FORMULATION COMPRISING PHENYLAMINOPYRIMIDINE DERIVATIVE AS ORAL SOLUTION

FIELD OF THE INVENTION
The present invention is concerned with a stable oral aqueous solution comprising Imatinib or pharmaceutically acceptable acid addition salts or polymorphs thereof, process for preparing such solution and their use in the treatment of Chronic Myeloid Leukemia, Gastrointestinal Stromal Tumors and the like.

BACKGROUND OF THE INVENTION
Imatinib mesylate is a protein-tyrosine kinase inhibitor; it inhibits the abnormal functioning Bcr-Abl tyrosine kinase, which is produced by the Philadelphia chromosome abnormality, found in chronic myeloid leukemia (CML). Imatinib inhibits cell proliferation and induces apoptosis (programmed cell death) in the Bcr-Abl cell lines and in the leukemic cells generated by CML. Imatinib also inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation. More recently, the drug has been approved for the treatment of mesenchymal cell neoplasms of the intestinal tract.

It has now been discovered that Imatinib mesylate can be used as a treatment for patients suffering from hepatic fibrosis based on its ability to downregulate stellate cell activation in culture and in vivo.

Imatinib mesylate is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. It was also reported that mean absolute bioavailability is 98%. Biotransformation of Imatinib mesylate is via hepatic metabolism and cytochrome P450 enzymes (especially CYP3A4). Imatinib mesylate is converted to its main circulating active metabolite, a N-desmethylated piperazine derivative. This derivative, in vitro, has potency similar to Imatinib mesylate and comprises about 15% of the AUC (area under the curve) for Imatinib mesylate. When imatinib mesylate is orally administered, the elimination half-lives of Imatinib mesylate and its major active metabolite, the N-desmethyl derivative, are approximately 18 and 40 hours, respectively and the time to reach peak concentration is 2 to 4 hours.
Imatinib mesylate is presently available as tablet form of 100 mg and 400 mg. The approved dosage range for imatinib mesylate in the treatment of CML is 400 mg to 800 mg (400 mg twice a day) and 600 mg per day for gastrointestinal stromal tumors (GIST).

It was reported that amounts of imatinib mesylate effective to treat hepatic fibrosis would broadly range between about 50 mg and about 600 mg per day and preferably between about 50 mg and about 200 mg per day administered orally.

EP 0564409 patent discloses the preparation of [(4-(4-methylpiperazin-l-ylmethyl)-N-4-[methyl-3-(4-pyridin-3-yl) pyrimidin-2-yl amino) phenyl] benzamide (Imatinib) and the use thereof especially as an antitumor agent.

U.S. Patent publication no. 20060173182 corresponding PCT application no. PCT/GB04/00018 discloses process of preparing Imatinib.

US patent no. 5521184 disclosed 'Pyrimidine derivatives and process for the preparation thereof and in equivalent applications in other countries. The above patent provides method of preparation of formulation of conventional tablets comprising active ingredient, wheat starch, lactose, colloidal silicic acid, talc and magnesium stearate.

The disclosure of the different polymorphic forms has been highlighted by WO 99/03854 and related US patents like US patent no. 7544799 and 6894051 entitled 'Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use'. In addition, US patent publication no. 20020115858 corresponding to EP0998473 and Australian patent no. 740713 also discloses the same. The above mentioned prior art discloses process for the preparation of β -crystal form of 4-(4-methylpiperazin-1-ylmethyl) - N- (4-methyl - 3- (4-pyridin-3-yl) pyrimidin-2-ylamino) phenyl]-benzamide methanesulfonate, and one of the examples specifies process for manufacture of conventional tablets containing 100 mg of the active substance, crystalline lactose, avicel, PVPPXL, aerosil and magnesium stearate. Also one of the examples specifies preparation of hard gelatin capsules with 100 mg of the above compound as active ingredient, avicel, PVPPXL, aerosil and magnesium stearate.

The US Patent publication no. 20050143389 disclosed a method of treating of hepatic fibrosis with imatinib mesylate.

WO 06/040779 discloses gastric floating matrix formulation containing Imatinib, which provides in a single dose to float for a period of 12 hours.

