GB2594242A

GB2594242A - A stable and ready to administer liquid pharmaceutical composition of topiramate

Info

Publication number: GB2594242A
Application number: GB2005448.2A
Authority: GB
Inventors: Patel Kamlesh; Kumar Neerumalla Suresh
Original assignee: Syri Ltd
Current assignee: Syri Ltd
Priority date: 2020-04-14
Filing date: 2020-04-14
Publication date: 2021-10-27
Also published as: GB202005448D0

Abstract

A stable liquid pharmaceutical composition for oral administration comprising (a) topiramate, or its pharmaceutically acceptable salts thereof, present in a range of 0.05% w/v to 5% w/v, (b) a mixture of at least two solubilizers, and (c) a non-aqueous solvent, is provided. Preferably, the non-aqueous solvent is selected from the group consisting of glycerol, isopropyl myristate, isopropyl palmitate, almond oil, olive oil, isopropyl alcohol or a combination thereof. Preferably, the mixture of at least two solubilizers is selected from the group consisting of propylene glycol, polyethylene glycol, polysorbates, ethanol, polyhydric alcohol, poloxamer, or combination thereof, and wherein the non-aqueous solvent is glycerol. The liquid pharmaceutical composition may further comprise a sweetener and a flavouring agent. A process for the preparation of the stable liquid pharmaceutical composition is also provided. A composition comprising 1) 5mg/ml or 10mg/ml topiramate; 2) a mixture of solubilizers selected from propylene glycol, polyethylene glycol 400, polysorbate 80 and ethanol having a total concentration of 0.1mg/ml to 100mg/ml; 3) 0.8mg/ml sodium saccharin; 4) glycerol; and 5) 0.65mg/ml levomenthol is outlined.

Description

Title: A Stable and ready to administer liquid pharmaceutical composition of Topiramate. Field of Invention: [1] The present invention relates to the field of pharmaceutical composition. In particular, it relates to liquid pharmaceutical composition of Topiramate. The present invention also relates to the process for preparing the liquid pharmaceutical composition of Topiramate.

Background of Invention:

[2] Topiramate was first time disclosed in U.S. Patent No. 4,513,006 and is used as anti-convulsant agent.

[03] It is sulfamate substituted monosaccharide with some activity against carbonic anhydrase. It is known to be a compound having a structure: [4] Chemically, topiramate is designated as 2,3:4,5 bis 0 (1 methylethylidene) I3 D fructopyranose sulfamate. It has the molecular formula Cl2H211\108S and a molecular weight of 339.4. Topiramate has a utility as sodium channel blocker, an anticonvulsant medicine used as monotherapy and as an adjunctive therapy in the treatment of partial and generalized tonic-clonic seizures and the seizures associated with Lennox gastaut syndrome in adults and children who are at least 2 years old. Some brands of Topiramate such as Trokendi XReand Qudexy XR®are also used to prevent migraine headaches in adults and adolescents who are at least 12 years old.

[5] Topiramate is white to off white powder with a bitter taste. It is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Its solubility in water is 9.8 mg/ml. Due to its sensitivity towards light and moisture, the powder is preserved in tight, light resistant container and stored at room temperature.

[6] Initially, Topiramate was granted a regulatory approval in form of tablets bearing the brand name ropamax®. But tablets aren't considered to be the dosage form suitable for every segment of patients.

[7] A sprinkle Capsule is sold in the market with the brand name Topamax®. These are small beads sprinkled on soft food before consumption and swallowed by the paediatric patients along with the food. The main concern with this dosage form is that the unintentional chewing of beads may compromise the safety and efficacy of the loaded drug and also, the unpleasant taste of drug may lead to poor compliance.

[8] Other brands of Topiramate such as Trokendi XR®, and Qudexy XR® are available as extended release capsules. Capsule is considered to be one of the complicated dosage forms to manufacture and administer, especially to the patients who are unable to swallow. Moreover, the extended release dosage form doesn't provide a drug release over a period of time which is longer than the release from an immediate release composition.

