WO2009121178A1 - Nouvelles formulations pharmaceutiques orales à libération contrôlée - Google Patents

Nouvelles formulations pharmaceutiques orales à libération contrôlée Download PDF

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Publication number
WO2009121178A1
WO2009121178A1 PCT/CA2009/000418 CA2009000418W WO2009121178A1 WO 2009121178 A1 WO2009121178 A1 WO 2009121178A1 CA 2009000418 W CA2009000418 W CA 2009000418W WO 2009121178 A1 WO2009121178 A1 WO 2009121178A1
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WO
WIPO (PCT)
Prior art keywords
layer
controlled
release
release bead
water
Prior art date
Application number
PCT/CA2009/000418
Other languages
English (en)
Inventor
Vinayak Pathak
Kiran Lagu
Naresh Talwar
Original Assignee
Pharmascience Inc.
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 Pharmascience Inc. filed Critical Pharmascience Inc.
Priority to CA2718753A priority Critical patent/CA2718753A1/fr
Publication of WO2009121178A1 publication Critical patent/WO2009121178A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the present invention relates to controlled release beads comprising a pharmaceutically active ingredient, to a formulation containing the controlled release beads, and to a method of preparing the controlled release beads.
  • the invention relates to controlled release beads comprising tolterodine or a pharmaceutically acceptable salt thereof.
  • these beads generally consist of an inert core, a first layer of polymer (i.e. a "seal-coat") applied onto the inert core, a layer containing the pharmaceutically active ingredient (i.e. a drug-containing layer), and an outer layer for controlling the release rate of the drug contained from the drug-containing layer.
  • a first layer of polymer i.e. a "seal-coat”
  • a layer containing the pharmaceutically active ingredient i.e. a drug-containing layer
  • an outer layer for controlling the release rate of the drug contained from the drug-containing layer.
  • Examples of such controlled release beads can be seen in the following references: United States Patent Nos. 5,783,215, 6,630,162, 6,770,295, and 6,911,217 (corresponds to Canadian Patent No. 2,350,061), International Patent Application WO 2004/105735, and Canadian Patent Application No. 2,472,237.
  • United States Patent No. 5,783,215 (Arwiddson et al., issued July 21, 1988) is directed to a controlled release bead comprising a core around which is a drug- containing layer (in this case, the drug was furosemid) dispersed into a hydrophilic polymer, an optional second layer of hydrophilic polymer, and an outer membrane layer effective for controlled release of the active ingredient.
  • U.S. Patent No. 6,630,162 discloses controlled-release beads comprising: (i) a core unit of a substantially water-soluble or water swellable inert material; (ii) a first layer on the core unit of a substantially water-insoluble polymer; (iii) a second layer covering the first layer and containing an active ingredient; and (iv) a third layer on the second layer of polymer effective for controlled release of the active ingredient.
  • granules comprising a drug and a carrier material in size of 0.1 ⁇ 1 mm, said carrier material is hydrophobic material in case of drug with water- solubility of 1 mg/ml or more and said carrier material is hydrophilic material in case of drug with water-solubility of less than 1 mg/ml;
  • a matrix in which said granules are embedded comprising swelling and erodible polymer and swelling-regulating material;
  • a release-modifying layer comprising hydrophobic release-modifying polymer, hydrophilic release-modifying polymer, pH-dependent release- modifying polymer or a mixture thereof.
  • a "seal-coat” (usually consisting of a water insoluble polymer) between the inert core and the layer containing the active ingredient, tolterodine, in controlled release beads. Such is done to isolate the drug from the core surface and to avoid any potential drug-core chemical interactions.
  • each coated unit contained therein comprises: (a) a core; (b) a first layer surrounding at least a portion of the core, the first layer comprising tolterodine and one or more hydrophilic polymers; and (c) a second layer surrounding at least a portion of the first layer and comprising one or more polymers effective for controlled release of the tolterodine from the first layer.
