WO2019132832A1

WO2019132832A1 - Tablet compositions of fesoterodine fumarate

Info

Publication number: WO2019132832A1
Application number: PCT/TR2018/050860
Authority: WO
Inventors: Nur PEHLIVAN AKALIN; Kerim AKKAYA; Ezgi USLU
Original assignee: Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2017-12-25
Filing date: 2018-12-21
Publication date: 2019-07-04

Abstract

The present invention relates to extended release tablet compositions comprising fesoterodine fumarate and at least one coating comprising coating agents and the compositions are stable against fesoterodine degradation over an extended period of time. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the extended release tablet compositions of fesoterodine fumarate.

Description

TABLET COMPOSITIONS OF FESOTERODINE FUMARATE

Field of the Invention

Background of the Invention

Fesoterodine fumarate is the fumarate salt form of fesoterodine, a competitive muscarinic receptor antagonist with muscle relaxant and urinary antispasmodic properties. Fesoterodine is rapidly hydrolyzed in vivo into its active metabolite 5-hydroxy methyl tolterodine, which binds and inhibits muscarinic receptors on the bladder detrusor muscle, thereby preventing bladder contractions or spasms caused by acetylcholine. This results in the relaxation of bladder smooth muscle and greater bladder capacity, in addition to a reduction in involuntary muscle contractions and involuntary loss of urine. The active metabolite does not interact with alpha-adrenergic, serotonergic, histaminergic and excitatory amino acid receptors and is eliminated via renal excretion.

The chemical name of fesoterodine fumarate is (E)-but-2-enedioic acid;[2-[(1 R)-3- [di(propan-2-yl)amino]-1 -phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate. Its empirical formula is CsoFI^NOy and has the following structural Formula I:

Formula I The drug fesoterodine fumarate is the active ingredient in a product being sold as TOVIAZ® tablets to treat urinary incontinence and frequency problems. Inactive ingredients are glyceryl behenate, hypromellose, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.

Fesoterodine fumarate is known in the art for its potency in treating urinary incontinence. However, fesoterodine may exhibit substantial degradation under stress conditions. It is believed that hydrolyzation and oxidation are among the major mechanisms resulting in degradation.

In the prior art, there are also several patents which disclose an extended release tablet composition comprising fesoterodine mostly in oral pharmaceutical dosage forms. However, these compositions have some problems.

US2015182629 patent application discloses a pharmaceutical composition comprising fesoterodine fumarate. In order to ensure stability, the application had not been mentioned the importance of the coating and any coating agents.

WO2010043408 discloses microencapsulated fesoterodine; wherein fesoterodine is present in a core which is surrounded by shell; the shell contains excipients which modify the release of fesoterodine. The microencapsulated fesoterodine is further formulated in the form of tablets. But, the described process in the application is complex, time consuming and costs are high.

There is thus still a need for a physically and chemically stable composition comprising fesoterodine that are stable against fesoterodine degradation over an extended period of time.

In the present invention, the certain coating agents were used and so while the stable formulation is provided so, the formulation provides desired stability, desired dissolution profile and excellent hardness. Also, the formulation has been developed by using cost- effective and time-saving process which is a simple method according to the prior art. Detailed Description of the Invention

The main object of the present invention is to provide an extended release tablet composition comprising fesoterodine fumarate which provides desired stability, dissolution profile and excellent hardness by using the improved coating.

Another object of the present invention is to provide an extended release tablet composition comprising fesoterodine fumarate which is more stable against degradation over storage period and also provide desired extended release of the drug.

The term“extended release” may be defined as reaching desired plasma levels of an active agent of interest throughout a determined period of time and providing the drug release at a uniform and constant rate. Fesoterodine fumarate is highly soluble in water. High solubility affects the dissolution profile and it may cause dose dumping which is a result of too rapid release of the active agent. In this present invention, to provide an extended release and to control the release rate, release retarding agents have been used.

According to one embodiment of the present invention, the extended release composition comprising fesoterodine fumarate is in the dosage form of tablet. Tablet form is selected from the group comprising bilayer tablet, multilayer tablet, mini tablet, intraoral tablet, sublingual tablet, effervescent tablet, rapid release tablets, intra-tablet tablet, inlay tablet, tablet in tablet, film-coated tablet or enteric-coated tablet.

According to one embodiment of the present invention, the extended release tablet composition comprises fesoterodine fumarate and at least one coating comprising coating agents wherein the amount of fesoterodine fumarate is between 0.5% and 25.0% w/w of the composition and the amount of the coating agents is between 0.1 % and 10.0% w/w of the composition.

According to another embodiment of this present invention, said coating is film coating.

In one embodiment of this present invention, the amount of fesoterodine fumarate is between 0.5% and 15.0% w/w, preferably between 1 .0% and 8.0% w/w of the composition. According to one embodiment of the present invention, the extended release tablet composition is coated with suitable coating agents so that fesoterodine fumarate was not affected by stress conditions such as heat, humidity.

