Pharmaceutical Compositions Comprising Levocetirizine

Abstract

The present invention relates to a pharmaceutical composition comprising levocetirizine. The invention relates specifically to a dry syrup formulation.

Claims

1-23. (canceled)

24. A pharmaceutical composition, in a solid form, allowing an oral administration of an unit dose ranging from 0.50 mg to 25.00 mg of levocetirizine dihydrochloride as active ingredient, and containing active granules comprising the active ingredient, a polyol fraction comprising one or more solid water-soluble polyols having a molecular weight below 950 g/mol, with a molar ratio between the polyol fraction and the active ingredient higher than 50, at least one solid water-soluble polyol being mannitol, and a buffering system, which contributes to maintain the pH of the whole pharmaceutical composition between 4.0 and 7.0 when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water; and wherein the active granule is buffered at a concentration ranging from 1.10.sup.−4 mol/l to 1.10.sup.−2 mol/l when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water.

25. The composition according to claim 24, wherein the composition comprises 0.1 to 2.0% per weight of active compound with respect to the total weight of the composition.

26. The composition according to claim 24 wherein the composition comprises active granules in an amount of 25 to 100% with respect to the total weight of the pharmaceutical composition.

27. The composition according to claim 24 wherein the active granule comprises a buffering system which contributes to maintain the pH of the whole pharmaceutical composition in a range of pH 5.5±0.5 when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water.

28. The composition according to claim 24 wherein the buffering system is selected among pharmaceutical acceptable salts of phosphate, citrate, tartrate, acetate, fumarate, gluconate, used as such or in combination with their respective related acid, or mixtures thereof.

29. The composition according to claim 24 wherein the active granules contain at least a water-soluble excipient selected from water soluble polymer, cyclodextrin or mixtures thereof.

30. The composition according to claim 6 wherein the cyclodextrin is selected among alpha cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin sulfo alkyl ether cyclodextrin, gamma-cyclodextrin or mixture thereof.

31. The pharmaceutical composition according to claim 24, wherein it contains active granules in an amount of 25 to 100% with respect of the total weight of the composition, these active granules comprising 0.1 to 2% of levocetirizine as active ingredient, with respect of the total weight of the composition, at least 50% of a solid water-soluble polyol having a molecular weight below 950 g/mol, with respect of the total weight of the composition, and a buffering system at a concentration ranging from 1.10.sup.−4 mol/l to 1.10.sup.−2 mol/l of buffering system, when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water, which contributes to maintain the pH of the pharmaceutical composition between 4.0 and 7.0.

32. The pharmaceutical composition according to claim 24, wherein it contains active granules in an amount of 50 to 100% with respect of the total weight of the composition, these active granules comprising 0.1 to 1.0% of levocetirizine as active ingredient, with respect of the total weight of the composition, at least 70% of a solid water-soluble polyol having a molecular weight below 350 g/mol, with respect of the total weight of the composition, a buffering system at a concentration ranging from 2.10.sup.−4 mol/l to 5.10.sup.−3 mol/l of buffering system, when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water, which contributes to maintain the pH of the pharmaceutical composition in a range of pH 5.5±0.5, a water soluble excipient selected among a cyclodextrin, the molar ratio between cyclodextrin and the active ingredient being between 0 to 4; a water soluble polymer, the weight ratio between the polymer and the granule being between 0 to 2%; or mixture thereof.

33. The pharmaceutical composition according to claim 24, wherein the active granules comprise a core which comprises at least a solid water-soluble polyol having a molecular weight below 950 g/mol; a first coating applied onto the core, and comprising at least an excipient; a second coating applied onto the first coating and comprising the active ingredient and a buffering system.

34. The pharmaceutical composition according to claim 33, wherein the excipient of the first coating is a water-soluble excipient selected from water soluble polymer, polymer dispersion, cyclodextrin, and mixtures thereof.

35. The pharmaceutical composition according to claim 33, wherein the second coating comprises 0.1 to 4% per weight of active ingredient with respect to the total weight of the pharmaceutical composition.

36. The pharmaceutical composition according to any of the claim 33, wherein the second coating comprises a buffering system which contribute to maintain the pH of the second coating and of the whole pharmaceutical composition between 4.0 and 7.0, when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water.

37. The pharmaceutical composition according to any of the claim 33, wherein the second coating comprises cyclodextrin.

38. A pharmaceutical composition according to claim 33, wherein the composition comprises a core which comprises at least mannitol; a first coating applied onto the core, and comprising at least cyclodextrin; and a second coating applied onto the first coating, and comprising levocetirizine, a buffering system and at least a water-soluble excipient.

39. The pharmaceutical composition according to claim 38, wherein the composition allows an oral administration of a unit dose ranging from 1.00 mg to 10.00 mg of levocetirizine, as active ingredient, and comprises a core which comprises at least mannitol; a first coating applied onto the core, and comprising at least beta-cyclodextrin, the molar ratio between cyclodextrin and levocetirizine being comprised between 0 and 3, and comprising also a buffering system which contributes to maintain the pH between 4.5 and 6.5, when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water; a second coating applied onto the first coating, and comprising levocetirizine at least a water-soluble excipient, and a buffering system which contributes to maintain the pH between 4.5 and 6.5, when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water; and optionally, a final water-soluble coating applied onto the second coating.

40. A pharmaceutical composition according to claim 33, wherein the composition comprises a core which comprises at least mannitol; a first coating applied onto the core, and comprising at least hydroxypropyl methylcellulose or hydroxypropyl cellulose; and a second coating applied onto the first coating, and comprising levocetirizine, at least cyclodextrin and comprising also a buffering system which contributes to maintain the pH between 4.5 and 6.5, when the pharmaceutical composition containing 5 mg of active ingredient is dissolved in 100 ml of water.

41. The pharmaceutical composition according to claim 24, wherein the composition is in the form of a tablet, orally disintegrating tablet and a capsule.

