DESC:Field of the invention
The present invention relates to oral liquid pharmaceutical compositions comprising Cyclizine or pharmaceutically acceptable salts thereof and process for the preparation of it.
Background of the invention
This invention relates to liquid oral compositions of Cyclizine or its pharmaceutically acceptable salt.

Cyclizine (1-benzhydryl-4-methylpiperazine) is a known antiemetic useful in the treatment of motion sickness, nausea and vomiting caused by narcotic analgesics or by general anaesthetics in the post-operative period and vomiting associated with radiotherapy. Its preparation is described in GB 655839.

The exact mechanism by which Cyclizine can prevent or suppress both nausea and vomiting from various causes is unknown. Cyclizine increases lower oesophageal sphincter tone and reduces the sensitivity of the labyrinthine apparatus. It may inhibit the part of the midbrain known collectively as the emetic centre.

Oral solid dosage forms and solution for injection of Cyclizine are known in the art. Cyclizine Hydrochloride Tablets (50 mg, Valoid® Tablets, Amdipharm UK Limited) are approved in UK. Cyclizine Lactate Injection (50 mg/mL, Valoid® Injection Amdipharm UK Limited) is approved in UK. Cyclizine paediatric syrup (12.5 mg/5mL) is approved in South Africa for the prevention and treatment of nausea and vomiting, particularly motion sickness and also symptomatic treatment of vertigo due to Meniere's disease and other labyrinthine disturbances.

GB 906422 patent claims prolonged release tablet dosage form of Cyclizine Hydrochloride.

GB 1018125 patent discloses that Cyclizine can be administered in the form of self-propelling medicament composition in the form of inhalations.

GB 1021959 claims a pharmaceutical composition consisting of Cinnarizine and/or its acid addition salts in admixture with Cyclizine and/or Chloro Cyclizine and/or their acid addition salts.

ZA 200001002 B relates to an inclusion complex of Cyclizine and an unsubstituted or substituted beta- or gamma-Cyclodextrin, and to pharmaceutical compositions containing such an inclusion complex, oral dosage forms like sublingual or buccal tablets, buccal patches or nasal inhalation powders or suppositories, for the treatment of nausea and vomiting including motion sickness.

US 3188273 claims the tasteless Cyclizine Pamoate salt and its compositions. To mask the bitter taste of Cyclizine drug, it was used in the form of Cyclizine Pamoate salts.

Solid formulations suffer from certain shortcomings such as difficulty in swallowing, particularly for certain groups of patients, e.g., paediatrics and geriatrics, resulting in negative patient compliance. Further, high doses of active ingredient lead to large-sized solid dosage forms which aggravate this problem. Also, there remains a tendency to divide the solid compositions such as tablets into small pieces in order to ease the administration, which may ultimately result in inaccurate dosing and or dose dumping. In regards to this, liquid compositions such as solutions and suspensions provide the best substitute over solid compositions. Liquid dosage forms are easy to administer, thereby leading to enhanced patient compliance. Also the onset of action is rapid in liquid formulations as compared to solid dosage forms.
Although liquid formulations are advantageous, there remain some difficulties involved in formulating such compositions. The important requirement of these compositions is to provide the stability of desired solution or suspension throughout the shelf life, as inaccurate dosing may lead to sub-therapeutic or toxic effects.

A common problem associated with liquid oral dosage forms is the unpleasant taste of the drug. Various chemical and physical methods like addition of flavouring and sweetening agents, microencapsulation, granulation, ion exchange resins, formation of inclusion complexes, bitterness inhibitors, multiple emulsions, prodrug approach, gel formation and development of liposomes are used for masking the unpleasant taste of the compositions.

Rapid onset of action is desirable in treating motion sickness. It is preferable to administer Cyclizine Hydrochloride in liquid oral compositions with improved organoleptic properties than to administer Cyclizine in solid oral dosage forms.

Summary of the Invention

The present invention relates to stable liquid oral compositions of Cyclizine Hydrochloride.

An aspect of the invention is directed to a solution composition comprising Cyclizine Hydrochloride.

The present invention relates to a stable solution composition comprising Cyclizine Hydrochloride and solubility enhancer wherein the solubility enhancer is Cycloderxtrin derivative.

The present invention further relates to a stable solution composition comprising Cyclizine Hydrochloride, Cyclodextrin derivative and other pharmaceutically acceptable excipients.

The present invention further relates to the process for the preparation of stable solution composition comprising Cyclizine Hydrochloride, Cyclodextrin derivative and other pharmaceutically acceptable excipients.

