TR201820589A2 - STABLE PHARMACEUTICAL COMPOSITION CONTAINING PHESOTHERODINE - Google Patents

Abstract

The invention relates to a stable pharmaceutical composition comprising fesoterodine or its pharmaceutically acceptable salt, solvate, hydrate, enantiomer, polymorphs or a combination thereof and a method of manufacture thereof.

Description

DESCRIPTION STABLE PHARMACEUTICAL COMPOSITION WITH FESOTERODINE Technical Field of Invention The invention includes fesoterodine or its pharmaceutically acceptable salt, solvati, hydrate, a stable pharmaceutical product containing the enantiomer, polymorphs, or a combination thereof. It concerns the composition and its production method.

State of the Art Fesoterodine is a muscarinic receptor antagonist. responsible for the therapeutic effects active metabolite of fesoterodine, 5-hydroxymethyltolterodine (desfesoterodine. Overactive symptoms (increased urination frequency) that may occur in patients with bladder syndrome and/or urgency and/or urinary incontinence). on the bladder Its effects are inhibition of bladder contraction and reduction of detrusor pressure. Chemical name 2-[(1R)-3-[bis(propan-2-yl)amino]-1-phenylpropyl]-4-(hydroxymethyl)phenyl 2-methylproponate and its structural formula is given below.

Formula-1 TOViaz® containing fesoterodine fumarate as 4 mg and 8 mg Extended Release tablets is in the market. The active substance in the reference product is easily degradable. Since it is a substance, xylitol is used as a stabilizer. This is EP2029I34 BI patent specified in the scope. In the production of the composition prepared by wet granulation in the relevant patent from xylitol, sorbitol, polydextrose, isomalt, dextrose and combinations thereof explains the use of the selected stabilizer.

EP2508175 A1 patent application xylitol, sorbitol, polydextrose, isomalt and dextrose describes the dry formulation of fesoterodine without Dry formulation direct printing or tablet compression after dry granulation.

EP2508173 A1 patent application in the production of the compound prepared by wet granulation from sucrose, polyethylene glycol, cyclodextrin, inaltodextrin and combinations thereof. explains the use of the selected stabilizer.

EP2867199 B1 patent fesoterodine fumarate as glyceryl behenate and stabilizer describes a stable pharmaceutical composition containing a mixture of citric acid and pre-gelatinized starch.

It has been stated that direct compression is more stable than dry granulation and wet granulation.

EP2964261 A1 patent application of moisture sensitive drug, fructose, xylitol and maltitol with an excipient selected from the group consisting of a mixture and combinations thereof. granulation is described. Moisture-sensitive active ingredient in combination with an excipient It has been stated that the granulation may be wet or dry. Also, in dry granulation, a granulation with excipient, moisture-sensitive drug and fructose or moisture-sensitive drug xylitol and maltitol.

As a result of the work done by the inventors, fesoterodine, its salts, They obtained a more stable pharmaceutical composition containing their solvates.

Other applications of this invention will be described in more detail below.

Description of the Invention The subject of the present invention is fesoterodine or its pharmaceutically acceptable stable containing salt, solvate, hydrate, enantiomer, polymorphs, or a combination thereof. obtaining a product and its production method.

The main object of the present invention is to use fesoterodine, which is sensitive to moisture and temperature, or having the appropriate impurity profile in a pharmaceutical composition containing its salts, solvates to obtain a stable product.

As used herein, the term "fesoterodine" refers to fesoterodine and its pharmaceutical acceptable salt, solvate, hydrate, enantiomer, polymort or a combination thereof means combination, Preferably fesoterodine fumaraf, In a preferred embodiment of the invention, the pharmaceutical composition tablet and capsule solid dosage can be selected from the forms. Preferably, the composition is in tablet form, with extended saline properties.

In practice of the present invention, the terms "composition" and "formulation" should replace can be used as

The tablet production method of fesoterodine is a moisture and temperature sensitive active ingredient. It was chosen as dry granulation because of its The term "dry granulation" It includes mixture and compactor processes. Exposure of the active substance to less physical processing stability is better provided.

dgo for particle size distribution of the active ingredient used in the present formulation The value is preferably less than 150 µm, more preferably between 100 µm and 150 µm. Here The average particle size of the particles meant by the expression "d50 particle size" used is the volume mean particle diameter. "d90 particle size" With the expression, it refers to the particle diameter where 90% of the particles are by volume. d90 For example, laser diffraction, which is one of the measurement methods with known values, It can be measured in a measuring device (eg malvern Mastersizer). In laser diffraction device Measurements were made by the age method.