42. The pharmaceutical composition according to claim 24, wherein the composition is in the form of dry syrup or granulate, that can be filled in a sachet or any appropriate dosing device.

Description

EXAMPLE 1

[0265] An aqueous solution of levocetirizine dihydrochioride, β-cyclodextrine, acesulfame K, Na citrate, mannitol and flavor were prepared according to table 1. The pH of the solution was adjusted to 5.5 with HCl. Then the composition were prepared by spray drying of the aqueous solution.

[0266] The obtained granules were further densified by dry compaction.

[0267] The content of active material and the stability were assessed in different conditions. The results are given in Table 2.

[0268] It can be seen that the granules have a good homogeneity and no degradation of levocetirizine could be observed.

[0269] Dissolution of a therapeutic dose of 5 mg of levocetirizine dihydrochloride in 50 ml of water took less than 2 minutes.

TABLE-US-00001 TABLE 1 Composition example 1 MATERIAL QUANTITY % Levocetirizine HCl 0.326 β-cyclodextrin 2.561 Acesulfame K 0.094 Trisodium citrate•2H2O 0.796 Mannitol DC 400 96.141 Strawberry flavor 0.082 TOTAL 100.0

[0270] Mannitol (Mannitol DC400) is a granulated powder mannitol having an average particle size of about 300-400 μm, Na citrate (trisodiumcitrate) and HCl are used as buffering agent, Acesulfame K (acesulfame potassium) is used as sweetner, β-cyclodextrine is used as taste masking agent, Strawberry flavor is used as flavoring agent.

TABLE-US-00002 TABLE 2 Stability results example 1 Content in active drug (%) Time 40° C./75% HR 25° C./60% HR 0 101.45 ± 2.95 98.14 ± 2.86 2 weeks 101.05 ± 0.33 108.30 ± 1.47  8 weeks 104.59 ± 2.05 104.2 ± 1.77

[0271] As shown in experimental results of Table 2, the obtained composition was stable and homogenous.

[0272] The obtained composition had no bitter taste.

EXAMPLE 2

[0273] The composition containing levocetirizine dihydrochloride were prepared by fluid bed granulation process.

[0274] All materials except mannitol and strawberry flavors were dissolved in water and granulated with mannitol and then dried. The pH of the solution was about 6.0 After drying, the granules were mixed with strawberry flavor.

TABLE-US-00003 TABLE 3 Composition example 2 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Trisodium citrate•2H2O 3.2 Mannitol DC 300 q.s. Acesulfame K 0.37 Strawberry flavor 0.1 B-cyclodextrin 2.5 Total 100

[0275] Mannitol (Mannitol DC300) is a granulated powder mannitol having an average particle size of about 250-350 μm. Trisodium Critrate is used as buffering agent to obtain a pH 6.0.

[0276] The abbreviation q.s. means “quantum satis”, adding enough mannitol to achieve the total weight.

[0277] Acesulfame K (acesulfame potassium) is used as sweetner. β-cyclodextrine is used as taste masking agent. Strawberry flavor is used as flavoring agent.

[0278] The content of active material and the stability were assessed in different conditions. The obtained composition was stable and homogeneous. It had an acceptable taste and palatability. The obtained composition had no bitter taste.

[0279] The obtained composition was an immediate release composition.

EXAMPLE 3

[0280] The composition containing levocetirizine dihydrochloride were prepared by fluid bed granulation process.

[0281] All materials except mannitol and strawberry flavors were dissolved in water and granulated with mannitol, and then dried. The pH of the solution was 5.5. After drying, the granules were mixed with strawberry flavor.

TABLE-US-00004 TABLE 4 Composition example 3 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Trisodium citrate•2H2O 1.5 Citric acid (monohydrate) 0.3 Mannitol DC 400 q.s. Sucralose 0.1 Strawberry flavor 0.1 beta-cyclodextrin 1.25 Total 100

[0282] Mannitol (Mannitol DC400) is a granulated powder mannitol having an average particle size of about 300-400 μm, trisodium citrate and citric acid are used as buffering agent. sucralose is used as sweetner; β-cyclodextrine is used as taste masking agent. Strawberry flavor is used as flavoring agent.

The content of active material and the stability were assessed in different conditions.
The obtained composition was stable and homogeneous. It had an acceptable taste and palatability. The obtained composition had no bitter taste.

[0283] The obtained composition was an immediate release composition.

EXAMPLE 4

[0284] The composition containing levocetirizine dihydrochloride were prepared by fluid bed granulation process.

All materials except mannitol and strawberry flavors were dissolved in water and granulated with mannitol, and then dried. After drying, the granules were mixed with strawberry flavor.

TABLE-US-00005 TABLE 5 Composition example 4 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Trisodium citrate•2H2O 3.0 Citric acid (monohydrate) 0.6 hydroxypropylmethylcellulose 3 Mannitol DC 400 q.s. Sucralose 0.1 Strawberry flavor 0.1 Beta-cyclodextrin 1.25 Total 100

[0285] Mannitol (Mannitol DC400) is a granulated powder mannitol having an average particle size of about 300-400 μm.

[0286] Trisodium citrate and citric acid are used as buffering agent. Hydroxypropyl-methylcellulose (Pharmacoat® 603) is a soluble binder. Sucrelose is used as sweetner. B-cyclodextrine is used as taste masking agent. Strawberry flavor is used as flavoring agent.

[0287] The content of active material and the stability were assessed in different conditions. The obtained composition was stable and homogeneous. It had an acceptable taste and palatability. The obtained composition was an immediate release composition.

[0288] 1 g of dry syrup prepared in Example 4 was directly placed in the mouth of the subject and taste was evaluated on a 3-point scale. No bitterness was detected.

EXAMPLE 5

[0289] The composition containing levocetirizine dihydrochloride were prepared by fluid bed granulation process.

