GB2564444A

GB2564444A - Liquid pharmaceutical composition of flecainide

Info

Publication number: GB2564444A
Application number: GB1711091.7A
Authority: GB
Inventors: Patel Kamlesh; Maganbhai Patel Sanjaykumar
Original assignee: Syri Ltd
Current assignee: Syri Ltd
Priority date: 2017-07-10
Filing date: 2017-07-10
Publication date: 2019-01-16
Anticipated expiration: 2037-07-10
Also published as: GB2564444B; GB201711091D0

Abstract

A liquid pharmaceutical composition comprising flecainide or pharmaceutically acceptable salts thereof in the range from about 1mg/ml to 20mg/ml, at least a sweetener in the range from 0.05 to 0.5% w/v, a buffer system and at least one preservative, wherein the pH of the composition is from about 5.0 to 6.5 is provided. Flecainide is preferably in the form of an acetate salt. The sweetener is preferably selected from acesulfame potassium, sucralose, cyclamate, saccharin, saccharin sodium and aspartame, in particular sucralose. The buffer system may be selected from glacial acetic acid, sodium acetate trihydrate, citric acid, sodium citrate, sodium dihydrogen phosphate, disodium phosphate, trometamol (Tris), hydrochloric acid, ascorbic acid, and sodium ascorbate as single or any combination thereof. The preferred buffer system is glacial acetic acid and sodium acetate trihydrate. The preservative is preferably selected from methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sodium benzoate, benzoic acid, potassium sorbate and combination thereof. The preferred buffer is methyl paraben. A process for the preparation of said liquid pharmaceutical composition as herein defined is also provided. A liquid composition comprising flecainide acetate, sucralose, methyl paraben (methyl parahydroxylbenzoate) and a buffer system which comprises mixture of glacial acetic acid and sodium acetate trihydrate as herein defined is provided.

Description

Title: Liquid pharmaceutical composition of Flecainide

Field of the invention

The present invention relates to a liquid pharmaceutical composition of Flecainide or pharmaceutically acceptable salts thereof. The present invention also relates to a process for preparing the same. The pharmaceutical composition of the present invention is suitable for oral administration.

Background of the invention

Flecainide acetate is an antiarrhythmic agent used to prevent and treat tachyarrhythmias (abnormal fast rhythms of the heart). It is used to treat cardiac arrhythmias including paroxysmal atrial fibrillation (episodic irregular heartbeat originating in the upper chamber of the heart), paroxysmal supraventricular tachycardia (episodic rapid but regular heartbeat originating in the atrium), and ventricular tachycardia (rapid rhythms of the lower chambers of the heart). Flecainide works by regulating the flow of sodium in the heart, causing prolongation of the cardiac action potential. GB1508015 discloses Flecainide and its salts along with process for preparing the same. Flecainide Acetate is chemically known as benzamide, N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)- monoacetate. It is a white to slightly off-white crystalline powder, with a pKa of 9.3 and it has an aqueous solubility of 48.4 mg/mL at 37°C. The structural formula of Flecainide acetate is given below:

Flecainide acetate (commercially available from Riker Laboratories, Inc. under the trade designation Tambocor® brand Flecainide acetate) is an antiarrhythmic agent that is clinically effective for the suppression of ventricular arrhythmias. Conventional release or immediate release Flecainide acetate tablets are to be administered twice daily to maintain effective plasma levels.

Currently available marketed formulations are in the form of solid oral formulation i.e. tablet and intravenous injection solutions. When Flecainide is prescribed to paediatric populations,

the appropriate dose is prepared by using a commercially available tablet formulation and grinding the tablet in to a vehicle. The vehicle is ordinarily purified water.

In pharmaceutical formulation, the majority of the market is covered by solid oral formulations because of ease of manufacturing, ease of storage, beneficial stability etc. However, on the other hand, there are patient populations who have difficulties swallowing tablets, for example children, elderly people, patients who also suffer with a mental disorder, patients suffering from nausea and when patient is travelling and might have very little or no access to water. In all such cases, the solid formulations appear to be non-viable and may result in patient non-compliance, with the consequence that there might be medication error or discontinuation of medication.

In absence of any oral liquid formulation available in the market, hospitals & dispensaries generally follow a practice of preparing extemporaneous suspensions from available solid formulation and triturating the same followed by adding water. If required syrup can be added to make the suspension palatable. The same practice is observed for Flecainide where the commercially available tablet formulation is crushed and mixed with water and syrup or some sweetener to prepare a palatable oral suspension for the patient.

