WO2013001542A1

WO2013001542A1 - An optimized bilayered tablet with two active antibiotics: cefadroxil and clavulanic acid

Info

Publication number: WO2013001542A1
Application number: PCT/IN2011/000686
Authority: WO
Inventors: Kumar Vijay AGGARWAL; Sanjeev GOEL; Umakant MISHRA
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-06-30
Filing date: 2011-10-03
Publication date: 2013-01-03
Anticipated expiration: 2013-12-30

Abstract

This invention discloses optimized pharmaceutical formulation for bilayer tablet form comprising at least one antibiotic or a pharmaceutically acceptable salt thereof, and at least one dissolution enhancing agent sufficient to substantially dissolve said one aqueous diluent, binder, disintigrants, Film forming agents, moisture barrier agents. Both ingredient in a single dosages form at same time with high solubility and stability by over coming cross interaction or chemical incompatibilities between two different physical, chemical and physicochemical drug molecules by physical separation, and to enable the development of different drug release profile both in immediate release and immediate release with extended release and promoting patient convenience and compliance.

Description

DETAILED DESCRIPTION OF INVENTION

This invention relates to a stable, bioavailability bilayer tablet which contains antibiotic agents Cefadroxil and Clavulanic acid with less reconstitution time.

This medication is a cephalosporin-type antibiotic used to treat a wide variety of bacterial infections.

This invention exhibits a slow dissolution rate of the antibiotic formulations. The chemical stabilities is major desire characteristic in the case of antibiotic tablet obtained after reconstitution.

Bilayer tablet is a formulation of two or more active ingredients combined in a single dosage form available in certain fixed doses.

The invention is therefore advantageous in that it allows the formation of a stable bilayer tablet containing two active pharmaceutical agents. Other advantages include the ability of the pharmaceutical formulation to be antibiotic .and stored suitable to be reconstituted as an aqueous solution, which solution is suitable to be administered to a patient in need thereof. Batch of tablet made in accordance with given formula were stored in blister strip/sealed container together with commercially available tablets with similar levels of actives storage was at 40 degree C. and relative humidity 75%. After 4week storage, it was evident that there was marked discoloration and bulging in the reference tablets where as that of the invention tablets remain unchanged (as it is) the brown discoloration are due to potassium clavulanate inactivation. This indicated that the stability of potassium clavulanate in the invention tablets has been markedly enhanced.

l Enhanced chemical stability of the pharmaceutical formulation means the pharmaceutical formulation is stable, Enhanced chemical stability of the both active ingredients means the bilayer tablet is suitable for storage from 20..degree C. to about 30..degree. C. preferably for about 18 months or more.

One advantage of the stability of the active pharmaceutical ingredients is extended pharmaceutical product shelf life. Extended pharmaceutical shelf life offers significant economic advantages.

In yet another embodiment, the present invention discloses stable pharmaceutical formulations comprising two active pharmaceutical ingredients and at least one dissolution enhancing agent sufficient to substantially dissolve both ingredients in at least one aqueous diluent.

In a further embodiment, the above-described formulations comprising cefadroxil and clavulanic acid

In accordance with the present invention, it is provided for an improved, stabilized and less reconstitution time based pharmaceutical composition for bilayer tablet. Cefadroxil

Cefadroxil is a semi synthetic cephalosporin antibiotic intended for oral administration. It is a white to yellowish- white crystalline powder. It is chemically designated as 5-Thia-l-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(4-hydroxyphenyl)acetyl]amino]-3-methyl-8- oxo-, monohydrate, [6R-[6a,7p'(R*)]]-. It has the molecular formula C16H17N3O5S^»H20 and the molecular weight of 381.40. It's white to off white, crystalline powder slightly soluble in water very slightly soluble in alcohol, practically insoluble in chloroform and ether. A 5% suspension in water has pH of 4.0-6.0 and water 4.0% to 6.0% Max. Cefadroxil is a broad spectrum antibiotic of the cephalosporin type, effective in gram- positive and gram- negative bacterial infections. It is a bactericidal antibiotic. Cefadroxil is a first generation cephalosporin antibacterial drugs that is the para-hydroxy derivative of cefalexin and is used similarly in the treatment of mild to moderate susceptible infections, such as the bacterium streptococcus pyogenes,cousing the disease popularly called strepthroat or streptococcal tonsillitis, urinary tract infection(UTI) reproductive tract infection (RTI) and skin infections.