All materials except mannitol, anhydrous silicon dioxide and strawberry flavors were dissolved in water solution at pH 5.5, granulated with mannitol and dried. After drying, the granules were mixed with strawberry flavor and anhydrous silicon dioxide.

TABLE-US-00006 TABLE 6 Composition example 5 MATERIAL QUANTITY % Levocetirizine HCl 0.30 Trisodium citrate•2H2O 2.33 Citric acid (monohydrate) 0.35 hydroxypropylcellulose 0.03 Mannitol DC 300 q.s. Sucralose 0.19 Strawberry flavor 0.1 Beta-cyclodextrin 1.13 Anhydrous silicon dioxide 0.5 Total 100

[0290] Mannitol (Pearlitol® DC300) is a granulated powder mannitol having an average particle size of about 250-350 WI.

[0291] Trisodium citrate (hydrated) and citric acid (hydrated) are used as buffering agent. Hydroxypropyl-cellulose (Klucel® EF) is a soluble binder. Sucralose is used as sweetner. B-cyclodextrine (Kleptose®4PC) is used as taste masking agent. Strawberry flavor is used as flavoring agent, Anhydrous silicon dioxide (Aerosil®200) is used as anti-caking agent

[0292] The content of active material and the stability were assessed in different conditions. The obtained composition was stable and homogeneous. It had an acceptable taste and palatability. The obtained composition was an immediate release composition.

EXAMPLE 6

[0293] The composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0294] The composition is according to Table 7.

[0295] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0296] The results are given in Table 8.

[0297] It can be seen that the granules had a good homogeneity and no degradation of the Levocetirizine could be observed.

[0298] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

TABLE-US-00007 TABLE 7 Composition example 6 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 Beta-cyclodextrin 2.57 Total 100
Mannitol (Mannitol DC400) is a granulated powder mannitol having an average particle size of about 300-400 μm. Trisodium citrate and HCl are used as buffering agent. Acesulfame K (acesulfame potassium) is used as sweetner. β-cyclodextrin is used as taste masking agent. Strawberry flavor is used as flavoring agent.

TABLE-US-00008 TABLE 8 Stability results example 6 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 97.9 ± 0.8% 99.0 ± 2.7% 98.9 ± 0.7%
As shown in experimental results of Table 8, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 7

[0299] The composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0300] The compositions is according to Table 9.

[0301] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0302] The results are given in Table 10.

[0303] It can be seen that the granules had a good homogeneity and no degradation of levocetirizine could be observed.

[0304] Moreover, the composition was substantialy free from the taste of Levocetirizine when placed on the human tongue in dry form or when dispersed in water.

[0305] Dissolution of a therapeutic dose of 5 mg of levocetirizine dihydrochloride in 50 ml of water took less than 2 minutes.

TABLE-US-00009 TABLE 9 Composition example 7 MATERIAL QUANTITY % Levocetirizine HCl 0.16 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 Beta-cyclodextrin 1.28 Total 100
Mannitol (Mannitol DC400) is a granulated powder mannitol having an average particle size of about 300-400 μm. Trisodium citrate and HCl are used as buffering agent. Acesulfame K (acesulfame potassium) is used as sweetner. β-cyclodextrin is used as taste masking agent. Strawberry flavor is used as flavoring agent.

TABLE-US-00010 TABLE 10 Stability results example 7 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 100.0 ± 0.3% 97.3 ± 0.4% 97.7 ± 0.3%
As shown in experimental results of Table 10, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability. The obtained composition had no bitter taste.

EXAMPLE 8

[0306] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0307] The compositions is according to Table 11.

[0308] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0309] The results are given in Table 12.

[0310] It can be seen that the granules had a good homogeneity and no degradation of levocetirizine could be observed.

[0311] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

The composition complied with the requirements.

TABLE-US-00011 TABLE 11 composition example 8 MATERIAL QUANTITY % Levocetirizine HCl 0.16 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 Beta-cyclodextrin 1.28 Total 100

TABLE-US-00012 TABLE 12 Stability results example 8 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 97.9 ± 0.3% 96.8 ± 0.3% 98.4 ± 1.0%
As shown in experimental results of Table 12, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability. The obtained composition had no bitter taste.

EXAMPLE 9

[0312] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0313] The compositions is according to Table 13.

[0314] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0315] The results are given in Table 14.

[0316] It can be seen that the granules had a good homogeneity and no degradation of levocetirizine could be observed.

[0317] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

The composition complied with the requirements.

TABLE-US-00013 TABLE 13 Composition example 9 MATERIAL QUANTITY % Levocetirizine HCl 0.32 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 Hydroxypropyl β-cyclodextrin 3.15 Total 100

TABLE-US-00014 TABLE 14 Composition example 9 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 100.0 ± 0.6% 95.8 ± 0.4% 99.9 ± 0.6%

[0318] As shown in experimental results of Table 14, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 10

[0319] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0320] The compositions is according to Table 15.

[0321] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0322] The results are given in Table 16.

[0323] It can be seen that the granules had a good homogeneity and no degradation of levocetirizine could be observed.

Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.
Dissolution of a therapeutic dose of 5 mg of levocetirizine dihydrochloride in 50 ml of water took less than 2 minutes.

TABLE-US-00015 TABLE 15 Composition example 10 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 Methyl β-cyclodextrin 3.3 Total 100

TABLE-US-00016 TABLE 16 Stability results example 10 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 102.3 ± 0.3% 97.8 ± 0.5% 98.8 ± 0.6%
As shown in experimental results of Table 16, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 11

[0324] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0325] The compositions is according to Table 17.

[0326] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0327] The results are given in Table 18.

[0328] It can be seen that the granules had a good homogeneity and no degradation of levocetirizine could be observed.

