The present invention relates to a pharmaceutical composition for oral use comprising cetirizine or an optically active isomer thereof or pharmaceutically acceptable salt thereof and microcrystalline cellulose wherein cetirizine is adsorbed on microcrystalline cellulose.
Cetirizine is a generic name for 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid and is typically provided as a dihydrochloride salt. Cetirizine is an orally active and selective H1-receptor antagonist currently prescribed for the treatment of seasonal allergies in patients aged 2 years and older.
For patients, such as children, who have difficulty swallowing in conventional tablets or capsules, chewable tablets are widely used in the pharmaceutical industry. In addition, chewable tablets avoid mishaps that may occur with liquids, such as spillage and stains.
One of the drawbacks to oral delivery systems however, is the situation where the drug to be administered is bitter, bad tasting, odorous or in some manner unpleasant especially to children. Many efforts have been made in the past to "taste mask" these compounds either through elaborate flavor and/or sweetener delivery systems, or by encapsulation with a polymer, fat, carbohydrate or other similar materials. These taste-masking methods basically prevent the bitter tasting components of the drug from contacting the taste buds during oral ingestion yet break down and release the active upon dissolution in the stomach.
US 4,650,663 discloses the preparation of an oral pharmaceutical delivery system in which an unpleasant tasting anti-tussive such as noscapine, carbetapentane citrate or clophedianol hydrochloride is adsorbed onto magnesium silicate flakes and incorporated into a chewable tablet or lozenge.
US 6,027,746 discloses a soft chewable gelatin capsule having incorporated therein a drug dispersed in an oral suspension comprising a medicament adsorbate comprising magnesium trisilicate and silicon dioxide as carrier.
US 6,455,533 relates to a solid pharmaceutical composition for oral administration comprising cetirizine, an optically active isomer thereof or a pharmaceutically acceptable salt thereof and at least one cyclodextrin. In this patent, a complex is first formed between cyclodextrin and cetirizine, which is then formulated into a dosage form.
WO 03/059328 relates to an oral pharmaceutical composition containing at least two separate formulations, one formulation wherein comprises cetirizine and second formulation that is free of drug comprises one or more polyols.
US 2003/0215503 relates to a palatable chewable tablet comprising (a) cetirizine or a pharmaceuticaily acceptable salt thereof, (b) a sweetener, (c) a combination of a grape flavoring and a vanilla flavoring in a ratio from about 4:1 to 2:1, (d) a cyclodextrin, and (e) one or more additional excipients.
There still exists a need for a palatable formulation for cetirizine medicaments that assist in compliance especially with children. We have now developed a cetirizine adsorbate comprising microcrystalline cellulose as carrier; thereby masking the bitter taste of the drug.
Hence, in one of the aspects there is provided a pharmaceutical composition for oral use comprising cetirizine or an optically active isomer thereof or pharmaceuticaily acceptable salt and microcrystalline cellulose thereof wherein cetirizine is adsorbed on microcrystalline cellulose. The ratio of drug: carrier may vary from 1:1 to 1:50.
In other aspect, there is provided a process for the preparation of a pharmaceutical composition for oral use comprising cetirizine or an optically active isomer thereof or pharmaceuticaily acceptable salt thereof and microcrystalline cellulose wherein cetirizine is adsorbed on microcrystalline cellulose.
In another aspect, there is provided a method of treating or preventing seasonal allergic rhinitis, perennial allergic rhinitis and chronic urticaria in a mammal in need thereof comprising administering to the mammal a pharmaceutical composition for oral use comprising cetirizine or an optically active isomer thereof or pharmaceuticaily acceptable salt thereof and microcrystalline cellulose wherein cetirizine is adsorbed on microcrystalline cellulose.
In other aspect, there is provided a process for the preparation of a pharmaceutical composition for oral use comprising cetirizine or an optically active isomer thereof or pharmaceuticaily acceptable salt thereof wherein cetirizine is adsorbed on to microcrystalline cellulose and adsorbates are prepared by granulation or slurry technique or spray drying.
"Cetirizine" as employed herein is intended to include not only the free compound but also any pharmaceuticaily acceptable salt thereof. Preferred are acid addition salts, especially the dihydrochloride. "Cetirizine" is also intended to cover individual enantiomers as well as the racemate. In particular, cetirizine includes cetirizine dihydrochloride, levocetirizine dihydrochloride or efletirizine dihydrochloride.