The oral solution dosage form can be a viable alternative for patients who have problems in swallowing the tablet dosage form. It provides assurance of dosage uniformity upon administration to patients and eliminates difficulty of administration. An oral solution can also provide physicians more flexibility in designing dosage regimens for patients. Imatinib oral solution is suitable for administration to both pediatric and geriatric patients while also compensating for a good organoleptic properties and remaining suitably stable. Hence the development of a liquid oral formulation is therefore desirable since it offers improved patient compliance.

From the perspectives of ease of use, accuracy of dose and bioavailability; oral solution dosage forms are generally preferred to be in form of a solution.

None of the above said prior arts discloses and/or envisages an oral solution hence the above drawback was contemplated in our invention.

Since Imatinib mesylate is having all the above favorable features suitable to formulate an oral solution, the work on present invention was taken up.

The present invention, relates to design and development of an oral solution containing Imatinib mesylate and a process for its preparation, indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) in chronic phase, accelerated phase, blast crisis and GIST.

There is a need to work on formulations and process thereof, which proves better therapeutic efficacy, ease of oral administration and to be economical for large-scale production.

OBJECTIVES OF THE INVENTION

Accordingly, the main objective of the present invention is to design and develop an oral solution containing Imatinib or its pharmaceutically acceptable salts and polymorphs such as α, β or α 2 thereof for the treatment of CML, GIST and the like.

Another objective of this invention is to provide an alternative dosage form to existing tablets.
Another objective of the present invention is to provide a liquid composition which is amenable to high concentrations of Imatinib, is stable.

Another objective of the present invention is to provide uniform distribution of the active agent with a palatable taste.

Another objective of this invention is to provide a desirable oral formulation for the treatment of small children and elderly patients to swallow easily.

Yet another objective of the present invention is to provide simple process for the preparation of a stable aqueous formulation of Imatinib.

Yet another objective of the present invention is to reduce the fluctuations in blood plasma concentration by giving a uniform liquid dosage form and enhancing patient compliance.

Accordingly, further objective of this invention is to provide the pharmaceutical composition of an oral solution to achieve better therapeutic levels for the therapy against aforementioned diseases.

Accordingly, further objective of this invention is to meet the particular needs of patients who have difficulty in swallowing solid oral dosage forms.

More especially, the objective of the present invention is to develop a process for preparing the oral solution comprising active ingredient, diluents, cosolvents, buffering agents, sweetening agents, coloring agents, flavoring agents and chelating agents.

STATEMENT OF INVENTION

Accordingly, the main embodiment of the present invention is to design and develop a stable aqueous oral formulation that can be swallowed easily and comprising Imatinib including its pharmaceutically acceptable salts and polymorphs thereof, a process for its preparation, where in the said formulation has pH in the range of about 2 to 5.5 for the treatment of CML, GIST and the like in small children and elderly patients.

DETAILED DESCRIPTION OF THE INVENTION

An aqueous solution for oral administration in humans comprising of therapeutically effective amount of Imatinib or its pharmaceutically acceptable salts and polymorphs thereof, one or more diluents, water miscible solvents, viscosity regulating agent, stabilizing agent, preservatives, buffering agents, chelating agent, antioxidant, sweetening agent, flavoring agent and coloring agent with a pH ranging from 2 to 5.5; intended to treat Chronic Myeloid Leukemia, Gastrointestinal Stromal Tumor.

The formulation of the present invention comprises wherein the oral solution contains a therapeutically effective pharmaceutical ingredient, Imatinib or its pharmaceutically acceptable salts and polymorphs such as a, P or 0,2 used in the range of about 0.1% to about 30% by weight relative to the total weight of the composition.

The diluent in the formulation of the present invention as used herein refers to an agent or mixture of agents, when added to a formulation makes the formulation thicker or less concentrated and may also improve manufacturability. Diluents of the present invention can also serve other functions. For example a diluent can also serve as a bulk sweetener. Representative diluents include, but are not limited to, sucrose, sorbitol, xylitol, maltitol, dextrose, fructose, liquid glucose and mixtures thereof. A preferred diluent of the present invention is sucrose.

The diluent used either single or in combinations in the range of about 5% to about 80% by weight relative to the total weight of the composition.