Particle size of the active substance, since the active substance contains low flow properties. It is important in terms of mixing uniformity and content uniformity.

In the present invention, the pharmaceutically acceptable adjuvant used in the composition matter; filler (diluent), dispersant, binder, glidant (lubricant), lubricant, stabilizer, release modifying agent (controlled release agent) or their He can be chosen from among his wives and is not limited to that.

The “filler (diluent)” mentioned in the present invention is calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, sugar, such as cellulose, lactose, maltose, fructose, sucrose, glucose, dextrose, dextrate and so on, sugar alcohol such as mannitol, erythritol, lactylol, maltitol, xylitol, sorbitol and the like, methylcellulose polymers, microcrystalline cellulose and other cellulose derivatives, starches or modified starches (potato starch, wheat starch, corn starch, rice starch, pre- gelatinized corn starch), magnesium carbonate, magnesium oxide or a mixture of these can be selected from among, but is not limited to this. The preferred filler is lactose, microcrystalline cellulose or a mixture thereof.

In the present invention, "dispersive" cross-linked polyvinylpyrrolidone (eg crospovidone, polypiliplasdon XL®, kollidon CL®), corn starch and dried sodium starch glycolate starches such as; gums such as alginic acid, sodium alginate, guar gum, croscarnellose sodium, microcrystalline cellulose and its salts, carboxymethyl cellulose, low substituted hydroxypropyl cellulose products such as cellulose or a mixture thereof, but limited to is not.

In the present invention, "glidant" colloidal silicon dioxide, aluminum silicate, magnesium silicate, powdered cellulose, talc, tribasic calcium phosphate or a mixture thereof. can be selected but not limited to that. The preferred glidant is colloidal silicon dioxide and is talk7.

The "lubricant" in the present invention is sodium oleate, sodium stearate, sodium benzoate, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acids, zinc stearate, polyethylene glycol, glyceryl behenate may be selected from talc or mixtures thereof, but limited to is not. The preferred lubricant is glyceryl behenaf.

The "stabilizer" in the present invention is sugar alcohols, maltodextrin or mixtures thereof. can be selected from among, but is not limited to this. The sugar alcohols mannitol and maltitol can be selected among The preferred stabilizer is mannitols.

The "binding" natural and synthetic gums (acacia, tragacanth, tragacanth) mentioned in the present invention sodium alginate, celluloses and beegum), hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl inethyl cellulose, starch (such as corn starch and pre-gelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), such as polyvinylpyrrolidone (povidone) synthetic polymers, ethylcellulose, hydroxyethylcellulose, polyethylene oxide, mixtures thereof or similar ones are mentioned, but not limited to this.

The “release modifying agent” mentioned in the present invention is agar, alginic acid, sodium alginate, carbomer, carrageenan, guar gum, gum acacia, hydroxypropylmethyl cellulose (hypromellose), hydroxypropylmethyl cellulose acetyl succinate, hydroxypropylmethyl cellulose phthalate, methyl cellulose, polyethylene oxide, polyvinyl alcohol, sodium hyaluronate, xanthan gum, povidone, chitosan or It can be selected among the mixtures of these, but is not limited to this. Preferably hydroxypropyl methyl cellulose chloride.

Various types of hydroxypropyl methyl cellulose vary according to viscosity and degree of substitution. available in degrees. According to the viscosity values in 2° w/w aqueous solutions at 20 OC they are classified. In the present invention, hydroxypropyl methyl cellulose is used as the release modifying agent. (HPMC) is used, preferably high-viscosity HPMC (with 75,000- Desired release profile using low-viscosity HPMC (2500- combination) has been obtained.

