DESC:[0001] FIELD OF THE INVENTION

[0002] The present invention relates to orally disintegrating strips of ondansetron or its pharmaceutically acceptable salt thereof and the process for preparation thereof. In particular, the present invention relates orally disintegrating strips comprising ondansetron or its pharmaceutically acceptable salts thereof, polymer mixture consisting of hydroxypropyl methylcellulose and polyvinylpyrrolidone, polysorbate 80 as the surfactant and glycerol as the plasticizer.

[0003] BACKGROUND OF THE INVENTION

[0004] Ondansetron, a selective blocking agent of serotonin 5-HT3 receptor is indicated for the nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy and postoperative nausea and/or vomiting. Ondansetron is chemically represented as

[0005] Ondansetron is a white to off-white powder that is soluble in water and normal saline, having intensely bitter taste.

[0006] Ondansetron is commercially available as the conventional oral solid dosage forms in strengths of 4mg and 8mg as orally disintegrating tablets and films in Europe (Zofran® from Novartis).

[0007] Ondansetron is commercially available as Setofilm®; Orodispersible film (containing ondansetron base) in two strengths as 4mg and 8mg. Each 8mg Setofilm contains Poly (vinyl alcohol), Macrogol 1000, Acesulfame potassium, glycerol, titanium dioxide, rice starch, levomenthol and Polysorbate 80.

[0008] EP2248519B1 discloses the non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, wherein said film comprises 15.84 % ondansetron as base, 43.56 % polyvinylalcohol, 11.88 % polyethylene glycol, 3.96 % glycerol anhydrous, 19.80 % rice starch, 0.40 % acesulfam K, 0.59 % titanium dioxide, 1.98 % menthol and 1.98 % polysorbate per film, all percentages being by weight.

[0009] Despite the wide existence of teachings for making ondansetron oral disintegrating films (strips) in the prior art, however, still there is a need for providing an economically feasible, improved, stable oral dissolving strips that is easy to make and that can accommodate drugs like ondansetron.

[0010] OBJECTS OF THE INVENTION

[0011] In one object of the present invention to provide orally disintegrating strip dosage forms containing ondansetron or its pharmaceutically acceptable salts thereof that mimic the pharmacokinetic profile of orally administered drug products such as ondansetron orally disintegrating tablets.

[0012] In another object the present invention provides an orally dissolving strip dosage forms containing ondansetron or its pharmaceutically acceptable salts thereof, so that they follow the same metabolic and bio absorption pathways, and obtain the same pharmacokinetic profiles, as existing orally administered drugs such as orally dissolving tablets (ODT).

[0013] Another object of the present invention is to provide methods of treatment for nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy and postoperative nausea and/or vomiting using the orally disintegrating strips of the present invention, and methods that provide bioequivalence to orally administered drug products such as orally disintegrating tablets (ODT).

[0014] SUMMARY OF THE INVENTION

[0015] The present invention provides orally disintegrating strips of ondansetron or its pharmaceutically acceptable salts thereof that are formulated or administered for gastrointestinal absorption of ondansetron or ondansetron hydrochloride as the active pharmaceutical agent, and that are bioequivalent to and interchangeable with existing orally administered drug products. These strip dosage forms quickly disintegrate in the mouth when exposed to saliva; and they are absorbed predominantly through the gastrointestinal tract. Most importantly, these dosage forms are specifically formulated to meet exact bioavailability requirements, or to be bioequivalent to existing orally disintegrating tablets (ODT).

[0016] One embodiment of the invention relates to an orally disintegrating strip comprising
(a) about 8.0% w/w to about 16.0% w/w of ondansetron or its pharmaceutically acceptable salt thereof,
(b) about 7.0% w/w to about 10.0% w/w of polacrilin potassium,
(c) polymer mixture consisting of about 20% w/w to about 40% w/w hydroxypropyl methylcellulose and about 5% w/w to about 15% w/w of polyvinylpyrrolidone,
(d) about 1.0% w/w to about 5.0% w/w of polysorbate 80 and
(e) about 5% w/w to about 15% w/w of glycerol.

[0017] In a further embodiment of the invention relates to an orally disintegrating strip comprising
(a) about 8.0% w/w to about 16.0% w/w of ondansetron or its pharmaceutically acceptable salt thereof,
(b) about 7.0% w/w to about 10.0% w/w of polacrilin potassium,
(c) polymer mixture consisting of about 20% w/w to about 40% w/w hydroxypropyl methylcellulose and about 5% w/w to about 15% w/w of polyvinylpyrrolidone,
(d) about 1.0% w/w to about 5.0% w/w of polysorbate 80,
(e) about 5% w/w to about 15% w/w of glycerol,
(f) about 5% w/w to about 15% w/w of sucralose and
(g) 0.01% w/w to about 0.10% w/w of titanium dioxide.

