Title of Invention

BIOLOGICALLY EQUIVALENT, STABLE ORAL PHARMACEUTICAL SOLUTION OF TRAZODONE

Abstract

The present invention discloses a liquid pharmaceutical formulation for oral administration to a subject in need thereof which comprises a biologically equivalent and therapeutically effective amount of Trazodone or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable liquid carrier, one or more taste-enhancing/masking agents, preservatives, colouring agents and a buffering agent.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970)&The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "Biologically equivalent, stable oral pharmaceutical solution of Trazodone" 2. APPLICANT (a) NAME: URSAM PHARMA (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: St. Jude Apartment, Guirim, Bardez, Mapusa, Goa - 403507, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical field: The present invention relates to liquid pharmaceutical composition for oral administration comprising serotonin reuptake inhibitor or its pharmaceutically acceptable salts in association with pharmaceutically acceptable liquid carrier for the treatment of depression or other central nervous system diseases. More particularly the present invention relates to a biologically equivalent and physicochemically stable oral pharmaceutical solution composition comprising trazodone or its pharmaceutically acceptable salt. Background and prior art Trazodone was first disclosed in US patent 3381009, is a special type of antidepressant used to treat depression or sleeplessness and also used to treat other conditions. Trazodone regulates the mood by increasing the available amount of certain brain chemicals. Trazodone is a generic name given to 2-[3-[4-(3-chlorophenyl)-l-piperazinyl]propyl]-l,2,4-triazolo[4,3-a]pyridine-3(2H)-one, which is having the following structure. In recent years, Trazodone has been increasingly used as an antidepressant in elderly population. It is also used as an agent to calm agitated patients - particularly in the long term nursing facilities due to its sedative and anti-anxiety properties. Moreover, its use at bedtime to treat mild insomnia is especially convenient since the usage does not need to be monitored as other benzodiazepine related drugs which are controlled and have abuse potentials. Reported prior arts describe various trazodone formulations in association with serotonin precursor or in association with B6 or in association with folate source used 2 for the treatment of depression disclosed as in EP1266659, US6191133, and US5739136 all of which are incorporated herein by reference in their entirety. Trazodone HC1 is also useful in elderly depressed patients, in whom daily dosage requirements are normally reduced because of pharmacokinetic changes associated with aging (i.e., reductions in both hepatic clearance and protein binding). In these patients, antidepressant therapy is usually initiated at a low dosage and increased over a 7- to 10-day period to achieve the initial target dosage and may have to be increased further in some patients in order to achieve the best results. A patient friendly suitable dosage form, such as liquid which can be very easily and continuously titrated up or downwards with increments of fractions of milliliters is thus a significant benefit over solid dosage forms which can not be used in fine dose titrations. Slow tapering of the antidepressant medication is often practiced after few years of treatment if the patient is completely asymptomatic and is not experiencing or anticipating significant stressors. Again, liquid dosage form which can be very easily and continuously tapered downwards by using fractions of milliliters is thus a significant benefit over the solid dosage forms. For very old and smaller patients, when the prescribed dosage of Trazodone are much smaller, such as 6.25, 12.5, or 25 mg, the pharmacist has to cut the tablet in half, or quarter, and in some cases even to one eighth since such small dose tablets or capsules are commonly not available. It is not only inconvenient to divide these many a times un-scored dosage forms but it also results in erroneous dose delivery due to imprecision in cutting. The oral solution formulation of Trazodone is thus ideal since fraction of a dose can be very easily measured as a solution using an oral syringe or calibrated spoon. The oral liquid is also desirable in the case of severely ill or incapacitated patients needing medications administered through gastric or nasal tubes. In these patients, nurses always prefer liquid products as it also eliminates the need for crushing the solid dosages to administer through the tubes. It is clear from the above discussion, that a pharmaceutically stable and biologically equivalent solution of Trazodone HC1 for oral administration is required for a large section of patient population. However, no such stable liquid formulation of 3 Trazodone for oral administration is available for convenient deliveries to convalescent, geriatric, and pediatric populations. Hence, the present invention of liquid dosage form for oral administration is aimed to fulfill this unmet need. The present invention offers technical advancement and also has economic significance for elderly, invalid and infant patient community. Objective of the invention: The main objective of the present invention is aimed to provide liquid pharmaceutical composition comprising Trazodone HC1 for oral administration for geriatric, and pediatric patients. The other objective of the present invention is to provide novel liquid formulation for oral administration which is aesthetically desirable, pharmaceutical^ elegant, physico-chemically stable over extended period of time and pharmacokinetically bioequivalent to the currently marketed tablet formulation. Further objective is to provide palatable formulation for patient compliance. Summary of the invention: The present invention discloses liquid pharmaceutical solution for oral administration to a subject in need thereof which comprises a therapeutically effective amount of Trazodone or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable liquid carrier. In the present invention, the formulation is provided such that it is palatable, its optimum solubility is maintained for extended period of time, long term chemical stability is ensured, and it is pharmacokinetically equivalent to the other solid oral dosage forms using excipients such as co-solvents, one or more taste-enhancing/masking agents, preservatives, and a buffering agent. The invention also provides process for preparation thereof.. Detailed description of the invention: The present invention describes a liquid pharmaceutical solution for oral administration to a subject in need thereof which comprises a therapeutically effective amount of Trazodone or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable liquid carrier. 