TECHNICAL FIELD OF THE INVENTION:

The present invention relates to a synergistic bilayer pharmaceutical tablet composition comprising combination of H1 receptor antagonist-Levocetirizine and H2 receptor antagonist-Ranitidine along with pharmaceutically acceptable excipients, in a stable oral dosage form. This stable synergistic bilayer pharmaceutical tablet composition is effective in managing allergic conditions and urticaria rather than use of Levocetirizine alone.

BACKGROUND AND PRIOR ART OF THE INVENTION:

Histamine is responsible for the wheal and flare reaction in various allergic conditions. Classical antihistamines are the drugs which block the H1 receptors and are widely used in various allergic conditions, whereas H2 blockers are mainly used for acid peptic disease. Although H1 receptor-mediated actions of histamine are primarily responsible for vasodilatation, vasopermeability and itching, it has been observed that combined blocking of both HI and H2 receptors may provide better relief. Some researchers provided additional evidence that H2 receptors are present in the human cutaneous microcirculation and add support to the clinical observation of therapeutic efficacy of HI plus H2 blockers in some patients with chronic urticaria. It has been suggested that the combination of H1 antagonist and H2 antagonist inhibits the release of allergic mediators.

Roughly 15% of the histamine receptors in the skin are H2-receptors. On this basis, H2-receptor antagonists (e.g., ranitidine, cimetidine) have been used in the treatment of drug-induced and acquired angio-oedema. It is reported that H1 antagonists are beneficial in relieving nasal itching, sneezing, and rhinorrhea in patients with allergic rhinitis. But they have a lesser effect on nasal blockade. Concomitant administrations of an H1 antagonist with an H2 antagonist have been reported to improve the symptoms of allergic rhinitis and enhance the wheal suppression in the skin test.

Levocetirizinedihydrochloride is an orally active H1-receptor antagonist, R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. It is chemically R-[2-[4-[(4-chlorophenyl) phenylmethyl]-l-piperazinyl] ethoxy] acetic acid dihydrochloride with molecular weight of 461.82. Levocetirizinedihydrochloride is a white, crystalline powder, soluble in water. Levocetirizine dihydrochloride has the following structural formula:

Levocetirizine dihydrochloride is a potent and selective antagonist of peripheral Hl-receptors. Binding studies revealed that Levocetirizine has high affinity for human Hl-receptors. Levocetirizine has an affinity 2-fold higher than that of cetirizine. Pharmacodynamic studies in healthy volunteers demonstrated that, at half the dose, Levocetirizine has comparable activity to cetirizine, both in the skin and in the nose. Levocetirizine is rapidly and extensively absorbed after oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet. Levocetirizine is indicated in symptomatic treatment of allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria.

Ranitidine hydrochloride (C13H22N4O3S.HCI) is a histamine H2-receptor antagonist, chemically N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio] ethyl] - N'-methyl-2-nitro-l, 1 ethenediamine, HC1 with a molecular weight of 350.87. Ranitidine hydrochloride is a white to pale yellow, practically odourless, crystalline powder. It is sensitive to light and to moisture. It is very soluble in water, moderately soluble in alcohol and sparingly soluble in chloroform. A 1% solution in water has a pH of 4.5 to 6.0. It has a slightly bitter taste and sulfurlike odor.Ranitidine hydrochloride has the following structural formula:-


Ranitidine hydrochloride is histamine H2-receptors, including receptors on the gastric cells useful in inhibiting stomach acid. Ranitidine hydrochloride is 50% absorbed after oral administration, compared to an intravenous (IV) injection. Ranitidine HC1 is indicated in short-term treatment and maintenance of duodenal ulcer, benign gastric ulcer, GERD and treatment of endoscopically diagnosed erosive esophagitis. Ranitidine may be given by mouth or parenterally by the intravenous or intramuscular routes. Ranitidine hydrochloride is available in film coated tablet, effervescent tablet and syrup dosage forms.Strengths and doses are expressed in terms of the base.

The Japanese Patent Application No. JP4089428 has generally cited polymorphonuclear leukocyte activator for treatment of hardly curable infectious diseases such as periodontal diseases, athlete's foot, and opportunistic infection; there have been no specific attempt to provide an improved combination of Levocetrizine opportunistic candidates for obtaining enhanced efficacy in the treatment of allergic conditions.