This practice, in pharmacies and dispensaries, of dispensing extemporaneous suspensions prepared from a solid formulation can create medication error and potentially fatal conditions. This is especially relevant for drugs which fall in low therapeutic index. Further, the stability of such extemporaneous suspensions are very limited and cannot be stored for longer period.

Flecainide Acetate is soluble in water and absolute alcohol. Flecainide Acetate falls under Class I of BCS (Biopharmaceutical Classification System) because of its high solubility and high permeability. However, due to the method of preparing extemporaneous suspension by crushing a tablet formulation, the resulting, final formulation will remain in suspension form rather than solution form because of the excipients present in the tablet formulation, which may or may not be soluble in water.

Allen et al studied the stability of drugs commonly prescribed for use in oral liquid dosage forms but not commercially available as such. Baclofen 10 mg/mL, captopril 0.75 mg/mL, diltiazem hydrochloride 12 mg/mL, dipyridamole 10 mg/mL, and flecainide acetate 20 mg/mL were prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus (Paddock Laboratories), and cherry syrup and placed in 120-mL amber, clear polyethylene terephthalate bottles. (Am J Health SystPharm. 1996 Sep 15;53(18):2179-84.) The study concluded that, like extemporaneously prepared compositions, the compositions were not suitable for long time storage.

To overcome the problems associated with extemporaneous preparation of liquid formulations of flecainide an oral liquid formulation is required. In the case of liquid formulations, widely known and used formulations are in the form of solution and/or suspension. A suspension formulation further offers many drawbacks of physical stability issues (such as sedimentation and compaction), difficulty in formulation development, as well as uniform and accurate dosing being a challenge.

Still there is a need existing in the society for liquid pharmaceutical formulation or composition of Flecainide which overcome all the problems discussed above and which is suitable for oral administration without any stability or dose uniformity issue. Inventors of the present invention have addressed these issues and provided a liquid pharmaceutical composition suitable for oral administration comprising Flecainide or pharmaceutically acceptable salts thereof.

Summary of the invention

The present inventors of the present invention performed different research and trials for developing stable and orally suitable liquid composition comprising Flecainide or pharmaceutically acceptable salts thereof. Especially the present inventors carried out various research to formulate a liquid composition, which remain stable for longer period of time, and optionally offer acceptable taste for oral administration. Improvements in the stability of the liquid formulation may be measured against an extemporaneously prepared formulation, formed from a crushed tablet of flecainide.

The main aspect of the present invention is to provide a liquid pharmaceutical composition comprising Flecainide or pharmaceutically acceptable salts thereof in the range from about 1 mg/ml to 20 mg/ml, at least a sweetener in the range from 0.05 to 0.5 % w/v, a buffer system and at least one preservative, wherein the pH of the composition is from about 5.0 to 6.5.

Another aspect of the present invention is to provide a process for preparing liquid pharmaceutical composition comprising steps of; a) adding a preservative in purified water and, b) adding a sweetener, c) adding a buffer to maintain pH from about 5.0 to 6.5, d) adding Flecainide or a pharmaceutically acceptable salts thereof, e) optionally adding a flavoring agent and f) adding purified water to make up to final volume and keeping pH between 5.0 to 6.5.

As per one more aspect, the liquid pharmaceutical composition for use in a method of treatment of a) AV nodal reciprocating tachycardia, arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways and b) Paroxysmal atrial fibrillation in patients with disabling symptoms when treatment need has been established and in the absence of left ventricular dysfunction in human.

Equally, in one aspect of the invention there is provided a method of treatment of a) AV nodal reciprocating tachycardia, arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways and b) Paroxysmal atrial fibrillation in patients with disabling symptoms when treatment need has been established and in the absence of left ventricular dysfunction in human, wherein the method comprises administering a therapeutically effective amount of a liquid pharmaceutical composition of the present invention.

Yet one more aspect of the present invention is to provide a liquid pharmaceutical composition comprising about 1 mg/ml to about 20 mg/ml of Flecainide acetate, about 0.05 to about 0.5 % w/v sucralose, about 0.58 to 0.87 % w/v of buffer system, which comprises mixture of glacial acetic acid and sodium acetate trihydrate, about 0.05 to about 0.5 %w/w of Methyl parahydroxybenzoate and composition is having pH in the range from about 5.0 to about 6.5.