[9] There is no orally administered liquid composition available in the market. Therefore, in the absence of those solutions, extemporaneous preparations are being dispensed as oral suspension with the strength of 20mg/m1 in which topiramate tablet is pulverized to a fine powder and blended with Ora-plus and Ora-sweet to final volume. The major drawback of such kind of preparation is that it carries the risk of non-standardised compositions, lack of uniformity in dosing, lack of long term physical stability and possible microbial contamination.

[10] European patent number 1,888,030 discloses Paediatric liquid composition of topiramate which is under clinical trials. In brief, the composition intended for paediatric patients is pre-concentrate liquid for oral administration which is reconstituted with an aqueous medium along with sweeteners and flavours before administration. The composition of this kind also increases the chances of dosage error and consumes valuable time in case of emergency. The reconstituted composition has a shelf life of up to six weeks.

[11] Not a single oral liquid composition is available in Unites states. However, as per the recent updates, FDA has approved its investigational new drug (IND) application for its first ever liquid composition (Oral suspension) of topiramate, providing a new delivery alternative for the therapy used in epilepsy and migraine. In comparison with solution, suspension are known to be a less stable form due to their ability of sedimentation and forming a cake at the bottom of container which sometimes becomes difficult to re-disperse and thus uniformity of solid particles throughout the external phase is not maintained. Suspension comes with other obstacles like dissatisfactory pourability, extra care while handling and transporting.

[12] Oral suspension of Topiramate is approved and being sold in United Kingdom, having the strength of 10 mg/ml and 20 mg/ml. Apart from the general complications of suspension, this marketed composition requires special precautions for handling. In addition to that, the suspension cannot be administered with ease at the time of emergency as the administration is done through syringe.

[13] To overcome the above constrains of prior art and the already marketed formulations, the inventors of present invention have surprisingly come up with a ready-to administer and physically stable liquid composition of Topiramate for the treatment of seizure, which is made with the simple and uncomplicated procedure. In case of paediatric or geriatric patients who face difficulty in swallowing the tablet or capsule, the liquid composition becomes more desirable. The liquid pharmaceutical composition of present invention is administered without reconstitution or any extra precautions of its handling.

Summary of Invention: [14] [15] [16] [17] [18]

Since Topiramate is a powder with a bitter taste, the complete solubility of such powder in solvent is necessary to increase the palatability and acceptance of the composition and also having the stability concern, stable composition is the main object of present invention.

Disclosed herein is a stable, ready-to-administer liquid pharmaceutical composition comprises topiramate or its pharmaceutically acceptable salts thereof.

An aspect of current invention is to provide a stable liquid pharmaceutical composition comprising topiramate or its pharmaceutically acceptable thereof present in the range of about 0.05% w/v to about 5% w/v, mixture of at least two solubilizers and a non-aqueous solvent In an embodiment, the liquid pharmaceutical composition comprises a combination of two solubilizers; more preferably, combination of three solubilizers; most preferably, combination of four solubilizers.

One more aspect of the present invention is to provide process of preparation of the liquid composition as claimed in claim 13.

Description:

[19] Topiramate has a bitter taste with a low solubility in water and is unstable in presence of light and moisture. Hence, the present invention is based on the selection and combination of suitable solubilizers in order to combat the low solubility issues of active ingredient and to provide the kind of composition which is homogenous, stable & has a long shelf life which doesn't get affected in the presence of external factors and at the same time can be administered easily.

[20] The present invention is designated as "stable" if they provide the same or less amount of total impurities when exposed to the wide range of system parameters i.e. temperature or relative humidity. In particular, the stable compositions of the present invention have been found to exhibit 1% or less, preferably 0.8% or less of total impurities.

[21] The term "ready-to-administer" means the liquid composition is mixed with solvent and prepared at the time of manufacture and can be taken immediately at the time of administration without any reconstitution and dilution.

[22] The term "mixture of at least two solubilizers "means that two or more than two substances which are used to improve the solubility of a poor water soluble drug.

[23] In one of the embodiments, a liquid pharmaceutical composition of present invention comprises the combination of at least three solubilizers and preferably four solubilizers.

[24] In another embodiment, the mixtures of solubilizers are selected from the group consisting of non-ionic surfactant, ionic surfactant, hydrophilic polymer, ethanol, and polyhydric alcohol.