The present invention relates to a stable solution composition comprising Cyclizine Hydrochloride, Cycloderxtrin derivative and pharmaceutically acceptable excipients selected from preservatives, stability enhancers, sweeteners and flavours.
The present invention relates to an oral solution composition comprising Cyclizine Hydrochloride in the concentration of 0.1 % to 10 %, Cycloderxtrin derivative in the concentration of 0.5% to 15 %, bulk sweeteners in the concentration of 20 % to 30%, artificial sweeteners in the concentration of 0.1% to 1%, preservative in the concentration of 0.1 % to 5%, Bitter Blocker and flavours in the concentration of 0.01 % to 1%.
An oral solution composition of Cyclizine Hydrochloride is stable at pH 4 to 6, preferably at pH 4.5 to 5.5.

An another aspect of the invention is directed to a suspension composition comprising Cyclizine.

The present invention relates to a suspension composition comprising Cyclizine Hydrochloride with improved organoleptic properties by using taste masking agent wherein the taste masking agent is Disodium Pamoate.

The present invention relates to a suspension composition comprising Cyclizine Hydrochloride with improved organoleptic properties by using taste masking agent Disodium Pamoate and other pharmaceutically acceptable excipients.

The invention further relates to the process for the preparation of a suspension composition comprising Cyclizine Hydrochloride with improved organoleptic properties by using taste masking agent Disodium Pamoate and other pharmaceutically acceptable excipients.

The present invention relates to an oral liquid suspension composition comprising of Cyclizine Hydrochloride, Disodium Pamoate, preservatives, wetting agents, suspending agents, sweeteners and flavours.
The present invention relates to an oral suspension composition comprising of Cyclizine Hydrochloride in concentration of 0.1 to 10 %, Disodium Pamoate in the concentrations of 1 to 5 %, Microcrystalline Cellulose and Carboxymethyl Cellulose (Avicel RC 591) in the concentrations of 0.1 to 3 %, Citric Acid Monohydrate in the concentrations of 0.1 to 2 %, Polysorbate 20 in the concentrations of 0.1 to 3 %, Sodium Benzoate in the concentrations of 0.1 to 2 %, Trisodium Citrate in the concentrations of 0.2 to 3 % , Sodium Saccharin in the concentrations of 0.05 to 1 % and Banana flavour in the concentrations of 0.05 to 2 %.
The present invention relates to an oral stable suspension composition comprising of Cyclizine Hydrochloride in concentration of 0.1 to 10 %, Disodium Pamoate in the concentrations of 1 to 5 %, Xanthan gum in the concentrations of 0.1 to 2 %, Polysorbate 80 in the concentrations of 0.01 to 2 %, Sodium Benzoate in the concentrations of 0.1 to 1 %, Sucralose in the concentrations of 0.01 to 1 % , Sucrose in the concentrations of 1 to 20 %, Peppermint flavour in the concentrations of 0.05 to 2 %, Simethicone Emulsion in the concentration of 0.01 to 2 % and Citric acid as well as Sodium Chloride for the adjustment of pH.
An oral suspension composition of Cyclizine Hydrochloride is stable at pH 4 to 6, preferably at pH 4.5 to 5.5.

One of the aspects of the present invention is to improve the bioavailability of Cyclizine Hydrochloride liquid oral compositions as compared to solid oral dosage forms.

Brief Description of Drawings

Figure 1: Comparison of Drug Release Profile of Example II Vs. Valoid Tablets
Figure 2: Comparison of Drug Release Profile of Example III Vs. Valoid Tablets

Detailed Description of the Invention
The present invention to be understood more readily by reference to the following detailed description of the invention and the examples provided therein. It is to be understood that this invention is not limited to the specific methods, formulations, and conditions described, as such may vary.

The main object of the present invention is directed to the liquid oral compositions of Cyclizine Hydrochloride having improved storage stability.

Another object of the present invention is directed to the liquid oral compositions of Cyclizine Hydrochloride providing rapid onset and high absorption of Cyclizine Hydrochloride.

The liquid oral compositions of Cyclizine Hydrochloride which is to be administered orally to patients who have difficulty in swallowing.

The liquid oral compositions of Cyclizine Hydrochloride wherein flexible dosing is possible.

Cyclizine has a very strong bitter taste. There are also provided taste masked liquid oral compositions of Cyclizine Hydrochloride with an improved organoleptic characteristic.