Both the drugs i.e. Levocetirizine and Ranitdine are widely used for their perspective indications mentioned above. Recent research shows that the combination of HI and H2 receptor antagonists shows an additive effect in controlling allergy and urticaria conditions. Hence, in this purview, there is a need to develop a single oral dosage form containing combination of Levocetirizine (HI receptor antagonist) and Ranitidine (H2 receptor antagonist) along with pharmaceutically acceptable excipients, in the form of stable synergistic bilayered tablet that prevents interaction between these two drugs and provides a stable formulation for at least 2 years, which delivers enhanced efficacy in treatment of allergic conditions and urticaria.

RATIONALE OF THE COMBINATION:

H1 antihistamine administration is primary way of treating minor allergic symptoms such as rash, itchy, watery eyes, congestion, wheal and flare. Some patients have more severe allergic symptoms and may have recurrence of presenting manifestations after initial HI antagonist therapy. In these patients, the additional antiallergic treatments other than HI antagonist therapy are necessary. There were various literatures demonstrating the synergistic effects of HI and H2 receptors antagonist in the treatment of allergic conditions and premedication in anesthesia and surgery. There are numerous literature supporting the rationale of using the combination of HI and H2 antagonists in urticarial disease not responding to H1 blockers alone. Therefore, in the present invention, the combination of Ranitidine (H2 receptor antagonist) and Levocetirizine (HI receptor antagonist) is formulated as a single dosage for the treatment of the above said conditions.

SUMMARY OF THE INVENTION:

The present invention discloses a stable synergistic bilayer pharmaceutical tablet composition comprising combination of H1 receptor antagonist, Levocetirizine and H2 receptor antagonist, Ranitidine along with pharmaceutically acceptable excipients, which provides better results in the treatment of allergic conditions and urticaria rather than use of Levocetirizine alone. The invention further discloses the process for preparation of said pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION:

In accordance with the above, the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In a preferred embodiment, the present invention describes a stable synergistic bilayer pharmaceutical tablet composition comprising a first layer containing HI receptor antagonist Levocetirizinein combination with second layer containing H2 receptor antagonist Ranitidine along with pharmaceutically acceptable excipients, useful for the treatment of allergic conditions and urticaria Accordingly, the first layer containing Levocetirizine is present in an amount of 2.5 to 5 mg and the second layer containing Ranitidine is present in an amount of 150 to 300 mg.

The present invention further directed to process for preparation of the stable synergistic bilayer pharmaceutical tablet composition that prevents interaction between Levocetirizine and Ranitidine and thus provides a stable composition for at least 2 years of its storage period.

In another embodiment, the stable synergistic bilayer pharmaceutical tablet composition of the present invention comprising combination of Levocetirizine and Ranitidine along with the pharmaceutically acceptable excipients that are selected from the group comprising, disintegrants, diluents, granulating agents, solvents film coating agents and colourants.

Accordingly, the said stable synergistic bilayer pharmaceutical tablet composition is prepared by using suitable diluents such as microcrystalline cellulose, maize starch, lactose, mannitol and Dicalcium phosphate alone or in combination, in the range of 20 -80%.

Suitable disintegrants are selected from croscarmellose sodium, crosslinked povidone, sodium starch glycolate, maize starch, pregelatinized starch alone or in combination, in the range of_2 -10%.

Suitable lubricants are selected from magnesium stearate, stearic acid, talc and colloidal silicon dioxide alone or in combination, in the range of 0.2 - 2.0%.

Suitable plasticizers are selected from triacetin, diethyl phthalate, tributylsebacate or polyethylene glycol (PEG) alone or in combination, in the range of 5 - 30% of coating formula.

Suitable granulating agents are selected from hypromellose, ethylcellulose, methyl cellulose, povidone, polyvinyl alcohol alone or in combination in the range of 1 - 5%.

Suitable solvents that can be used for the purpose of granulation are selected from Isopropyl alcohol, Methylene chloride alone or in combination, in the range of 10 - 50%.

Suitable film coating agents are selected from Hypermellose, ethyl cellulose, propyl cellulose, methyl cellulose, polyvinyl alcohol, polymethacrylates alone or in combination, in the range of 1 - 10 of tablet weight%.

Suitable colourants are selected from Lake colour, in the range of 0.1 - 2.0% and suitable pigments are selected from Titanium dioxide, 10 - 50% of coating formula.