[25] A non-ionic surfactant as referred to herein includes a non-ionisable surface-active agent which reduces the surface tension of a liquid and thus allows it to foam or wet a solid.

Non-limiting examples of non-ionic surfactants that can be used in the topiramate liquid composition are polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers, polyoxyethylene castor oil derivatives, polyoxyglycerides, vitamin E polyethylene glycol succinate, and macrogol 15 hydroxystearate.

[26] As per a preferred embodiment, polysorbates are polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[27] An ionic surfactant as referred to herein includes a surface-active agent with ionisable group(s) which reduces the surface tension of a liquid and thus allows it to foam or wet a solid. In a preferred embodiment, ionic surfactants that can be used in topiramate liquid composition are sodium lauryl sulfate and docusate sodium.

[28] A hydrophilic polymer as referred to herein includes a compound of high molecular weight derived by the addition of many smaller units and which has a strong affinity for water. Non-limiting examples of hydrophilic polymers that can be used in the topiramate liquid composition are povidone (e.g.) Povidone K25 or 29/32), copovidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

[29] A polyhydric alcohol as referred to herein includes a compound with more than one hydroxyl group. In a preferred embodiment, the polyhydric alcohols that can be used in the topiramate liquid composition are propylene glycol, polyethylene glycol, sorbitol, and mannitol.

[30] Polyethylene glycol as referred herein includes a polymer of ethylene glycol formed by the reaction of ethylene oxide and water. In a preferred embodiment, examples of polyethylene glycols that can be used in the topiramate liquid composition are polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400.

[31] In a preferred embodiment of the said liquid pharmaceutical composition, the mixture of solubilizers specifically includes propylene glycol, polyethylene glycol-400, polysorbate 80 and ethanol.

[32] The amount of individual solubilizer present in the said liquid pharmaceutical composition may be preferably in the range of from about 0.01 % w/v to about 10 % w/v, more preferably in the range from about 0.05 % w/v to about 9% w/v, and most preferably from about 0.10% w/v to about 8% w/v.

[33] The amount of propylene glycol is preferably present in the range of about 0.30%- 0.55% w/v, more preferably about 0.32%-0.48% w/v and most preferably about 0.36%-0.44% w/v.

[34] The amount of polyethylene glycol-400 is preferably present in the range of about 0.10%-0.25% w/v, more preferably about 0.12%-0.19% w/v and most preferably 0.14%0.17% w/v.

[35] The amount of polysorbate 80 is preferably present in the range of about 0.30%- 0.55% w/v, more preferably about 0.32%-0.48% w/v and most preferably about 0.36%-0.44% w/v.

[36] The amount of ethanol is preferably present in the range of about 4.0%-8.0% w/v, more preferably about 4.8%-7.2% w/v and most preferably about 5.4%-6.6% w/v.

[37] In an embodiment, the solubiliser is a mixture of ethanol and polyethylene glycol.

[38] In an embodiment, the solvent is glycerol.

[39] In an embodiment, the solubiliser is a mixture of ethanol and polyethylene glycol and the solvent is glycerol.

[40] In an embodiment, the solubiliser is a mixture of polyethylene glycol, polysorbate (e.g. polysorbate 80), propylene glycol and ethanol.

[41] In an embodiment, the solvent is glycerol.

[42] In an embodiment, the solubiliser is a mixture of polyethylene glycol, polysorbate (e.g. polysorbate 80), propylene glycol and ethanol and the solvent is glycerol.

[43] In an embodiment, the solubiliser is a mixture of ethanol and polysorbate (e.g. polysorbate 80).

[44] In an embodiment, the solvent is glycerol.

[45] In an embodiment, the solubiliser is a mixture of ethanol and polysorbate (e.g. polysorbate 80) and the solvent is glycerol.

[46] In an embodiment, the solubiliser is a mixture of polysorbate (e.g. polysorbate 80), propylene glycol and ethanol.

[47] In an embodiment, the solvent is glycerol.

[48] In an embodiment, the solubiliser is a mixture of polysorbate (e.g. polysorbate 80), propylene glycol and ethanol and the solvent is glycerol.