4 The present invention has overcome the major challenges of formulating an oral solution of Trazodone HC1 including a) masking of the bitter and tingling taste of the drug, b) maintaining optimum solubility of the drug, c) ensuring long term stability, and d) ensuring bioequivalence to the solid dosage forms using formulation excipients suitable for chronic administration and suitable for administration to both pediatric and geriatric patients. In a preferred embodiment, the present invention is directed to a liquid formulation of Trazodone or its pharmaceutically acceptable salts, wherein the formulation comprises a therapeutically effective amount of Trazodone in a liquid carrier, which contain polyhydric alcohol, polyhydroxy sugar, taste-enhancing/masking agent, preservative, buffering agent and water or combination thereof. The liquid carrier is water and contains other miscible co-solvents selected from the group consisting of ethanol, benzyl alcohol, polyhydric alcohols such as glycerin, propylene glycol, sorbitol, and polyethylene glycols. The taste-enhancing/masking agents comprise one or more sweeteners, or flavoring agents. The sweeteners comprise one or more natural sweeteners such as selected from the group consisting of sucrose, fructose, dextrose, maltose, glucose and glycerin, one or more semi-synthetic natural sweeteners selected from the group consisting of maltitol, xylitol, sorbitol and mannitol, or one or more synthetic sweeteners selected from the group consisting of saccharin, acesulfame potassium, and aspartame. The flavoring agents are selected from the group consisting of cherry, orange, peppermint, strawberry, aniseed, peach, raspberry and orange cream. The pharmaceutically acceptable preservatives comprise one or more anti-microbial preservatives, one or more antioxidants, and one or more chelating agents. The antimicrobial preservatives are selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, benzoic acid, sodium benzoate, benzyl alcohol, sorbic acid and potassium sorbate. The antioxidants are selected from the group consisting of sodium metabisulfite, sodium bisulfite, propyl gallate, sodium ascorbate and ascorbic acid. 5 The buffering agent is selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, and their salts wherein the resulting solution has a pH from 2.5 to 5.5; adjusted using either alkali or acid. The various embodiments of the present invention comprising Trazodone HC1 and other carefully selected excipients, show: a) good physical stability; b) maintains solubility of the Trazodone and other excipients upon storage under normal and stress conditions; and c) are non-bitter and pleasant in flavor, by virtue of the composition of the formulation. In a more preferred embodiment, the liquid formulation of the present invention contains at least one or more of the following components: about 0.5 to about 5% by weight of Trazodone HC1, about 5% to about 40%> by weight of polyhydric alcohol, about 30% to about 70%> by weight of polyhydroxy sugar, about 5%> to about 20%> by weight of polyethylene glycol, about 5% to about 20% by weight of propylene glycol, about 5% to about 60% by weight of glycerin, about 0.05% to about 0.25% by weight of preservative, about 0.05% to about 0.2% by weight of artificial sweetener, about 0.05% to about 0.1 % by weight of artificial flavoring agent, and about 0.05% to about 2% by weight of buffering agent and the rest being made up with purified water. The pH of such embodiment is carefully adjusted to 2.5 to 5.5 pH units using either alkali or acid. In another embodiment, the liquid formulation comprises a therapeutically effective amount of Trazodone or its pharmaceutically acceptable salt, a sorbitol based carrier that comprises about 40% to about 70% by weight of D-sorbitol, about 5% to about 20%) by weight of polyethylene glycol, about 5% to about 20% by weight of propylene glycol, about 5% to about 60% by weight of glycerin, about 0.05% to about 0.25% by weight of preservative, about 0.05% to about 0.2% by weight of artificial sweetener, about 0.05% to about 0.1%) by weight of artificial flavoring agent, and about 0.05%) to about 2% by weight of buffering agent and the rest being made up with purified water. The pH of such embodiment is carefully adjusted to 2.5 to 5.5 pH units using alkali or acid. 6 In another embodiment, the liquid formulation comprises a therapeutically effective amount of Trazodone or its pharmaceutically acceptable salt, a reduced calorie sugar based carrier that comprises about 30% to about 65% by weight of Xylitol, about 5% to about 20% by weight of polyethylene glycol, about 5% to about 20% by weight of propylene glycol, about 5% to about 60% by weight of glycerin, about 0.05% to about 0.25% by weight of preservative, about 0.05% to about 0.2% by weight of artificial sweetener, about 0.05% to about 0.1 % by weight of artificial flavoring agent, and about 0.05% to about 2% by weight of buffering agent and the rest being made up with purified water. The pH of such embodiment is carefully adjusted to 2.5 to 5.5 pH units using alkali or acid. In another embodiment, the liquid formulation comprises a therapeutically effective amount of Trazodone or its pharmaceutically