[0329] Dissolution of a therapeutic dose of 5 mg of levocetirizine dihydrochloride in 50 ml of water took less than 2 minutes.

TABLE-US-00017 TABLE 17 Composition example 11 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 α-cyclodextrin 2.1 Total 100

TABLE-US-00018 TABLE 18 Stability results example 11 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 94.5 ± 0.6% 95.5 ± 0.7% 99.0 ± 0.6%

[0330] As shown in experimental results of Table 18, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 12

[0331] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0332] The compositions is according to Table 19.

[0333] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0334] The results are given in Table 20.

[0335] It can be seen that the granules had a good homogeneity and no degradation of the Levocetirizine could be observed.

[0336] Moreover, the composition was substantialy free from the taste of Levocetirizine when placed on the human tongue in dry form or when dispersed in water.

TABLE-US-00019 TABLE 19 Composition example 12 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Lactose q.s. Acesulfame K 0.1 Strawberry flavor 0.1 β-cyclodextrin 2.56 Total 100

[0337] Lactose is used as diluent. Sodium citrate and HCl are used as buffering agent. Acesulfame K (acesulfame potassium) is used as sweetner. β-cyclodextrin is used as taste masking agent. Strawberry flavor is used as flavoring agent.

TABLE-US-00020 TABLE 20 Stability results example 12 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 100.1 ± 0.9% 98.3 ± 3.0% 108.4 ± 0.5%
As shown in experimental results of Table 20, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 13

[0338] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

The compositions is according to Table 21.

[0339] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0340] The results are given in Table 22.

[0341] It can be seen that the granules had a good homogeneity and no degradation of levocetirizine could be observed.

[0342] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

Dissolution of a therapeutic dose of 5 mg of levocetirizine dihydrochloride in 50 ml of water took less than 2 minutes.

TABLE-US-00021 TABLE 21 Composition example 13 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 β-cyclodextrin 0.86 Total 100

TABLE-US-00022 TABLE 22 Stability results example 13 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month 99.9 ± 0.5% 99.4 ± 0.6%

[0343] As shown in experimental results of Table 22, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 14

[0344] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0345] The compositions is according to Table 23.

[0346] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0347] The results are given in Table 24.

[0348] It can be seen that the granules had a good homogeneity and no degradation of levocetirizine could be observed.

[0349] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

Dissolution of a therapeutic dose of 5 mg of levocetirizine dihydrochloride in 50 ml of water took less than 2 minutes.

TABLE-US-00023 TABLE 23 Composition example 14 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 β-cyclodextrin 1.7 Total 100

TABLE-US-00024 TABLE 24 Stability results example 14 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month 99.3 ± 2.2% 97.5 ± 0.6%

[0350] As shown in experimental results of Table 24, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 15

[0351] The composition containing levocetirizine dihydrochloride were prepared by fluid bed granulation process.

[0352] All materials except mannitol, anhydrous silicon dioxide and strawberry flavors were dissolved in water solution at pH 5.5, granulated with mannitol and then dried. After drying, the granules were mixed with strawberry flavor, a part of the mannitol and anhydrous silicon dioxide.

TABLE-US-00025 TABLE 25 Composition example 15 MATERIAL QUANTITY % Levocetirizine HCl 0.3 Trisodium citrate•2H2O 2.3 Citric acid (monohydrate) 0.3 hydroxypropylcellulose 0.03 Mannitol DC 300 (intra granular) q.s. Mannitol DC 300 (extra granular) 5.0 Sucralose 0.2 Strawberry flavor (extra granular) 0.1 Beta-cyclodextrin 1.1 Anhydrous silicon dioxide (extra granular) 0.5

[0353] Mannitol (PearRole DC300) is a granulated powder mannitol having an average particle size of about 250-350 μm.

[0354] Trisodium citrate (hydrated) and citric acid (hydrated) are used as buffering agent. Hydroxypropyl-cellulose (Klucel® EF) is a soluble binder. Sucralose is used as sweetner. B-cyclodextrine (Kleptose® 4PC) is used as taste masking agent. Strawberry flavor is used as flavoring agent, Anhydrous silicon dioxide (Aerosil®200) is used as anti-caking agent

The obtained composition was stable and homogeneous. It had an acceptable taste and palatability. The obtained composition was an immediate release composition.

EXAMPLE 16

[0355] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 5.5 with HCl prior to spray drying.

[0356] The compositions is according to Table 27.

[0357] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0358] The results are given in Table 28.

[0359] It can be seen that the granules had a good homogeneity and no degradation of levocetirizine could be observed.

[0360] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

[0361] Dissolution of a therapeutic dose of 5 mg of levocetirizine dihydrochloride in 50 ml of water took less than 2 minutes.

TABLE-US-00026 TABLE 27 Composition example 16 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 β-cyclodextrin 3.43 Total 100

TABLE-US-00027 TABLE 28 Stability results example 16 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 99.7 ± 0.7% 98.2 ± 0.6% 98.7 ± 0.2%
As shown in experimental results of Table 28, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 17 (COMPARISON EXAMPLE)

[0362] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 4.0 with HCl prior to spray drying.

[0363] The compositions is according to Table 29.

[0364] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0365] The results are given in Table 30.

[0366] It can be seen that the granules had a good homogeneity but a trend for decrease in assay could be observed. This was a sign for levoceririzine degradation.

[0367] Dissolution of a therapeutic dose of 5 mg of levocetirizine dihydrochloride in 50 ml of water took less than 2 minutes.

TABLE-US-00028 TABLE 29 Composition example 17 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 β-cyclodextrin 2.57 Total 100

TABLE-US-00029 TABLE 30 Stability results example 17 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 100.2 ± 0.7% 95.5 ± 0.4% 92.8 ± 1.2%
As shown in experimental results of Table 30, the obtained composition was not stable.

EXAMPLE 18

[0368] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 4.5 with HCl prior to spray drying.