  • the present invention provides the beneficial advantage of smoothing the inert core's surface thereby providing a more consistent surface area, which consequently allows for improved coating quality when the drug layer and the controlled release membrane layers are applied thereon and also allows for easier manufacturing.
  • a controlled-release bead containing a pharmaceutically active ingredient comprising:
  • the controlling release polymeric system comprises a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer.
  • the core is made of materials which are substantially water insoluble, such as microcrystalline cellulose and starch. Also preferably, the core has a diameter ranging from about 0.05 to about 2 mm.
  • the amount of water-soluble polymer in the first layer ranges from about 2% to about 30% (w/w) of the controlled-release bead.
  • the second layer constitutes from about 0.1 to about 30% (w/w) of the controlled release bead.
  • the third layer constitutes from about 5% to about 30% (w/w) of the controlled release bead.
  • the pharmaceutically active ingredient is selected from the group consisting of: tolterodine, the 5-hydroxymethyl metabolite of tolterodine, the (S)- enantiomer of tolterodine, the 5-hydroxymethyl metabolite of the (S)-enantiomer of tolterodine, the racemate of tolterodine, its prodrug forms and pharmacologically acceptable salts thereof.
  • the pharmaceutically active ingredient is tolterodine or a pharmacologically acceptable salt thereof.
  • the present invention provides for a controlled-release bead containing a pharmaceutically active ingredient wherein the pharmaceutically active ingredient released in in vitro USP dissolution testing is not more than about 30% after 1 hour, from about 30% to about 60% (preferably from about 30% to about 50%, and more preferably about 30% to about 40%) after 3 hours, and not less than about 60% to about 90% after 7 hours.
  • the water-soluble polymer of the first layer is selected from the group consisting of: cellulose ethers, povidone, and copovidone.
  • the polymer in the second layer is selected from the group consisting of: cellulose ethers, povidone and copovidone.
  • the controlling release polymeric system in the third layer is selected from the group consisting of: ethyl cellulose, ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof.
  • a multiple unit formulation comprising the controlled release beads according to the present invention.
  • the multiple unit formulation is in the form of a capsule or a tablet.
  • a controlled release bead containing a pharmaceutically active ingredient which method comprises the steps of:
  • the controlling release polymeric system comprises a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer.
  • the preparation of the multiple unit formulation comprises the additional step of transforming the beads manufactured according to the present invention into a pharmaceutical formulation, such as by filling a predetermined amount of the beads into a capsule, or compressing the beads into tablets.
  • the beads are optionally "cured", usually in a fluid bed system or in a tray dryer system, by heating to a temperature of about 30- 80 degrees Celsius for 30 to 180 minutes, for example.
  • the beads are then cooled below about 35°C before stopping the process.
  • the pharmaceutical formulations according to the invention are intended for oral administration.
  • the particular choice of MCC beads in the present invention provides attractive physical-chemical properties, such as low friability and is a good choice of core unit on which other substrates can be applied thereon;
  • the present invention provides a uniform surface on which other layers can be applied thereon.
  • Such can be, for example, achieved by applying a water soluble coat containing hydroxypropylcellulose (i.e. a choice of film forming polymer).
  • a first layer disposed over the core comprising a substantially water-soluble polymer, wherein the first layer constitutes more than about 2%, and more preferably, from about 2% to about 30% w/w of the final bead composition;
  • a second layer disposed over the first layer, the second layer containing the pharmaceutically active ingredient and a polymer, wherein the second layer constitutes from about 0.05% to about 60%, and more preferably, from about 0.1% to 30% w/w of the final bead composition;
  • a third layer disposed over the second layer, the third layer comprising a controlling release polymeric system, wherein the third layer constitutes from about 1% to about 50%, more preferably from about 5% to about 30% w/w of the final bead composition; and (v) the remaining weight percentage composition of the beads is attributed to the cores, which are preferably microcrystalline cellulose (MCC) spheres.
