WO2015188794A1 - A stabilized formulation of fesoterodine - Google Patents

A stabilized formulation of fesoterodine Download PDF

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Publication number
WO2015188794A1
WO2015188794A1 PCT/CZ2015/000058 CZ2015000058W WO2015188794A1 WO 2015188794 A1 WO2015188794 A1 WO 2015188794A1 CZ 2015000058 W CZ2015000058 W CZ 2015000058W WO 2015188794 A1 WO2015188794 A1 WO 2015188794A1
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WO
WIPO (PCT)
Prior art keywords
weight
fesoterodine
pharmaceutical formulation
trehalose
cellulose
Prior art date
Application number
PCT/CZ2015/000058
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English (en)
French (fr)
Inventor
Daniel PECEK
Ales VOGL
Petra PODHORNA
Original Assignee
Zentiva, K.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2015188794A1 publication Critical patent/WO2015188794A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Definitions

  • the invention relates to stable pharmaceutical formulations containing fesoterodine [2- [(lJ3 ⁇ 4 -3-(di(propan-2-yl amino]-l-phenylpropyI]-4-(hydroxymethyl)phenyl3 2-methyl propanoate of formula I, or its salts, solvate or ester, and a method of their preparation.
  • Fesoterodine is an antimuscarinic agent the use of which has been approved for the treatment of symptoms associated with the overactive bladder syndrome.
  • fesoterodine is available as the product Toviaz® in the form of tablets with extended release for administration once a day in the strengths of 4 mg and 8 mg.
  • 1-phenylpropyl] -4- [hydroxy methyl] phenyl isobutyrate is a new antimuscarinic agent, which functionally acts as a prodrug. It is quickly and extensively hydrolyzed in the body by ubiquitous non-specific esterases to 5-hydroxymethyl tolterodine (-HMT), which is an active metabolite responsible for all antimuscarinic activity.
  • -HMT 5-hydroxymethyl tolterodine
  • Fesoterodine is an ester that is considerably prone to degradation after in vivo administration as well as during storage under stress conditions, e.g. in a wet environment and at high temperatures. Hydrolysis and oxidation are considered to be the main mechanisms leading to degradation of fesoterodine.
  • Fesoterodine was included in the generic application W01998043942 and it was specifically claimed in the application W01999/058478.
  • the application W02007/141298 deals with the problem of fesoterodine stabilization in pharmaceutical formulations for oral administration.
  • Degradation of fesoterodine during stability testing was prevented with the use of a stabilizer selected from the group of xylitol, sorbitol, polydextrose, isomalt, dextrose and their combinations; xylitol being mentioned as especially preferable.
  • stabilizers were used in relatively high concentrations, namely in the ratio of the active substance to the stabilizer of 1:9 (by weight .
  • fesoterodine stability of fesoterodine in the formulation is solved by addition of fibrous material in the quantity of 1:50 to 1:2 (fesoterodine : fibrous material, by weight).
  • fibrous material in the quantity of 1:50 to 1:2 (fesoterodine : fibrous material, by weight).
  • Fibrous materials alginate, gelatine, agar, Arabic gum, xanthan, carrageenan and tragacanth, especially kappa-carrageenan, are mentioned.
  • agar is used in the ratio of 1:10 and 1:20 (fesoterodine : fibrous material, by weight) and kappa-carrageenan in the ratio of 1:10 (fesoterodine : fibrous material, by weight).
  • fesoterodine was first granulated with a stabilizer selected from the group of sucrose, polyethylene glycol, cyclodextrin and their combinations. This granulate was subsequently used for the preparation of a pharmaceutical formulation. According to the authors of the application WO2012/136838 the ratio between fesoterodine and the stabilizer should be preferably in the range of 1:1 to 1:20.
  • sucrose, polyethylene glycol, maltodextrin and cyclodextrin were used as stabilizers
  • the ratio of fesoterodine to the stabilizer was always 1:9, i.e. the same ratio as in the above mentioned application W02007/141298 was used.
  • sucrose was also used in the 1:12 and 1:16 ratios.
  • the contents of impurities after two weeks' storage on an open dish at 60°C and 21% relative humidity varied between 1.8% and 7.8% [except the formulation containing maltodextrin, where the content of impurities was 15.9%).