An aspect the invention is directed to a solution composition comprising Cyclizine Hydrochloride.

The liquid oral solution composition comprising of Cyclizine Hydrochloride and one or more pharmaceutically acceptable excipients selected from the group comprising solubility enhancers, microbial preservatives, sweeteners and flavours.

An another aspect the invention is directed to a suspension composition comprising Cyclizine Hydrochloride.

The liquid oral suspension composition comprising Cyclizine Hydrochloride, taste masking agents, buffers, suspending agents, wetting agents microbial preservatives, sweeteners and flavours.

Aqueous solubility of Cyclizine Hydrochloride is very low (less than 1mg/cm3 at 25 ºC). In this invention, solubility enhancers like Cyclodextrin derivatives (a-Cyclodextrin, ß-Cyclodextrin and ?-Cyclodextrin) are used in the liquid oral solution of Cyclizine Hydrochloride. Among the Cyclodextrins, Hydroxypropyl-ß-Cyclodextrin, which has higher water solubility, lower renal toxicity and haemolytic activity and slightly sweet in taste is preferred over other Cyclodextrin derivatives. Cyclizine Hydrochloride forms inclusion complex with Hydroxypropyl-ß-Cyclodextrin which increases the solubility of Cyclizine Hydrochloride and in turn decreases the chances of precipitation and recrystallization and thus improves the storage stability of Cyclizine Hydrochloride solution and also incorporates sweet taste to the solution.

Preservatives are included in preparations to kill or inhibit the growth of micro-organisms unknowingly introduced during manufacture or use and are therefore essential ingredients.

The choice of a suitable preservative for a preparation depends on pH, compatibility with other ingredients, the route of administration, dose and frequency of administration of the preparation, partition coefficients with ingredients and containers or closures, degree and type of contamination, concentration required, and rate of antimicrobial effect.

Microbial preservatives are selected from the group of Sodium Benzoate, Benzoic Acid, Boric Acid, Sorbic Acid and their salts thereof, Benzyl Alcohol, Benzalkonium Chloride, Propyl Parabens or their mixtures thereof.

In addition to its advantageous organoleptic property i.e. flavouring property, Benzoic Acid salts are also preservative and are used to prevent microbial spoilage of the oral Cyclizine solutions in a concentration from 0.02 to 1 %, preferably in the concentration of 0.1 to 0.5 %. The benefits of Sodium Benzoate are that it is colorless, odourless, readily soluble, and generally is compatible with other ingredients.

The pharmaceutically acceptable sweeteners comprise at least one artificial sweetener such as but not limited to Stevia, Aspartame, Sucralose, Neotame, Acesulfame potassium (Ace-K), Saccharin, and Advantame preferably Sucralose and optionally a bulk sweetener such as but not limited to Sorbitol, Mannitol, Fructose, Sucrose, Maltose, Isomalt, Glucose, Hydrogenated Glucose Syrup, Xylitol, Caramel and Honey.

The artificial sweetener is conveniently employed in the concentration of from 0.01 % to 3.5 % (w/v) based on the total volume of the final formulation, and preferably is about 0.05 to 2 % (w/v). Bulk sweetener is employed in the concentration of 1 % to 30 % (w/v).

Cyclizine Hydrochloride has a very bitter taste and hence the bitter taste is masked with some flavours. The pharmaceutically acceptable flavours for masking the bitter taste of Cyclizine Hydrochloride are selected from the group, fruit flavours such as Cherry, Raspberry, Black currant, Orange flavour, Strawberry flavour, Caramel Chocolate flavour, Mint cool flavour (Peppermint Supreme), Fantasy flavour and the like pharmaceutically acceptable strong flavours. Ion exchange resins like Carbomer, Amberlite can be used as taste making agents. Other taste masking agents are Bitter Blockers, Disodium Pamoate, Cyclodextrins and Tannic Acid, preferred one is Disodium Pamoate and/or Bitter Blockers.

In one of the preferred aspect of the invention, Orange flavour in the concentration of 0.01% to 1 % is preferably used in combination of Bitter Blocker in the concentration of 0.01% to 1 % for masking the taste of Cyclizine Hydrochloride in Cyclizine Hydrochloride solution. In Cyclizine Hydrochloride suspension, Disodium Pamoate is used in the concentrations of 1% to 5% and Banana flavour or Peppermint Supreme in the concentrations of 0.05 to 2 %.