  • MCC microcrystalline cellulose
  • the cores typically have a diameter ranging from about 0.05 to about 2 mm.
  • the cores comprise a water-insoluble inert material, and may be any such material that is conventionally used as cores or any other pharmaceutically acceptable water- insoluble material made into beads or pellets.
  • Conventional beads are known to be in the shape of spheres and are made of extruded spheres typically comprised of excipients such as MCC.
  • the substantially water-soluble material in the first layer can be selected from the group consisting of: cellulose ethers, povidone, copovidone, polyvinyl alcohol, polyethylene glycol graft polymers, polyethylene oxide, and combinations thereof.
  • the second layer containing the pharmaceutically active ingredient comprises the pharmaceutically active ingredient and a polymer.
  • the polymer can be either a water-soluble or water-insoluble polymer.
  • Exemplary polymers that can be used in the second layer include cellulose ethers, povidone, copovidone, or any other pharmaceutically acceptable polymer.
  • Suitable polymers for use in the third layer for controlling the drug release may be selected from water-insoluble polymers or water-soluble polymers, or a combination thereof.
  • water-insoluble polymers include, but are not limited to, ethyl cellulose, ammonia-alkyl methacrylate copolymer, methacrylate copolymers, and mixtures thereof.
  • Other components that can be included in the third layer (i.e. the controlled release layer), include mixtures of polyvinyl acetate with povidone and sodium lauryl sulphate.
  • a wide variety of pharmaceutically active ingredients may be used in conjunction with the present invention. While the active ingredient usually is a low or medium dose drug, also high-dose drugs may be contemplated for use in the present invention.
  • a pro-drug is to be understood herein as being a pharmacological substance (e.g. drug) which is administered in an inactive (or significantly less active) form. Once administered, the pro-drug is metabolized in the body (in vivo) into the active compound. In other words, a pro-drug is an inactive (or significantly less active) precursor of a drug, converted into an active form in the body by normal metabolic processes.
  • a pro-drug is to be understood herein as being a pharmacological substance (e.g. drug) which is administered in an inactive (or significantly less active) form. Once administered, the pro-drug is metabolized in the body (in vivo) into the active compound.
  • a pro-drug is an inactive (or significantly less active) precursor of a drug, converted into an active form in the body by normal metabolic processes.
  • pharmaceutically acceptable salt refers to salts of an active ingredient that are physiologically tolerated by a user.
  • the pharmaceutically active ingredient is tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3- phenylpropanamine, as well as the corresponding (S)-enantiomer, the racemate and the active 5-hydroxymethyl metabolites, prodrug forms and pharmaceutically acceptable salts thereof.
  • Useful analogues to the above compounds are disclosed in, for example, International Patent Application WO98/43942 (published October 8, 1998).
  • the beads and multiple unit formulation, respectively, according to the present invention can be suitable for administering the above-mentioned drug tolterodine, and would likewise be suitable for its related compounds, for example:
  • the fraction of active ingredient that is released in vitro is preferably not more than about 30% after 1 hour, from about 40 to about 85% after 3 hours, and not less than about 80% after 7 hours.
  • Controlled release formulation according to the present invention allows for a well controlled release of tolterodine, and thereby a substantially constant serum level of active moiety or moieties to be maintained in the patient for up to 24 hours.
  • Formulations according to the present invention are intended for once daily or twice daily oral administration, depending on the desired drug release profiles.
  • active moiety or moieties is meant, in the case of tolterodine and its related compounds, the sum of free or unbound (i.e.
  • tolterodine and its corresponding (S)-enantiomer and racemate and the preparation thereof are described in, for example, United States Patent No. 5,382,600 (Jonsson et al., issued January 17, 1995).
  • United States Patent No. 5,559,269 describes an active (R)-5- hydroxymethyl metabolite of tolterodine (as well as the (S)-5-hydroxymethyl metabolite).
