advantageous due to the fact that they provide different using methods for old patients, children and babies.

Effervescent formulations according to present invention comprise effective amounts of cefixime, effective amounts of clavulanic acid, effervescent couple and at least one other pharmaceutically acceptable excipient.

Effervescent formulation comprises a mixture which upon getting in touch with water gives off carbon dioxide. Effervescent compositions of this sort usually comprise an alkali or alkali earth metal carbonate or hydrogen carbonate, especially sodium hydrogen carbonate and an acid or acidic salt which upon contact with water gives off carbon dioxide.

Acid can be a pharmaceutically acceptable anhydrous organic or inorganic acid, preferably citric acid, monosodium citrate, tartaric acid, fumaric acid, malic acid, their salts or preferably a mixture thereof. Alkali component that can be used in the present invention can be selected from but not limited with sodium, carbonates and bicarbonates of potassium and calcium and/or sodium glycine carbonate or a mixture thereof.

Pharmaceutical formulations according to present invention may comprise pharmaceutically acceptable excipients selected from a group comprising disintegrants, viscosity increasing agents, fillers, drying agents, lubricants, diluents, binders, glidants, anti-foaming agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents. Disintegrants used in the present invention provides easy and fast dispersion of the dosage form in the water. Disintegrant can be selected from but not limited with polymers having high dispersion capacity such as cross linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, products known with trademarks Crospovidone®, Polyplasdone®. Binders can be selected from, but not limited with, a group comprising potato, wheat or corn starch, microcrystalline cellulose for example products known with the trademarks Avicel®, Filtrak®, Heweten® or Pharmacel® hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose Type 2910 USP, hypromellose and polyvmylpyrolidone.for example Povidone® K30 (BASF).

Clavulanic acid and its derivatives (for example potassium clavulanate) are very sensitive to humidity. For this reason, in formulations of the present invention potassium clavulanate can be used with a humidity absorbing agent, wherein ratio of potassium clavulanate to humidity absorbing agent is preferably in the ratio of 1 : 1. Humidity absorbing agent has a large surface area and small pore volume, this way it would preserve its activity even under highly humid conditions and this provides improved flow properties to the compound.

As humidity agent one or more of agents which can be selected from the group comprising silica, colloidal silica, such as colloidal silica anhydrous for example Aerosil®, magnesium trisilicate, powdered cellulose, Cabosil®, magnesium oxide, calcium silicate, Syloid®, starch, talk. In the present invention preferably Syloid® is used. In formulations of the present invention potassium clavulanate is preferably used with syloid in an amount in the ratio of 1 : 1.

As lubricant one or more of magnesium stearate, aluminium stearate, calcium stearate, PEG 4000 - 8000 and/or talc can be used.

Sweetening agent can be selected from but not limited with a group comprising sodium chloride, aspartam, dextrose, fructose, sucralose, sodium cyclamate, mannitol, maltose, saccharide and/or pharmaceutically acceptable salts thereof.

Flavoring agents used in the present invention can be selected from a group comprising banana flavor, strawberry flavor, lemon flavor, orange flavor, peach flavor, vanilla flavor or similar natural fruits or might have the flavor of a natural herb.

Formulations according to present invention comprise;

• Cefixime in the range of 5-70%

• Clavulanic acid in the range of 1-30%

• Effervescent couple in the range of 10-80%

• Disintegrant in the range of 1 - 10%

• Lubricant in the range of 0.1 -2%

• Sweetener in the range of 1 -5% • At least one other pharmaceutically acceptable excipient in the range of 0.1-10% by weight

In formulations according to present invention as effervescent couple preferably sodium hydrogen carbonate - citric acid; as sweetener preferably aspartam; as binder preferably PEG 6000 and at least one other pharmaceutically acceptable excipient is used.

Tablets, granules and/or powders according to invention may comprise cefixime and potassium clavunate in amounts up to maximum allowed daily dose in the unit dosage forms. In single dose of the formulations according to present invention; approximately 50 to 1000 mg of cefixime and approximately 20 to 300 mg of potassium clavulanate can be used. Formulations according to present invention may preferably comprise 100 mg cefixime and 62.5 mg potassium clavulanate; 200 mg cefixime and 125 mg potassium clavulanate; 400 mg cefixime and 125 mg potassium clavulanate.

In formulations of the present invention, ratio of cefixime and potassium clavulanate is in the range of 1:0.01 to 1:10 by weight. However, other amounts of these active agents in other ratios can be used as well.

Although potassium clavulanate is the most stable form of clavulanic acid, it is unstable against humidity. For this reason, formulations comprising clavulanic acid derivatives such as potassium clavulanate should be prepared under dry conditions, preferably at 0.5% relative humidity or at least at temperature of 60 °C. If applicable the components of the formulation may be dried beforehand.

