Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the present invention relates to a stable pharmaceutical com position comprising Fesoterodine or pharm aceutical ly acceptable salt thereof; wherein the composition is devoid of sugar alcohols used as stabilizer. Further, the present invention discloses processes for the preparation of the said pharmaceutical composition prepared by direct compression.
• Fesoterodine is chemically 2-[( I R)-3-(diisopropylamino)- l -phenylpropyl]-4- (hydroxymethyl)phenyl isobutyrate. Fesoterodine is a prodrug; which gets rapidly de-esterified to its active metabol ite (R)-2-(3-diisopropylam ino- l - phenylpropyl)-4-hydroxymethyl-phenol or 5-hydroxymethyl tolterod ine (5- HMT), which is a m uscarin ic receptor antagonist. Molecular form ula of chemical structure:
• W099/58478 discloses novel derivatives of 3,3-diphenyipropylam ines which cover Fesoterodine. Further, WOO I /35957 discloses stable salts of Fesoterodine including Fesoterodine hydrogen fumarate. Fesoterodine is marketed under trade name Toviaz ® ; which contains Fesoterodine fumarate as active ingredient and is approved as extended-release tablet for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. it is bel ieved that Fesoterodine may undergo substantial degradation under stress conditions, e.g., in a humid environment and at increased temperature. Probable reasons for degradation of Fesoterodine are hydrolysis and oxidation. To overcome the said problem several approaches are reported as fol lows:
• Fesoterodine is currently marked as Toviaz® wh ich is extended-release tablet contains 4 or 8 mg of Fesoterodine fumarate as active ingredient and following inactive ingredients: glyceryl behenate, hypromellose, indigo carm ine alum inum lake, lactose monohydrate, soya lecithin, microcrystal l ine cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium diox ide, and xyl itol.
• the composition uses xyl itol as stabilizer to control the degradation of Fesoterod ine.
• US78077 15 discloses a pharmaceutical composition comprising Fesoterodine or salt thereof and a pharmaceutically acceptable stabilizer, wherein stabilizer is selected from the group consisting of sorbitol, xylitol, polydextrose, isomalt, dextrose, and combinations thereof, preferably a sugar alcohol selected from xylitol and sorbitol.
• stabilizer is selected from the group consisting of sorbitol, xylitol, polydextrose, isomalt, dextrose, and combinations thereof, preferably a sugar alcohol selected from xylitol and sorbitol.
• US78077 15 further discloses that wet granulation method for preparation of composition is preferable over dry granulation and direct compression.
• WO201 0/043408 discloses microencapsulated Fesoterodine; wherein Fesoterodine is present in 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.
• WO201 1 /050961 discloses a composition, comprising Fesoterodine and fiber, wherein fiber is selected from alginate, gelatin, agar, gum arabic, tragacanth, xanthan gum and carrageenan. Focus of WO201 1 /050961 is to prepare a composition comprising Fesoterodine and fiber; wherein fiber act as stabilizer as well as sustained release adjuvant.
• WO201 1 /1 1 7884 d iscloses a pharmaceutical composition comprising of Fesoterodine or its salts, wherein the said pharmaceutical composition is devoid of sugar stabilizer.
• Fesoterodine compositions are prepared using judicial combination of excipients, without using sugar alcohol.
• the inventors of the present invention tried to develop a stable extended release pharmaceutical composition of Fesoterodine or its salt by j ud icial use of excipients as disclosed in WO20 1 1 / I I 7884, however failed to obtain a stable extended release pharmaceutical composition of Fesoterodine or its salt.
• First objecf of the invention is to provide a stable pharmaceutica l com position of Fesoterodine or its salt, wherein the said pharmaceutical composition is devoid of sugar alcohol.
• Another object of the invention is to provide processes for the preparation of stable pharmaceutical composition of Fesoterodine or its salt, where in the said pharmaceutical composition is devoid of sugar alcohol.
• Another object of the invention is to provide a stable pharmaceutical composition of Fesoterodine or its salt, wherein the total impurity in the said pharmaceutical composition is not more than 2% w/w after subjecting the said pharmaceutical composition to a storage cond ition of 40°C / 75% RH for a period of 3 month.
• Another object of the invention is to provide a stable pharmaceutical composition of Fesoterodine or its salt, wherein the total impurity in the said composition is not more than 2% w/w, impurity A and impurity C are not present in an amount more than 0.625% w/w individually; after subjecting the said pharmaceutical composition to a storage cond ition of 40°C / 75% RH for a period of 3 month.
• Present invention provides a stable pharmaceutical composition of Fesoterodine or its salt and process for the preparation of the same; wherein the said pharmaceutical composition is devoid of sugar alcohol.
• the incremental innovation of the present invention relates to use of amorphous hydrated si licon dioxide (eg. product marketed as SYLOID® FP) and pre-dried excipients for the preparation of a stable pharmaceutical composition of Fesoterodine or its salt.