From the present invention it is found that the two drugs i.e. Levocetirizine and Ranitidine are incompatible to each other both physically and chemically. Hence, it is difficult to formulate the same in single tablet dosage form. Therefore, various options were tried by the inventors of the present invention to avoid the direct contact between the two actives. Firstly, one of the active ingredient is coated and mixed with the other active during granulation or lubrication stage, to prevent interaction between them in the dosage form; Secondly, the Levocetirizine and Ranitidine are granulated separately and filled in capsules, and finally the Levocetirizine and Ranitidine are granulated separately and are compressed as a bilayered tablet or Levocetirizine granules are compressed into tablet and inlayed into the Ranitidine granules to produce inlay tablet dosage form. The final dosage form is coated to protect the active ingredients from humidity.

Trial 1: Regular tablet dosage form

Direct compressible grade ranitidine hydrochloride, microcrystalline cellulose, croscarmellose sodium and Levocetirizine hydrochloride are mixed for 10 min. in a mixer. Magnesium stearate passed through # 60mesh and is then added and mixed for another 5 min. The blend is then compressed to get a tablet containing Levocetirizine dihydrochloride and Ranitidine. The dosage form is then coated to protect Ranitidine with coating materials that include hypromellose 15 cps, titanium dioxide, triacetin and colourants. Since, Ranitidine hydrochloride is sensitive to moisture, non-aqueous solvents are preferred.

The samples prepared by the above method shows mottling like appearance during stability at accelerated and long term conditions with colour change and reduction in content of Levocetirizine hydrochloride.

Trial 2: Capsule dosage form

Levocetirizine dihydrochloride is mixed with croscarmellose sodium and microcrystalline cellulose and is granulated with hypromellose and/or ethyl cellulose in such a way that the granules should release at least 85% drug within 30 min. of dissolution testing in purified water. Direct compressible grade Ranitidine hydrochloride, croscarmellose sodium and magnesium stearate are added to the Levocetirizine dihydrochloride granules and are filled in hard empty gelatin and hypromellose capsules.

The sample prepared by Trial 2 is found to be better than Trial 1 in terms of chemical stability.

Trial 3: Inlay/Bi-layered tablet dosage form

Levocetirizine granules: Levocetirizine dihydrochloride and microcrystalline cellulose are mixed and granulated with hypromellose and or ethyl cellulose using aqueous or non¬aqueous solvent to form granules. The said granules are dried and further mixed with Croscarmellose sodium and magnesium stearate to obtain uniform Levocetrizine granules.

Ranitidine granules: Direct compressible grade Ranitidine hydrochloride, microcrystalline cellulose and croscarmellose sodium are mixed for 10 min. in a mixer. Magnesium stearate passed through # 60mesh and is then added and mixed for another 5 min.

The Ranitidine and Levocetirizine granules as prepared above are compressed suitably to get a bi-layered tablet or Levocetirizine dihydrochloride granule is compressed into a tablet and inlayed into Ranitidine granules to get inlay tablets. The dosage form is then coated to protect Ranitidine with coating materials that include hypromellose 15 cps, titanium dioxide, triacetin and colourants. Since, Ranitidine hydrochloride is sensitive to moisture, non-aqueous solvents are preferred.

The samples prepared by Trial 3 are found to be better than Trial 1 and Trial 2 in terms of chemical stability.

The preferred dose according to the present invention is 2.5/150, 5/150 and 5/300 mg of Levocetirizine and Ranitidine respectively.

Some typical examples illustrating the embodiments of the present invention are provided; however, these are exemplary only and should not be regarded as limitations of the present invention.

Process for manufacturing:

i. Sifting Ranitidine hydrochloride and diluent through #30 mesh and mix for 10 min; ii. sifting disintegrant and lubricant through #60 mesh and added to the contents of step (i) followed by continuous mixing for 5 min; iii. sifting Levocetirizine dihydrochloride and diluent through #40 mesh and mix for 10 min; iv. dissolving hypromellose in solvents to get a clear binder solution;

v. granulating the contents of step (iii) with the contents of step (iv) followed

by drying the granules and sifting the dried granules through # 30 mesh; vi. sifting disintegrant, diluent and colourant through #60 mesh and direct compressible grade diluent through #30 mesh and mixing with the dried granules of step (v); vii. compressing the bi-layered tablet using suitable rotary press; viii. preparing coating solution and coat the compressed bi-layered tablet to get a weight gain of 3-5 % w/w. Example 2: Stability Data

Long Term Stability Data:

Interpretation of Results:

1. Bi-layered tablet or inlay tablet shows better stability of combination of Levocetirizine dihydrochloride and Ranitidine hydrochloride than the standard tablet/capsule dosage forms.