[49] In an embodiment, the solubiliser is a mixture of polyethylene glycol, polysorbate (e.g. polysorbate 80) and ethanol.

[50] In an embodiment, the solvent is glycerol.

[51] In an embodiment, the solubiliser is a mixture of polyethylene glycol, polysorbate (e.g. polysorbate 80) and ethanol and the solvent is glycerol.

[52] In an embodiment, the solubiliser is a mixture of polyethylene glycol, propylene glycol and ethanol.

[53] In an embodiment, the solvent is glycerol.

[54] In an embodiment, the solubiliser is a mixture of polyethylene glycol, propylene glycol and ethanol and the solvent is glycerol.

[55] Non-limiting examples of liquid pharmaceutical composition for oral administration include solution, emulsion, suspension, drops, elixir, extemporaneous preparation, mixture, linctus, and syrup.

[56] The term "pharmaceutically acceptable salts of topiramate "as used herein include but are not limited to salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Suitable pharmaceutically-acceptable acid addition salts of topiramate may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, [3-hydroxybutyric, malonic, galactaric and galacturonic acid. Preferably Topiramate as used herein is in the form of free base.

[57] The term "about" as and where used in this specification should be construed as ±10% of the mentioned value.

[58] As used herein, the term "% w/w" refers to the weight of a component based on the total weight of a final composition.

[59] As used herein, the term "% w/v" as used herein refers to the weight of a component based on the total volume of a final composition.

[60] In an embodiment, the liquid pharmaceutical composition of the present invention is chemically and physically stable without any problem of sedimentation, cake formation, precipitation or crystallization during stability study and further overcame problem of unpleasant taste.

[61] Further liquid pharmaceutical composition of the present invention shows a suitable stability and reproducibility.

[62] The liquid pharmaceutical composition of present invention comprises topiramate or its pharmaceutically acceptable salt thereof in the range of from about 0.05 % w/v to about 5 % w/v, mixture of at least two solubilizers and a non-aqueous solvent.

[63] In one of the embodiments, the liquid pharmaceutical composition comprises topiramate or its pharmaceutically acceptable salt in the range from about 0.05%w/v to about 5%w/v, preferably from about 0.1%w/v to about 4%w/v, more preferably from about 0.3%w/v to about 3%w/v and most preferably from about 0.5%w/v to about 1%w/v.

[64] The quantity taken for the topiramate should be based on its dried weight or according to the strength of the composition. Meaning if the salt of topiramate is used to prepare the liquid composition then the quantity of active ingredient should be calculated from the corresponding amount of topiramate base form, its molecular weight, molecular weight of the salt to be used and the strength to be prepared.

[65] One embodiment of the liquid composition of present invention, vehicle or solvent is selected from glycerol, olive oil, almond oil, isopropyl myristate, isopropyl myristate, isopropyl palmitate, isopropyl alcohol or their mixtures thereof. Preferably glycerol is used as a solvent. In one embodiment, the liquid pharmaceutical composition of present invention comprise at least 70% of the vehicle, preferably at least 80%, more preferably at least 85% and most preferably at least 90% of total composition.

[66] The liquid pharmaceutical composition in accordance with the present invention may further comprise preservative, flavouring agent and sweetening agent as inactive excipients.

[67] Non limiting examples of flavouring agent are menthol, wine, butterscotch, orange, levomenthol, cherry, raspberry, honey, strawberry, bubblegum, grape, vanilla, cardamom, and fruit punch flavours. Preferably, the flavouring agent is levomenthol. The amount of flavouring agent may be present in the range of about 0 %w/v to about 0.6% w/v.

[68] Non-limiting examples of sweeteners are sucralose, aspartame, acesulfame potassium, saccharin sodium, sucrose, fructose, aspartame, cyclamate, stevia, glucose, mannitol, sorbitol and high fructose corn syrup. Preferably, the sweetener is saccharin (e.g. sodium saccharin). The amount of sweetening agent may be present in the range of about 0% w/v to about 0.7% w/v.

[69] Non-limiting examples of preservatives are methylparaben, ethylparaben, propylparaben, benzoic acid, ethanol and sorbic acid.