[0018] In a further embodiment of the invention relates to an orally disintegrating strip consisting of
(a) about 8.0% w/w to about 16.0% w/w of ondansetron or its pharmaceutically acceptable salt thereof,
(b) about 7.0% w/w to about 10.0% w/w of polacrilin potassium,
(c) polymer mixture consisting of about 20% w/w to about 40% w/w hydroxypropyl methylcellulose and about 5% w/w to about 15% w/w of polyvinylpyrrolidone,
(d) about 1.0% w/w to about 5.0% w/w of polysorbate 80,
(e) about 5% w/w to about 15% w/w of glycerol,
(f) about 5% w/w to about 15% w/w of sucralose,
(g) 0.01% w/w to about 0.10% w/w of titanium dioxide and
(h) one or more excipients selected from colorants and flavoring agents.

[0019] DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention relates to an orally disintegrating strip comprising ondansetron or its pharmaceutically acceptable salts thereof as an active ingredient.

[0021] The pharmaceutically active ingredient is specifically ondansetron as a base or ondansetron hydrochloride as a salt. More specifically ondansetron hydrochloride salt used in the present invention is ondansetron hydrochloride dihydrate.

[0022] The present invention provides an orally disintegrating strip comprising
(a) about 8.0% w/w to about 16.0% w/w of ondansetron or its pharmaceutically acceptable salt thereof,
(b) about 7.0% w/w to about 10.0% w/w of polacrilin potassium,
(c) polymer mixture consisting of about 20% w/w to about 40% w/w hydroxypropyl methylcellulose and about 5% w/w to about 15% w/w of polyvinylpyrrolidone,
(d) about 1.0% w/w to about 5.0% w/w of polysorbate 80 and
(e) about 5% w/w to about 15% w/w of glycerol.

[0023] The present invention further provides an orally disintegrating strip comprising
(a) about 8.0% w/w to about 16.0% w/w of ondansetron or its pharmaceutically acceptable salt thereof,
(b) about 7.0% w/w to about 10.0% w/w of polacrilin potassium,
(c) polymer mixture consisting of about 20% w/w to about 40% w/w hydroxypropyl methylcellulose and about 5% w/w to about 15% w/w of polyvinylpyrrolidone,
(d) about 1.0% w/w to about 5.0% w/w of polysorbate 80,
(e) about 5% w/w to about 15% w/w of glycerol,
(f) about 5% w/w to about 15% w/w of sucralose,
(g) 0.01% w/w to about 0.10% w/w of titanium dioxide and
(h) one or more excipients selected from group consisting of flavouring agents or coloring agents.

[0024] The flavouring agents that can be used in the present invention include those known to the skilled artisan, such as artificial flavouring agents. These flavouring agents may be chosen from synthetic flavor oils and flavoring aromatics, and/or oils, oleo resins. Also useful are artificial or synthetic fruit flavouring agents such as vanilla, banana, chocolate, coffee, cocoa and citrus oil, including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. These flavouring agents can be used individually or in admixture. Commonly used flavouring agents include mints such as peppermint, artificial vanilla, cinnamon derivatives.

[0025] Coloring agents that can be used in the present invention include dyes suitable for food, drug and cosmetic applications. These colorants are known as FD&C dyes and lakes. The materials acceptable for the foregoing spectrum of use are preferably water-soluble, and include carmosine, FD&C Blue No. 2, which is the disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dye known as Green No. 3 comprises a triphenylmethane dye and is the monosodium salt of 4-[4-N-ethyl-p-sulfobenzylamino) diphenyl-methylene]-[1-N-ethyl-N-p-sulfonium benzyl)-2,5-cyclo-hexadienimine]. A full recitation of all FD&C and D&C dyes and their corresponding chemical structures may be found in the Kirk-Othmer Encyclopedia of Chemical Technology, Volume 5, Pages 857-884, which text is accordingly incorporated herein by reference.

[0026] Examples

[0027] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at room temperature, and pressure is at or near atmospheric.

[0028] Example 1

[0029] Table 1 depicts a representative strip formulation that contains 4.99mg of ondansetron hydrochloride dihydrate (equivalent to 4mg of ondansetron base), in order to promote gastrointestinal absorption.