The solvents or cosolvents in the present invention may include but not restricted to water, ethanol, polyethylene glycols (PEG), propylene glycol, glycerin, sorbitol, benzyl alcohol and the like. Solvents or cosolvents of the present invention can also serve other functions. For example a solvent or cosolvent can enhance palatability. A preferred solvent or cosolvent of the present invention is glycerin.

The solvent or cosolvent used either single or in combinations in the range of about 1% to about 40% by weight relative to the total weight of the composition.

The formulation of the present invention may include an appropriate amount of viscosity regulating agents; effective to stabilize the pharmaceutically active agent within the aqueous composition or used to increase the viscosity of the solution. A viscosity regulating agents of the present invention may include but not restricted to one or more of polymeric materials preferably polyvinyl pyrrolidone and hypromellose.
Optionally other viscosity regulating agents include polyacrylate and polyacrylate copolymer resins, celluloses and cellulose derivatives for example methyl-, ethyl- and propyl celluloses; hydroxyalkyl-celluloses, hydroxyl propyl celluloses, hydroxylpropylalkyl celluloses and the like including xanthan gum, polyvinyl resins, polyethylene glycol, polyethylene oxide, sorbitol, sucrose, xylitol, dextrose, fructose, maltitol, sugar, sodium alginate and the like.

The viscosity regulating agents used either single or in combinations in the range of about 0.05% to about 10% by weight relative to the total weight of the composition.

The formulation of the present invention may include an appropriate amount of stabilizing agents for the production of aqueous solution. A preferred stabilizing agent of the present invention may include but not restricted to aminoacids such as glutamic acid, cysteine, glycine and the like.

The stabilizing agent used either single or in combinations in the range of about 0.1% to about 3% by weight relative to the total weight of the composition.

The formulation of the present invention may include an appropriate amount of chelating agents in a suitable concentration range to stabilize the product during storage. A preferred chelating agent of the present invention may include disodium edetate and the like.

Optionally other agents may include but not restricted to edetic acid, tartaric acid, malic acid, citric acid and salts thereof.

The chelating agent used either single or in combinations in the range of about 0.01% to about 5% by weight relative to the. total weight of the composition.

Compositions of the present invention may include an appropriate amount of sweeteners used for better patient acceptability of the dosage form and also enhances the flavor system. Additionally sweetening agents are conveniently employed in low concentrations. A preferred sweetening agent of the present invention may include sucralose and the like.

Optionally, non-limiting examples of sweeteners may include but not restricted to saccharin, sodium saccharin, potassium saccharin, cyclamate, sodium cyclamate, aspartame, sucralose, thaumatin, acesulfame potassium, altitame, neotame, xylose, ribose, mannose, galactose, neohesperidin dihydrochalcone and the like.

The sweetening agent used either single or in combinations in the range of about 0.01% to about 5% by weight relative to the total weight of the composition.

Compositions of the present invention may include an appropriate amount of preservatives to prevent growth of micro organisms. A preferred anti microbial agents of the present invention is selected from the group of methyl paraben, propyl paraben or salts and the like.

Optionally other preservatives include but not restricted to butyl paraben, ethyl paraben, benzoic acid and its derivatives such as sodium benzoate, benzyl alcohol, sorbic acid, potassium sorbate, benzalkonium chloride and the like.

The preservatives used either single or in combinations in the range of about 0.005% to about 1% by weight relative to the total weight of the composition.

Compositions of the present invention may include an appropriate amount of antioxidants in a suitable concentration range to prevent oxidation. A preferred antioxidant of the present invention may include sodium metabisulfite.

Optionally other agents include but not restricted to ascorbic acid, sodium sulfite, sodium bisulfate, sodium thiosulfate, sodium ascorbate, sodium formaldehydesulfoxylate, malic acid, alkyl gallates like propyl gallate, lauryl gallate, or octyl gallate.

The antioxidant used either single or in combinations in the range of about 0.01% to about 3% by weight relative to the total weight of the composition.

Compositions of the present invention may include an appropriate amount of buffering agents to adjust the pH of the solution. The solutions according to present invention have a pH of about 2 to 5.5. A preferred buffering agent of the present invention is selected from citric acid, sodium citrate or mixture thereof.

Optionally other agents include but not restricted to phosphoric acid, succinic acid, tartaric, lactic acid, acetic acid and salts thereof, sodium hydroxide, sodium phosphate, sodium chloride, disodium hydrogen phosphate, sodium hydrogen carbonate, monosodium phosphate, monopotassium phosphate, potassium citrate and mixtures thereof.