acceptable salt, a reduced calorie sugar based carrier that comprises about 30% to about 65% by weight of Maltitol, about 5% to about 20% by weight of polyethylene glycol, about 5% to about 20% by weight of propylene glycol, about 5% to about 60% by weight of glycerin, about 0.05% to about 0.25% by weight of preservative, about 0.05%> to about 0.2% by weight of artificial sweetener, about 0.05% to about 0.1%) by weight of artificial flavoring agent, and about 0.05%) to about 2% by weight of buffering agent and the rest being made up with purified water. The pH of such embodiment is carefully adjusted to 2.5 to 5.5 pH units using alkali or acid. In yet another embodiment, the liquid formulation comprises a therapeutically effective amount of Trazodone or its pharmaceutically acceptable salt, a self preserving carrier base that comprises about 5% to about 60% by weight of glycerin, about 5% to about 20% by weight of propylene glycol, about 0.05% to about 0.2% by weight of artificial sweetener, about 0.05% to about 0.1%) by weight of artificial flavoring agent, and about 0.05% to about 2% by weight of buffering agent and the rest being made up with purified water. The pH of such embodiment is carefully adjusted to 2.5 to 5.5 pH units using alkali or acid. The composition of the present invention containing Trazodone Hydrochloride (HC1) formulated as liquid dosage form for oral administration is useful for treating depression and can also be used successfully in the treatment of aggressive behavior, 7 control of cravings for alcohol, treatment of cocaine withdrawal as well as in the treatment of panic disorder or agoraphobia. The composition is especially useful in a patient population consisting of geriatric, pediatric, bed-ridden, and/or intubated patients, and others who experience difficulty in swallowing solid dosage forms. The liquid formulation has been shown to be chemically compatible with many other common edible fluids, such as juices, sauces, and other foods and thus can be administered with ease by mixing or dispersing the medication as a part of regular feeding. Other major attribute of such embodiment of Trazodone oral solution is its proven bioequivalence with a commercially available leading brand of solid dosage tablet. One such embodiment of Trazodone oral solution was investigated in a single dose, oral relative bioavailability study in which comparison with a leading brand conventional release Trazodone hydrochloride 50 mg tablet formulation was performed. In this double blind, cross-over, bioequivalence study using healthy human male volunteers, it was found that at 90% confidence interval (CI), both AUC and C-max of Trazodone from the preferred liquid formulation for oral administration conformed well within the bioequivalence prescribed limits (80-125%), set by international regulatory agencies, such as United States Food and Drug Administration, MCA, as well as European Union drug approval agencies. Proof of such bioequivalence of the subject embodiment is extremely important in clinical as well as pharmacy practice since switchover from the tablet to liquid formulation for oral administration can occur automatically without the need for physician's approval. Stability data: The composition of the present invention shows excellent chemical stability upon storage under normal and stress conditions; maintains more than 95% of its initial content when exposed to 45° C for three months; 98% of its initial content when exposed to 40° C/75% Relative Humidity for three months; and more than 98% of its initial content when stored at room temperature for three years. The following examples further illustrate the present invention. 8 EXAMPLE 1 In a suitable manufacturing container, 300 milliliters of purified water (of pharmacopoeial quality such as USP) was added. To this 40 gm of citric acid was added and agitated until dissolved. To this solution, 100 gm of propylene glycol was added and 20 ± 0.5 gm of Trazodone HCl was dissolved with vigorous agitation using at least 100 RPM. Upon complete dissolution of the Trazodone HCl, 100 gm of glycerin was added, followed by the addition of 1284 gm of sorbitol solution (70%) (of pharmacopoeial quality such as USP). In two separate containers, 4 gm of sodium benzoate in 25 ml of purified water, and 2 gm of sodium saccharin in 25 ml of purified water were dissolved and the resulting solutions were added to the manufacturing container. The solution was stirred for about 15 minutes and the pH of the solution was checked and adjusted, if required, to optimum of 4.5, using 1 N sodium hydroxide solution or IN hydrochloric acid solution. The resulting solution was then adjusted to the final volume of 2 L using the purified water. The final solution was then clarified using 200-400 mesh stainless steel or 25-50 micron polypropylene filters. EXAMPLE 2 In a suitable manufacturing container, 250 milliliters of purified water (of pharmacopoeial quality such as USP) was added. To this 20 gm of citric acid and 5 gm of sodium citrate was added and agitated until dissolved. To the solution, 50 gm of propylene glycol was added and 25 ± 0.5 gm of Trazodone HCl (of pharmacopoeial quality such as USP)was dissolved with vigorous agitation using at least 100 RPM. Upon complete dissolution of the Trazodone HCl, 100 gm of glycerin (of pharmacopoeial quality such as USP) was added, followed by the addition of 800 gm of xylitol. In two separate containers, 4 gm of sodium benzoate in 25 ml of purified water, and 2 gm of sodium saccharin and 1 gm of orange flavor in 25 ml of water were dissolved and the resulting solutions were added to the manufacturing container. The solution was stirred for about 15 minutes and the pH of the solution was checked and adjusted, if required, to optimum of 4.5, using 1 N sodium hydroxide solution or IN hydrochloric acid solution. The resulting solution was then adjusted to the final volume of 2 L using the purified water. The final solution was 9 then clarified using 200-400 mesh stainless steel or 25-50 micron polypropylene filters. EXAMPLE 