The suspending agent is used for suspending the drug particles. Most of the suspending agent work by increasing the viscosity of the medium. In practice a suspending agent is selected from the group consisting of Methyl Cellulose, Hydroxyethyl Cellulose, Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Hydroxy Ethyl Propyl Cellulose, starches such as Maize starch, Corn starch, Potato starch, Rice starch and Wheat starch, Carboxy Vinyl polymers, Carboxymethyl Cellulose and salts thereof, Microcrystalline Cellulose and gums like Guar gum, Xanthan gum, Arabic gum. A preferred suspending agent is microcrystalline cellulose and carboxymethyl cellulose sodium commercially known as Avicel RC 591 or Xanthan gum in the concentrations from 0.05 % to 5 % w/v, preferably in the concentrations from 0.1 % to 3 % w/v.

The buffer system for maintaining the pH of the liquid oral composition of Cyclizine Hydrochloride in the range from 4 to 6, preferably 4.5 to 5.5 comprises an aqueous mixture of an appropriate amount of an acid such as but not limited to Phosphoric, Succinic, Tartaric, Lactic, or Citric Acid, and a base, in particular, Disodium Hydrogen Phosphate or Sodium Hydrogen Carbonate. The preferred buffer system is Citric Acid Monohydrate and Trisodium Citrate Dihydrate. Buffering agents used in the present invention ranges from 0.01 to 10 % w/v, preferably 0.05 to 5 % w/v. Optionally Sodium Chloride is added for the adjustment of pH.

Wetting agents are surfactants that lower the interfacial tension and contact angle solid particles and liquid vehicle. Non-ionic surfactants are most commonly used as wetting agents in pharmaceutical suspension. The usual concentration of surfactant varies from 0.05 to 1 % w/v and depends on the solids content intended for suspension. The use of surfactants as wetting agents will also retard crystal growth. Wetting agents include but not limited to Sorbitan Monolaurate, Polysorbate 20, Polysorbate 80, Sodium Lauryl Sulphate or combinations thereof in the concentrations of 0.01 % to 2 % w/v.

A suspension of the invention also comprises from about 0.01 to about 0.3 % by weight based on the total weight of the suspension of a conventional anti foaming agent such as Simethicone emulsion, Dimethicone, Polyethylene Glycol and Polypropylene Glycol. Antifoaming agents inhibit or reduce the formation of gas bubbles in the final formulation.

In one of the aspect of the present invention liquid oral composition comprises Cyclizine Hydrochloride, Hydroxypropyl- ß-Cyclodextrin in stable, homogenous solution dosage form.

According to an embodiment of the present invention, oral solution composition comprises Cyclizine Hydrochloride in an amount of 0.1 % to 10% of total weight of the pharmaceutical solution, more preferably 1% to 2% of total weight of the pharmaceutical solution.

According to an embodiment of the present invention, the liquid oral composition of Cyclizine or salt thereof comprising 1 % by weight of Cyclizine Hydrochloride for the prevention and treatment of nausea and vomiting including; motion sickness, nausea and vomiting caused by narcotic analgesics and by general anaesthetics in the post-operative period, vomiting associated with radiotherapy, especially for breast cancer.

According to an embodiment of the invention, said oral pharmaceutical solution comprises Hydroxypropyl-ß-Cyclodextrin in an amount of 0.5% to 15% of total weight of the pharmaceutical solution, more preferably 2 % to 6 % of total weight of the pharmaceutical solution.

According to an embodiment of the present invention, said oral solution composition comprises;
a) 0.1 to 10 % by weight of Cyclizine Hydrochloride,
b) 0.5 to 15 % by weight of Hydroxy Propyl-ß-Cyclodextrin,
c) 20 to 30 % by weight of Sucrose,
d) 0.1 to 1 % by weight of Sucralose,
e) 0.05 to 0.5% by weight of Sodium Benzoate,
f) 0.01 to 1 % by weight of Bitter Blocker,
g) 0.01 to 1 % by weight of Orange Flavour.

According to an embodiment of the invention, the process for preparation of the said oral pharmaceutical solution comprises;
1. Mixing of Hydroxypropyl -ß-Cyclodextrin with water.
2. Addition of Cyclizine Hydrochloride to the step 1 mixture.
3. Heating of water and Sucrose to 80º C and cooling to 45-50° C.
4. Mixing of mixtures of step 2 and 3.
5. Addition of Sucralose and Sodium Benzoate to the mixture of step 4.
6. Addition of Bitter Blocker and Orange Flavour to the mixture of step 5.
7. Finally, make up the volume to required quantity optionally with pH adjustment.