The buffering agents used either single or in combinations to adjust pH (2 to 5.5) in the range of about 0.01% to about 5% by weight relative to the total weight of the composition.

Compositions of the present invention may include an appropriate amount of pharmaceutically acceptable color to provide a product with a more aesthetic and/or distinctive appearance.

Optionally other agents includes natural or synthetic dyes but not restricted to Carmoisine, FD&C Yellow No.5, FD&C Yellow No.6, FD&C Red No.3, FD&C Red No.20, FD&C Blue No.2, D&C Green No.5, D&C orange No.5, D&C Red No.8, caramel and the like.

The coloring agents used either single or in combinations in the range of about 0.001% to about 2% by weight relative to the total weight of the composition.

Compositions of the present invention comprise neutraceutically acceptable flavoring agents to impart a pleasant flavor and often odor to a pharmaceutical preparation and can enhance patient compliance by making the composition more palatable.

Optionally, non-limiting examples of flavoring agents may include but not restricted to cherry, vanilla, honey, lemon, strawberry, raspberry, black current, caramel chocolate, mint cool, fantasy flavor, bubble gum, citrus, lemon, lime, apple, apricot, peppermint, spearmint peach, pear, plum flavor and the like.
The flavoring agent used either single or in combinations in the range of about 0.01% to about 10% by weight relative to the total weight of the composition.

An aqueous solution may further include one or more pharmaceutically acceptable additives.

An aqueous solution of the present invention is easily administrable for pediatric and geriatric patients and thus patient compliance can be achieved.

The present invention containing pharmaceutical active agent equivalent to base is present at concentrations of 100 mg per 5 mL, 400 mg per 5 mL, 600 mg per 5 mL and 800 mg per 5 mL may be prepared with the above mentioned excipients using different proportions.

A pharmaceutical composition of the present invention may be used in the treatment of the human or animal body by therapy.

A process for the preparation of an aqueous oral solution comprising a therapeutically effective amount of Imatinib or its pharmaceutically acceptable salts and polymorphs thereof, mixing with one or more diluents in water followed by addition of water miscible solvent, a viscosity regulating agent, stabilizing agent, preservatives, buffering agents, chelating agent, antioxidant, sweetening agent, flavoring agent and coloring agent, where in the said solution has a pH from 2 to 5.5.

The amount of Imatinib mesylate and other polymorphs such as α , β or 012 thereof, required as a daily dose in treatment will vary not only with the route of administration, the nature of the disease condition being treated and the age, weight and condition of the patient will ultimately be at the discretion of the attendant physician. A suitable daily dose for use in treatment of Chronic Myeloid Leukemia,

Gastrointestinal Stromal Tumors and the like will generally be in the same range. It may be appropriate to administer the required dose as two, three, four or more sub doses at appropriate intervals throughout the day.

The formulations of the present invention were found to be stable throughout the stability testing storage period.

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the rationale and scope of the invention.

Figure 1 shows the bioavailability study of the formulation of the present invention and tablet dosage form of Imatinib.

The details of the process of the invention are provided in the examples given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. The preparation of the present invention that can be administered by the oral route is carried out according to the following process:

EXAMPLES
The components illustrated by the examples 1 to 25 are expressed in % by weight based on each composition.

In a specific embodiment the present invention provides a process for preparation of a composition, which comprises intimately mixing Imatinib with water miscible solvent containing preservatives followed by the addition of syrup base, viscosity regulating agent, buffering agent, flavoring agent, sweetener, coloring agent, chelating agent and an antioxidant for the intimate mixing until a clear solution is obtained or as mentioned under individual examples.

The compositions of Example 1 to 25, contains the

Table: 1

The processing steps involved in manufacturing an aqueous solution given in example 1 to 4 were given below:

1. Syrup base was prepared by dissolving sucrose in purified water.

2. Methyl paraben and propyl paraben were dissolved in glycerin under continuous stirring with application of heat; the solution is left to cool at room temperature and added to step (1).

3. Polyvinylpyrrolidone, sodium metabisulfite and disodium edetate were dissolved in purified water under continuous stirring and added to step (2); pH of the solution was adjusted to a desired value as needed by adding citric acid monohydrate and sodium citrate dihydrate.