Effervescent tablet formulations according to present invention may be shaped according to conventional tablet compression techniques. Shape of the effervescent tablet may be one of the conventional shapes such as round, spherical, block or rectangular.

Formulations of the present invention can be used for the manufacture of a medicament for use in treatment of infections that are resistant to antibiotics. Said infectious diseases are; upper respiratory tract infections (acute otitis media, acute sinusitis, acute streptococci tonsilo pharangitis), urinary tract infections, commonly acquired pneumonia and skin and soft tissue infections.

Pharmaceutical formulations of the present invention can be prepared by techniques known in the art; such as wet granulation or dry granulation. In addtion to the method which comprises dry or wet granulation of both of the active agents; the method given below which comprises wet granulation of only one of the active agents can be used. Said method comprises the steps of; a) Preparation of effervescent cefixime granulate by blending an effective amount of cefixime, effervescent couple and other pharmaceutically acceptable excipients, wet granulation of the mixture by the appropriate granulation solution and drying of the said granules at 60°C until humidity ratio is 0.5% and sieving said granules

b) Preparation of the final mixture by addition of potassium clavulanate:syloid (1:1) mixture, at least one lubricant and at least one other excipient into the cefixime granulate prepared in the first step

c) Optionally compressing the final mixture in the form of tablets or filling the final mixture into the sachets.

In another process according to present invention the entire mixture can be separated in the form of two granulates. The first granulate may comprise effective amount of cefixime, effervescent couple and at least one other pharmaceutically acceptable excipient and the second granulate may comprise clavulanic acid:syloid mixture. Afterwards, these two granulates can be combined and mixed and may be optionally compressed in the form of tablets or filled into the sachets. Granulates may comprise other pharmaceutically acceptable excipients.

Examples given below are for demonstrating the invention. These examples do not limit the scope of the invention and they are evaluated with respect to the description of the invention given above.

EXAMPLES

1. Effervescent Formulation

For preparation of the granulate comprising cefixime; effervescent couple, disintegrant, sweetener and effective amount of cefixime is mixed and is granulated with sufficient amount of deionized water. The obtained granules are dried at 60°C to have humidity of 0.5% and sieved.

Effective amount of potassium clavulanate:syloid (1:1), lubricant and at least one other pharmaceutically acceptable excipients is added to the cefixime granulate and mixed, this way the final mixture is prepared. Optionally, the mixture is compressed in the form of tablets or filled into sachets.

Claims

1. A pharmaceutical formulation comprising pharmaceutically effective amount of cefixime and clavulanic acid and/or their pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms, amorphous forms and/or combinations thereof characterized in that it shows effervescent property upon contact with water.

2. A pharmaceutical formulation according to claim 1, wherein said formulation is in the form of effervescent granules.

3. A pharmaceutical formulation according to claim 1, wherein said formulation is in the form of effervescent tablets.

4. A pharmaceutical formulation according to claim 1, wherein clavulanic acid is in the form of potassium clavulanate salt.

5. A pharmaceutical formulation according to claim 1, wherein potassium clavulanate in the formulation is preferably used together with a humidity absorbing agent, preferably with syloid.

6. A pharmaceutical formulation according to claim 5 wherein the ratio of potassium clavulanate:syloid is preferably 1 :1.

7. A pharmaceutical formulation according to any of the preceding claims wherein said formulation is prepared as a single pharmaceutical composition comprising both of the active agents.

8. A pharmaceutical formulation according to any of the preceding claims wherein amount of cefixime in a single dose is in the range of 50 to 1000 mg; amount of potassium clavulanate in a single dose is in the range of 20 to 300 mg.

9. A formulation according to any of the preceding claims wherein ratio of cefixime and potassium clavulanate is in the range of 1 :0.01 to 1 :10.

10. A pharmaceutical formulation according to any of the preceding claims wherein said formulation comprises pharmaceutically acceptable excipients selected from a group comprising viscosity increasing agents, fillers, drying agents, lubricants, diluents, binders, glidants, anti-foaming agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.

11. A process for preparation of the pharmaceutical formulation according to any of the preceding claims wherein said process comprises separate or combined granulation of a mixture of cefixime and clavulanic acid or granulation of only one of the active agents by using the granulation techniques present in the state of the art..

12. A process according to claim 11 wherein said granulation process is wet or dry granulation.

13. A process according to claim 11 wherin cefixime, effervescent couple and at least one other pharmaceutically acceptable excipient is granulated with wet granulation.

14. A process according to claim 11 wherein potassium clavulanate:syloid (1:1) mixture and at least one other pharmaceutically acceptable excipient is added to the cefixime granulate obtained by wet granulation.