Microcrystalline cellulose is a purified, partially depolymerized cellulose prepared by treating alpha-cellulose, obtained as a pulp from fibrous plant material, with mineral acids. The degree of polymerization is typically less than 400. It is available in various grades varying in the particle size, moisture, flow and other physical properties. The various available grades include Avicel PH 101, 102, 103, 105, 112 and 200 supplied by FMC corporation; Emocel 50M and 90M supplied by Edward Mendell and Vivacel 101, 102, 12 and 20 supplied by Rettenmaier. Microcrystalline cellulose in the present invention acts as a carrier for the adsorption of the drug so as to mask the bitter taste of it. Grades with finer particle size such as Avicel PH 105 and Vivacel 20 (having a nominal mean particle size of 20 urn) are more suitable as a carrier because they do not leave a chalky taste in the mouth as well as provide a larger surface area for adsorption.
The adsorbate once prepared may be formulated with pharmaceuticaily acceptable inert excipients, to prepare pharmaceutical composition like tablet, pills, capsules or granules. The compositions include chewable tablet, suckable tablet, chewable soft gelatin capsule and dry granules.
The pharmaceutical composition or adsorbate may further comprise pharmaceuticaily acceptable inert excipients. The term "pharmaceuticaily acceptable inert excipients" as used herein includes all excipients used in the art of manufacturing solid dosage forms. Examples include sweeteners, binders, diluents, surfactants, lubricants/glidants, coloring agents, flavours, and the like.
Sweeteners include natural sweeteners such as sucrose, dextrose, fructose, invert sugar, mannitol, sorbitol, and the like, as well as synthetic sweeteners such as saccharin, aspartame, acesulfame potassium, cyclamates, and other commercial artificial sweeteners well-known to those of skill in the art.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, microcrystalline cellulose and the like.
Specific examples of diluents include lactose, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered and starch.
Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Examples of coloring agents include any FDA approved colors for oral use. It may include Iron oxide, Lake of Tartrazine, Lake of Quinoline Yellow, Lake of Sunset Yellow, Aluminium Lake (blue), Lake of Erythrosine, Lack of Carmosine Ponceau, Allura Red.
Suitable flavorings include both natural and artificial flavors, and mints such as peppermint, menthol, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed, and the like are contemplated. The flavorings are generally utilized in amounts that will vary depending upon the individual flavor, and may, for example, range in amounts of about 0.5% to about 3% by weight of the final composition weight.
The pharmaceutical composition may optionally be coated with functional and/or non-functional layers comprising film-forming polymers, if desired.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like. Alternatively, commercially
available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
The adsorbate can be prepared by granulation and/or slurry techniques or spray drying. These processes involve the initial step of dissolving the drug in a suitable solvent and then mixing with the carrier. Solvent concentrations may vary widely but are generally from about 15% to about 60% by weight of the carrier. When mixing is performed with low amounts of solvent, for example 15% to about 35% by weight of the carrier, the resulting granulated product is removed and dried. When higher solvent concentrations are employed a slurry is formed containing the drug and carrier. Solvent concentrations may range from about 30% to 60% by weight of the total composition for optimum results. The solvent is then removed and the adsorbate recovered and dried to a free flowing powder.
Any solvent may be used in the process to prepare the adsorbate, provided it is capable of dissolving cetirizine. Representative solvents include water, methanol, ethanol and isopropanol with water being the preferred solvent.
According to one of the embodiment, adsorbate is prepared by granulation comprising the steps of:
i) dissolving cetirizine or an optically active isomer thereof or pharmaceutically
acceptable salt thereof in a solvent,
ii) granulating the carrier with above dispersion or solution,
iii) drying the said granules to obtain the adsorbates.
According to another embodiment, adsorbate is prepared by slurry technique comprising the steps of:
i) dissolving cetirizine or an optically active isomer thereof or pharmaceutically
acceptable salt thereof in a solvent,
ii) forming a slurry with the carrier
iii) removing the solvent to obtain the adsorbates.
According to one of the embodiment, adsorbate is prepared by spray drying comprising the steps of:
i) dissolving cetirizine or an optically active isomer thereof or pharmaceutically
acceptable salt thereof in a solvent,
ii) spray drying the said solution to obtain the adsorbates.
According to another embodiment, the adsorbate prepared may be formulated into a tablet or
capsule dosage form. The pharmaceutical composition is prepared comprising the steps of:
i) blending cetirizine adsorbates and one or more pharmaceutically acceptable excipients,
ii) optionally granulating the blend of step i)
iii) lubricating the blend of step i) or granules of step ii)
iv) compressing the blend into suitable size tablets or filling into capsules.
The granulation may be carried out by wet or dry granulation. The dry granulation may be
carried out using slugging or by compaction.
The following examples illustrate the invention but should not be construed as limiting the scope of the invention.
EXAMPLE 1 - CETIRIZINE CHEWABLE TABLET