4. Pharmaceutical active agent was added to step (3) under stirring.

5. Sweetening agent was added to step (4) under stirring.

6. Color was dissolved in purified water and added to step (5) under stirring.

7. Flavor was added to the solution obtained in step (6)

8. Finally the volume was adjusted with water.
Sorbitol solution (70% w/v) in an amount of 40% w/v and 20% w/v was added in the example 2 and 4 respectively.

Table: 2

The formulations given in examples 5 to 8 were prepared using similar procedure described in example 1 to 4. Parabens were replaced with Benzoic acid in example 7. Malic acid and Propyl gallate were used as antioxidants in example 7 and 8 respectively.

Table: 3
The formulations given in examples 9 to 12 were prepared using similar procedure described in example 1 to 4. Carboxy methyl cellulose sodium, Xanthan gum and Hypromellose were used as viscosity regulating agents in examples 9, 10 and 11 respectively. Combination of Xanthan gum and Hydroxy propyl cellulose were used as viscosity regulating agents in example 12.

Table: 4
The formulations given in examples 13 to 16 were prepared using similar procedure described in example 1 to 4. Parabens were replaced with Benzoic acid in example 13. Malic acid was used as an antioxidant in example 13.

Table: 5

The formulations given in examples 17 to 20 were prepared using similar procedure described in example 1 to 4. Parabens were replaced with Benzoic acid in examples 17, 18 and 20.

Table: 6

The formulations given in examples 21 to 25 were prepared using similar procedure described in example 1 to 4. Propylene glycol was used as a solvent in example 22 and 23. Hypromellose, Hydroxy propyl cellulose, Polyethylene glycol and Polyethylene oxide were used as viscosity regulating agents in examples 22, 23, 24 and 25 respectively. Parabens were replaced with Sodium benzoate in example 22 and 23.

BIOAVAILABILITY STUDY FOR THE COMPOSITIONS IN ACCORDANCE WITH THE INVENTION:
The plasma kinetics of the oral solution as described in above mentioned examples have been compared with those of the Imatinib tablets (manufactured using pharmaceutically acceptable additives) in a comparative study. This comparative study was carried out with wistar albino rats; weighing 150-210 grams which were divided into different sets of study (two rats in each set) and fasted overnight prior to dosing, but were permitted water ad libitum. Both formulations were administered at the dose of 20 mg/kg body weight. Blood samples were collected by puncturing retero-orbital sinus of the anaesthetized rats (with anesthetic ether) at different intervals post administration. Blood collection was done in prefilled heparin centrifugation tubes.

The blood samples collected were subjected for the subsequent centrifugation and followed by analytical procedure with the use of LCMS technique. The areas under the blood drug concentration versus time curves were calculated by the trapezoidal rule. The analysis was done with respect to AUC (area under curve) and Cmax (maximum concentration).

The average AUC and Cmax values from typical trial runs are shown in the following table.

Table: 7
The aforementioned table gives an account of the bioavailability (AUC, Cmax) of the Imatinib tablet dosage form and formulation in the present invention.

ADVANTAGES OF THE INVENTION

a) Oral solution of a phenylaminopyrimidine derivative for example Imatinib is prepared which is used as BCR-ABL tyrosine kinase inhibitor for the treatment of Chronic Myeloid Leukemia, Gastrointestinal Stromal Tumors and the like.

b) Patient compliance can be achieved with the oral solution as it is easy to be administered so particularly preferable in pediatric and geriatric patients.

c) The advantage further encompasses the stability aspects and the formulation is found to be stable throughout the period of the stability study.

d) Industrial applicability: as ease of manufacturing procedure for the scale-up batches and more economical.

e) Particularly till date, the use of this said derivative in an orally administrable solution is not commercially available.

f) Imatinib oral solution can be viable alternative to patients who cannot swallow solid dosage forms.

We Claim:

1. An oral aqueous solution comprising Imatinib mesylate in an amount from about 0.1% to 30% by weight relative to the total weight of the composition.

2. The oral aqueous solution according to claim 1 which comprises a, P or ci2 polymorphs of Imatinib or its pharmaceutically acceptable salts.