2. The final product releases at least 85% of Levocetirizine dihydrochloride and Ranitidine hydrochloride in 30 min.

3. Convenient single dosage form, where this combination is required.

4. Stable for at least 2 years from the manufacture.

We claim,

1. A stable synergistic bilayer pharmaceutical tablet composition comprising a first layer containing H1 receptor antagonist Levocetirizine in combination with second layer containing H2 receptor antagonist Ranitidine along with pharmaceutically acceptable excipients, useful in managing allergic conditions and urticaria.

2. The stable synergistic bilayer pharmaceutical tablet composition according to claim 1, wherein a first layer containing Levocetirizine is present in an amount of 2.5 to 5 mg.

3. The stable synergistic bilayer pharmaceutical tablet composition according to claim 1, wherein a second layer containing Ranitidine is present in an amount of 150 to 300 mg.

4. The stable synergistic bilayer pharmaceutical tablet composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from the group comprising of emulsifiers, disintegrants, diluents, plasticizers, granulating agents, film coating agents, colourants and pigments.

5. The stable synergistic bilayer pharmaceutical tablet composition according to claims 1 and 4, wherein the said diluents are selected from microcrystalline cellulose, maize starch, lactose, mannitol and Dicalcium phosphate alone or in combination, in the range of 20 - 80%.

6. The stable synergistic bilayer pharmaceutical tablet composition according to claims 1 and 4, wherein the said disintegrants are selected from croscarmellose sodium, crosslinked povidone, sodium starch glycolate, maize starch, pregelatinized starch alone or in combination present in the range of 2 - 10 %.

7. The stable synergistic bilayer pharmaceutical tablet composition according to claims 1 and 4, wherein the said lubricants are selected from magnesium stearate, stearic acid, talc and colloidal silicon dioxide alone or in combination in the range ofO.2-2.0%.

8. The stable synergistic bilayer pharmaceutical tablet composition according to claims 1 and 4, wherein the said plasticizers are selected from triacetin, diethyl phthalate, tributylsebacate or polyethylene glycol (PEG) alone or in combination, present in the range of 5 - 30 % of coating formula.

9. The stable synergistic bilayer pharmaceutical tablet composition according to claims 1 and 4, wherein the said granulating agents are selected from hypromellose, cellulose ether, polyvinyl alcohol alone or in combination, present in the range of 1 - 5%.

10. The stable synergistic bilayer pharmaceutical tablet composition according to claims 1 and 4, wherein the said film coating agents are selected from hypermellose, ethyl cellulose, propyl cellulose, methyl cellulose, polyvinyl alcohol, polymethacrylates alone or in combination, present in the range of 1 - 10 % of tablet weight.

11. The stable synergistic bilayer pharmaceutical tablet composition according to claims 1 and 4, wherein the said colourants are selected from Lake colour, sunset yellow present in the range of 0.1 - 2.0%.

12. The stable synergistic bilayer pharmaceutical tablet composition according to claims 1 and 4, wherein the said pigments are selected from Titanium dioxide present in the range of 10 - 50 % of coating formula.

13. A process for preparation of stable synergistic bilayer pharmaceutical tablet composition comprising,.

Sifting Ranitidine hydrochloride and diluent through #30 mesh and mix for 10 min; ii. sifting disintegrant and diluent through #60 mesh and added to the contents of step (i) followed by continuous mixing for 5 min;

iii. sifting Levocetirizine dihydrochloride and emulsifier through #40 mesh

and mix for 10min; iv. dissolving hypromellose in solvent to get a clear binder solution; v. granulating the contents of step (iv) with the contents of step (iii) followed

by drying the granules and sifting the dried granules through # 30 mesh; vi. sifting disintegrant, diluent and colourant through #60 mesh and direct compressible grade emulsifier through #30 mesh and mixing with the dried, granules of step (v); vii. compressing the bi-layered tablet using suitable rotary press; viii. preparing coating solution and coat the compressed bi-layered tablet to get a weight gain of 3-5 % w/w.

14. The process for preparation of stable synergistic bilayer pharmaceutical tablet composition according to claim 13, wherein the solvents are selected from isopropyl alcohol, methylene chloride alone or in combination present in the range of 10-50%.