Suitable coating agents are selected from the group comprising ammonium methacrylate copolymer mixture, triethyl citrate, talc, silicon dioxide, polymethacrylates, hydroxypropyl methylcellulose, sodium lauryl sulfate, glyceryl monocaprylocaprate, polyvinyl alcohol (PVA), lactose monohydrate, hydroxypropyl cellulose, polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers, ethylcellulose dispersions, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), titanium dioxide or mixtures thereof.

According to one embodiment of the present invention, preferably, the coating agent is ammonium methacrylate copolymer mixture.

Especially, used ammonium methacrylate copolymer mixture as a coating agent ensure protection of the tablet from stress conditions such as heat, humidity. So, tablet compositions are more stable against degradation over an extended period of time even under stress conditions.

According to one embodiment of the present invention, preferably, the coating agents are ammonium methacrylate copolymer mixture, triethyl citrate, talc, silicon dioxide.

In one embodiment of the present invention, coating the extended release tablet composition comprises;

The coating comprises;

- 0.1% to 5.0% by weight of ammonium methacrylate copolymer mixture

- 0.1% to 1.5% by weight of triethyl citrate

- 0.1% to 3.0% by weight of talc

- 0.1% to 1.5% by weight of silicon dioxide of the composition.

According to another embodiment of this present invention, the extended release tablet composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising release retarding agents, stabilizers, diluents, lubricants or the mixtures thereof. According to this embodiment, the polymer as release retarding agent is selected from the group comprising hydroxyl propyl methylcellulose (HPMC) such as HPMC E4M and HPMC K100, glyceryl behenate, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethylcellulose, methacrylic acid - ethyl acrylate copolymer, polymethylmetacrylate or copolymers, polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidine, glyceryl dibehenate, polyethylene oxide, polyethylene glycol, cellulose acetate, vinyl acetate/croton ic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, copolymer of acrylic or methacrylic acid esters, polyoxyethylene -alkyl ethers, sodium lauryl sulfate (SLS), silica or mixtures thereof.

Preferably the polymer release retarding agents are hydroxyl propyl methylcellulose, glyceryl dibehenate.

In one embodiment of this present invention, the amount of release retarding agent is between 1 .0 % and 60.0 % w/w, preferably 3.0 % and 55.0 % w/w, more preferably 5.0 % and 50.0 w/w, more preferably 9.0 % and 43.0 w/w of the composition.

According to this embodiment, the ratio of fesoterodine fumarate to the release retarding agent is in the range of between 0.1 :7 and 7:0.1 by weight, preferably between 0.1 :5 and 5:0.1 by weight, more preferably 0.1 :4 and 4:0.1 by weight of the composition.

According to an embodiment of the present invention, the extended release tablet composition comprises at least one sugar as stabilizer.

According to an embodiment of the present invention, stabilizers are selected from the sugars which are sucrose, fructose, maltitol, mannitol, lactitol or mixtures thereof.

In one embodiment of this present invention, the extended release tablet composition comprises fructose or sucrose or fructose-sucrose mixture as stabilizer.

According to one embodiment of the present invention, the fructose-sucrose mixture is a stabilizer which also has binder properties. In addition, it further enhances excellent pharmacotechnical properties (i.e. flowability, compressibility and homogeneity).

In one embodiment of this present invention, the amount of the fructose-sucrose mixture is between 1 .0% and 40.0% by weight of the composition, preferably it is between 5.0% and 35.0% by weight, more preferably it is between 10.0% and 30.0% by weight of the composition.

Suitable diluents are selected from the group lactose monohydrate, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose dihydrate or mixtures thereof.

In one embodiment of this present invention, the extended release tablet composition comprises lactose monohydrate, microcrystalline cellulose mixture as a diluent.

According to another embodiment of this present invention, the amounts of diluents are between 10.0% and 50.0% w/w of the composition, preferably the amounts of diluents are between 15.0% and 45.0% w/w of the composition.

Suitable lubricants are selected from the group from talc, calcium silicate, powdered cellulose, starch, colloidal silicon dioxide or mixtures thereof.

In one embodiment of this present invention, the extended release composition comprises talc as a lubricant.

According to another embodiment of this present invention, the lubricants are between 0.1% and 5.0% w/w of the composition.

In one embodiment of the present invention, the extended release tablet composition comprises;

- 0.5 % - 25.0 % fesoterodine fumarate

- 0.1 % - 10.0 % coating agents which are ammonium methacrylate copolymer mixture, triethyl citrate, talc, silicon dioxide.

In one embodiment of the invention, the extended release tablet composition comprises;

0.50 % - 25.0 % by weight of fesoterodine fumarate

0.90 % - 35.0 % by weight of fructose

0.10 % - 5.00 % by weight of sucrose

2.50 % - 25.0 % by weight of lactose monohydrate

2.50 % - 25.0 % by weight of microcrystalline cellulose

0.20 % - 5.00 % by weight of glyceryl dibehenate 0.40 % - 23.0 % by weight of hydroxypropyl methylcellulose

0.10 % - 5.00 % by weight of talc

0.1 % - 10.0 % by weight of coating agents which are ammonium methacrylate copolymer mixture, triethyl citrate, talc, silicon dioxide.

The extended release tablet composition of the present invention may be prepared by direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying or solvent evaporation.