3 In a suitable manufacturing container, 250 milliliters of purified water (of pharmacopoeia! quality such as USP) was added. To this 20 gm of citric acid and 5 gm of sodium citrate was added and agitated until dissolved. To the solution, 80 gm of propylene glycol was added and 50 ± 0.5 gm of Trazodone HCl (of pharmacopoeial quality such as USP) was dissolved with vigorous agitation using at least 100 RPM. Upon complete dissolution of the Trazodone HCl, 80 gm of glycerin was added, followed by the addition of 900 gm of maltitol (of pharmacopoeial quality such as NF). In two separate containers, 4 gm of sodium benzoate in 25 ml of purified water, and 2 gm of sodium saccharin in 25 ml of water were dissolved and the resulting solutions were added to the manufacturing containers. The solution was stirred for about 15 minutes and the pH of the solution was checked and adjusted, if required, to optimum of 4.5, using 1 N sodium hydroxide solution or IN hydrochloric acid solution. The resulting solution was then adjusted to the final volume of 2 L using the purified water. The final solution was then clarified using 200-400 mesh stainless steel or 25-50 micron polypropylene filters. EXAMPLE 4 In a suitable manufacturing container, 300 milliliters of purified water (of pharmacopoeial quality such as USP) was added. To this 25 gm of citric acid was added and agitated until dissolved. To the solution, 50 gm of propylene glycol was added and 25 ± 0.5 gm of Trazodone HCl was dissolved with vigorous agitation using at least 100 RPM. Upon complete dissolution of the Trazodone HCl, 1200 gm of glycerin (of pharmacopoeial quality such as USP) was added. The solution was stirred for about 15 minutes and the pH of the solution was checked and adjusted, if required, to optimum of 4.5, using 1 N sodium hydroxide solution or IN hydrochloric acid solution. The resulting solution was then adjusted to the final volume of 2 L using the purified water. The final solution was then clarified using 200-400 mesh stainless steel or 25-50 micron polypropylene filters. 10 claim: 1. A stable liquid pharmaceutical formulation suitable for oral administration comprising Trazodone HC1 in the concentration range of 0.5 to 50 mg/ml, a pharmaceutical^ suitable liquid carrier, one or more taste-enhancing/masking agents, preservatives, and a buffering agent. 2. The liquid pharmaceutical formulation as claimed in claim 1 wherein the pH of the formulation ranges from 2.5 to 5.5. 3. The liquid pharmaceutical composition as claimed in claim 1, wherein said suitable liquid carrier comprises water, optionally in association with a water-miscible cosolvent selected from the group comprising ethanol, benzyl alcohol or polyhydric alcohols such as glycerin, propylene glycol, sorbitol, and polyethylene glycols in the amount varying from 5% to 70%. 4. The liquid pharmaceutical formulation as claimed in claim 1 wherein said taste enhancing/masking agent comprises sweeteners or flavoring agents. 5. The liquid pharmaceutical formulation as claimed in claim 4 wherein said sweetener is selected from natural sweetener comprising sucrose, fructose, dextrose, maltose, glucose and glycerin; semi-synthetic natural sweetener comprising poly hydroxy sugars such as maltitol, xylitol, sorbitol and mannitol and synthetic sweetener comprising saccharin, acesulfame potassium and aspartame either alone or in combinations thereof. 6. The liquid pharmaceutical formulation of claim 5, wherein the polyhydroxy sugar is selected from sorbitol, xylitol and maltitol present in amounts ranging from 40% to 70% by weight, 30% to 65% by weight and 30% to 65% by weight respectively. 7. The liquid pharmaceutical formulation as claimed in claims 1 and 4 wherein said flavoring agent is selected from the group comprising cherry, orange, peppermint, strawberry, aniseed, peach, raspberry and orange cream in amounts ranging from 0.05 to 0.1% by weight. 8. The liquid pharmaceutical formulation as claimed in claim 1 wherein said preservative comprises anti-microbial preservatives, anti-oxidants and chelating agents in the range of 0.05% to 0.25%. 9. The liquid pharmaceutical formulation as claimed in claim 8, wherein said anti-microbial preservative is selected from the group comprising 11 methylparaben, ethyl paraben, propylparaben, butylparaben, benzoic acid, sodium benzoate, benzyl alcohol, sorbic acid and potassium sorbate. 10. The liquid pharmaceutical formulation as claimed in claim 8, wherein said antioxidants is selected from the group comprising sodium metabisulfite, sodium bisulfite, propyl gallate, sodium ascorbate and ascorbic acid. 11. The liquid pharmaceutical formulation as claimed in claim 1, wherein said buffering agent is selected from lactic acid, citric acid, tartaric acid and acetic acid and their salts in amounts ranging from 0.05 to 2% by weight. 12. The liquid pharmaceutical formulation as claimed in claim 2 wherein said pH is adjusted to 2.5 to 5.5 using acid or alkali selected from Hydrochloric acid or sodium hydroxide. 13. The liquid pharmaceutical formulation as claimed in claim 1 , wherein glycerin is present as self-preserving agent in amounts ranging from 5% to 60% by weight by weight. 14. A method of treating depression in a subject in need of treatment comprising administering to said subject the liquid pharmaceutical formulation comprising an effective amount of an anti-depressant as claimed in any of the claims 1 to 13. 15. A stable liquid pharmaceutical formulation suitable for oral administration as substantially described herein with reference to the foregoing examples 1 to 4. Dated this 3rd day of October 2005 12 Abstract: The present invention discloses a liquid pharmaceutical formulation for oral administration to a subject in need thereof which comprises a biologically equivalent and therapeutically effective amount of Trazodone or a pharmaceutical ly acceptable salt thereof in association with a pharmaceutically acceptable liquid carrier, one or more taste-enhancing/masking agents, preservatives, colouring agents and a buffering agent. 13