Detailed description of the invention

The present invention relates to a liquid pharmaceutical composition comprising Flecainide or pharmaceutically acceptable salts thereof in the range from about 1 mg/ml to 20 mg/ml, at least a sweetener, at least a buffer in aqueous medium.

The term "pharmaceutically acceptable salts" as used herein includes any salt prepared by conventional methods known in the art. Examples of such salts are acid addition salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, acetylsalicylic (aspirin), and the like; amino acid such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartate, glutamine, lysine, arginine, tyrosine and proline; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like; metal salts formed by alkali metals such as sodium, potassium, and the like; and a salt formed by an ammonium ion and the like.

In a preferred embodiment, Flecainide or a pharmaceutically acceptable salt present in the liquid pharmaceutical composition is Flecainide Acetate.

In one embodiment, the Flecainide Acetate is present in the range from about 1 mg/ml to 20 mg/ml, preferably in the range from about 2.5 to 15 mg/ml, more preferably in the range from about 2.5 to 10 mg/ml, most preferably 5 mg/ml.

The term "about" as and where used in this specification means ±10 % of the mentioned value. However, when the term “about” is used in connection with pH, it should be considered as ±2 unit of the pH value.

The term “formulation” and “composition” as used herein conveys the same meaning and can be used interchangeably.

To keep the liquid pharmaceutical composition of the present invention stable for a longer period, the pH should be maintained such that the composition is acidic or neutral. As per one embodiment, pH of the composition should be in the range from about 4.0 to 7.0, preferably in the range from about 5.0 to 6.5.

The inventors of the present invention have carried out research by preparing composition at different pH level and concluded effective pH range from 4.0 to 7.0. A composition with a pH outside of this range, above or below, will have an impact on stability, the impact on stability is significant when the pH is above 7.0. When the composition is prepared with a final acidic pH that is below about 4.0, there is not much impact on stability but the composition fails in terms of patient compliance. If the composition is prepared with alkaline pH above 7.0, the composition also has a problem with the chemical stability as well as physical stability. When the composition is prepared with a pH in the range from 5.0 to 6.5, it exhibits physical and chemical stability along with patient compliance.

Therefore, as per one embodiment, the pH of the final composition is to be kept in the range 5.0 to 6.5. To maintain the pH in the effective range that is 5.0 to 6.5, a buffer system is added in the composition.

The buffer system in the present invention may be selected from glacial acetic acid, sodium acetate trihydrate, Citric Acid, Sodium Citrate, Sodium Dihydrogen Phosphate, Disodium Phosphate, Trometamol (Tris), Hydrochloric Acid, Ascorbic Acid, Sodium Ascorbate as single or any combination thereof.

More preferably, the buffer system comprises mixture of glacial acetic acid and sodium acetate trihydrate, mixture of citric acid and sodium citrate hydrate, a mixture of citric acid and potassium citrate, a mixture of acetic acid and sodium acetate, a mixture of malic acid and sodium glutamate, a mixture of glycine and sodium carbonate, and a mixture of maleic acid and sodium lactate. Most preferably the buffer system comprises a mixture of glacial acetic acid and sodium acetate trihydrate.

As per one embodiment, the buffer system is present in an amount of less than 1 % w/v. As per one embodiment, the buffer system is present in the range from about 0.5 to about 0.9 % w/v or from about 0.58 to about 0.87 % w/v, preferably about 0.725 % w/v.

In an embodiment the buffer system comprises a mixture of glacial acetic acid and sodium acetate trihydrate in an amount from about 0.58 to 0.87 % w/v.

As per the present invention, the composition may be prepared in aqueous medium. The aqueous medium used for preparing pharmaceutical composition is selected from the group consisting of purified water, ethanol and a mixture thereof, preferably purified water.