[0369] The compositions is according to Table 31.

[0370] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0371] The results are given in Table 32.

[0372] It can be seen that the granules had a good homogeneity and no degradation of the levocetirizine could be observed.

[0373] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

[0374] The composition complied with the requirements.

TABLE-US-00030 TABLE 31 Composition example 18 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 β-cyclodextrin 3.43 Total 100

TABLE-US-00031 TABLE 32 Stability results example 18 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 99.8 ± 0.8% 100.3 ± 0.8% 97.5 ± 1.2%
As shown in experimental results of Table 32, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 19

[0375] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 7.0 with NaOH prior to spray drying.

[0376] The compositions is according to Table 33.

[0377] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0378] The results are given in Table 34.

[0379] It can be seen that the granules had a good homogeneity and no degradation of the levocetirizine could be observed.

[0380] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

[0381] The composition complied with the requirements.

TABLE-US-00032 TABLE 33 Composition example 19 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 β-cyclodextrin 3.43 Total 100

TABLE-US-00033 TABLE 34 Stability results example 19 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 101.1 ± 0.9% 100.7 ± 0.3% 97.8 ± 0.3%

[0382] As shown in experimental results of Table 34, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 20

[0383] Composition containing levocetirizine dihydrochloride were prepared by spray drying of an aqueous solution containing all materials. The pH of the solution was adjusted to 6.0 with HCl prior to spray drying.

[0384] The compositions is according to Table 35.

[0385] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0386] The results are given in Table 36.

[0387] It can be seen that the granules had a good homogeneity and no degradation of the levocetirizine could be observed.

[0388] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

[0389] The composition complied with the requirements.

TABLE-US-00034 TABLE 35 Composition example 20 MATERIAL QUANTITY % Levocetirizine HCl 0.33 Trisodium citrate•2H2O 0.8 Mannitol DC 400 q.s. Acesulfame K 0.1 Strawberry flavor 0.1 β-cyclodextrin 3.43 Total 100

TABLE-US-00035 TABLE 36 Stability results example 20 Content in active drug (%) - 40° C./75% RH (n = 5) T 0 T 1 Month T 3 Months 99.2 ± 1.6% 100.4 ± 0.3% 99.5 ± 0.5%

[0390] As shown in experimental results of Table 36, the obtained composition was stable and homogeneous. It had an acceptable taste and palatability.

EXAMPLE 21

[0391] Composition containing levocetirizine dihydrochloride were prepared by fluid bed granulation process.

[0392] All materials except mannitol and strawberry flavors were dissolved in water and granulated with mannitol, and then dried. The pH of the solution was 5.5.

[0393] After drying, the granules were mixed with strawberry flavor.

The compositions is according to Table 37.

[0394] The content of active material and the stability were assessed at 40° C./75% RH in a closed HDPE bottle.

[0395] The results are given in Table 38.

[0396] It can be seen that the granules had a good homogeneity and no degradation of the levocetirizine could be observed.

[0397] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water. 1 g of dry syrup prepared in Example 21 was dissolved in 10 mL of water and taste was evaluated on a 3-point scale. No bitterness was detected. 19 of dry syrup prepared in Example 21 was directly placed in the mouth of the subject and taste was evaluated on a 3-point scale. No bitterness was detected.

[0398] The composition complied with the requirements.

TABLE-US-00036 TABLE 37 Composition example 21 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Sucralose 0.20 Mannitol DC 300 95.29 Trisodium citrate•2H2O 2.47 Citric acid (anhydrous) 0.33 β-cyclodextrin (Kleptose standard) 1.26 Strawberry flavor 0.10 hydroxypropylcellulose 0.03 Total 100.00

TABLE-US-00037 TABLE 38 Stability results example 20 Content in active drug (%) - 40° C./75% RH T 0 (n = 10) T 1 Month (n = 2) T 3 Months Assay 98.0 ± 2.2% 94.9 98.9% Impurities Within Within Within ICHQ3b ICHQ3b ICHQ3b limits* limits limits Sum of degradation products - 40° C./75% RH (n = 2) T 0 T 1 Month T 3 Months 0.0% 0.0% 0.1% *ICH Q3b limits are set at 0.5% for individual specificed identified impurities and 0.2% for individual unspecified impurities.

[0399] As shown in experimental results of Table 38, there was no degradation. The composition was stable.

EXAMPLE 22

[0400] Composition containing levocetirizine dihydrochloride were prepared by wet granulation process.

[0401] All materials except mannitol were dissolved in water and granulated with mannitol and dried. The pH of the solution was 5.0.

The compositions is according to Table 39.

[0402] The content of active material and the stability were assessed at 40° C./75% RH in an opened HDPE bottle.

[0403] The results are given in Table 40.

[0404] It can be seen that the granules had a good assay and no significant degradation of the levocetirizine could be observed.

[0405] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water. 1 g of dry syrup prepared in Example 22 was dissolved in 10 mL of water and taste was evaluated on a 3-point scale. No bitterness was detected.

[0406] The composition complied with the requirements.

TABLE-US-00038 TABLE 39 Composition example 22 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Sucralose 0.10 Mannitol DC 300 q.s. Trisodium citrate•2H2O 2.17 Citric acid (anhydrous) 0.53 β-cyclodextrin (Kleptose standard) 1.26 Total 100.00

TABLE-US-00039 TABLE 40 Stability results example 22 Content in active drug (%) - 40° C./75% RH (n = 2) T 0 T 1 Month * T 3 Months * Assay 100% 98.8 97.4% Impurities Within Within Within ICHQ3b ICHQ3b ICHQ3b limits** limits** limits** Sum of degradation products - 40° C./75% RH (n = 2) T 0 T 1 Month T 3 Months 0.0% 0.31% 0.49% **ICH Q3b (international guidance) limits are set at 0.5% for individual specificed identified impurities and 0.2% for individual unspecified impurities * relative to T 0

[0407] As shown in experimental results of Table 40, the obtained composition was stable and homogenous.