In another embodiment of the invention, besides the active ingredient and the glidant function A helper that has high adsorption potential and can provide moisture adsorption, emission modifier, preferably containing colloidal silicon dioxide, and a relatively low amount of water agent, preferably hydroxypropylmethyl cellulose (HPMC), with a separate dry mix process mixed, the remaining auxiliary substances are passed through the compactor and dried. added to the mix. Thus, with the active ingredient sensitive to humidity and temperature, high water other auxiliary materials containing the amount of pressure are not passed through the compactor together. With the effect of water dilution and accordingly the realization of the hydrolysis reaction is inhibited, that is, no solvent is used and thus drying Since there is no exposure to the process, the hydrolysis reaction of the active substance sensitive to temperature and humidity is blocked. In addition, by passing the remaining auxiliary materials in the process through the compactor. The sensitivity of the formulation to process changes has been reduced and the powder flow has been improved.

Thus, the problems encountered while formulating the active ingredient of fesoterodine are eliminated. has been removed. Studies on comparison data and development of production method explained in detail in the examples section.

The object of the present invention is to produce an extended release pharmaceutical composition containing Fesoterodine. It is a production method and its feature is that it includes the following production steps: I. Fesoterodine, release modifying agent, at least one glidant, and optionally at least one the pharmaceutically acceptable excipient is mixed and optionally sieved, ii. release modifying agent, at least one glidant, and optionally at least one one pharmaceutically acceptable excipient is mixed and optionally sieved, iii. also in a separate place a release modifying agent, stabilizer, at least one glidant and optionally at least one pharmaceutically acceptable excipient is mixed and mixed with the mixture obtained in step (ii), iv. Optionally, at least one pharmaceutical grade of the mixture obtained in step (iii) acceptable excipient is added, v. The mixture obtained in step (iv) is passed through the compactor and sieved, vi. The mixture obtained in step (v) is added to the mixture obtained in step (i), mixed and pressed in tablet form.

The object of the present invention is to produce an extended release pharmaceutical composition containing Fesoterodine. It is a production method and its feature is that it includes the following production steps: I. Fesoterodine, high Viscosity release modifying agent, at least one glidant, and optional At least one pharmaceutically acceptable excipient is mixed and optionally is eliminated depending, ii. high-viscosity release modifying agent, glidant and optionally at least one pharmaceutically acceptable excipient is mixed and optionally iii. also in a separate place a low viscosity release modifying agent, stabilizer and at least one glidant and optionally at least one pharmaceutically acceptable adjuvant the substance is mixed and mixed with the mixture obtained in step (ii), iv. Optionally, at least one pharmaceutical grade of the mixture obtained in step (iii) acceptable excipient is added, v. The mixture obtained in step (iv) is passed through the compactor and sieved, vi. The mixture obtained in step (v) is added to the mixture obtained in step (i), mixed, vii. into the desired dosage form.

In one embodiment of the invention, the high viscosity release used in step (i) Ratio of modifying agent to high viscosity release modifying agent used in step (ii) 111 to 1:10, preferably 1:6.5”.

Another object of the present invention is an extended release drug containing fesoterodine fumarate. It is the production method of the pharmaceutical composition and its feature includes the following production steps. includes: I. fesoterodine fumarate, high viscosity hydroxypropyl methyl cellulose and silicon dioxide mixed and optionally sieved, ii. high viscosity hydroxypropyl inethyl cellulose, lactose monohydrate, microcrystalline cellulose and talc are mixed and optionally sieved, iii. Likewise, in a separate place, low viscosity hydroxypropyl methyl cellulose, mannitol and silicon dioxide is sieved and mixed with the mixture obtained in step (ii), iv. Add glyceryl behenate to the mixture obtained in step (iii) and the mixture is obtained, v. The mixture obtained in step (iv) is passed through the compactor and sieved. vi. The mixture obtained in step (v) is added to the mixture obtained in step (i), vii. tablet is pressed. viii. preferably the tablets are coated.

In a preferred embodiment of the invention, the high level used in step (i) high viscosity used in step (ii) of viscous hydroxypropyl methyl cellulose The ratio of hydroxypropyl methyl cellulose is 121 to 1:10, preferably 1:6.5.

In one embodiment of the present invention, the preferred coating technique is film coating.