The sweetener as per present invention may be selected from acesulfame potassium, sucralose, cyclamate, saccharin, saccharin sodium and aspartame or mixtures thereof. Preferably, the sweetener is sucralose. The sweetener may be present in the range from about 0.05 to about 0.5 % w/v. In an embodiment the sweetener is 0.05 to about 0.5 % w/v sucralose,

Preferred preservatives for present invention are selected from methyl parahydroxybenzoate (methyl paraben), ethyl parahydroxybenzoate (ethyl paraben), propyl parahydroxybenzoate (propyl paraben), butyl parahydroxybenzoate (butyl paraben), isobutyl parahydroxybenzoate (isobutyl paraben), isopropyl parahydroxybenzoate (isopropyl paraben), benzyl parahydroxybenzoate (benzyl paraben), Sodium Benzoate, Benzoic acid, Potassium Sorbate and combinations thereof. More preferred preservative is Methyl parahydroxybenzoate. The preservative may be added in the range from 0.05 to 0.5 % w/v.

In an embodiment the preservative is methyl parahydroxybenzoate and is present in the range from 0.05 to 0.5 % w/v.

As per one embodiment, the composition further comprises a flavoring agent. Preferred flavoring agents are selected from artificial flavors, artificial fruit flavors, natural flavors, natural fruit flavors, flavor enhancers or mixtures thereof. Natural flavors, artificial flavors or mixtures thereof include, and are not limited to, mint (such as peppermint or spearmint), menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificial chocolate or bubble gum. Natural fruit flavors, artificial fruit flavors or mixtures thereof include, and are not limited to, cherry, grape, orange, strawberry or lemon. Flavor enhancers include, and are not limited to, citric acid. The liquid pharmaceutical composition of the present invention may be considered to represent a taste masking composition when it comprises a flavouring agent. A flavoring agent used in the taste masking composition may be present in a range of from about 0.05 to about 0.5 % w/v, preferably, in a range from about 0.07 to about 0.5 %w/v.

As per one embodiment, the liquid pharmaceutical composition of the present invention is to be used for treatment of a) AV nodal reciprocating tachycardia, arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways and b) Paroxysmal atrial fibrillation in patients with disabling symptoms when treatment need has been established and in the absence of left ventricular dysfunction in human.

As per one embodiment, of the present invention, the pH plays a critical role in the chemical stability as well as physical stability.

As per one embodiment, the liquid pharmaceutical composition of the present invention is prepared by a process comprising the steps of a) adding a preservative to purified water and, b) adding a sweetener, c) adding a buffer to maintain pH from about 5.0 to 6.5, d) adding Flecainide or a pharmaceutically acceptable salts thereof, e) optionally adding a flavoring agent and f) adding purified water to make up to final volume and keeping pH between 5.0 to 6.5.

As per one embodiment, present invention provides a liquid pharmaceutical composition comprising about 1 mg/ml to about 20 mg/ml of Flecainide acetate, about 0.05 to about 0.5 % w/v sucralose, about 0.58 to 0.87 % w/v of buffer system, which comprises a mixture of glacial acetic acid and sodium acetate trihydrate, about 0.05 to about 0.5 % w/v of Methyl parahydroxybenzoate and composition is having pH in the range from about 5.0 to about 6.5.

As per one preferred embodiment of present invention is to provide a liquid pharmaceutical composition comprising about 5 mg/ml of Flecainide acetate, about 0.1 % w/v sucralose, about 0.725 % w/v of buffer system, which comprises mixture of glacial acetic acid and sodium acetate trihydrate, about 0.1 % w/w of Methyl parahydroxybenzoate and composition is having pH in the range from about 5.0 to about 6.5.

Hereinafter, the present invention is described more specifically by the following examples, but these are provided only for illustration purposes and the present invention is not limited thereto.

Example

Example 1

Process: a) Methyl parahydroxybenzoate was added in purified water with mixing, b) Sucralose was added to step a) with stirring, c) glacial acetic acid and sodium acetate trihydrate were added to step b) to adjust pH from about 5.0 to 6.5, d) Flecainide acetate were added to step c) with stirring, e) Strawberry flavor was added to step d) and f) purified water was added to step e) to make up to final volume and keeping pH between 5.0 to 6.5.

Example 2: Comparative Example

Process: As per Example 1.

Example 3: Comparative Example

Process: As per Example 1 except sodium hydroxide was added to adjust final pH at 8.0.