EXAMPLE 23

[0408] Composition containing levocetirizine dihydrochloride were prepared by wet granulation process.

[0409] All materials except mannitol were dissolved in water and granulated with mannitol and dried. The pH of the solution was 6.0.

The compositions is according to Table 41.

[0410] The content of active material and the stability were assessed at 40° C./75% RH in an opened HDPE bottle.

[0411] The results are given in Table 42.

[0412] It can be seen that the granules had a good assay and no significant degradation of the levocetirizine could be observed.

[0413] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

[0414] The composition complied with the requirements.

TABLE-US-00040 TABLE 41 Composition example 23 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Sucralose 0.10 Mannitol DC 300 q.s. Trisodium citrate•2H2O 2.73 Citric acid (anhydrous) 0.17 β-cyclodextrin (Kleptose standard) 1.26 Total 100.00

TABLE-US-00041 TABLE 42 Stability results example 23 Content in active drug (%) - 40° C./75% RH (n = 2) T 0 T 1 Month * T 3 Months * Assay 100.0% 101.1% 100.8% Impurities Within Within Within ICHQ3b ICHQ3b ICHQ3b limits** limits** limits** Sum of degradation products - 40° C./75% RH (n = 2) T 0 T 1 Month T 3 Months 0.0% 0.14% 0.46% * relative to T 0 **ICH Q3b limits are set at 0.5% for individual specificed identified impurities and 0.2% for individual unspecified impurities

[0415] As shown in experimental results of Table 42, the obtained composition was stable and homogenous.

EXAMPLE 24

[0416] Composition containing levocetirizine dihydrochloride were prepared by wet granulation process.

[0417] All materials except mannitol were dissolved in water and granulated with mannitol and dried. The pH of the solution was 5.5.

The compositions is according to Table 43.

[0418] The content of active material and the stability were assessed at 40° C./75% RH in an opened HDPE bottle.

[0419] The results are given in Table 44.

[0420] It can be seen that the granules had a good assay and no significant degradation of the levocetirizine could be observed.

Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water. 1 g of dry syrup prepared in Example 25 was dissolved in 10 mL of water and taste was evaluated on a 3-point scale. No bitterness was detected.

[0421] The composition complied with the requirements.

TABLE-US-00042 TABLE 43 Composition example 24 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Sucralose 0.10 Mannitol DC 300 q.s. Trisodium citrate•2H2O 2.47 Citric acid (anhydrous) 0.33 β-cyclodextrin (Kleptose standard) 1.26 Total 100.00

TABLE-US-00043 TABLE 44 Stability results example 24 Content in active drug (%) - 40° C./75% RH (n = 2) T 0 T 1 Month * T 3 Months * Assay 100.0% 99.2% 98.8% Impurities Within Within Within ICHQ3b ICHQ3b ICHQ3b limits** limits** limits** Sum of degradation products - 40° C./75% RH (n = 2) T 0 T 1 Month T 3 Months 0% 0.37% 0.50% * relative to T 0 **ICH Q3b limits are set at 0.5% for individual specificed identified impurities and 0.2% for individual unspecified impurities
As shown in experimental results of Table 44, the obtained composition was stable and homogenous.

EXAMPLE 25 (COMPARISON EXAMPLE)

[0422] Composition containing levocetirizine dihydrochloride were prepared by wet granulation process.

[0423] All materials except mannitol were dissolved in water and granulated with mannitol and dried. The pH of the solution was not controlled with a buffer

The compositions is according to Table 45.

[0424] The content of active material and the stability were assessed at 40° C./75% RH in an opened HDPE bottle.

[0425] The results are given in Table 46.

[0426] It can be seen that the granules showed a significant degradation of the levocetirizine.

TABLE-US-00044 TABLE 45 Composition example 25 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Sucralose 0.10 Mannitol DC 300 q.s. β-cyclodextrin 1.26 (Kleptose standard) Total 100.00

TABLE-US-00045 TABLE 46 Stability results example 25 Content in active drug (%) - 40° C./75% RH (n = 2) T 0 T 1 Month * T 3 Months * Assay 100.0% 74.4% 74.3% Impurities Within Out of Out of ICHQ3b ICHQ3b ICHQ3b limits** limits** limits** Sum of degradation products - 40° C./75% RH (n = 2) T 0 T 1 Month T 3 Months 0% 25.6% 23.8% * relative to T 0 **ICH Q3b limits are set at 0.5% for individual specificed identified impurities and 0.2% for individual unspecified impurities

[0427] This comparative example showed that a buffer system is needed to ensure appropriate stability of the composition.

EXAMPLE 26

[0428] Composition containing levocetirizine dihydrochloride were prepared by wet granulation process.

[0429] All materials except mannitol were dissolved in water and granulated with mannitol and dried. The pH of the solution was 5.5.

The compositions is according to Table 47.

[0430] The content of active material and the stability were assessed at 40° C./75% RH in an opened HDPE bottle.

[0431] The results are given in Table 48.

[0432] It can be seen that the granules had a good assay and no significant degradation of the levocetirizine could be observed.

[0433] Moreover, the composition was substantialy free from the taste of levocetirizine when placed on the human tongue in dry form or when dispersed in water.

1 g of dry syrup prepared in Example 26 was dissolved in 10 mL of water and taste was evaluated on a 3-point scale. No bitterness was detected.

[0434] The composition complied with the requirements.