Cephalosporins are bactericidal because of their inhibition of cell-wall synthesis. Cefadroxil has been shown to be active against the following organisms both in vitro and in clinical infections for example Beta-hemolytic streptococci, Staphylococci, including penicillinase- producing strains,Streptococcus (Diplococcus) pneumoniae, Escherichia coli ,Proteus mirabilis ,Klebsiella species ,Moraxella (Branhamella) catarrhalis thereof.

The dosage of Cefadroxil is almost completely absorbed from the gastrointestinal tract. After doses of 500 mg and 1 g by mouth, peak plasma concentrations of about 16 and 30 micrograms/mL respectively are obtained after 1.5 to 2 hours. Although peak concentrations are similar to those of cefalexin, plasma concentrations are more sustained. Dosage with food does not appear to affect the absorption of cefadroxil.

About 20% of cefadroxil is reported to be bound to plasma proteins. The plasma half-life of cefadroxil is about 1.5 hours and is prolonged in patients with renal impairment.

Cefadroxil is widely distributed to body tissues and fluids. It crosses the placenta and appears in breast milk.

More than 90% of a dose of cefadroxil may be excreted unchanged in the urine within 24 hours by glomerular filtration and tubular secretion; peak urinary concentrations of 1.8 mg/mL have been reported after a dose of 500 mg. Cefadroxil is removed by haemodialysis. Cefadroxil is given by mouth in the form of tablet, capsule, and oral suspension, and doses are expressed in terms of the anhydrous substances. Cefadroxil is used as an antibiotic prophylaxis before dental procedure in case of penicillin allergy.

Mechanism of action

Cefadroxil is a bactericidal and acts by inhibition of bacterial cell wall synthesis. It passes through porin channels in the bacterial cell wall and binds to the penicillin binding proteins,(PBPs) in the cell membrane this leads to reduced synthesis of peptidoglycan and results in damages of cell wall. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin-binding proteins (PBPs).PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors)to crosslink the peptidoglycan.Beta-lactam antibiotics mimic this site and competitively inhibit PBP cross linking of peptidoglycan.

Clavulanic acid

Clavulanic acid is a beta-lactamase inhibitor Combined with a class of beta-lactam group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete beta-lactamase, which otherwise inactivates most beta-lactam group antibiotics by breaking of beta lactam ring The bioavailability is "well absorbed".

The name is derived from the streptomyces clavuligerus which produces clavulanic acid. A beta-lactamase inhibitor is a drug given in conjunction with a beta-lactam antibiotic. Although the inhibitor does not usually have significant antibiotic activity on its own, it inhibits activity

of beta-lactamase, a protein that confers resistance of beta-lactam antibiotics to bacteria. Beta- lactamase inhibitors in clinical use include clavulanic acid and its potassium salt. In its most common form the potassium salt potassium clavulanate is combined with beta-lactam antibiotic .

Potassium clavulanate diluted is a dry mixture of potassium clavulanate and MCC or silica , colloidal anhydrous silica are colloidal hydrated silica, more hygroscopic moisture and temperature sensitive having pH 4.8 to 8 water not more than 2.5 %. It can be freely soluble in water, slightly soluble in ethanol 95%.

Mechanism of action of Clavulanic acid

Clavulanic acid has small basic antimicrobial activity, despite sharing the beta-lactam ring that is characteristic of beta-lactam antibiotics. However, the similarity in chemical structure allows the molecule to interact with the enzyme beta-lactamase secreted by certain bacteria to confer resistance to beta-lactam antibiotics. Clavulanic acid is a suicide inhibitor, its covalently bonding to a serine residue in the active site of the beta-lactamase.

This restructures the clavulanic acid molecule, creating a much more reactive species that is attacked by another amino acid in the active site, permanently inactivating it, and thus inactivating the enzyme. This inhibition restores the antimicrobial activity of beta-lactam antibiotics against lactamase-secreting-resistant bacteria.

Mode of action of both ingredients

Cefadroxil is a first generations Cephalosporin antibiotic, effective against a wide spectrum of sensitive gram positive, Gram negative and anaerobic bacterial pathogens including beta- lactamase producing strains. It has high affinity for penicillin binding proteins with varying site of activity. It acts by inhibition of bacterial cell wall synthesis. The elimination half-life is about 2-3 hours, with little variation over the usual therapeutic dosage range.

Clavulanic acid is a naturally derived beta lactamase inhibitor produced by streptomyces clavuligerus. Clavulanic acid is an irreversible inhibitor of intracellular and extra cellular beta- lactamases, demonstrating concentration-dependent and competitive inhibition. It has a high affinity for the class A beta-lactamases.