Table 1: Representative Formulation of Ondansetron hydrochloride dihydrate orally dissolving strip dosage form
S.No Ingredient Amount per strip (mg) Amount per strip (%)
1. Ondansetron hydrochloride dihydrate 4.99 11.34
2. Polacrilin Potassium 4.00 9.09
3. Sucralose 4.00 9.09
4. Polysorbate 80 1.50 3.41
5. Polyvinylpyrrolidone 4.51 10.25
6. Vanilla Flavour 2.50 5.68
7. Banana Flavour 3.00 6.82
8. Titanium dioxide 0.02 0.05
9. Hydroxypropyl methylcellulose 15.48 35.18
10. Glycerol 4.00 9.09
TOTAL 44.00 100.0

[0030] Example 2

[0031] Table 2 depicts a representative strip formulation that contains 9.98mg of ondansetron hydrochloride dihydrate (equivalent to 8mg of ondansetron base), in order to promote gastrointestinal absorption.

Table 2: Representative Formulation of Ondansetron hydrochloride dihydrate orally dissolving strip dosage form
S.No Ingredient Amount per strip (mg) Amount per strip (%)
1. Ondansetron hydrochloride dihydrate 9.98 11.34
2. Polacrilin Potassium 8.00 9.09
3. Sucralose 8.00 9.09
4. Polysorbate 80 3.00 3.41
5. Polyvinylpyrrolidone 9.02 10.25
6. Vanilla Flavour 5.00 5.68
7. Banana Flavour 6.00 6.82
8. Titanium dioxide 0.04 0.05
9. Hydroxypropyl methylcellulose 30.96 35.18
10. Glycerol 8.00 9.09
TOTAL 88.00 100.0

[0032] Example 3 – Comparative Ondansetron Bioavailability study

[0033] A clinical study was conducted to compare the bioavilability profile and pharmacokinetic parameters of two products containing 8mg of ondansetron base: (1) ondansetron hydrochloride dihydrate orally disintegrating strip having the formula reported in Table 2, and (2) Zofran® 8mg Orodispersible tablets Novartis Pharma.

[0034] The study was oral open label, balanced, randomized, two-treatment, two sequence, two-period, single dose, crossover, with seven-day washout period under fasting conditions. Orally disintegrating tablet (Reference Product) and orally disintegrating strip (Test Product) as disclosed in Table 2 was allowed to dissolve in the subject’s mouth before the patient was asked to swallow. The study included 23 healthy human subjects (N) between 18 – 45 years of age.

[0035] The summary of the bioequivalence parameters is represented in Table 3.

Table 3: Summary of bioequivalence parameters of the Reference product and Test product (strip composition as disclosed in table 2)

,CLAIMS:1. An orally disintegrating strip comprising
(a) 8.0% w/w to 16.0% w/w of ondansetron or its pharmaceutically acceptable salt thereof; 5
(b) 7.0% w/w to 10.0% w/w of polacrilin potassium;
(c) polymer mixture consisting of 20% w/w to 40% w/w hydroxypropyl methylcellulose and 5% w/w to 15% w/w of polyvinylpyrrolidone;
(d) 1.0% w/w to 5.0% w/w of polysorbate 80 and
(e) 5% w/w to 15% w/w of glycerol. 10
2. The orally disintegrating strip as claimed in claim 1, wherein the strip comprises ondansetron hydrochloride.
3. The orally disintegrating strip as claimed in claim 2, wherein the strip 15 comprises ondansetron hydrochloride dihydrate.
4. An orally disintegrating strip comprising
(a) 8.0% w/w to 16.0% w/w of ondansetron or its pharmaceutically acceptable salt thereof; 20
(b) 7.0% w/w to 10.0% w/w of polacrilin potassium;
(c) polymer mixture consisting of 20% w/w to 40% w/w hydroxypropyl methylcellulose and 5% w/w to 15% w/w of polyvinylpyrrolidone;
(d) 1.0% w/w to 5.0% w/w of polysorbate 80;
(e) 5% w/w to 15% w/w of glycerol; 25
(f) 5% w/w to 15% w/w of sucralose and
(g) 0.01% w/w to 0.10% w/w of titanium dioxide.
30
12
5. An orally disintegrating strip consisting of
(a) 8.0% w/w to 16.0% w/w of ondansetron or its pharmaceutically acceptable salt thereof;
(b) 7.0% w/w to 10.0% w/w of polacrilin potassium;
(c) polymer mixture consisting of 20% w/w to 40% w/w hydroxypropyl 5 methylcellulose and 5% w/w to 15% w/w of polyvinylpyrrolidone;
(d) 1.0% w/w to 5.0% w/w of polysorbate 80;
(e) 5% w/w to 15% w/w of glycerol;
(f) 5% w/w to 15% w/w of sucralose;
(g) 0.01% w/w to 0.10% w/w of titanium dioxide and 10
(h) one or more excipients selected from colorants and flavoring agents.