[70] One embodiment of the present invention, said liquid pharmaceutical composition for an oral administration comprises; 1) 5 mg/ml or 10 mg/ml of Topiramate 2) Mixture of solubilizers including propylene glycol, polyethylene glycol 400, polysorbate 80 & Ethanol having total concentration of 0.1 maim! to 100 mg/ml.

3) 0.8 mg/ml of sodium saccharin 4) Glycerol 5) 0.65 mg/ml of levomenthol [71] Another embodiment of the present invention relating to the process for the preparation of said liquid pharmaceutical composition for an oral administration, which comprises of; 1. Adding sweetener to 70% of total volume of vehicle and mixing to obtain a clear solution; 2. Adding and dissolving flavouring agent into a solubilizer and mixing to get a clear solution; 3. Adding and mixing the mixture of remaining solubilizers into step 2 to get a clear solution.

4. Adding and dissolving Topiramate into step 3 solution and mixing to get a clear solution 5. Adding the solution of step d into step 1 solution and mixing to get a clear solution 6. Rinsing the step 4 container using 5 % vehicle of total batch size and mixing into the solution of step e to get a clear solution.

7. Making up the final volume with vehicle and mixing to get the final clear colourless solution.

[72] Yet another embodiment of the present invention describes a detailed step-wise process to prepare said pharmaceutical composition. The steps are provided below: 1. Adding sweetener to 70% of vehicle, dissolving using silverson mixer at the speed of 4000 to 5000 rpm for 55 to 60 minutes to get a clear solution; 2. Separately, adding and dissolving levomenthol into ethanol (absolute) by mixing for 5 to 10 minutes using silverson mixer at the speed 4000 to 5000 rpm to get a clear colourless solution.

3. Adding and mixing PEG, propylene glycol and polysorbate 80 into step 2 solution and mixing it for 2 to 5 minutes using silverson mixer at the speed 4000 to 5000 rpm to get a clear colourless solution.

4. Adding and dissolving topiramate into step 3 solution and mixing it for 10 to 15 minutes using silverson mixer at the speed 4000 to 5000 rpm to get a clear colourless solution.

5. Adding step 4 solution into step 1 solution and mix it for 45 to 50 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get a clear colourless solution.

6. Rinsing the step 4 container using 5% glycerol of total batch size and mixing into step 5 solution for 5 to 10 minutes using silverson mixer to get a clear colourless solution.

7. Making up the volume with glycerol and mixing it for 15 to 20 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get a clear colourless solution.

[73] The present invention solves the problem of stability and most importantly, ease of administration at the time of emergency. Due to being non-aqueous composition, the liquid pharmaceutical composition has very less chances of microbial contamination. In addition to that, the liquid pharmaceutical composition of present invention is found to be stable for 90 days after opening of the container.

[74] To make a stable liquid pharmaceutical composition, extensive solubility studies using various combinations of solubilizers were performed to identify the appropriate combination of solubilising agents.

[75] Embodiment of the present invention has been described by way of following

examples:

Example 1

(I) Sodium saccharin is added into 70% of total volume of glycerol of batch size and dissolved by using 3 silverson mixer at the speed of 4000 to 5000 rpm for 55 to 60 minutes to get clear colourless solution. (II) Separately, levomenthol is added and dissolved into ethanol by mixing for 5 to10 minutes using silverson mixer at the speed 4000 to 5000 rpm to get a clear colourless solution. (III) Polyethylene glycol is added into step II solution and mixed for 2 to 5 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get a clear colourless solution. (IV) Topiramate is added and dissolved into step III solution and mixed for 10 to 15 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get a clear colourless solution. (V) Step IV solution is added into step I solution and mixed for 45 to 50 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get a clear colourless solution. (VI) Container of step IV is rinsed using 5% glycerol of total batch size and mixed into step V solution for 5 to 10 minutes using silverson mixer to get a clear colourless solution. (VII) The final volume is made up with glycerol and mixed for 15 to 20 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get clear colourless solution.