This wide range of beta-lactamases which includes the plasmid-mediated TEM and SHV enzymes is found frequently in members of the Enterobacteriaceae, Heamophilus influenzae and Neisseria gonorrhoeae. The chromosomally mediated beta-lactamases of Klebsiella pneumoniae, Proteus mirabilis, proteus vulgaris, Bacteroides fragilis and Moraxella catarrhalis are also inhibited, as are the extended-spectrum beta-lactamases. The frequency of beta- lactamases mediated resistance ha continued to rise over the years, but the majority of clinically significant beta-lactamases are inhibited by potassium clavulanate.

Although clavulanic acid does have some degree of bactericidal activity, its principal role is as beta-lactamase inhibitor. Beta-lactam antibiotics, such as the penicillin's and cephalosporins, act by disrupting the development of bacterial cells walls thus causing the disintegration of the bacteria. However, some bacteria acquire the genes to produce enzymes which inactivate this mode of action. So called beta-lactamases- drastically reducing the efficacy of this class of antibiotics.

Clavulanic acid has a similar structure to the beta-lactam antibiotics but binds irreversibly to the beta-lactamase enzymes as suicide inhibitor. Used in combination with the beta-lactam antibiotics. It has become one of the most prescribed antibiotics prolonging the effective life of antibiotics. Cefadroxil is found to be ineffective against bacteria which produces ESBL (Extended- Spectrum Beta-Lactamases) enzyme and resistance is seen in such types of bacteria. The combination of Cefadroxil and clavulanic acid (Beta-Lactamaes inhibitor) provides a solution for treatment of bacterial infections caused by beta lactam resistant pathogens.

They are prescription antibiotic medication. It is used to treat a variety of infections. The combination of cefadroxil and clavulanic acid (beta-lactamases inhibitor) provides a solution for treatment of bacterial infections caused by beta lactam resistant pathogens. Cefadroxil is used to treat multiple bacterial infections in different parts of the body. Cefadroxil and clavulanic acid can be used as a second line therapy where cefadroxil alone is not able to show its bactericidal activity. Clavulanic acid acts as beta-lactamase inhibitor thus making cefadroxil effective against resistant bacteria.

Cefadroxil is generally well tolerated; well absorbed following oral administration and absorption is not affect by the presence of food. Presence of food increases the absorption of drugs.

The pharmaceutical formulation of the invention comprises diluents, binder and disintigrants, lubricant, antiadherent, Film forming agents, moisture barrier agent, glidants and pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical formulation further comprises Diluent which is important in the pharmaceutical industry. They are inactive ingredients that are added to tablets and capsules in addition to the active drug. These additives may be used as binders, disintegrants (help the tablet break apart in the digestive system), or flavor enhancers. Some very common diluents in tablets include starch, cellulose derivatives, magnesium stearate and Micro crystalline cellulose powder (MCCP) thereof. In a preferred embodiment, the diluent agent in the pharmaceutical formulation is MCCP. It used as diluents, binder and disintigrants effective in tableting large dose drugs, low compressible drugs, pressure sensitive drugs and MCCPH 200 has best flow rate in direct compressible and dry granulation binder maintain high level of compressibility and minimizing problem of weight variation and content uniformity.

In another embodiment, the pharmaceutical formulation further comprises lubricant which is a substance introduced between two moving surfaces to reduce the friction between them, improving efficiency. Preferably TALC, AEROSIL.

In another embodiment, the pharmaceutical formulation further comprises Anti-adherent which Prevents sticking to punch faces or in the case of encapsulation, lubricants prevent sticking to machine dosators, tamping pins. Preferably MAGNESIUM STEARATE/Sodium steryl fumarate more preferably Magnesium Stearate.

In another embodiment, the pharmaceutical formulation further comprises Glidant which is enhancing product flow by reducing interparticulate friction. Preferably MAGNESIUM STEARATE, TALC and AEROSIL.

In another embodiment, the pharmaceutical formulation further comprises binder which preferably HPMC. It does not interact with drugs due to non ionic character has superior stability provide variety of function (water retention, thickening, reduce surface tension and improve solubility of drugs.

In another embodiment, the pharmaceutical formulation further comprises Film forming agents, moisture barrier agents which preferably Ethylcellulose.

In another embodiment, the pharmaceutical formulation further comprises plastisizer for film coating which preferably dibutylpthalate, PEG 6000 and triacetin more preferably dibutylpthalate.

In another embodiment, the pharmaceutical formulation further comprises white pigment and opacifying agents in film coating mixes for tablet preferably titanium dioxide.