3. The oral aqueous solution according to any preceding claim, wherein the pH of the solution is about 2 to 5.5.

4. The oral aqueous solution according to any preceding claim further comprises one or more pharmaceutically acceptable additives.

5. The oral aqueous solution according to claim 4, wherein the pharmaceutically acceptable additives comprise one or more of diluents, water miscible solvents, viscosity regulating agent, stabilizing agent, preservatives, buffering agents, chelating agent, antioxidant, sweetening agent, flavoring agent and coloring agent.

6. The oral aqueous solution according to claim 5, wherein the diluent is selected from bulk sweeteners consisting of sucrose, sorbitol, xylitol, maltitol, dextrose, fructose, liquid glucose or mixtures thereof.

7. The oral aqueous solution according to claim 6, wherein the diluent is present in an amount of about 5% by weight to about 80% by weight relative to the total weight of the composition.

8. The oral aqueous solution according to claim 5, wherein the solvent or co solvent is selected from glycerin or propylene glycol or mixtures thereof.

9. The oral aqueous solution according to claim 8, wherein the solvent or co solvent is present in an amount of about 1% by weight to about 40% by weight relative to the total weight of the composition.

10. The oral aqueous solution according to claim 5, wherein the viscosity regulating agent is selected from polyvinyl pyrrolidone, hypromellose, xanthan gum, hydroxyl propyl cellulose, carboxy methyl cellulose sodium, polyethylene glycol, polyethylene oxide or mixtures thereof.

11. The oral aqueous solution according to claim 10, wherein the viscosity regulating agent is present in an amount of about 0.05% by weight to about 10% by weight relative to the total weight of the composition.

12. The oral aqueous solution according to claim 5, wherein the stabilizing agent is selected from aminoacids such as glutamic acid, cysteine, glycine or mixtures thereof.

13. The oral aqueous solution according to claim 12, wherein the stabilizing agent is present in an amount of about 0.1% by weight to about 3% by weight relative to the total weight of the composition.

14. The oral aqueous solution according to claim 5, wherein the chelating agent is disodium edetate.

15. The oral aqueous solution according to claim 14, wherein the chelating agent is present in an amount of about 0.01% by weight to about 5% by weight relative to the total weight of the composition.

16. The oral aqueous solution according to claim 5, wherein the sweetening agent is sucralose.

17. The oral aqueous solution according to claim 16, wherein the sweetening agent is present in an amount of about 0.01% by weight to about 5% by weight relative to the total weight of the composition.

18. The oral aqueous solution according to claim 5, wherein the flavoring agent is selected from aqueous based flavors, either individually or in combination.

19. The oral aqueous solution according to claim 18, wherein the flavoring agent is present in an amount of about 0.01% by weight to about 10% by weight relative to the total weight of the composition.

20. The oral aqueous solution according to claim 5, wherein the preservative is selected from methyl paraben, propyl paraben or salts or benzoic acid or sodium benzoate thereof, either individually or in combination.

21. The oral aqueous solution according to claim 20, wherein the preservative is present in an amount of about 0.005% by weight to about 1% by weight relative to the total weight of the composition.

22. The oral aqueous solution according to claim 5, wherein the antioxidant is selected from sodium metabisulfite, propyl gallate or malic acid.

23. The oral aqueous solution according to claim 22, wherein the antioxidant is present in an amount of about 0.01% by weight to about 3% by weight relative to the total weight of the composition.

24. The oral aqueous solution according to claim 5, wherein the buffering agent is selected from citric acid, sodium citrate or mixture thereof.

25. The oral aqueous solution according to claim 24, wherein the buffering agent is present in an amount of about 0.01% by weight to about 5% by weight relative to the total weight of the composition.

26. The oral aqueous solution according to claim 5, wherein the coloring agent is selected from aqueous based colors, either individually or in combination.

27. The oral aqueous solution according to claim 26, wherein the coloring agent is present in an amount of about 0.001% by weight to about 2% by weight relative to the total weight of the composition.

28. A process for producing an aqueous oral solution according to any one of preceding claims, which process comprises mixing with one or more diluents in water followed by addition of water miscible solvent, viscosity regulating agent, stabilizing agent, preservatives, chelating agent, antioxidant, sweetening agent, flavoring agent and coloring agent and buffering agent to maintain the pH of the solution from about 2 to 5.5.