  • the formulations described in the examples contained commonly used pharmaceutical auxiliary substances (microcrystalline cellulose, lactose, corn starch, polyvinyl pyrrolidone, talc, magnesium stearate, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, silicon dioxide, magnesium stearate).
  • auxiliary substances microcrystalline cellulose, lactose, corn starch, polyvinyl pyrrolidone, talc, magnesium stearate, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, silicon dioxide, magnesium stearate.
  • the application WO2012/136839 describes a dry formulation of fesoterodine free from stabilizers from the group of xylitol, sorbitol, polydextrose, isomalt and dextrose, in which fesoterodine is homogeneously mixed with at least one polymer controlling the release of fesoterodine from the formulation.
  • a precondition for such formulations should be elimination of any humidity from the formulation process, as well as from the formulation itself, and at the same time homogeneous admixing of the polymer controlling releasing.
  • the contents of impurities after two weeks' storage on an open dish at 60°C and 21% relative humidity varied between 4.5% and 5.3%.
  • the aim of this invention was to prepare a stable pharmaceutical formulation containing fesoterodine that can be produced by standard pharmaceutical production processes and that will be stable under common storage conditions even with the use of a low concentration of the stabilizer (weight ratio of fesoterodine to the stabilizer 1:2 to 1:5).
  • the invention provides stable pharmaceutical formulations of fesoterodine, containing trehalose in a concentration weight ratio of fesoterodine or its pharmaceutically acceptable salt to trehalose of 1:0.5 to 1:5; wherein surprisingly high stabilization was achieved with the use of a low concentration of the stabilizer trehalose.
  • the formulation in accordance with the present invention can be prepared by common methods, i.e. both wet granulation and dry granulation or direct tabletting. Description of figures
  • the aim of the present invention was to find a composition of a pharmaceutical formulation containing fesoterodine that would be chemically stable, could be prepared by common pharmaceutical production methods and would exhibit excellent dissolution characteristics.
  • fesoterodine is meant to refer to the chemical structure 2-[(lR)-3- [diisopropylamino -l-phenylpropyl]-4-(hydroxymethyl ⁇ phenyl isobutyrate, or possibly its salts, especially the hydrogen fumarate.
  • concentration of fesoterodine, preferably in the hydrogen fumarate form, is in the pharmaceutical formulations in accordance with the invention in the range of 1 to 8 mg (related to fesoterodine), preferably 4 and 8 mg (related to fesoterodine) per drug form unit
  • the application W02010/043408 solves the stabilization by micro-encapsulation, i.e. a complicated process that does not meet the requirement of commonly available pharmaceutical production technology.
  • the application WO2011/050961 suggests natural fibrous material as the stabilizer, which can however be itself a source of chemical impurities and in addition it may be subject to microbial decay, to say nothing of the animal origin of some preferred substances (e.g. gelatine), which may be limiting for some patient groups (vegetarians, religious point of view).
  • Trehalose has proved to be such a stabilizer as it surprisingly provided high stabilization achieved with a surprisingly low concentration of the stabilizer.
  • concentration commonly used and preferred in documents known from the art WO2007/141298, WO2012/136838, i.e. the 1:9 concentration (active substance to the stabilizer, by weight)
  • no stabilization of the formulation by trehalose has occurred (see the comparative Example A and Example 7).
  • One aspect of this invention is a stabilized pharmaceutical formulation of fesoterodine or one of its pharmaceutically acceptable salts, wherein trehalose is used as the stabilizer in a concentration weight ratio of fesoterodine or its pharmaceutically acceptable salt to trehalose of 1:0.5 to 1:5 (by weight).
  • concentration weight ratio of fesoterodine or its pharmaceutically acceptable salt to trehalose 1:0.5 to 1:5 (by weight).
  • the formulation in accordance with the present invention can be prepared bycommon procedures, i.e. both wet granulation and dry granulation or direct tabletting.
  • the composition containing fesoterodine, preferably in the form of fesoterodine hydrogen fumarate, which is described in this patent, can be generally used for dosage forms with immediate, extended, pulse or delayed release, or for their mutual combination.