• Present invention provides a stable pharmaceutical composition of Fesoterodine or its salt, wherein the composition is devoid of sugar alcohol; and amorphous hydrated silicon dioxide and pre-dried excipients are used for the preparation of the said stable composition.
• the pharmaceutical com position of Fesoterodine or its salt according to the present invention are prepared by direct compression techniques. Direct compression techniques are wel l know to a person skilled in the art and are well-documented in reference l iteratures for pharmaceutical sciences. Further, according to the present invention, the pharmaceutical composition of Fesoterodine or its salt is devoid of sugar alcohol.
• sugar alcohol used hereinafter in the present invention relates to hydrogenated form of carbohydrate, whose carbonyl group has been reduced to a primary or secondary hydroxy! group.
• sugar alcohols include inositol, erythritol, xyl itol, mann ito l, sorbitol, dulcitol, iditol, isomalt, maititol, lactitol, ribitol, arabitol and the likes thereof.
• amorphous hydrated si licon dioxide (eg. product marketed as SYLOID® FP) is used in the preparation of a stable pharmaceutical composition comprising Fesoterodine or its salt.
• Amount of amorphous hydrated si l icon dioxide used in pharmaceutical com position is proportionate to the amount of Fesoterodine or its salt used in the sa id composition. Accordingly, the ratio of Fesoterodine or its sal t to amorphous hydrated silicon dioxide used in the said pharmaceutical composi tion is 4 : 1 to 1 : 10.
• ratio of Fesoterodine or its salt to, amorphous hydrated si licon dioxide in the said pharmaceutical composition is 1 : 1 to 1 :4.
• Exemplary product SYLOID® FP is avai lable in different grades eg., SYLOI D® 63 FP, SY LOI D® 72FP, SYLOI D® 244FP characterized by unique combination of adsorptive capacity, meso-porosity, particle size and surface morphology.
• one or more than one grade of SYLOID® FP may be incorporated in the said composition to achieve the said objectives of the invention.
• the pre-dried excipients are used for the preparation of a stable pharmaceutical composition of Fesoterod ine or its salt.
• the term "pre-dried excipients" herei nafter refers to pharmaceutical excipients having a moisture content of not more than 2% w/w of the sa id excipient.
• all the excipients used in the pharmaceutical composition are dried to achieve LOD (loss on drying) below 2% w/w, preferably all the excipients having percentage weight of more than 2 % w/w in the said composition are pre-dried.
• composition of Fesoterodine or its pharmaceutical ly acceptable salt are sol id oral dosage forms, eg. tablets.
• the said solid oral dosage form can be for immediate release, extended release, sustained release, prolonged release etc. of Fesoterodine or its pharmaceutically acceptable salt from the said dosage form.
• compositions selected for the said sol id oral dosage form would depend on the type of solid oral dosage form.
• Pharmaceutical excipients used in the said pharmaceutical composition of Fesoterodine or its salt may be selected from conventional tablet excipients such as binder, diluent, lubricant, disintegrant, glidant, rate-controll ing agents, and the l ikes thereof.
• Amount of pharmaceutical excipients to be used in the sa id pharmaceutical composition may vary according to the requirement of fin i shed dosage form .
• diluent may include but not l im ited to lactose anhydrous, lactose monohydrate, spray dried lactose, dicalcium phosphate, calcium phosphate tribasic, calcium carbonate, calcium sulfate, starch, corn starch, potato starch, wheat starch, pregelatinized starch, cellu lose microcrystalline, silicified microcrystal l ine cellulose, cellulose microcrystal line powdered and m ixtures thereof.
• binder may include but not limited to acacia, carbomer, carboxymethylcellulose, cel lulose m icrocrystalline, copovidone, gelatin, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, hypromel lose acetate succinate, methyl cellulose, ethyl cellulose, polyethylene oxide, povidone, starch, pregelatinized starch, ammonio methacrylate copolymer and mixtures thereof.
• rate control ling polymer may include but not lim ited to hydroxypropyl methyl cellu lose, ethyl cel lu lose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methylcellulose, sodium carboxymethylcel l lose and or a m ixture thereof and l ike thereof.
• disintegrant may incl ude but not l im ited to cellulose microcrystalline, croscarmel lose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, starch, pregelatinized starch and m ixtures thereof.
• lubricant may include but not limited to calcium stearate, glyceryl behenate, magnesium stearate, mineral oil light, polyethylene glycol, castor oi l, sodium stearyl fumarate, starch, stearic acid, talc, hydrogenated vegeta ble oi l, zinc stearate, sodium benzoate and mi xtures thereof.
• gl idant may include but not l im ited to calcium silicate, magnesium silicate, col loidal sil icon d ioxide, talc and m ixtures thereof.
• accelerated stabi lity cond itions are storage conditions for the pharmaceutical composition of Fesoterodine or its salt, wherein the said composition is stored at 40°C / 75% RH for a period of 3 month.
