EP2528584A1

EP2528584A1 - Water dispersible cefdinir and clavulanic acid formulations for treatment of bacterial infections

Info

Publication number: EP2528584A1
Application number: EP11706649A
Authority: EP
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-01-29
Filing date: 2011-01-28
Publication date: 2012-12-05
Also published as: WO2011093827A1; WO2011093821A1; TR201000686A1

Abstract

Present invention relates to water dispersible pharmaceutical formulations comprising cefdinir 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 and for use in treatment of infectious diseases caused by resistant bacteria.

Description

WATER DISPERSIBLE CEFDINIR AND CL AVULANIC ACID FORMULATIONS FOR TREATMENT OF BACTERIAL INFECTIONS

Field of the invention

Present invention relates to water dispersible pharmaceutical formulations comprising cefdinir 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.

Beta lactam antibiotics are a group of antibiotics for which it is possible to develop resistance. Many of the bacteria prevent the activity of the beta lactam antibiotics by producing beta lactamase enzyme.

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

Beta-lactam antibiotics can be basicly classified in 5 groups;

1. Penicillins

2. Cephalosporins

3. Monobactams

4. Carbapenems

5. Beta-lactamase inhibitors (clavulanate, sulbactam, tazobactam) 7-aminocephalosporanic acid forms the core of the cephalosporins. Cephalosporins are classified with different generations with respect to their antibacterial spectrum. From first generation to third generation gram (+) activity decreases and gram (-) activity increases.

Cefdinir is shown with Formula (I):

As described in the patent application numbered EPO 105459 (Bl) cefdinir is a beta-lactam antibiotic that is effective for the treatment of infectious diseases caused by pathogenic gram positive and gram negative bacteria.

Cefdinir and its pharmaceutically acceptable salts have been disclosed in EPO 105459. Amorphous cefdinir, crystalline cefdinir, potassium salt of cefdinir and tertiary amine salt of cefdinir are disclosed in EP1749013, EP0304019, EP1943256 and EP1786793 respectively.

Clavulanic acid that is shown with Formula II is a beta lactamase inhibitor:

(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).

In state of the art, there are several studies disclosing combined use of beta lactam antibiotics and beta lactamase enzyme inhibitors for prevention of antibiotic resistance. In the last years, combined penicilin preparates comprising combination of beta lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam and penicilin derivatives like amoxicillin, ticarcillin, piperacillin whose activity spectrum also encompasses the resistant bacteria has been developed. Patent applications numbered W095/28927 and EP 1269996 disclose use of amoxicillin 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 the ratio 14: 1.

Commercially available cefdinir preparates are in tablet, capsule or suspension forms. Although, bioavailability data for the tablet form is unknown, the bioavailability data is estimated to be approximately 21% for 300 mg capsule form and 25% for the suspension form . Accordingly, highest bioavailability is obtained from the oral solutions. Clavulanic acid and beta lactam formulations known in the state of the art are in tablet, suspension and capsule forms (Augmentin®, Augmentin-Duo®). Commercially available Augmentin® is a film tablet formulation comprising clavulanic acid. Said tablet disperses in water at 37 °C in a relatively long time, e.g. 10- 15 minutes.

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

Although, cefdinir is an effective agent in antimicrobial treatment, solution forms comprising this compound has not yet been developed. The reason for this is the fact that cefdinir shows a hydrophobic character and it has solubility and wettability problems upon contact with water.

Cefdinir and clavulanate show quite different water solubility properties. Cefdinir does not dissolve in water on the other hand clavulanate is freely soluble in water. Low water solubility of cefdinir acts as a limiting factor for effective use of this compound in oral solutions. When instability of clavulanate in aqueous mediums is taken into account, it is possible to predict that degradation of the compound may take place in presence of aqueous solution. Clavulante has the maximum stability at a range of pH 5.0 to 6.8.

Suspension dosage forms named as "dry powder syrup" comprise dry powder comprising multiple doses of the medicament which will be ready to use upon dispersion of the powder in a suitable solvent (e.g. water). Said powder is usually kept in a bottle. According to the prescribed dose, the patient takes necessary amount of the suspension. This kind of multiple dose containing liquid dosage forms are usually used by the pediatric patients. However, the disadvantage of this dosage form is the fact that clavulanate can be hydrolyzed upon prolonged contact with water. After the addition of water or during the storing of the suspension activity of clavulanate can be reduced or it may totally lose its effect.

