WO2012131690A1

WO2012131690A1 - Drug delivery form as a bilayer tablet

Info

Publication number: WO2012131690A1
Application number: PCT/IN2011/000435
Authority: WO
Inventors: Kumar Vijay AGGARWAL; Sanjeev GOEL; Umakant MISHRA
Original assignee: Aggarwal Kumar Vijay; Goel Sanjeev; Mishra Umakant
Priority date: 2011-03-30
Filing date: 2011-06-30
Publication date: 2012-10-04

Abstract

This invention is based upon pharmaceutical bilayer tablet composition. It comprises a first outer region is cefixime which partly surrounds an inner center, a second outer region is clavulanate potassium which also partly surrounds the center, and the outer regions together form a continuous assorted layer fully surrounding the center. Dry granulation method use for both layers by selection of inert and thermostable excipients.Each film coated tablet contains cefixime and clavulanate potassium active pharmaceuticals ingredients. It is particularly suitable for mostly bacterial and microbial infection and diseases. Both drugs having different physicochemical properties to overcome chemical interference between both drugs and maximum stability and bioavailability achieved by this novel drug formation as bilayer tablet More stability can be observed in the case of chemical interference. 100% Bioavaility can be found.

Description

TITLE- "Drug delivery form as a bilayer tablet."

DETAILED DESCRIPTION OF INVENTION

Accordingly, in one aspect, this invention is based on the formulation of the bilayer tablet which comprises of two active pharmaceutical ingredients clavulanate potassium and Cefixime. The drug comes in tablets, chewable tablets, and a suspension (liquid) form. It is taken every 8 or 12 hours, depending on the particular product and dosage.

The main components of this bilayer tablet is following

Cefixime

Cefixime is an oral third generation cephalosporin antibiotic, having pH 2.6 to 4.1 and water content 9 to 12 %. It is used to treat a wide variety of bacterial infections like gonorrhea, tonsilitis, and pharyngitis thereof. It can easily soluble in methanol, sparingly soluble in ethanol (95%).Cefixime is a semi-synthetic (partially man-made), oral antibiotic in the cephalosporin family of antibiotics. The cephalosporin family includes cephalexin (Keflex), cefaclor (Ceclor), cefuroxime (Zinacef), cefpodoxime (Vantin), cefprozil (Cefzil), and many injectable forms. Like other cephalosporins, cefixime stops bacteria from multiplying by preventing bacteria from forming the walls that surround them. The walls are necessary to protect bacteria from their environment and to keep the contents of the bacterial cell together; bacteria cannot survive without a cell wall. Cefixime is active against a very wide spectrum of bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes (the cause of strep throat), Hemophilus influenzae, Moraxella catarrhalis, E. coli, Klebsiella, Proteus mirabilis, Salmonella, Shigella, and Neisseria gonorrhoeae.

l Cefixime is effective for infections of the middle ear (otitis media), tonsillitis, throat infections (pharyngitis), laryngitis, bronchitis, and pneumonia caused by susceptible bacteria. It also is used for treating urinary tract infections and gonorrhea as well as acute bacterial bronchitis in patients with chronic obstructive pulmonary disease (COPD).

Clavulanic acid

It's beta-lactamase inhibitor Combined with a class of β-lactam antibiotics group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete beta-lactamase. The bioavailability is "well absorbed".

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 (usually combined with amoxicillin or ticarcillin), sulbactam and tazobactam.lt can be freely soluble in water, slightly soluble in ethanol 95%.

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 %. Both these drug not matched in physical and chemical properties and loss the potency in mixed form and ultimately bioavailability of drug and finally response of drug. Clavulanic acid a potent beta lactamase inhibitor is very sensitive to pH, temperature and humidity .The expression of the hydrolysis kinetics has to be determined. In the present work (Potassium Clavulanate) PC degradation rate from various sources was investigated at temperature of 10, 20, 25, 30 and 40degree Cel. and pH value 4.5 and 6. The result showed that first order kinetics explained very well, the hydrolysis kinetics and the Arrhenius equation could be applied to established a relationship between the degradation rate constant and temperature at both pHs. It has been observed that (Potassium Clavulanate) PC much more unstable than that from standard solution and from a commercially available medicine. Also it was observed that (Potassium Clavulanate) PC more stable at pH 6 than 4.5 pH irrespective of the clavulanic source. To overcome these factors tablets manufactured in bilayred form.

Mode of action of Clavulanic acid

Clavulanic acid has small basic antimicrobial activity, despite sharing the β-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, 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.

They both are not interfering with each other without any problem. More stability can be observed in the case of chemical interference. 100%Bioavaility can be found.

Dry granulation method use for both layers by selection of inert and thermostable excipients.Each film coated tablet contains cefixime and clavulanate potassium active pharmaceuticals ingredients.