The following examples are intended to highlight certain embodiments of the invention, but should not be construed as limiting the scope thereof.

Example I: Cyclizine Hydrochloride oral solution is prepared with composition given in Table 1.
Table 1
Sr. No. Ingredient Quantity
mg/mL
1 Cyclizine Hydrochloride 10.00
2 Hydroxy propyl-ß- Cyclodextrin 40.00
3 Sucrose 240.00
4 Sucralose 6.00
5 Sodium Benzoate 3.60
6 Flavor (Bitter Blocker) 0.20
7 Orange Flavor 0.20
8 Purified water QS to 1 mL

The process of the formulations is carried out as follows:
1. Hydroxypropyl-ß-Cyclodextrin was added to water and was stirred for 30 min in vessel I.
2. Cyclizine Hydrochloride was added to the vessel I and was further stirred for 30 min.
3. In another vessel II i.e vessel II, water and Sucrose were heated to 80º C with stirring and were then cooled to 45-50° C.
4. Mixtures in the vessels I and II were further mixed together and stirred for 15 min.
5. To this solution, Sucralose and Sodium Benzoate were added and stirred for 30 min.
6. After 30 min, to this solution, Bitter Blocker and Orange Flavour were added and are further stirred for 30 min.
7. Finally, the volume was made up to required quantity.

In an embodiment of the present invention, an oral suspension composition comprises Cyclizine Hydrochloride, Disodium Pamoate, Polysorbate 20 or Polysorbate 80 and Sodium Benzoate.

According to an embodiment of the present invention, said oral pharmaceutical suspension comprises Cyclizine Hydrochloride in an amount from about 0.1 % to 10 % of total weight of the pharmaceutical suspension, more preferably 1% to 2% of total weight of the pharmaceutical suspension.

According to an embodiment of the invention, said oral pharmaceutical suspension comprises Disodium Pamoate in an amount from about 1 % to 5% of total weight of the pharmaceutical suspension, more preferably 2 % to 4 % of total weight of the pharmaceutical suspension.

According to an embodiment of the present invention, said oral liquid pharmaceutical suspension of Cyclizine Hydrochloride comprises;
a) 0.1 to 10 % by weight of Cyclizine Hydrochloride,
b) 1 to 5 % by weight of Disodium Pamoate,
c) 0.1 to 2 % by weight of Avicel RC 591,
d) 0.1 to 2 % by weight of Citric Acid,
e) 0.1 to 2 % by weight of Polysorbate 20,
f) 0.1 to 1 % by weight of Sodium Benzoate,
g) 0.2 to 3 % by weight of Trisodium Citrate,
h) 0.05 to 1 % by weight of Sodium Saccharine,
i) 0.05 to 2 % by weight of Banana Flavour.

According to an embodiment of the invention, the process for preparation of the said oral pharmaceutical suspension comprises;
1. Preparation of Avicel RC 591 dispersion in water.
2. Preparation of Disodium Pamoate mixture by dissolving Disodium Pamoate in water and adding to Avicel dispersion and adding Citric Acid Monohydrate solution in water to Disodium Pamoate and Avicel RC 591 mixture.
3. Preparation of Cyclizine Hydrochloride drug dispersion by dispersing Cyclizine Hydrochloride in water by adding heated Polysorbate 20 and Trisodium Citrate dihydrate to it.
4. Addition of Cyclizine Hydrochloride dispersion to Disodium Pamoate mixture with continuous stirring.
5. Dissolution of Citric Acid Monohydrate and Trisodium Citrate Dihydrate in water and addition to the mixture obtained in step 4.
6. Dissolution of Sodium Benzoate in water and addition to mixture obtained in step 5.
7. Dissolution of Saccharin Sodium in water and addition to Avicel dispersion. Addition of this mixture to the mixture obtained in step 6.
8. Addition of Banana Flavour in the mixture obtained in step 7.
9. Finally, make up the volume to required quantity with pH adjustment.

Example II: Cyclizine Hydrochloride oral suspension is prepared with composition given in Table 2.