  • achievement of an extended release profile with the most suitable length of fesoterodine release of at least 24 hours, and hence for dosing once a day is preferred.
  • This dosing regimen ensures continuous supply to the drug to the blood stream, which allows to reduce the exposure of the organism to the active substance while maintaining the therapeutic efficiency. It is preferably also possible to achieve compensation of deviations in the plasmatic concentration of the drug, which leads to a better tolerance of the drug and to a reduction of the frequency of occurrence of undesirable effects.
  • the preferred stable pharmaceutical composition containing fesoterodine preferably in the form of fesoterodine hydrogen fumarate, makes it possible to achieve a suitable dissolution profile in 900 ml of phosphate buffer with pH 6.8 at 75 rpm and the temperature of 37.0 ⁇ O.S°C in the USPII dissolution device (paddles).
  • the minimum rate of released drug in the first hour of the dissolution test is 20%, by the sixth hour at least 50% is released and by the twentieth hour at least 75% of the drug is released.
  • Optimum polymers controlling releasing of the drug are substances from the group of hydrophilic polymers, but hydrophobic polymers or their combinations may also be used.
  • Suitable hydrophilic polymers include, e.g.: hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium salt of carboxymethyl cellulose, hydroxypropyl cellulose, polysaccharides, polyacrylates and other similar polymers and polymers known from the prior art
  • Suitable hydrophobic polymers include: ethyl cellulose, glyceryl palmitostearate, waxes (carnauba, montan glycol), hardened vegetable oil, glycerol monostearate, stearyl alcohol, glyceryl behenate and other similar polymers and polymers known from the prior art.
  • a stable pharmaceutical composition containing fesoterodine is prepared by homogeneous mixing of fesoterodine, preferably in the form of fesoterodine hydrogen fumarate, preferably with a representative of the group of hydrophilic polymers, preferably from the hydroxypropyl methyl cellulose group.
  • the amount of this polymer that guarantees extended release of fesoterodine hydrogen fumarate from the dosage form is in the range of from 20% by weight to 70% by weight, related to the total weight of the dosage form.
  • the selected dosage form is preferably a tablet, coated tablet or hard capsule.
  • Other possible dosage forms for oral administration are: a multi-layered tablet with controlled release, pellets, pellets in a capsule, mini-tablets in a hard or soft capsules, or other dosage forms issuing from the prior art which is known to those skilled in the art.
  • the selected dosage form is preferably coated with a coating layer ensuring minimization of the impact of humidity on the tablet core; coating systems containing polyvinyl alcohol, or hydroxypropyl cellulose as an integral constituent being suitable candidates for this purpose.
  • the coating layer may further include softeners, fillers and colorants.
  • Humidity can be further reduced within the primary package by incorporation of a desiccant, e.g. based on silicates, which are, together with the dosage form, enclosed in a package with low permeability for air humidity.
  • a desiccant e.g. based on silicates
  • Suitable materials for the production of packages with such characteristics include, e.g., high-density polyethylene, or polychlorotrifluoroethylene or aluminium foil.
  • the space inside the primary package is filled with an inert gas, preferably nitrogen.
  • the final dosage form may be packed in an aluminium blister package with the thickness of 0.45 mm, closed with aluminium foil with the thickness of 0.025 mm and subsequently in a secondary package (paper box). Stability of the formulation can be further enhanced by packing in an inert protective atmosphere.
  • the preparation process of the stable pharmaceutical composition containing fesoterodine, preferably in the form of fesoterodine hydrogen fumarate uses routine processes available for dosage form formulation, such as direct mixing of constituents, compacting, fluid granulation, high-speed granulation, tabletting and coating. Very advantageously, a process step can be incorporated that will ensure close contact of the stabilizer with the active substance, which can be achieved by methods of mixing, granulation, spray drying, pelletizing and other methods issuing from the prior art, which are known to those skilled in the art.
  • the proposed stable pharmaceutical compositions containing fesoterodine hydrogen fumarate have been subjected to stability evaluation in the conditions of 40°C at 75% relative humidity for 3 months.
  • the selected stable compositions were prepared using the method of dry or wet granulation of fesoterodine hydrogen fumarate with the defined group of auxiliary substances and then admixing of other extragranular components that should add volume up to the desired tablet weight, lubricate the mixture during the tabletting process or further contribute to achievement of the desired dissolution profile.