The film coating can be a functional or non-functional coating. preference in current invention The coating obtained is a non-functional coating and the appearance of the product, the ease of swallowing, the product It was used to improve stability and mechanical strength. Coating material; polymer, plasticizer, colorant, surfactants, flavoring agent, gloss It contains broad components such as donor agent, solvent. The main component is polymers. cellulose derivatives (hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, such as methylhydroxy ethyl cellulose, ethyl cellulose sodium carboxymethyl cellulose), glycols (polyethylene glycol), vinyl (such as polyvinyl pyrrolidone), acrylic (such as ethylacrylate-methylmethacrylate copolymer) can be selected among

The coating used in an embodiment of the present invention is non-functional coating. It is a polyvinyl alcohol based coating. Its advantage over cellulose derivative coatings is oxygen and moisture permeability is lower.

In another embodiment of the present invention, the solvent used in the film coating is water, organic solvent and mixtures thereof. used in film coating The solvent is water. Environmental effects, safety effects and end of residues of organic volatiles Water was preferred because of its disadvantages such as controlling the product. The pharmaceutical composition of the invention containing fesoterodine fumarate and said pharmaceutical A clear and detailed understanding of the new and distinctive aspect of the method of manufacture of the compound Various examples of the studies carried out are given below in order to provide This The examples are for illustrative purposes only and are not intended to limit the scope of protection. should not be evaluated. Examples raw material mg Fesoterodine Fuinrate 8.0 Xylitol 72.0 Granule 80.0 Fesoterodine fumarate and granules containing xylitol Lactose and microcrystalline 77' 50 cellulose blend high viscosity low viscosity Glyceryl behanate 10.0 Core Tablet 320.0 Coating material 14.40 Film-coated tablet 334.40 Fesoterodine fumarate is mixed with xylitol and wet in a quick mixer granulator using water. Granules are obtained by granulation. Until the granules drying loss is less than 0.5% dried and sieved. The resulting granules are mixed with lactose and microcrystalline cellulose. (My wife-l). On High Viscosity HPMC, low viscosity HPMC and talc mix-1 is added and mixed. The final mixture is obtained by adding glyceryl behenate to this mixture.

Claims (8)

REQUESTS l. It is a production method of a stable extended release pharmaceutical composition containing fesoterodine. Its feature is i. Mixing and optionally eliminating fesoterodine, a release modifying agent, at least one glidant, and optionally at least one pharmaceutically acceptable excipient, ii. mixing and optionally eliminating a release modifying agent, at least one glidant, and optionally at least one pharmaceutically acceptable excipient in a separate location, iii. likewise, mixing the release modifying agent, stabilizer, at least one glidant and optionally at least one pharmaceutically acceptable excipient in a separate place and mixing it with the mixture obtained in step (ii), iv. optionally adding at least one pharmaceutically acceptable excipient to the mixture obtained in step (iii), V. passing the mixture obtained in step (iv) through the compactor and sifting, vi. The mixture obtained in step (v) includes the production steps of adding the mixture obtained in step (i), mixing and pressing in tablet form. 2. A pharmaceutical composition according to claim 1, comprising at least one pharmaceutically acceptable excipient, filler (diluent), dispersant, binder, glidant (lubricant), lubricant (lubricant), stabilizer, release modifying agent (controlled release agent). ) is that. 3. According to claim, the release modifying agent with high and low viscosity is hydroxypropyl inethyl cellulose. 4. According to claim 2, the glidant is silicon dioxide and talc. 5. The filler according to claim 2 is lactose, microcrystalline cellulose or a mixture thereof. 6. The lubricant according to claim 2 is glyceryl behenate. 7. According to claim 2, the stabilizer is mannitol. 8. Production method of a stable extended release pharmaceutical composition containing Fesoterodine according to claim 1, characterized in that i. mixing and optionally sieving of fesoterodine fumarate, high viscosity hydroxypropyl methyl cellulose and silicon dioxide, ii. mixing and optionally sieving of high viscosity hydroxypropyl methyl cellulose, lactose monohydrate, microcrystalline cellulose and talc in a separate place, iii. in the same way, sieving low-viscosity hydroxypropyl methyl cellulose, inannitol and silicon dioxide in a separate place and mixing it with the mixture obtained in step (ii), iv. adding glyceryl behenate to the mixture obtained in step (iii) and obtaining the mixture, v. passing through the compactor and sieving the mixture obtained in step (iv). vi. Adding the mixture obtained in step (i) to the mixture obtained in step (v), vii. tablet pressing. viii. preferably tablets coating, production steps.