TABLE-US-00046 TABLE 47 Composition example 26 MATERIAL QUANTITY % Levocetirizine HCl 0.31 Sucralose 0.10 Mannitol DC 300 q.s. Trisodium citrate•2H2O 4.12 Citric acid (anhydrous) 0.56 β-cyclodextrin (Kleptose standard) 1.26 Total 100.00

TABLE-US-00047 TABLE 48 Stability results example 26 Content in active drug (%) - 40° C./75% RH (n = 2) T 0 T 1 Month * T 3 Months * Assay 100.0% 99.2% 98.6% Impurities Within Within Within ICHQ3b ICHQ3b ICHQ3b limits** limits** limits** Sum of degradation products - 40° C./75% RH (n = 2) open dish T 0 T 1 Month T 3 Months 0% 0.24% 0.51% * relative to T 0 **ICH Q3b limits are set at 0.5% for individual specificed identified impurities and 0.2% for individual unspecified impurities * relative to T 0
As shown in experimental results of Table 48, the obtained composition was stable and homogenous.

EXAMPLE 27 LEVOCETIRIZINE DRY SYRUP COMPOSITION

[0435] The dry syrup was prepared by wet granulation process according to the invention with the following composition (Table 49).

TABLE-US-00048 TABLE 49 Composition example 27 Material % Part Levocetirizine HCl 0.325 Coating 2 Betacyclodextrin 2.667 coating 2 Acesulfame K 0.090 coating 2 Trisodium citrate•2H2O 0.415 coating 1 Trisodium citrate•2H2O 0.415 coating 2 Hydroxypropylmethyl 5.767 Coating 1 cellulose HPMC 5 cp Mannitol DC 400 90.098 Core Strawberry flavor 0.224 Coating 2 Total 100.0

[0436] Mannitol (Mannitol DC400) is a granulated powder mannitol having an average particle size of about 300-400 μm. Trisodium citrate and HCl are used as buffering agent. Hydroxypropylmethyl cellulose (HPMC 5 cp) is used as polymer to separate the second coating from the core. Acesulfame K (acesulfame potassium) is used as sweetener.

Beta-cyclodextrin (Kleptose® DC) is used as taste masking agent.
Strawberry flavor is used as flavoring agent.

[0437] The granules were prepared by spraying an aqueous solution of the materials (hydroxypropylmethyl cellulose and sodium citrate) from the first coating onto the mannitol core particles.

[0438] After drying, an aqueous solution containing the materials (levocetirizine, beta-cyclodextrin, flavor, Na citrate, Acesulfame K) from the second coating was sprayed onto the intermediate granules.

Both spray solutions were buffered at pH 5.5, by using HCl to adjust pH.
A fluid bed coater was used to the purpose.

[0439] The compositions were placed at 40° C.-75% relative humidity (RH) during 2 weeks. Table 50 gives the results of this stability study.

TABLE-US-00049 TABLE 50 stability results example 27 Time Content of levocetirizine week (40° C./75% RH) 0 98.22 ± 0.98 1 98.81 ± 0.35 2 95.22 ± 1.41

[0440] The results show the composition was homogeneous and stable. The pharmaceutical composition was completely soluble within less than 2 minutes in a glass containing about 50 ml of water at room temperature.

[0441] The composition complied with the requirements.

1 g of dry syrup prepared in Example 27 was directly placed in the mouth of the subject and taste was evaluated on a 3-point scale. No bitterness was detected.

EXAMPLE 28: LEVOCETIRIZINE DRY SYRUP COMPOSITION

[0442] The dry syrup was prepared by wet granulation process with the following composition (Table 51).

TABLE-US-00050 TABLE 51 Composition example 28 Material % Part Levocetirizine HCl 0.484 coating 2 Betacyclodextrin 3.968 coating 1 Acesulfame K 0.133 coating 2 Trisodium citrate 0.616 coating 1 Trisodium citrate 0.616 coating 2 Mannitol DC 400 93.846 Core Strawberry flavor 0.336 extra-granular phase Total 100.0

[0443] Mannitol (Mannitol DC400) is a granulated powder mannitol having an average particle size of about 300-400 μm. Sodium citrate and HCl are used as buffering agent. Acesulfame K (acesulfame potassium) is used as sweetner. Beta-cyclodextrin (Kleptose® DC) is used as taste masking agent. Strawberry flavor is used as flavoring agent.

[0444] The granules were prepared by spraying an aqueous solution of the materials from the first coating onto the mannitol core particles.

[0445] After drying, a solution containing the materials from the second coating was sprayed onto the intermediate granules.

[0446] Both spray solutions were buffered at pH 5.5, by using HCl to adjust pH.

[0447] A fluid bed coater was used to the purpose.

Strawberry flavor was added to the granules by physical mix.

[0448] The compositions were placed at 40° C.-75% relative humidity (RH) during 4 weeks. Table 52 gives the results of this stability study.

TABLE-US-00051 TABLE 52 stability results example 28 Time Content in week levocetirizine 0 99.04 ± 3.28 2 98.38 ± 1.23 4 104.55 ± 2.29 

[0449] The results show the composition was homogeneous and stable. The pharmaceutical composition was completely soluble within less than 2 minutes in a glass containing about 50 ml of water at room temperature.

[0450] The composition complied with the requirements.

1 g of dry syrup prepared in Example 28 was directly placed in the mouth of the subject and taste was evaluated on a 3-point scale. No bitterness was detected.

EXAMPLE 29

Levocetirizine Dry Syrup Composition

[0451] The dry syrup was prepared by wet granulation process with the following composition

TABLE-US-00052 TABLE 53 Composition example 29 Material % Part Levocetirizine HCl 0.3 Coating 2 Betacyclodextrin 1.1 coating 2 Sucralose 0.090 coating 2 Trisodium citrate•2H2O 2.2 coating 2 Citric acid (monohydrate) 0.3 coating 2 hydroxypropylcellulose 0.03 coating 2 Hydroxypropylmethyl cellulose 5 Coating 1 Mannitol DC 300 q.s. Core Strawberry flavor 0.224 Extra Granular phase Mannitol DC 300 2.5 Extra Granular phase Colloidal anhydrous silica 0.5 Extra Granular phase

[0452] Mannitol (Mannitol DC300) is a granulated powder mannitol having an average particle size of about 250-350 μm. Trisodium citrate and citric acid are used as buffering agent. Hydroxypropylmethyl cellulose (HPMC 5 cp) is used as polymer to separate the second coating from the core. Sucralose is used as sweetener. Beta-cyclodextrin (Kleptose® 4 pc) is used as taste masking agent.