Example 4: Stability analysis

The composition as prepared in Example 1, 2 and 3 were analysed for pH, Density, Assay and Related substance after 1 month stability at 40°C temperature and results are as provided below;

Results of initial (Day 0) samples ND: Not detected MHB: Methyl parahydroxy Benzoate, SMUI: Single max unknown impurity

Results after 1 month stability at 40°C

ND: Not detected MHB: Methyl parahydroxy Benzoate, SMUI: Single max unknown impurity

Thus as per results, the composition prepared in Example 1 and Example 2 appears to be more stable in term of degradation compared to composition of Example 3. However, composition of Example 1 fails in term of physical stability as well as in patient compliance. Example 2 is chemically and physically stable as well as acceptable in term of taste and appearance to patient.

Claims

1. A liquid pharmaceutical composition comprising Flecainide or pharmaceutically acceptable salts thereof in the range from about 1 mg/ml to 20 mg/ml, at least a sweetener in the range from 0.05 to 0.5 % w/v, a buffer system and at least one preservative, wherein the pH of the composition is from about 5.0 to 6.5.

2. The liquid pharmaceutical composition according to claim 1, wherein Flecainide is in the form of an acetate salt.

3. The liquid pharmaceutical composition according to claim 1 or 2, wherein Flecainide acetate is present in the range from about 2.5 to 15 mg/ml.

4. The liquid pharmaceutical composition according to claim 1, wherein the sweetener is selected from acesulfame potassium, sucralose, cyclamate, saccharin, saccharin sodium and aspartame or mixtures thereof.

5. The liquid pharmaceutical composition according to claim 3, wherein the sweetener is sucralose.

6. The liquid pharmaceutical composition according to any preceding claim, wherein buffer system is selected from glacial acetic acid, sodium acetate trihydrate, Citric Acid, Sodium Citrate, Sodium Dihydrogen Phosphate, Disodium Phosphate, Trometamol (Tris), Hydrochloric Acid, Ascorbic Acid, Sodium Ascorbate as single or any combination thereof.

7. The liquid pharmaceutical composition according to claim 5, wherein the buffer system is mixture of glacial acetic acid and sodium acetate trihydrate.

8. The liquid pharmaceutical composition according to any preceding claim, wherein the buffer system is present in the range from about 0.58 to about 0.87 % w/v.

9. The liquid pharmaceutical composition according to any preceding claim, wherein the preservative is selected from methyl parahydroxybenzoate (methyl paraben), ethyl parahydroxybenzoate (ethyl paraben), propyl parahydroxybenzoate (propyl paraben), butyl parahydroxybenzoate (butyl paraben), isobutyl parahydroxybenzoate (isobutyl paraben), isopropyl parahydroxybenzoate (isopropyl paraben), benzyl parahydroxybenzoate (benzyl paraben), Sodium Benzoate, Benzoic acid, Potassium Sorbate and combinations thereof.

10. The liquid pharmaceutical composition according to any preceding claim, further comprising a flavoring agent selected from artificial flavors, artificial fruit flavors, natural flavors, natural fruit flavors, flavor enhancers or mixtures thereof.

11. The liquid pharmaceutical composition according to any preceding claim, wherein the liquid pharmaceutical formulation is suitable for oral administration.

12. The liquid pharmaceutical composition according to any preceding claim for use in a method of treatment of a) AV nodal reciprocating tachycardia, arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways and b) Paroxysmal atrial fibrillation in patients with disabling symptoms when treatment need has been established and in the absence of left ventricular dysfunction in human.

13. A liquid pharmaceutical composition comprising about 1 mg/ml to about 20 mg/ml of Flecainide acetate, about 0.05 to about 0.5 % w/v sucralose, about 0.58 to 0.87 % w/v of buffer system, which comprises mixture of glacial acetic acid and sodium acetate trihydrate, about 0.05 to about 0.5 %w/w of Methyl parahydroxybenzoate and composition is having pH in the range from about 5.0 to about 6.5.

14. A liquid pharmaceutical composition comprising about 5 mg/ml of Flecainide acetate, about 0.1 % w/v sucralose, about 0.725 % w/v of buffer system, which comprises mixture of glacial acetic acid and sodium acetate trihydrate, about 0.1 %w/w of Methyl parahydroxybenzoate and composition is having pH in the range from about 5.0 to about 6.5.

15. A process for preparing a liquid pharmaceutical composition comprising steps of a) adding a preservative in purified water and, b) adding a sweetener, c) adding a buffer to maintain pH from about 5.0 to 6.5, d) adding Flecainide or a pharmaceutically acceptable salts thereof, e) optionally adding a flavoring agent and f) adding purified water to make up to final volume and keeping pH between 5.0 to 6.5.