MODE OF ACTION OF BOTH INGREDIENTS

Cefixime is highly stable in the presence of betalactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins due to the presence of beta- lactamases, may be

Susceptible to cefixime. However, cefixime was found to be ineffective against bacteria which produces ESBL enzyme and resistance is seen in such types of bacteria .Clavulanic acid is an irreversible 'suicide' inhibitor of intracellular and extra cellular β- lactamases, demonstrating concentration-dependent and competitive inhibition. It has a high affinity for the class A β-lactamases. This wide range of β-lactamases, which includes the plasmid-mediated TEM and SHV Enzymes, is found frequently in members of the Enterobacteriaceae, Haemophilus influenzae and Neisseria gonorrhoeae. The chromosomally mediated β-lactamases of Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Bacteroides fragilis and Moraxella catarrhalis are also inhibited, as are the extended-spectrum β-lactamases. The frequency of β-lactamase mediated resistance has continued to rise over the years, but the majority of clinically

significant β-lactamases are inhibited by clavulanate

They are prescription antibiotic medication. It is used to treat a variety of infections. Cefixime and clavulanate potassium is approved for use in children, including very young infants

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. For the formation of a cohesive slug, spray dried or powdered binders such as HPMC or microcrystalline cellulose may be added to the dry powder. Lubricants are added to reduce powder adhesion to the punches and to facilitate ejection of intact slugs from the dies. Initially large slugs are obtained by compressing powdered material containing excipients. The slugs are then forced through mesh screen breaking them into granules. The remaining lubricant is added to the granulation with gentle blending and the resulting material is compressed into tablet.

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 comprising of the following steps -

(i) Providing a first tablet layer composition by:

(a) DRYING- Betalactum antibiotic sensitive to moisture and to prevent hydrolytic cleavage, remove the extra cellular reactive moisture from active & excipients.

(b) DRY MIXING OF ALL INGRIEDIENTS-such as cefixime, MCCPH 200 , MCC Talc, Aerosil, HPMC and Magnesium Stearate .

(c) SLUGGING-large slugs are obtained by compressing powdered material containing excipients.

(d) DRY SCREENING- The slugs are than forced through mesh screen breaking them into granules.

(e) LUBRICATION- Mixing of the said premix with a lubricant to obtain a final blend for the first tablet layer optionally, adding other excipients and/or adjuvants (magnesium stearate) in any of steps a) to d);

(ii) Providing a second tablet layer composition by:

(iii) Mixing and/or granulating a Potassium Clavulanate with the constituents of a disintegrating tablet matrix and, optionally, further excipients and/or adjuvants (magnesium stearate). (f) Admixing of a lubricant (Aerosil, magnesium stearate, TALC)

(g) Obtain a final blend for the second tablet layer;

(iii) Introducing the first or the second tablet layer composition in a tablet press;

(iv) Compressing said tablet layer composition to form a tablet layer;

(v) Introducing the other tablet layer composition into the tablet press; and

(vi) Compressing both tablet layer compositions to form a bilayer tablet.

MCCP - It used as diluents, binder and disintigrant effective in tableting large dose drugs, low compressible drugs pressure sensitive drugs.

MAGNESIUM STEARATE- It is used as lubricant and antiadherent

HPMC- It used as binder since 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.

MCCPH 200- it used as diluent for best flow rate in direct compressible and dry granulation binder maintaing high level of compressibility and minimizing problem of weight variation and content uniformity.

TALC- It's used as a lubricant and glidants.

AEROSIL - It's used as a lubricant and glidants.

Claims

1. An oral bilayer tablet formulation comprising: (a) an active formulation layer comprising first outer region is cefixime pharmaceutically acceptable salt thereof which partly surrounds an inner center, a second outer region is clavulanate potassium which partly surrounds the center, and the outer regions together form a continuous assorted layer fully surrounding the center, (b) an inactive pharmaceutically accepted inert and thermo stable excipients or its pharmaceutically acceptable salt. Dry granulation method use for both layers by selection of inert and thermostable excipients

2. The bilayer tablet as claimed in Claim 1, wherein said excipients are diluents, binder, disintigrant, lubricant, antiadherent and glidants.

3. The bilayer tablet as claimed in Claim 1, wherein said 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 %.

4. The bilayer tablet as claimed in Claim 1, wherein said Both these drug not matched in physical and chemical properties and loss the potency in mixed form and ultimately bioavailability of drug and finally response of drug.

5. The bilayer tablet as claimed in Claim 1, wherein said cefixime is having pH 2.6 to 4.1 and water content 9 to 12 %.

6. The bilayer tablet as recited in Claim 2, wherein said these excipients are MCCP, Magnesium stearate, HPMC, MCCPH 200, TALC and Aerosil.

7. The bilayer tablet as recited in Claim 1 wherein said the whole manufacturing method is dry granulation method use for both layers by selection of inert and thermostable excipients.

8. The bilayer tablet as recited in Claim 1, wherein this compressed layer oral composition has the fast release layer with enhanced bioavailability.

9. The bilayer tablet as recited in Claim 1, wherein it is particularly suitable for mostly bacterial and microbial infection and diseases.

10. The bilayer tablet as recited in Claim 1, wherein the both layers are not interfering with each other and making present process more stable without the chemical interference with 100% bioavailability.

11. The bilayer tablet as recited in Claim 1, wherein both drugs having different physicochemical properties to overcome chemical interference between both drugs and maximum stability and bio availability achieved by this novel drug formation as bilayer tablet