In another embodiment, the pharmaceutical formulation further comprises super disintigrants in tablet for improving release of active substances, used as solubility enhancer. It rapidly exhibits high capillary activity and pronounced hydration capacity with little tendency to form gel which is preferably 1 venyl 2 pyrrolidinone (CLPVP).

In another embodiment, the pharmaceutical formulation further comprises super disintigrants in tablet for improving release of active substances. Which preferably cross carmilose sodium. The concentration of Cefadroxil in individual layer will be 56.25% to 68.75% preferably 62.5% for adult. Accordingly both layer tablet weight% will be36%to 44% preferably 40%. It can be available in various concentration for example 31.25%, 15.6% and 7.8% thereof. The concentration of Clavulanic acid in individual layer will be 25% to 50% preferably 27.80% and 13.5% thereof. Accordingly both layer tablet weight clavulanic acid % will be 9%to 11% preferably 10%.

It can be available in various concentration for example 40%, 30%,20%,10% thereof

Manufacturing Process

Dry Granulation:-This process of granulation is commonly used when the tablet ingredients are sensitive to moisture or are unable to withstand elevated temperature during drying. Under such conditions dry granulation is the method of choice provided the tablet ingredients have sufficient inherent binding or cohesive properties.

The essential steps are weighing, mixing, slugging, dry screening, lubrication and compression. The present bilayer tablet aims at formulating bilayer tablet of cefadroxil with potassium clavulanate both layer as fast release. In a further aspect, the present invention relates to an improvement in bilayer tableting technology and provides a method of producing a bilayer pharmaceutical tablet. The flowing examples illustrate the invention in further detail.

Core tablet composition:- (cefadroxil layer) cefadroxil monohydrate 540mg eq.to cefadroxil 500mg (quantity based on assay) Microcrystalline cellulose 40mg, Microcrystalline cellulose (PH 200) 138.335mg, Talc 3.333mg, 1-venyl 2-pyrrolidinone 40mg,Croscarmellose sodium 20.00mg, Aerosil 5mg, Magnesium stearate 6.666 mg, HPMC (hydroxypropyl methyl cellulose) 6.666 mg Total weight : 800mg .

Manufacturing procedure: all the ingredients excluding aerosil, half quantity of magnesium stearate, Croscarmellose sodium were blended together and compacted using a suitable roller compactor or slugged, the flakes or slugged material milled through an oscillating granulator/multimill to get suitable granules. The resultant granules blended with remaining excipients

Potassium clavulanate (second layer) composition :- potassium clavulanate diluted 308mg eq. to clavulanic acid 125mg (based on assay) , Microcrystalline cellulose (PH 200) 61mg, Microcrystalline cellulose 40mg, talc 2mg, 1-venyl 2-pyrrolidinone 20mg, Aerosil 3.334mg, Magnesium stearate 5 mg, HPMC (hydroxypropyl methyl cellulose) 10.666 mg Total weight : 450mg .

All ingredients excluding half quantity aerosil, magnesium stearate and 1 venyl 2- pyrrolidinone were blended together and compacted using a suitable roller compactor / slugged, the flakes/slugged material milled through an oscillating granulator or multi milled to get suitable granule. The resultant granules were blended with remaining excipients to obtain final blend for second layer.

Compression: - compressed the tablet using suitable compression machine, introducing the first or the second layer composition in a tablets press compressing said tablet layer composition to form a tablet layer, introducing the other tablet layer composition into the tablets press and compressing both tablets layer composition to form a bilayer tablet check the physical parameters such as hardness, friability, thickness, weight variation and disintegration test.

Coating formula :- film forming composition (protective coat ) HPMC E5 2.5mg, ethyl cellulose 2.5mg, dibutylpthalate 0.83mg, talc 0.43mg, titanium dioxide 0.83mg, isopropyl alcohol 41.66mg, methylene chloride 83.33mg, the protective film forming composition were prepared by dispersing the ingredients in solvent mixture. It was then applied by spray coating over tablet in a coating pan target weight gain 0.35-0.55%

film forming composition (film coat ) HPMC E15 12.5mg, dibutylpthalate 3.33mg, talc 0.93 mg, titanium dioxide 5mg, isopropyl alcohol 116.66mg, methylene chloride 350mg, the film forming composition were prepared by dispersing the ingredients in solvent mixture and filtered. The filtered solution was sprayed over previously coated tablet in a coating pan. Target weight gain 1.5-2.0%

Diseases can be cure by this combination are following- Uncomplicated Urinary Tract Infections coused by E.coli and proteus mirabilis.