Table 1

Ingredient Quantity (gm or m1/100 ml) Topiramate 1 gm Ethanol 6.00 gm Polyethylene glycol 0.16 gm Sodium saccharin 0.080gm Levomenthol 0.065gm Glycerol OS. 100 ml

Example 2

(I) Sodium saccharin is added into 70% of total volume of glycerol of batch size and dissolved by using silverson mixer at the speed of 4000 to 5000 rpm for 55 to 60 minutes to get clear colourless solution. (II) Separately, levomenthol is added and dissolved into ethanol by mixing for 5 to 10 minutes using silverson mixer at the speed 4000 to 5000 rpm to get a clear colourless solution. (III) Polysorbate 80, polyethylene glycol, and propylene glycol are added into step II solution and mixed for 2 to 5 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get a clear colourless solution. (IV) Topiramate is added and dissolved into step III solution and mixed for 10 to 15 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get a clear colourless solution. (V) Step IV solution is added into step I solution and mixed for 45 to 50 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get a clear colourless solution. (VI) Container of step IV is rinsed using 5% glycerol of total batch size and mixed into step V solution for 5 to 10 minutes using silverson mixer to get a clear colourless solution. (VII) The final volume is made up with glycerol and mixed for 15 to 20 minutes using silverson mixer at the speed of 4000 to 5000 rpm to get clear colourless solution.

Table 2

Ingredient Quantity (gm or m1/100 ml) Topiramate 0.500 gm Polysorbate 80 0.40 gm Ethanol 6.00 gm Polyethylene glycol 0.160 gm Propylene glycol 0.40 gm Sodium saccharin 0.080gm Levomenthol 0.065gm Glycerol QS. 100 ml

Example 3

The composition was prepared following the procedure of Example 2, except the amount of Topiramate is as set out in Table 3.

Table 3

Ingredient Quantity (gm or m1/100 ml) Topiramate 1.00 gm Polysorbate 80 0.40 gm Ethanol 6.00 gm Polyethylene glycol 400(PEG 400) 0.160 gm Propylene glycol 0.40 gm Sodium saccharin 0.080gm Levomenthol 0.065gm Glycerol QS. 100 ml

Example 4

The composition was prepared following the procedure of example-1, except step (Ill) where Polysorbate80 is added in place of PEG-400.

Table 4

Ingredient Quantity (gm or m1/100 ml) Topiramate 1 gm Polysorbate 80 0.40 gm Ethanol 6.00 gm Sodium saccharin 0.080gm Levomenthol 0.065gm Glycerol Q.S. 100 ml

Example 5

The composition was prepared following the procedure of example-2, except step (Ill) where the use of PEG 400 is omitted.

Table 5

Ingredient Quantity (gm or m1/100 ml) Topiramate 1 gm Polysorbate 80 0.40 gm Ethanol 6.00 gm Propylene glycol 0.40 gm Sodium saccharin 0.080gm Levomenthol 0.065gm Glycerol QS. 100 ml

Example 6

The composition was prepared following the procedure of example-2, except step (Ill) where the use of propylene glycol is omitted.

Table 6

Ingredient Quantity (gm or m1/100 ml) Topiramate 1 gm Polysorbate 80 0.40 gm Ethanol 6.00 gm Polyethylene glycol 400(PEG 400) 0.160 gm Sodium saccharin 0.080gm Levomenthol 0.065gm Glycerol Q.S. 100 ml

S

Example 7

The composition was prepared following the procedure of example-2, except step (Ill) where the use of polysorbate-80 is omitted.

Table 7

Ingredient Quantity (gm or m1/100 ml) Topiramate 1 gm Ethanol 6.00 gm Polyethylene glycol 400(PEG 400) 0.160 gm Propylene glycol 0.40 gm Sodium saccharin 0.080gm Levomenthol 0.065gm Glycerol Q.S. 100 ml Stability Data: [76] The stability study data of 12 months at following low to extreme conditions of temperature and relative humidity are available. 1) 25°C/60%RH 2) 30°C/65%RH 3) 2-8T Stability data for Example 2 Composition Pack: Amber glass bottle