(Table Removed)

PROCESS STAGE -1
1. Cetirizine was dissolved in purified water and microcrystalline cellulose was dispersed in
it.
STAGE - II
2. Microcrystalline cellulose and Acesulfame potassium were sifted through sieve.
3. The dispersion of step 1 was adsorbed on to the blend of step 2.
4. The wet material of step 3 was dried and milled into fine powder to obtain adsorbate.
STAGE - III
5. Povidone was dissolved in purified water and Acesulfame potassium was dispersed in the binder solution.
6. Microcrystalline cellulose, a part of Acesulfame potassium was sifted through sieve and blended with adsorbate of step 4.
7. The blend of step 6 was granulated with the dispersion of step 5 and granules were dried.
8. Colloidal Silicon Dioxide, remaining Acesulfame potassium, Peppermint flavour, cornstarch and microcrystalline cellulose were sifted through sieve.
9. Granules of step 7 and blend of step 8 were blended and lubricated with Magnesium stearate.
10. The blend was compressed into suitable size tablets.
Tablet obtained in Example 1 (10 mg) was subjected to stability study under 40°C and 75%RH as indicated in Table 1 in cold form blister pack and HDPE bottle pack.
TABLE 1: Results of stability evaluation of cetirizine chewable tablets (Examples 1) as percentage (w/w) related substances, over a period of 3 months at 40°C and 75% relative humidity.

(Table Removed)

EXAMPLE 2 - CETIRIZINE CHEWABLE TABLET

(Table Removed)
PROCESS
1. A solution of cetirizine hydrochloride was prepared in purified water.
2. Lactose Monohydrate, Acesulfame Potassium and Microcrystalline Cellulose were sifted through sieve and blended.
3. The blend of step 2 was granulated using cetirizine dispersion of step 1.
4. The granules were dried and sifted through sieve.
5. Lactose Monohydrate, Acesulfame Potassium and Microcrystalline Cellulose and colloidal silicon dioxide were sifted through sieve and blended well.
6. Granules obtained in step 4 and blend of step 5 were blended.
7. Magnesium stearate was sifted through sieve and above mixture was lubricated.
8. The blend was then compressed into suitable size tablets.
EXAMPLE 3 - CETIRIZINE CHEWABLE TABLET

(Table Removed)
PROCESS
1. Cetirizine was dissolve in purified water; microcrystalline cellulose (5mg) was added to cetirizine solution.
2. Lactose monohydrate, acesulfame potassium and microcrystalline cellulose were sifted through sieve and blended.
3. Blend of Step 2 was granulated with dispersion of step 1.
4. The wet material of step 3 was dried and milled into fine powder.
5. Microcrystalline Cellulose and a part of Acesulfame Potassium (of stage II) was sifted through sieve.
6. Blend of step 5 and adsorbate powder of step 4 were blended.
7. Binder solution was prepared by dissolving Povidone and remaining Acesulfame Potassium in purified water.
8. The blend of step 6 was granulated using the binder solution of step 7 and granules obtained were dried.
9. The extra granular excipients except Magnesium stearate were sifted through sieve.