• a stable pharmaceutical composition of Fesoterodine or its salt is characterized as a pharmaceutical composition of Fesoterodine or its pharmaceutically acceptable salt wherein the tota l impurity in the said composition is not more than 2% w/w, impurity A and impurity C are not present in an amount more than 0.625% w/w ind ividually; after subjecting the said pharmaceutical composition to a storage condition of 40°C / 75% RH for a period of 3 month.
• i mpurity A is chemically R-(+)-2-(3- diisopropylam ino- l -phenylpropyl)-4-hydroxymethyl phenol (5-HMT) and has a chemical structure as follows:
• impurity C of Fesoterod ine is R-(+)-isobutyric acid 4-isobutyroxy methyl-2-(3-di isoproplam ino- l -phenylpropy l)-phenyl ester and has a chemical
• packaging of the said composition can be done in bl ister packs or the said composition can be packed into HDPE bottle.
• the HDPE bottle may contain moisture absorbers includ ing but not limited to activated carbon, silicas, zeolites, molecular sieves and like thereof.
• the moisture absorber may be present in the form of a sachet, cartridge or canister.
• process for the preparation of the said composition involves direct compression wherein the critical steps to obtain a stable pharmaceutical composition of Fesoterodine or its pharmaceutically acceptable salt are: 1 ) Use of amorphous hydrated si l icone d ioxide as an excipient in the said composition and
• composition of the present invention can be optional ly fi lm coated with aqueous or non-aqueous coating material.
• step no. 2 and step no. 3 Drying the all exci pients of step no. 2 and step no. 3 to ach ieve LOD below 2% w/w.
• step 5 Adding suitable l ubricant and / or gl idant (optionally pre-dried) to the blend obtained in step 5.
• step 6 Compressing the blend obtained in step 6 to obtain tablet dosage form.
• the above process further optionally involves process of film coating.
• the film coating composition may be an aqueous or non-aqueous coating compos ition comprising of fi lm form ing agent and optionally plasticizer, anti-tacking agent, coloring agent and opacifier.
• Fol lowing examples describes the invention and its advantages with regards to pharmaceutical composition of Fesoterodine or its pharmaceutical ly acceptable sa lt.
• a comparison of accelerated stabi lity data are provided hereinafter for the pharmaceutical composition of Fesoterodine or its salt prepared by j udicial use of excipients as per known - art (Example 1 and Example 2) and the pharmaceutical composition disclosed accord ing to the present invention (Example 3 - 8) and pharmaceutical com position prepared without pre-drying of pharmaceutical excipients (Example 9).
• Example 1 was formulated with composition accord ing to below table.
• Blending blend the contents obtained in step no 1 .
• Lubrication lubricate the blend obtained in step no 2 with si fted magnesi um stearate.
• Example 2 was formulated with same composition as for example 1 ; with an exception that pre-dried excipients were used in the composition. Manufacturing process:
• Blending blend the contents obtained in step no 1 and step 2.
• Lubrication lubricate the blend obtained in step no 3 with sifted magnesium stearate.
• Examples 3-5 were formulated with composition according to the below table: Manufacturing procedure:
• Blending blend the contents obtained in step no 1 and step no 2.
• Lubrication lubricate the blend obtained in step no 3 with sifted magnesium stearate.
• Com pression compress the blend obtained in step no 4 to obta in tablet dosage form.
• Fi lm-coating Prepare the fi lm-coating composition and coat the tablets obtained in step no 5.
• Blending blend the contents obta ined in step no 1 and step no 2.
• Example 9 Composition of example 9 was qualitatively and quantitatively same as of example 7 except process for preparation of the composition. Process for preparation of example 9 does not involve step of pre-drying of excipients. Composition of example 9 was prepared by process given below.
• Blending blend the contents obtained in step no 1 and step no 2.
• Lubrication lubricate the blend obtained in step no 3 with sifted magnesium stearate.
• Film-coating Prepare the fi lm-coating composition and coat the tablets obtained in step no 5.
• the amount of impurity after 3 month accelerated stabi lity study at 40°C / 75%RH indicates that the pre-drying of excipients control total impurity levels but fails to control individual impurity A and impurity C.
• the amount of impurity after 3 month accelerated stabi lity study at 40°C / 75%R H ind icates that the pre-drying of exci pients and use of amorphous hydrated silicon d ioxide, control total impurity level and individual impurity levels of impurity A and impurity C; and render the pharmaceutical composition of Fesoterodine fumarate stable.
• stable pharmaceutical composition comprisi ng Fesoterodine or a pharmaceutical ly acceptable salt
• example 9 wherein the process for preparation of composition does not comprise step of pre-dry ing, the amount of impurity after 3 month accelerated stability study at 40°C / 75%RH indicates that the amount of impurity A is much higher than the composition of example 7.

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• 2013
  • 2013-03-19 WO PCT/IN2013/000174 patent/WO2013160909A1/fr not_active Ceased

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