Table 2
Sr. No. Ingredient Quantity
mg/mL
1 Cyclizine Hydrochloride 10.00
2 Disodium Pamoate Monohydrate 20.00
3 Avicel RC 591 8.00
4 Citric Acid Monohydrate 6.70
5 Polysorbate 20 5.00
6 Sodium Benzoate 2.00
7 Trisodium Citrate Dihydrate 10.67
8 Saccharine Sodium 2.00
9 Banana Flavor 3.50
10 Purified water QS to 1 mL

The process of the formulations is carried out as follows:
1. Microcrystalline Cellulose and Carboxymethyl cellulose (Avicel RC 591) were dispersed in purified water under homogenization and divided in 80:20 proportions.
2. Disodium Pamoate and Citric Acid Monohydrate were added to the 80 % dispersion obtained in Step 1 under homogenization.
3. Cyclizine Hydrochloride was dispersed in Purified water under stirring and to this dispersion; Polysorbate 20 (after heating at 40-50°C) and Trisodium Citrate Dihydrate were added.
4. Cyclizine Hydrochloride dispersion was added to Disodium Pamoate mixture obtained in Step 2.
5. Trisodium Citrate Dihydrate and Citric Acid Monohydrate were added to Step 4 mixture under slow stirring.
6. Sodium Benzoate was dissolved in Purified water under stirring and added to the mixture obtained in step 5.
7. Saccharin Sodium was dissolved in Purified water and was added to remaining 20 % dispersion of Step 1. Further, this mixture was added to the mixture obtained in step 6.
8. Banana Flavor was added to the mixture obtained in step 7 and mixed for 10 min.
9. The volume was made up with Purified water with pH adjustment and homogenized the final Suspension for 15 min.

Cyclizine Hydrochloride oral suspension composition of Example II was tested for its dissolution profile against Valoid ® Tablets from UK market (B. No. F0028) by using USP II apparatus at 25 rotations per minute (RPM) for Suspension and 50 RPM for tablets in 900 mL buffer of pH 1.2 as a dissolution media.
Comparative Dissolution Profile of Example II and Valoid Tablet is illustrated in Table 3 and Figure 1.
Table 3: The Comparative Dissolution Data
Time point
(Minute) Example II Valoid Tablets
(B. No. F0028)
Release (%) RSD Release (%) RSD
5 80.23 10.27 44.90 20.54
10 88.67 8.75 86.50 8.37
15 93.58 6.87 97.20 3.21
20 97.04 6.60 99.60 2.60
30 100.77 5.71 104.10 2.06
45 104.17 5.24 101.80 1.93
60 106.21 5.33 104.10 1.95

From Table 3 and Figure 1, there is rapid onset of release for Example II as compared to Valoid Tablets. Almost more than 80 % drug is released in first 5 min.
According to an embodiment of the present invention, said oral liquid pharmaceutical suspension of Cyclizine Hydrochloride comprises;
a) 0.1 to 10 % by weight of Cyclizine Hydrochloride,
b) 1 to 5 % by weight of Disodium Pamoate,
c) 0.1 to 2 % by weight of Xanthan gum,
d) 0.01 to 2 % by weight of Polysorbate 80,
e) 0.1 to 1 % by weight of Sodium Benzoate,
f) 0.01 to 1 % by weight of Sucralose,
g) 0.05 to 2 % by weight of Peppermint Supreme,
h) 1 to 20 % by weight of Sucrose,
i) 0.01 to 2 % by weight of Simethicone,
j) Citric Acid and Sodium Chloride for the adjustment of pH.

According to an embodiment of the invention, the process for preparation of the said oral pharmaceutical suspension comprises;
1. Preparation of Xanthan Gum Mucilage:
a. Preparation of clear Sodium Benzoate solution in water under stirring.
b. Addition of Xanthan Gum to this solution under stirring for 30 min to form a clear viscous solution.
c. Soaking of mucilage for not less than 2 hrs.
2. Preparation of Sugar Syrup:
a. Addition of Sucrose to hot purified water at 80-90ºC under stirring to form clear syrup.
b. Cooling of Sugar syrup to 40-45ºC.
3. Addition of Sugar Syrup to Xanthan Gum Mucilage:
a. Addition of Sugar syrup from Step 2 to Xanthan Gum Mucilage of Step 1 under homogenization for 15 min.
4. Preparation of Disodium Pamoate-Cyclizine HCl dispersion:
a. Addition of Cyclizine Hydrochloride to Polysorbate 80 which is taken in a clean beaker. Mixing of the slurry manually for 15-20 min until a change in flow property of Cyclizine Hydrochloride is observed.
b. Dissolution of Disodium Pamoate in Purified water. Addition of Cyclizine - Polysorbate 80 slurry to this solution and homogenization for 30 min.
5. Addition of Disodium Pamoate-Cyclizine Hydrochloride Dispersion to Xanthan Gum Mixture:
a. Addition of mixture obtained from step 4 to step 3 mixture under homogenization for 15 min.
6. Addition of Sucralose:
a. Dissolution of Sucralose in purified water and addition to step 5 suspension under stirring.
7. pH adjustment using Citric Acid and Sodium Chloride solution:
a. Preparation of buffer solution containing Citric Acid (10% w/w) and Sodium Chloride (0.5% w/w) and addition dropwise to step 6 suspension under stirring to obtain a final pH between 4.5-5.5.
8. Addition of Simethicone Emulsion and Peppermint Flavour:
a. Addition of Simethicone Emulsion and Peppermint Supreme to Step 7 suspension and stirring at slow speed for 30 min.
9. Adjustment of final volume:
a. Making up the final volume of suspension with purified water and homogenization of final suspension for 15 min.