For this reason, especially for pharmaceutical formulations comprising clavulanic acid and cefdinir that will be especially used for the treatment of infections caused by resistant bacteria new approaches that provide;

• Increased solubility and hence increased bioavailability of cefdinir,

• High stability

• Prolonged shelf life

• Accurate dosing

• Suitable for pediatric and geriatric use

• Higher bioavailability compared to the conventional dosage forms

Objective of the present invention is to eliminate the disadvatages of the formulations present in the state of the art, as described above, and to prepare improved pharmaceutical formulations.

These objectives were achieved by using an organic base. When active agents of the present invention are dispersed in a matrix, preferably an effervescent matrix, in presence of organic base powders, it was seen that granules and/or tablets comprising said matrix forms dispersions in water in an unexpected way.

By using an organic basic compound, inventors have obtained water soluble cefdinir compound and also solved the stability problem of clavulanate by adjusting the pH of the solution to 6 and thereby obtained water dispersible formulations with high bioavailability. The organic base is an amine having surfactant properties, preferably trometamol or meglumine. The term "clavulanic acid" refers to clavulanic acid and/or its pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms, amorphous forms and/or combinations thereof. The term cefdinir refers to cefdinir and/or its pharmaceutically acceptable salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations of thereof.

Clavulanic acid used in the present invention is in the form of a alkali metal salt, preferably in the form of potassium clavulanate.

Description of the Invention

First aspect of the invention is related to improved pharmaceutical formulations comprising therapeutically effective amount of cefdinir and clavulanic acid.

Formulations according to present invention are characterized by use of an organic base with surfactant property, preferably an organic amine, in order to overcome technical disadvatages of cefdinir such as low solubility and stability. Formulations prepared this way have surprisingly formed water dispersible and stable dispersions. The term "water dispersible" refers to all formulations that are effervescent or non-effervescent. Said formulations are characterized with their ability to easily disperse in aqueous medium.

Formulations can be manufactured in the form of water dispersible tablets, granules or powder.

Effervescent tablet/granules, dispersible tablet or sachet forms are more advantageous compared to the conventional forms due to the fact that they quickly disperse. Effervescent formulations disperse quickly and simultaneously and they disperse the active agents into the aqueous medium. The fact that each dose is prepared prior to use, leads to consumption of the dose right after the preparation. This phenomenon prevents degradation of the active agents with water and it also prevents the necessity to use antimicrobial agent and hence makes the formulation suitable for pediatric use too. An aspect of the invention is to manufacture a tablet or sachet which may be applied orally in the form of an aqueous dispersion or solution. Formulation disperse in the aqueous solutions in a rapid manner and can be applied orally and if needed with the help of a dropper. Formulations of this sort are more adventageous to use for geriatric patients, kids and babies. Pharmaceutical formulations can be in the form of granules or powders which may be filled into sachets or compressed in the form of effervescent or non-effervescent tablets. Especially effervescent formulations disperse rapidly and release the active agents, cefdinir and clavulanate into the aqueous medium. Additionally cefdinir solutions have a neutral taste and because of this reason they are appropriate to use with sweeteners. This way, formulations can be prepared in the form of oral preparates having a pleasant taste and can be given to the patients.

According to the invention water dispersible tablet, granule and/or powder formulations may comprise an effective amount of cefdinir; effective amount of clavulanic acid; organic base having surfactant property and at least one other pharmaceutically acceptable excipient.

Effervescent formulation according to present invention comprise pharmaceutically effective amount of cefdinir, pharmaceutically effective amount of clavulanic acid, basic organic compound, an effective effervescent couple and at least one other pharmaceutically acceptable excipient. Effervescent formulation comprises a mixture of components which gives off carbon dioxide gas upon contact with water. Effervescent components of this sort are generally an acid or an acidic salt which may give off carbon dioxide gas upon contact with an alkali or alkali earth metal carbonate or hydrogen carbonate and an aqueous solution.

Acid may be in powder form especially in the form of a non-aqueous organic or inorganic pharmaceutically acceptable acid; especially citric acid, monosodium citrate, tartaric acid, fumaric acid, malic acid salts or preferably a mixture thereof.

Alkali component which may be used in the formulations according to the present invention can be selected from but not limited with sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a mixture thereof. Effervescent formulations can be prepared by using known granulation methods wherein the active agents can be granulated togather or separately or wherein only one of the active agents are granulated and the other is mixed with formed granules.

In one of the methods proposed for the preparation, a mixture comprising cefdinir and an effervescent base is granulated by spraying the granulation solution consisting of deionized water and organic base. Granules obtained with this method are mixed with an effervescent couple and at least one pharmaceutically acceptable excipient. The obtained granules are dried in a way to have a maximum humidity of 0.5%. Potassium clavulanate:syloid mixture, at least one sweetener and at least one pharmaceutically acceptable excipient is added to the granules comprising effervescent couple, organic base and cefdinir and mixed again. The final mixture is optionally compressed in the form of tablet or might be stored in sachets and/or bottles in order to be dispersed later on.