Process for preparing the extended release tablet composition comprises the following steps;

a) Mixing fesoterodine fumarate with fructose and sucrose

b) Granulating the mixture with water then, sieving

c) Drying the mixture at 40°C until the humidity is less than 0.5%, then sieving the mixture

d) Adding lactose monohydrate, microcrystalline cellulose, glyceryl dibehenate, hydroxypropyl methylcellulose and then mixing

e) Then, adding talc and mixing

f) Then, pressing to form tablet

g) Coating tablets with coating agent which are ammonium methacrylate copolymer mixture, triethyl citrate, talc, silicon dioxide.

It has been found that using wet granulation process, granulating fesoterodine fumarate with the addition of excipients for wet granulation showed an improved stability of fesoterodine fumarate in the granulate and in the final pharmaceutical composition.

Also, it has been found that when the composition is prepared with using water-based granulation, resulting compositions possess improved stability.

The given below examples describes the extended release tablet composition comprising fesoterodine. Example 1 : Extended release tablet composition comprising fesoterodine

* Coating comprising:

Process for example 1 :

The process for preparation of the modified release composition comprises the following steps:

h) Mixing fesoterodine fumarate with fructose and sucrose

i) Granulating the mixture with water then, sieving

j) Drying the mixture at 40°C until the humidity is less than 0.5%, then sieving the mixture

k) Adding lactose monohydrate, microcrystalline cellulose, glyceryl dibehenate, hydroxypropyl methylcellulose and then mixing

L) Then, adding talc and mixing

m) Then, pressing to form tablet

n) Coating tablets with coating agents which are ammonium methacrylate copolymer mixture, triethyl citrate, talc, silicon dioxide.

Claims

1 . An extended release tablet composition comprising fesoterodine fumarate and at least one coating comprising coating agents wherein the amount of fesoterodine fumarate is between 0.5% and 25.0% w/w of the composition and the amount of the coating agents is between 0.1% and 10.0% w/w of the composition.

2. The extended release tablet composition according to claim 1 , wherein the amount of fesoterodine fumarate is between 0.5% and 15.0% w/w, preferably between 1.0% and 8.0% w/w of the composition.

3. The extended release tablet composition according to claim 1 , wherein said coating is film coating.

4. The extended release tablet composition according to claim 1 , wherein coating agents are selected from the group comprising ammonium methacrylate copolymer mixture, triethyl citrate, talc, silicon dioxide, polymethacrylates, hydroxypropyl methylcellulose, sodium lauryl sulfate, glyceryl monocaprylocaprate, polyvinyl alcohol (PVA), lactose monohydrate, hydroxypropyl cellulose, polyethylene glycol (PEG), polyvinyl alcohol- polyethylene glycol copolymers, ethylcellulose dispersions, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), titanium dioxide or mixtures thereof.

5. The extended release tablet composition according to claim 4, wherein the coating agent is ammonium methacrylate copolymer mixture.

6. The extended release tablet composition according to claim 4, wherein coating agents are ammonium methacrylate copolymer mixture, triethyl citrate, talc, silicon dioxide.

7. The extended release tablet composition according to claim 4, wherein the coating comprising;

- 0.1% to 5.0% by weight of ammonium methacrylate copolymer mixture

- 0.1% to 1.5% by weight of triethyl citrate

- 0.1% to 3.0% by weight of talc

- 0.1% to 1.5% by weight of silicon dioxide of the composition.

8. The extended release tablet composition according to claim 1 , further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising release retarding agents, stabilizers, diluents, lubricants or the mixtures thereof.

9. The extended release tablet composition according to claim 8, wherein at least one polymer as the release retarding agent is selected from the group comprising hydroxyl propyl methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethylcellulose, methacrylic acid - ethyl acrylate copolymer , polymethylmetacrylate or copolymers, polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidine, glyceryl behenate, glyceryl dibehenate, polyethylene oxide, polyethylene glycol, cellulose acetate, vinyl acetate/croton ic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, copolymer of acrylic or methacrylic acid esters, polyoxyethylene-alkyl ethers, sodium lauryl sulfate, silica or mixtures thereof.

10. The extended release tablet composition according to claim 9, wherein the amount of release retarding agent is between 1.0 % and 60.0 %, preferably 3.0 % and 55.0 %, more preferably 5.0 % and 50.0 w/w of the composition.

1 1. The extended release tablet composition according to claim 8, wherein the stabilizers are selected from the sugars which are sucrose, fructose, maltitol, mannitol, lactitol or mixtures thereof.

12. The extended release tablet composition according to claim 1 1 , wherein the stabilizers are fructose or sucrose or fructose - sucrose mixture.

13. The extended release tablet composition according to claim 8, wherein the diluents are selected from the group lactose monohydrate, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol. lactose anhydrous, lactose dihydrate or mixtures thereof.

14. The extended release tablet composition according to claim 13, wherein the amounts of diluents are between 10.0% and 50.0% w/w of the composition, preferably the amounts of diluents are between 15.0% and 45.0% w/w of the composition.

15. The extended release tablet composition according to any preceding claims, the composition comprising;