Strawberry flavor is used as flavoring agent. Colloidal anhydrous silica (aerosil 200) is used as flow enhancer/antisticking agent. Hydroxypropylcellulose (Klucel EF) is used as binder.

[0453] The granules were prepared by spraying an aqueous solution of the materials (hydroxypropylmethyl cellulose) from the first coating onto the mannitol core particles.

[0454] After drying, an aqueous solution containing the materials (levocetirizine, beta-cyclodextrin, Na citrate, citric acidand sucralose) from the second coating was sprayed onto the intermediate granules.

[0455] A fluid bed coater was used to the purpose.

[0456] The obtained granules were subsequently mixed with the extra-granular materials.

[0457] The obtained composition was homogeneous and stable. No significant degradation of the levocetirizine could be observed. 1 g of dry syrup prepared in Example 29 was directly placed in the mouth of the subject and taste was evaluated on a 3-point scale. No bitterness was detected.

[0458] The pharmaceutical composition was completely soluble within less than 2 minutes in a glass containing about 50 nil of water at room temperature.

[0459] The composition complied with the requirements.

EXAMPLE 30: LEVOCETIRIZINE ORODISPERSIBLE COMPOSITION

[0460] The granule containing levocetirizine dihydrochloride were prepared by fluid bed granulation process.

[0461] All materials except mannitol, were dissolved in water, granulated with mannitol and dried. After drying, the granules were mixed with extragranular excipients: mannitol, sodium starch glycolate, magnesium stearate and anhydrous silicon dioxide and then compressed on a tablet press to obtain an oro-dispersible tablet.

TABLE-US-00053 TABLE 54 Composition example 30 MATERIAL QUANTITY % Intra-granular phase Levocetirizine HCl 0.15 Trisodium citrate•2H2O 1.25 Citric acid (monohydrate) 0.2 hydroxypropylcellulose 0.02 Mannitol DC 300 48.87 Sucralose 0.05 Beta-cyclodextrin 0.6 Extra-granular phase Mannitol DC300 45 Sodium starch glycolate 3 Magnesium stearate 1 Anhydrous silicon dioxide 1.0 Total 100

[0462] Mannitol (Pearlitol® DC300) is a granulated powder mannitol having an average particle size of about 250-350 μm. it is used as granule carrier and as diluent.

[0463] Sodium citrate (hydrated) and citric acid (hydrated) are used as buffering agent. Hydroxypropyl-cellulose (Klucel SEF) is a soluble binder. Sucralose is used as sweetner. B-cyclodextrine (Kleptose® 4PC) is used as taste masking agent. Anhydrous silicon dioxide (Aerosil®200) is used as anti-caking agent. Magnesium Stearate is used as lubricant. Sodium starch glycolate is used as desintegrant.

[0464] The obtained composition was stable and homogeneous. It had an acceptable taste and palatability. The obtained composition was dissolved within less than 3 min, as per pharmacopeia test for disintegration of tablets and capsules.

1 g of oro-dispersible composition prepared in Example 30 was dissolved in 10 mL of water and taste was evaluated on a 3-point scale. No bitterness was detected.
It was an oro-dispersible tablet.

EXAMPLE 31: LEVOCETIRIZINE ORODISPERSIBLE TABLET

[0465] The granule containing levocetirizine were prepared by fluid bed granulation process.

[0466] All materials except mannitol, were dissolved in water, granulated with mannitol and dried. After drying, the granules were mixed with extragranular excipients: Pearlitol Flash® (combo excipient of mannitol and starch), sodium starch glycolate, magnesium stearate and anhydrous silicon dioxide and then compressed on a tablet press to obtain an oro-dispersible tablet.

TABLE-US-00054 TABLE 55 composition example 31 MATERIAL QUANTITY % Intra-granular phase Levocetirizine HCl 0.22 Trisodium citrate•2H2O 1.9 Citric acid (monohydrate) 0.3 hydroxypropylcellulose 0.03 Mannitol DC 300 73.3 Sucralose 0.08 Beta-cyclodextrin 0.9 Extra-granular phase Pearlitol Flash  ® 18.27 Sodium starch glycolate 3 Magnesium stearate 1 Anhydrous silicon dioxide 1.0 Total 100

[0467] Mannitol (Pearlitol® DC300) is a granulated powder mannitol having an average particle size of about 250-350 μm. it is used as granule carrier and as diluent.

[0468] Sodium citrate (hydrated) and citric acid (hydrated) are used as buffering agent. Hydroxypropyl-cellulose (Klucel® EF) is a soluble binder. Sucralose is used as sweetner. B-cyclodextrine (Kleptose®4PC) is used as taste masking agent. Anhydrous silicon dioxide (Aerosil® 200) is used as anti-caking agent. Magnesium Stearate is used as lubricant. Sodium starch glycolate is used as desintegrant.

[0469] The obtained composition was stable and homogeneous. It had an acceptable taste and palatability. 1 g of oro-dispersible composition prepared in Example 31 was dissolved in 10 mL of water and taste was evaluated on a 3-point scale. No bitterness was detected.

[0470] The obtained composition was dissolved within less than 3 min, as per pharmacopeia test for disintegration of tablets and capsules. It was an oro-dispersible tablet.

[0471] In all examples, levocetirizine dihydrochloride can be substituted by any other levocetirizine salt or by the free base, as this active material is solubilized in the spray solution prior to granulation. Only weight ratios should be adjusted accordingly.