  • the groups of substances compatible with the developed pharmaceutical composition comprise, besides the stabilizer: fillers, binders, glidants and disintegrants.
  • the stabilizer is, as discussed above, trehalose.
  • the preferred content of this substance in the system is 0.5 to 40% by weight, conveniently 1 to 25, most conveniently 1 to 15% by weight, the weight ratio of fesoterodine or its pharmaceutically acceptable salt to trehalose being in the range of 1:0.5 to 1:5.
  • Fillers supporting stability of the suggested composition can be: microcrystalline cellulose, starch, calcium hydrogen phosphate, calcium carbonate, magnesium carbonate and other compounds known from the prior art.
  • the preferred contents of these substances in the system are 1 to 50% by weight.
  • Binders supporting stability of the proposed composition can be: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, dextrin, polymethacrylates, pregelatinized starch, sodium alginate and other substances known from the prior art.
  • the preferred contents of these substances in the system are 0.5-10% by weight.
  • Disintegrants supporting stability of the proposed composition can be: sodium salt of crosscarmellose, pregelatinized starch, starch sodium glycolate, sodium salt of carmoxymethyl cellulose, crospovidone and other substances known from the prior art.
  • the preferred contents of these substances in the system are 0.5 to 5% by weight
  • Glidants supporting stability of the proposed composition can be: talc, magnesium and calcium stearate, colloidal silicon dioxide, stearic acid, hydrogenated vegetable oils, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, polyethylene glycol, sodium salt of stearyl fumarate, mineral oils, kaolin and other substances known from the prior art.
  • the preferred contents of these substances in the system are 0.5 to 20% by weight.
  • composition of stable pharmaceutical formulations is to illustrate the focus of this invention and not to limit its scope. Any other modifications of the composition or production methods are possible if they are implemented in line with maintaining the stability of the composition.
  • Fesoterodine was granulated with trehalose [weight ratio 1:5) in a high-speed mixer with the use of a mixture of water with ethanol and, after drying and screening through a sieve with the mesh size of 0.5 mm, the granulate was mixed with the rest of the auxiliary substances and homogenized.
  • a rotary press was used to produce tablets that were coated with a coating based on methyl cellulose and hydroxypropyl cellulose.
  • Fesoterodine was granulated with trehalose (weight ratio 1:2) in a high-speed mixer with the use of water and, after drying and screening through a sieve with the mesh size of 0.5 mm, the granulate was mixed with the rest of the auxiliary substances and homogenized.
  • a rotary press was used to produce tablets that were coated with a coating based on methyl cellulose and hydroxypropyl cellulose.
  • Fesoterodine was granulated with trehalose (weight ratio 1:1) in a high-speed mixer with the use of water and, after drying and screening through a sieve with the mesh size of 0.5 mm, the granulate was mixed with the rest of the auxiliary substances and homogenized.
  • a rotary press was used to produce tablets that were coated with coating based on methyl cellulose and hydroxypropyl cellulose.
  • fesoterodine was mixed with trehalose (weight ratio 1:0.5) and then with the other auxiliary substances.
  • a rotary press was used to produce tablets that were covered with coating based on methyl cellulose and hydroxypropyl cellulose.
  • Fesoterodine was granulated with trehalose (weight ratio 1:9) in a high-speed mixer with the use of a mixture of water with ethanol and, after drying and screening through a sieve with the mesh size of 0.5 mm, the granulate was mixed with the rest of the auxiliary substances and homogenized.
  • a rotary press was used to produce tablets that were coated with coating based on methyl cellulose and hydroxypropyl cellulose.
  • Fesoterodine was homogenized with the rest of the auxiliary substances, which provided the tabletting matter.
  • a rotary press was used to produce tablets that were coated with coating based on methyl cellulose and hydroxypropyl cellulose.
  • Tablets prepared in Examples 1-4 and A-B were subjected to a stability test under the conditions of 25°C/60% humidity and 40°C/75% humidity. The total contents of impurities were measured using the HPLC method at the beginning of the testing, after three months and after six months.