Example III: Cyclizine Hydrochloride oral suspension is prepared with composition given in Table 4.

Table 4
Sr. No. Ingredient Quantity
mg/mL
1. Cyclizine Hydrochloride 10.00
2. Disodium Pamoate 20.00
3. Xanthan Gum 3.00
4. Sodium Benzoate 4.00
5. Simethicone Emulsion 1.00
6. Polysorbate 80 1.00
7. Sucrose 100.00
8. Sucralose 0.50
9. Sodium Chloride q.s. to pH 4.5-5.5
10. Citric Acid (pH adjusting agent) q.s. to pH 4.5-5.5
11. Peppermint Supreme 2.00
12. Purified Water q.s. to 1mL

The process of the formulations is carried out as follows:
1. Preparation of Xanthan Gum Mucilage:
a. Required quantity of Sodium Benzoate was added to purified water under stirring to form clear solution.
b. Xanthan Gum was added slowly to this solution (Step a above) and was stirred for 30 min to form a clear viscous solution.
c. The mucilage was soaked for not less than 2 hrs.
2. Preparation of Sugar Syrup:
a. Sucrose was added to hot purified water at 80-90o C and stirred to form clear syrup.
b. Sugar syrup was cooled to 40-45o C.
3. Addition of Sugar Syrup to Xanthan Gum Mucilage:
a. Sugar syrup from Step 2 was added to Xanthan Gum Mucilage of Step 1 under homogenization for 15 min.
4. Preparation of Disodium Pamoate-Cyclizine Hydrochloride Dispersion:
a. Polysorbate 80 was weighed in a clean beaker and Cyclizine Hydrochloride was added to it. The slurry was mixed manually for 15-20 min until a change in flow property of Cyclizine Hydrochloride was observed.
b. Disodium Pamoate was dissolved in Purified water. Cyclizine -Polysorbate 80 slurry was added to this solution and was homogenized for 30 min.
5. Addition of Disodium Pamoate-Cyclizine Hydrochloride Dispersion to Xanthan Gum Mixture:
a. The mixture obtained from step 4 was added to step 3 mixture under homogenization for 15 min.
6. Addition of Sucralose:
a. Sucralose was dissolved in purified water and was added to the step 5 suspension under stirring.
7. pH Adjustment Using Citric Acid and Sodium Chloride Solution:
a. Buffer solution containing Citric Acid (10 % w/w) and Sodium Chloride (0.5% w/w) was prepared and was added dropwise to step 6 suspension under stirring until the final pH between 4.5-5.5 was obtained.
8. Addition of Simethicone Emulsion and Peppermint Flavour:
a. Simethicone Emulsion and Peppermint Supreme were added to Step 7 suspension and was stirred at slow speed for 30 min.
9. Adjustment of Final Volume:
a. The final volume of suspension was made up with purified water and was homogenized for 15 min.

Cyclizine Hydrochloride oral suspension composition of Example III was tested for its dissolution profile against Valoid ® Tablets from UK market (B. No. F0028) by using USP II apparatus at 35 rotations per minute (RPM) for Suspension and 50 RPM for tablets in 900 mL buffer of pH 1.2 as a dissolution media.
Comparative Dissolution Profile of Example III and Valoid Tablet are illustrated in Table 5 and Figure 2.
Table 5: The Comparative Dissolution Data
Time point
(Minutes) Example III Valoid Tablets
(B.No:F0028)
% Release RSD % Release RSD
5 97.94 7.30 44.90 20.54
10 96.41 4.04 86.50 8.37
15 98.42 2.68 97.20 3.21
20 99.78 2.75 99.60 2.60
30 100.42 1.86 104.10 2.06
45 101.43 1.51 101.80 1.93
60 101.57 1.39 104.10 1.95