Reproductive tract infection (RTI)

Pharyngitis and tonsillitis, caused by S.pyogenes.

Uncomplicated gonorrhea caused by N.gonorrhoeae

Acute and Chronic Bronchitis, caused by S. pneumoniae and H.influenzae (beta-lactamase positive and negative strains).

Skin infections Otitis Media caused by H.influenzae (beta-lactamase positive and negative strains) and S.pyogenes.

Claims

1. A bilayer tablet pharmaceutical composition comprises of cefadroxil and clavulanic acid.

2. A present invention comprises of the composition of bilayer tablet with two or more active ingredients with the pharmaceutically accepted excipients to provide two or more active pharmaceutical ingredient in a single dosages form at same time with high solubility and stability by over coming cross interaction or chemical incompatibilities between two different physical, chemical and physicochemical drug molecules by physical separation, and to enable the development of different drug release profile both in immediate release immediate release with extended release and promoting patient convenience and compliance.

3. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein both ingredients are in separate layer does not interact with each other .prevent cross interaction make it stable during the self life.

4. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein both API are in separate layer and do not directly effected the stability and bioavailability during self life.

5. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein it is to development of different drug release profile (one layer as immediate release and in other layer as extended release.

6. A bilayer tablet pharmaceutical composition as claimed in claim 5 wherein dissolution are not vary (predefined dissolution) because both drug not interact with each other due to both layer prepared separately. Selection of compatible and inert diluents for both drug are easy.

7. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein it is the best way to provide two or more active pharmaceuticals ingredients at a same time with high solubility and bioavailability by over coming cross interaction between two different physical, chemical and physicochemical drug molecules.

8. A bilayer tablet pharmaceutical composition as claimed in claim 2 wherein

Clavulanic acid (as potassium clavulanate) a potent beta-lactamases inhibitor is very sensitive to PH, temperature and humidity. The hydrolysis kinetics has to be determined. Clavulanic acid degradation rate from various sources was investigated at different temperature and PH tern. 10, 20, 25, 30 and 40, and pH value 4, 5, 6, and 7, It has been observed that clavulanic acid is more stable at pH-6, than 4, 5 and 7.

9. A bilayer tablet pharmaceutical composition as claimed in claim 7 wherein

Clavulanic acid having pH range 4.8-8.0 water 2.5% max. Cefadroxil a having pH approx 4.0-6.0 and water 6.0 max when mix together and prepared as a matrix tablet (mix form single layer) both the drugs would be in contact and cross interaction occur and increase the hydrolysis of both drug and make it unstable during the self life of the formulation.

10. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein it is prepared bilayer tablets as its improves and increase the stability and bioavailability by over come cross interaction between both the drugs in combination. Bilayer tablet of cefadroxil with potassium clavulanate is more stable with respect to stability studies in comparison to matrix tablet.

11. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein it is provide 2 or more active pharmaceutical ingredient in a single dosages form at same time with high solubility and stability by over coming cross interaction/ chemical incompatibilities between two different physical, chemical and physicochemical drug molecules by physical separation, and to enable the development of different drug release profile (both in immediate release) /(immediate release with extended release) and promoting patient convenience and compliance.

12. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein it provides an accurately measured dosage of the active ingredients in a convenient portable package, manufacturing process and techniques con provide tablet special properties for example sustained release or fast dissolving formulation.

13. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein Combination of Cefadroxil with clavulanic acid increase the spectrum of activity against beta-lactamase producing strains (also susceptible by this combination provides a solution for treatment of bacterial infection caused by beta-lactam resistant pathogens. Used to treat multiple bacterial infections in different parts of body. Absorption is not significantly modified by presence of food. Tablets are simple and convenient to use.

14. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein one advantage of the stability of bilayer tablet is extended pharmaceutical product shelf life. Extended phannaceutical shelf life offers significant economic advantages.

15. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein the concentration of Cefadroxil in individual layer will be 56.25% to 68.75% preferably 62.5% for adult. Accordingly both layer tablet weight% will be36%to 44% preferably 40%.It can be available in various concentration for example 31.25%,15.6% and 7.8% thereof.

16. A bilayer tablet pharmaceutical composition as claimed in claim 1 wherein the concentration of Clavulanic acid in individual layer will be 25% to 50% preferably 27.80% and 13.5% thereof, accordingly both layer tablet weight clavulanic acid % will be 9%to 11% preferably 10%.It can be available in various concentration for example 40%,30%,20%,10% thereof