Table 8

Stability Storage Description Wt/ml Assay (%w/w) Related substances by HPLC Station Condition (gni/m1) Topiramate Ethanol Metbylethylidenc SMUT Total (95,0% - (Absolute) fmctopyranosc (NMI' impurities 105%) (70.0% - (Imp. A) 0,2%) (NMT 110%) (NMT 0,5%) 1,0%) Initial Room A Clear 1.2151 98.80 92.51 ND ND -Temperat Colourless urn Solution 25°C/60 3M A Clear - 100.3 99.06 0.005 0,009 0.014 %RH Colourless (RRT-0,863) (RRT-Solution 0.892) 6 M A Clear 98.3 97.25 0.066 ND 0.066 Colourless (RRT-0.864) Solution 9M A Clear 1.230 99.80 - 0.120 ND 0.120 Colourless (RRT-0,872) Solution 12 M A Clear 98.80 0.096 ND 0.096 Colourless (RRT-0.899) Solution 30°C/65 A Clear 100.5 98.66 0.035 0,021 %RH Solution (RR-T-0,862) 0.897) 6 M A Clear - 99.2 97.56 0.112 ND 0.112 Colourless (RRT-0. 864) Solution 9 M A Clear 1.2287 97.2 - 0.238 ND 0.238 Colourless (RRT-0.871) Solution 12 M A Clear - 98.6 - 0.305 0,009 0.314 Colourless (RRT-0.900) (RRT-Solution 0.827) 2-8°C 3M A Clear - 100.3 98.75 ND ND -Colourless Solution 6 M A Clear - 97.9 95.36 0.015 ND 0.015 Colourless (RRT-0. 862) Solution 12 M A Clear 99.6 0.018 0.017 0.035 Colourless (RRT-0,898) (RRT-Solution 0.930) Stability data for Example 3 Composition Pack: Amber glass bottle

Table 9

Stability Storage Description Wt/inl Assay Wow/w) Assay Related substances by HPLC

Station Condition Description

Topiramate Ethanol Methylethylidcric SMUT Total (95.0% - (Absolute) fmctopyrTmose (Nivrr impurities 105%) (70.0% - (Imp. A) 0.2%) (NMT 110%) (WI' 0.5%) 1.0%) Initial Room A Clear 1.2206 97.54 98.19 ND ND _ Temperat Colourless UM Solution 25°C/60 3M A Clear - 99.2 101.77 0.028 ND 0.028 %RH Colourless (RRT-0.864) Solution 61\4 A Clear 98.1 97.28 0.080 ND 0.080 Colourless (RRT-0.866) Solution 91\4 A Clear 1.239 98.20 - 0.107 ND 0.107 Colourless (RRT-0.871) Solution 12 M A Clear 98.90 0.060 0.023 0083 Colourless (RRT-0.899) (RAT- . Solution 0,951) 30°C/65 %RH 3 M A Clear - 96.6 103.06 0.061 0.048 0.109 Colourless (RRT-0.862) (RRT-Solution 0.876) 6 M A Clear 98.7 98.72 0.203 ND 0.203 Colourless (RRT-0.869) Solution 9 M A Clear 1.238 98.6 0.255 ND 0.255 Colourless (RRT-0.872) Solution 12 M A Clear - 98.4 - 0.264 0.016 0.280 Colourless (RRT-0.899) (RRT-Solution 0.783) 2-8°C 3M A Clear - 99.2 101.56 ND ND -Colourless Solution 6 M A Clear 99,8 100.62 ND ND Colourless Solution 12 M A Clear 99.8 0.032 0.010 0.042 Colourless (RRT-0897) (RRT-Solution. 0,956) [77] The stability results indicate that the liquid composition of present invention can remain stable when exposed to an environment of mentioned temperature and humidity and the value of evaluation parameters also remain within the specification.