Documents:

1242-MUM-2005-ABSTRACT(15-10-2008).pdf

1242-mum-2005-abstract.doc

1242-mum-2005-abstract.pdf

1242-mum-2005-cancelled pages(15-10-2008).pdf

1242-MUM-2005-CLAIMS(15-10-2008).pdf

1242-mum-2005-claims(granted)-(15-10-2008).doc

1242-mum-2005-claims(granted)-(15-10-2008).pdf

1242-mum-2005-claims.doc

1242-mum-2005-claims.pdf

1242-MUM-2005-CORRESPONDENCE(15-10-2008).pdf

1242-mum-2005-correspondence(ipo)-(12-1-2009).pdf

1242-mum-2005-correspondence-received-ver-25102005.pdf

1242-mum-2005-correspondence-received.pdf

1242-mum-2005-description (complete).pdf

1242-MUM-2005-DESCRIPTION(COMPLETE)-(15-10-2008).pdf

1242-MUM-2005-FORM 1(3-10-2005).pdf

1242-mum-2005-form 18(28-11-2007).pdf

1242-mum-2005-form 2(15-10-2008).pdf

1242-mum-2005-form 2(granted)-(15-10-2008).doc

1242-mum-2005-form 2(granted)-(15-10-2008).pdf

1242-MUM-2005-FORM 2(TITLE PAGE)-(15-10-2008).pdf

1242-mum-2005-form 26(3-10-2005).pdf

1242-MUM-2005-FORM 3(15-10-2008).pdf

1242-mum-2005-form-1.pdf

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1242-mum-2005-form-2.pdf

1242-mum-2005-form-3.pdf