From Table 5 and Figure 2, there is rapid onset of release for Example III as compared to Valoid Tablets. Almost more than 95 % drug is released in first 5 min.
The stability of Cyclizine Hydrochloride Oral Suspension of Example III stored at temperature of 40ºC±2°C and relative humidity of 75%±5% was determined after 5 months.
Impurity levels were determined by gas chromatography method and the data is presented in Table 6 as a percentage of specific impurity. Physical parameters like appearance, viscosity and pH were compared at initial level and after 5 months. The suspension after storage at temperature of 40ºC±2°C and relative humidity of 75%±5% complies with the physical parameters when compared with the initial suspension.
Table 6: Impurity Data During Stability Evaluation
Name of the Impurity Specification Initial After 5 months
Impurity A Not more than 0.5% Not detected 0.03 %
Impurity B Not more than 0.5% Not detected 0.04 %
Single Maximum Unknown Impurity Not more than 0.2% Less than 0.05%
Less than 0.05%

Total Impurities Not more than 1.0% Less than 0.05% 0.130 %

Based on the above impurities profile during stability evaluation and physical characteristic evaluation, it can be concluded that the Cyclizine Hydrochloride Oral Suspension as per the present invention is stable as there is no increase in impurity level till 5 months storage at accelerated conditions.
,CLAIMS:We claim,
1. A liquid oral composition of Cyclizine or salt thereof with one or more pharmaceutically acceptable excipients.

2. The liquid oral composition as claimed in claim 1, is solution or suspension.

3. The liquid oral composition as claimed in claim 1, comprises one or more pharmaceutically acceptable excipient which is selected from the group consisting of buffers, suspending agents, antifoaming agents, salts, solubility enhancers, wetting agents, microbial preservatives, sweeteners, taste masking agents and flavours.

4. The liquid oral composition of Cyclizine or salt thereof as claimed in claim 2 , comprising
a) 0.1 to 10 % by weight of Cyclizine Hydrochloride,
b) 0.5 to 15 % by weight of Hydroxy Propyl-ß-Cyclodextrin,
c) 20 to 30 % by weight of Sucrose,
d) 0.1 to 1 % by weight of Sucralose,
e) 0.05 to 0.5% by weight of Sodium Benzoate,
f) 0.01 to 1 % by weight of Bitter Blocker,
g) 0.01 to 1 % by weight of Orange flavour.

5. A stable, taste masked liquid oral composition of Cyclizine or salt thereof comprising at least one taste masking agent and at least one pharmaceutically acceptable excipients.

6. The stable, taste masked liquid oral composition as claimed in claim 5, wherein the taste masking agent is selected from the group consisting of fruit flavours, bitter blockers, complexing agents, resins and Pamoic Acid salts.

7. The stable, taste masked liquid oral composition as claimed in claim 5, wherein the taste masking agent is Disodium Pamoate.

8. The stable, taste masked liquid oral composition of Cyclizine or salt thereof as claimed in claim 5, wherein the single maximum unknown impurity is not more than 0.2 % and total impurities are not more than 1 %, after storage at temperature of 40ºC ± 2°C and relative humidity of 75% ± 5% for 5 months.

9. The stable, taste masked liquid oral composition of Cyclizine or salt thereof comprising
a) 0.1 to 10 % by weight of Cyclizine Hydrochloride,
b) 1 to 5 % by weight of Disodium Pamoate,
c) 0.1 to 2 % by weight of Xanthan gum,
d) 0.1 to 2 % by weight of Polysorbate 80,
e) 0.1 to 1 % by weight of Sodium Benzoate,
f) 0.01 to 1 % by weight of Sucralose,
g) 0.05 to 2 % by weight of Peppermint Supreme,
h) 1 to 20 % by weight of Sucrose,
i) 0.01 to 2 % by weight of Simethicone,
j) Citric acid and Sodium Chloride for the adjustment of pH.

10. The stable, taste masked liquid oral composition of Cyclizine or salt thereof as claimed in claim 9, comprising 1 % by weight of Cyclizine Hydrochloride for the prevention and treatment of nausea and vomiting including; motion sickness, nausea and vomiting caused by narcotic analgesics and by general anaesthetics in the post-operative period, vomiting associated with radiotherapy, especially for breast cancer.