In another method according to present invention, the entire mixture can be prepared as two granulates. The first granulate may comprise effective amount cefdinir, effervescent couple, organic base and at least one excipient and the second granulate may comprise potassium clavulanate:syloid mixture. These two granulates can be combined later on and mixed and if desired they can be compressed in the form of tablets or may be filled into sachets or bottles. Granulates may comprise further additional pharmaceutical components.

Pharmaceutical formulations according to present invention may comprise other components such as pharmaceutically acceptable excipients selected from a group comprising disintegrants, viscosity increasing agents, fillers, humidity absorbing agents (humectants), lubricants, diluents, binders, glidants, anti-foaming agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.

Disintegrant used in the present invention is important since it enables the formulation to disperse in the water easily and in a rapid way. Disintegrants can be selected from a group comprising but not limited with polymers having high dispersion capacity, such as crosslinked hydroxypropyl cellulose, polyvinyl pyrrolidone, high molecular weight polymers, macrocrystalline cellulose, sodium starch glycolate, povidone.

Binders may be selected from a group comprising but not limited with potato starch, wheat starch, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, for example hydroxypropylmethylcellulose type 2910 USP, hypromellose and polyvinylpyrrolidone

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 absorbing agent one or more of agents which can be selected from the group comprising silica, colloidal silica, such as colloidal silica anhydrous, magnesium trisilicate, powdered cellulose, 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. Organic base according to present invention is an organic amine having surfactant property and can be selected from a group comprising D-glucamine, meglumine, trometamol (tris buffer). Organic base used in the present invention is preferably meglumine or trometamol.

By use of meglumine or trometamol cefdinir has a water soluble form and at the same time since the pH of the solution is adjusted to an approximate value of 6 the clavulanate is in the most stable form. This way, formulations that can be easily dissolved in water and that are stable and that have improved bioavailability have been developed.

Formulations according to present invention comprises

5-70% of cefdinir

1-30% of clavulanic acid

1-30%) of an organic base

10-80%) of effervescent couple

1-30% of disintegrant

0.1-2 % of lubricant

1-5% of sweetener

0.1-5%) of at least one pharmaceutically acceptable excipient In formulations of the present invention as effervescent couple sodium hydrogen carbonate and citric acid, as organic base preferably trometamol, as sweetener preferably sodium chloride, as binder preferably PEG 6000, as sweetener preferably sucralose, at least one pharmaceutically acceptable excipient and potassium clavulanate :syloid mixture in an amount of 1 : 1 ratio are used.

Tablets, granules and/or powders according to invention may comprise cefdinir 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 cefdinir and approximately 20 to 300 mg of potassium clavulanate can be used. In formulations of the present invention, ratio of cefdinir and potassium clavulanate is in the range of 1 :0.01 to 1 :10 by weight.

Formulations according to present invention may preferably comprise 300 mg cefdinir and 125 mg potassium clavulanate; 375 mg cefdinir and 62.5 mg potassium clavulanate; 600 mg cefdinir and 125 mg potassium clavulanate; 500 mg cefdinir and 125 mg potassium clavulanate; 125 mg cefdinir and 62.5 mg potassium clavulanate.

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% of humidity and at a tenmperature of at least 20 °C. If applicable the components of the formulation may be dried beforehand.

Water dispersible tablet formulations according to present invention may be shaped according to conventional tablet compression techniques. Shape of the dispersible 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. In another apect present invention provides use of water dispersible tablet, water soluble tablet, water dispersible granule, water soluble granule, water dispersible powder, water soluble powder, effervescent tablet, effervescent granule and effervescent powder for treatment of patients having infections caused by resistant bacteria.

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 spray granulation of only one of the active agents can be used. Said method comprises the steps of; a) Preparation of the granulate comprising cefdinir by blending pharmaceutically active amount of cefdinir and pharmaceutically acceptable excipients homogeneously, spray granulation of the mixture by using the granulation solution comprising water and organic base and addition of at least one pharmaceutically excipient to said granules, drying and sieving the formed mixture

b) Preparation of the final mixture by addition of potassium clavulanate:syloid (1 :1) mixture, at least one sweetener and at least one phamaceutically acceptable excipient to the granulate

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

The method described above can be used in preparation of effervescent tablets and granules as well. Additionally, effervescent couple is granulated in the first step. Potassium clavulanate:syloid (1 : 1) mixture is added to the obtained effervescent granulate and the final mixture is optionally compressed in the form of tablets to give effervescent tablets.