9. Granules of step 8 and blend of step 9 were blended.
10. Blend of step 10 was lubricated with magnesium stearate.
11. Blend of step 11 were compressed into suitable size tablets.
The composition of Example 1, 2 and 3 was tasted by a panel of five people and taste was found to be acceptable.

WE CLAIM:
1. A pharmaceutical composition for oral use comprising cetirizine or an optically active isomer thereof or pharmaceutically acceptable salt thereof and microcrystalline cellulose wherein cetirizine is adsorbed on microcrystalline cellulose.
2. The pharmaceutical composition according to claim 1 wherein pharmaceutical composition is solid composition selected from tablet, capsules, pills or granules.
3. The pharmaceutical composition according to claim 1 wherein solid composition includes chewable tablet, suckable tablet, chewable soft gelatin capsule and dry granules.
4. The pharmaceutical composition according to claim 1 optically active isomer is selected from the group consisting of cetirizine dihydrochloride, levocetirizine dihydrochloride or efletirizine dihydrochloride.
5. The pharmaceutical composition according to claim 1 wherein the ratio of drug to carrier to drug is 1:1 to 1:50.
6. The pharmaceutical composition according to claim 1 wherein the composition or the adsorbate further comprises other pharmaceutically acceptable inert excipients.
7. The pharmaceutical composition according to claim 6 wherein pharmaceutically acceptable inert excipients are selected from the group consisting of binders, sweetener, diluents, surfactants, lubricants/glidants, coloring agents and flavors.
8. A process for preparation of pharmaceutical composition according to claim 1 wherein adsorbate is prepared by granulation or slurry technique or spray drying.
9. The process for preparation of pharmaceutical composition according to claim 8 wherein adsorbate is prepared by granulation comprising the steps of:
i) dissolving cetirizine or an optically active isomer thereof or pharmaceutically
acceptable salt thereof in a solvent,
ii) granulating the carrier with above dispersion or solution,
iii) drying the said granules to obtain the adsorbates.
10. The process for preparation of pharmaceutical composition according to claim 9 wherein solvent is used in the concentration of 15 to 35% of the carrier weight.
11. The process for preparation of pharmaceutical composition according to claim 8 wherein adsorbate is prepared by slurry technique comprising the steps of:
i) dissolving cetirizine or an optically active isomer thereof or pharmaceutically
acceptable salt thereof in a solvent,
ii) forming a slurry with the carrier
iii) removing the solvent to obtain the adsorbates.
12. The process for preparation of pharmaceutical composition according to claim 11 wherein solvent is used in the concentration of 30 to 60% of the carrier weight.
13. The process for preparation of pharmaceutical composition according to claim 8 wherein adsorbate is prepared by spray drying comprising the steps of:
i) dissolving cetirizine or an optically active isomer thereof or pharmaceutically
acceptable salt thereof in a solvent,
ii) spray drying the solution.
14. The process for preparation of pharmaceutical composition according to any of the preceding claim wherein solvent is selected from the group consisting of water, methanol, ethanol, isopropanol and mixtures thereof.
15. The process for the preparation of pharmaceutical composition according to claim 1 comprising the steps of:
i) blending cetirizine adsorbates and one or more pharmaceutically acceptable
excipients, ii) optionally granulating the blend of step i) iii) lubricating the blend of step i) or granules of step ii) iv) compressing the blend into suitable size tablets or filling into capsules.
16. The process for the preparation of pharmaceutical composition according to claim 15 wherein granulation is carried out by dry or wet granulation technique.
17. The process for the preparation of pharmaceutical composition according to claim 16 wherein dry granulation is carried out by slugging or roller compacter.
18. The process for the preparation of pharmaceutical composition according to claim 16 wherein wet granulation is carried out with solvent or binder solution.
19. Use of the pharmaceutical composition as defined in any of the preceding claims for treating or preventing seasonal allergic rhinitis, perennial allergic rhinitis and chronic urticaria.
20. A pharmaceutical composition for oral use comprising cetirizine or an optically active isomer thereof or pharmaceutically acceptable salt thereof as herein described.