  • Reference solution 1 ml of the stock solution was diluted with the sample solvent to 100 ml.
  • Sample solution 10 tablets were thoroughly crushed and homogenized. 825 mg of crushed tablets [corresponding to 20 mg of fesoterodine fumarate) were dosed into a 20 ml volumetric flask and dissolved in 20 ml of the sample solvent.
  • the table presents the percentage values of the total content of impurities (by weight].
  • the formulations in accordance with Examples 1-4 were significantly more stable than the formulations in accordance with the comparative examples.
  • the concentrations of trehalose of 1:1 and 1:0.5 (fesoterodine fumarate : trehalose) have proved to be the most advantageous.

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PCT/CZ2015/000058 2014-06-09 2015-06-08 A stabilized formulation of fesoterodine WO2015188794A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2014-400 2014-06-09
CZ2014-400A CZ2014400A3 (cs) 2014-06-09 2014-06-09 Stabilizovaná formulace fesoterodinu

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WO2015188794A1 true WO2015188794A1 (en) 2015-12-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110151720A (zh) * 2019-05-09 2019-08-23 合肥信风科技开发有限公司 含非索罗定的药用组合物及其制备方法

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043942A1 (en) 1997-03-27 1998-10-08 Pharmacia & Upjohn Ab Novel compounds, their use and preparation
WO1999058478A1 (en) 1998-05-12 1999-11-18 Schwarz Pharma Ag Novel derivatives of 3,3-diphenylpropylamines
WO2007141298A1 (en) 2006-06-09 2007-12-13 Schwarz Pharma Ag Stabilized pharmaceutical compositions comprising fesoterodine
US20080138421A1 (en) * 2006-06-09 2008-06-12 Christoph Arth Pharmaceutical compositions comprising fesoterodine
WO2010043408A2 (de) 2008-10-17 2010-04-22 Ratiopharm Gmbh Mikroverkapseltes fesoterodin
WO2011050961A1 (de) 2009-10-30 2011-05-05 Ratiopharm Gmbh Zusammensetzung enthaltend fesoterodin und ballaststoffe
WO2011117884A1 (en) 2010-03-22 2011-09-29 Cadila Healthcare Limited Stable pharmaceutical compositions comprising fesoterodine
WO2012136839A1 (en) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Dry formulation and pharmaceutical composition comprising fesoterodine or a salt or a solvate thereof
WO2012136838A1 (en) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Pharmaceutical composition comprising fesoterodine
US20130236544A1 (en) * 2012-03-08 2013-09-12 Dr. Reddy's Laboratories Ltd. Stable pharmaceutical compositions of fesoterodine

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043942A1 (en) 1997-03-27 1998-10-08 Pharmacia & Upjohn Ab Novel compounds, their use and preparation
WO1999058478A1 (en) 1998-05-12 1999-11-18 Schwarz Pharma Ag Novel derivatives of 3,3-diphenylpropylamines
WO2007141298A1 (en) 2006-06-09 2007-12-13 Schwarz Pharma Ag Stabilized pharmaceutical compositions comprising fesoterodine
US20080138421A1 (en) * 2006-06-09 2008-06-12 Christoph Arth Pharmaceutical compositions comprising fesoterodine
WO2010043408A2 (de) 2008-10-17 2010-04-22 Ratiopharm Gmbh Mikroverkapseltes fesoterodin
WO2011050961A1 (de) 2009-10-30 2011-05-05 Ratiopharm Gmbh Zusammensetzung enthaltend fesoterodin und ballaststoffe
WO2011117884A1 (en) 2010-03-22 2011-09-29 Cadila Healthcare Limited Stable pharmaceutical compositions comprising fesoterodine
WO2012136839A1 (en) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Dry formulation and pharmaceutical composition comprising fesoterodine or a salt or a solvate thereof
WO2012136838A1 (en) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Pharmaceutical composition comprising fesoterodine
US20130236544A1 (en) * 2012-03-08 2013-09-12 Dr. Reddy's Laboratories Ltd. Stable pharmaceutical compositions of fesoterodine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110151720A (zh) * 2019-05-09 2019-08-23 合肥信风科技开发有限公司 含非索罗定的药用组合物及其制备方法

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