[78] The stability data of liquid pharmaceutical composition of example 2,from day one of the opening of the container to ninety days, are presented as below: ND -Not detected NMT-Not More Than HPLC-High Performance Liquid Chromatography SMUI-Single Maximum Unknown Impurity RRT-Relative Retention Time RH-Relative Humidity 1 Description Clear colourless solution Clear colourless solution Clear colourless solution Clear colourless solution Clear colourless solution 2 Odour Menthol Menthol Menthol Menthol Menthol 3 Assay of Topiramate by HPLC 47.50 -52.50 mg/5m1 (95.0-105.0% of label claim) 102.5% 100.6% 99.5% 100.4% 4 Related substances by HPLC Methylethylidene fructopyranose NMT 0.5% ND ND ND 0.033% Single maximum unknown impurity NMT 0.2% ND ND ND ND Total impurities NMT 1.0% ND ND ND 0.033%

Claims

Claims 1. A stable liquid pharmaceutical composition for oral administration comprising: (a)Topiramate or its pharmaceutically acceptable salts thereof present in the range of 0.05% w/v to 5% w/v, (b)mixture of at least two solubilizers, and (c) a non-aqueous solvent.
2. The stable liquid pharmaceutical composition for oral administration according to claim 1, wherein the non-aqueous solvent is selected from a group consisting of glycerol, isopropyl myristate, isopropyl palmitate, almond oil, olive oil, isopropyl alcohol, or combination thereof.
3. The stable liquid pharmaceutical composition for oral administration according to claim 2, wherein the non-aqueous solvent is glycerol.
4. The stable liquid pharmaceutical composition for oral administration according to any of claims 1 to 3, wherein Topiramate is solubilised in a mixture of more than two solubilizers.
5. The stable liquid pharmaceutical composition of any preceding claim, wherein the mixture of at least two solubilizers are selected from the group consisting of Propylene Glycol, Polyethylene Glycol, Polysorbates, Ethanol, polyhydric alcohol, poloxamer, or combination thereof, and wherein the non-aqueous solvent is glycerol.
6. The stable liquid pharmaceutical composition for oral administration according to claim 5, wherein the mixture of solubilizers include polyethylene glycol 400, propylene glycol, polysorbate 80, and ethanol.
7. The stable liquid pharmaceutical composition for oral administration according to any of the preceding claims, wherein the Topiramate or its pharmaceutically acceptable salts thereof is in the range of 0.5% w/v to 1% w/v, the mixture of at least two solubilizers is in the range of 0.01% w/v to 10% w/v and the non-aqueous solvent is glycerol.
8. The stable liquid pharmaceutical composition of any preceding claim, wherein the mixture of at least two solubilizers are selected from the group consisting of polyethylene glycol 400, propylene glycol, polysorbate 80, and ethanol in the amount of about 0.10 %-0.25 % w/v, about 0.30%-0.55% w/v, about 0.30%-0.55% w/v, and about 4.00%-8%w/v, respectively, and wherein the non-aqueous solvent is glycerol.
9. The stable liquid pharmaceutical composition for oral administration according to any of the preceding claims further comprises a sweetener and flavouring agent.
10. The stable liquid pharmaceutical composition for oral administration according to claim 9, wherein the sweetener is selected from the group consisting of Sodium saccharin, Aspartame, Stevia, Sucrose, Sucralose, Glucose, Fructose, Mannitol, Sorbitol, Acesulfame potassium, Cyclamate or mixtures thereof.
11. The stable liquid pharmaceutical composition for oral administration according to claim9 or claim 10, wherein the flavouring agent is selected from the group consisting of menthol, levomenthol, orange, cherry, litchi, strawberry, vanilla, cardamom and butterscotch.
12. The stable liquid pharmaceutical composition for oral administration according to any of the preceding claims wherein the pharmaceutical composition is ready to administer.
13. The process for preparing the stable liquid pharmaceutical composition of any of claims 1 to 11comprising steps of: a. Adding sweetener to 70% of total volume of vehicle and mixing to obtain a clear solution; b. Adding and dissolving flavouring agent into a solubilizer and mixing to get a clear solution; c. Adding and mixing the mixture of remaining solubilizers into step b to get a clear solution; d. Adding and dissolving Topiramate into step c solution and mixing to get a clear solution; e. Adding the solution of step d into step a solution and mixing to get a clear solution; f. Rinsing the step d container using 5 % vehicle of total batch size and mixing into the solution of step e to get a clear solution; g. Making up the final volume with vehicle and mixing to get the final clear colourless solution.