Examples seen below are given 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 cefdinir, effervescent couple is blended with cefdinir. For granulation, granulation solution comprising organic base and deionized water is added to the mixture and the mixture is blended until a granulate is obtained. The granules are then dired and sieved.

Pharmaceutically effective amount of potassium clavulante: syloid mixture, at least one pharmaceutically acceptable excipient and sweetener is then added to the cefdinir granulate and the final mixture is prepared. Optionally the final mixture is compressed in the form of tablets.

2. Water dispersible granule formulation

In the method which will be used to obtain the water dispersible granules, sefdinir and pharmaceutically acceptable excipients are mixed and subjected to spray granulation. Granules obtained with this method are dried and sieved. Potassium clavulanate: syloid (1 :1) mixture and at least one pharmaceutically acceptable excipient are added to the cefdinir granulete to obtain the final mixture. Optionally the final mixture is compressed in the form of tablets.

Claims

1. An orally applied, water dispersible pharmaceutical formulation which comprises;

a. Pharmaceutically effective amount of clavulanic acid and/or its pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms, amorphous forms and/or combinations thereof;

b. Pharmaceutically effective amount of cefdinir and/or pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorhous forms and/or combinations thereof

c. Organic base and

d. At least one other pharmaceutically acceptable excipient.

2. A pharmaceutical formulation according to claim 1 wherein said formulation is in granule or powder form.

3. A pharmaceutical formulation according to claim 1 wherein said formulation is in tablet form.

4. A pharmaceutical formulation according to claim 1 wherein said formulation is in effervescent or non-effervescent form.

5. A pharmaceutical formulation according to claim 1 to 5 wherein said formulation is prepared as a single composition comprising a mixture of two active agents.

6. A pharmaceutical formulation according to claim 1 to 5 wherein clavulanic acid is in the form of potassium clavulanate salt.

7. A formulation according to claim 7 wherein potassium clavulanate is used togather with a humidity absorbing agent, preferably with syloid.

8. A pharmaceutical formulation acording to claim 7 wherein potassium clavulanate: syloid ratio is preferably 1 :1.

9. A pharmaceutical formulation according to claim 1 wherein amount of cefdinir in a single dose is approximately 50 to 1000 mg; amount of potassium clavulanate in a single dose is approximately 20 to 300 mg.

10. A pharmaceutical formulation according to claim 1 wherein ratio of cefdinir to potassium clavulanate is in the range of 1 :0.01 to 1 :10.

11. A pharmaceutical formulation according to claim 1 wherein organic base is an organic amine which has surfactant property.

12. A pharmaceutical formulation according to claim 1 wherein organic base is selected from a group comprising D-glucamine, meglumine, trometamol (tris buffer).

13. Organic amine according to claim 4 wherein organic amine is preferably meglumine or trometamol.

14. A pharmaceutical formulation according to claims 1 to 6 characterized in that said formulation, upon dispersion in aqueous solutions that are at room temperature, gives a solution with a pH of approximately 5.50 to 6.8, preferably a pH of approximately 6.

15. A pharmaceutical formulation according to claim 5 wherein said formulation comprises as effervescent couple; sodium hydrogen carbonate and an acid or an acidic salt which upon contact with aqueous solution gives off carbon dioxide.

16. A pharmacetical formulation according to claim 16 wherein effervescent couple comprises sodium hydrogen carbonate and citric acid.

17. A pharmaceutical formulation according to claim 1 to 16 wherein said for mulation comprises at least one pharmaceutically acceptable excipient selected from a group comprising the viscosity agents, fillers, drying agents, lubricants, diluents, binders, glidants, anti-foaming agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.

18. A process for preparation of the pharmaceutical formulation according to any of the previous claims wherein said formulation is prepared with spray or dry granulation method

19. A process according to claim 19 wherein cefdinir, organic base and effervescent couple, which is used optionally, is granulated with spray granulation.

20. A process according to claim 20 wherein cefdinir granulate obtained by spray granulation is combined with potassium clavulanate:syloid (1 : 1) mixture and at least one pharmaceutically acceptable excipient.

21. A formulation according to claim 1 wherein said formulation is used for treatment of infectious diseases that are resistant to anitbiotics

22. Infectious diseases according to claim 16 are upper respiratory tract infections (acute otitis media, acute sinusitis, acute streptococcus tonsilo pharangitis), urinary tract infections, commonly acquired pneumonia and infections of skin and soft tissue.