  • the (S)-enantiomer, its non-cholinergic spasmolytic activity and use in the treatment of urinary and gastrointestinal disorders are described in International laid open application WO 98/03067 (published January 29, 1998).
  • the ratio of pharmaceutically active ingredient (i.e. drug) to polymer in the second layer of the controlled release beads is generally in the range of from about 1:100 to 100:1 w/w of drug to polymer.
  • the preparation of the multiple unit formulation comprises the additional step of transforming the beads manufactured according to the present invention into a pharmaceutical formulation, such as by filling a predetermined amount of the beads into a capsule, or compressing the beads into tablets.
  • the layering or coating operations are preferably performed by spraying a solution or dispersion of the respective layer materials onto the core, preferably in a fluid bed coating apparatus.
  • the beads are optionally "cured", usually in a fluid bed system or in a tray dryer system, by heating to a temperature of about 30- 80 degrees Celsius for 30 to 180 minutes, for example.
  • the beads are then cooled below about 35°C before stopping the process.
  • the pharmaceutical formulations according to the invention are intended for oral administration.
  • Core - MCC spheres manufactured by Celphere ® ) comprising about 70% w/w of the final bead. These MCC spheres are used as substrate on which further coatings can be applied.
  • First layer - comprises a water soluble polymer and consists about 5% w/w of the final bead. Since MCC is known to adsorb drug on its surface, it is important to provide a seal coat on the MCC spheres which also provides a uniform surface to undergo further processing (coating). This is achieved by providing a water soluble coat using hydroxypropylcellulose (HPC) as the film forming polymer.
  • HPC hydroxypropylcellulose
  • Second layer - a pharmaceutically acceptable active ingredient, in this case, tolterodine L-tartrate, combined with a polymer, such as for example HPC.
  • the second layer comprises about 12.2 % w/w of the final bead.
  • the w/w ratio of active ingredient to polymer is about 1:5.
  • the purpose of this second layer is to act as a drug supply.
  • Third layer - combination of ethylcellulose and HPC.
  • the third layer comprises about 13% w/w of the final bead.
  • the w/w ratio of ethylcellulose to HPC is about 90:10 .
  • the purpose of this third layer is to achieve drug release rate control.
  • solution #1 Approximately 140 grams of HPC was added into 2500 grams of purified water. This mixture was continuously mixed until a clear solution was obtained (solution #1). This solution #1 was sprayed onto about 2000 grams of MCC spheres (also known as beads) using a fluid bed bottom spray unit.
  • solution #5 9 grams of HPC was added to about 150 grams of purified water. This mixture was continuously mixed until a clear solution is obtained (solution #5). Approximately, 323 grams of an aqueous ethylcellulose dispersion was added to solution #5, thereby forming solution #6. This mixture (solution #6) is continuously mixed for at least 30 minutes before undergoing spraying. Solution #6 was then sprayed on to about 600 grams of the coated beads of the second layer using, once again, fluid bed coater equipped with bottom spray unit.
  • Example 2 Dissolution Study of Dosage Form of the Formulation of Example 1
  • solution #1 Approximately 140 grams of HPC was added into 2500 grams of purified water. This mixture was continuously mixed until a clear solution was obtained (solution #1). This solution #1 was sprayed onto about 2000 grams of MCC spheres (also known as beads) using a fluid bed bottom spray unit.
  • solution #4 40 grams of a pharmaceutical active ingredient, in this case tolterodine L- tartrate, was added to about 3000 grams of purified water. This mixture is continuously mixed until a clear solution is obtained (solution #2). In a separate solution (solution #3), 280 grams of HPC and colloidal silicon dioxide is added to about 1000 grams of purified water. This mixture is continuously mixed until a clear solution is obtained (solution #3). Solution #2 and solution #3 were then mixed together for at least 30 minutes, thereby forming solution #4. Solution #4 was sprayed on about 1000 grams of MCC coated spheres of the first layer using a fluid bed coater equipped with bottom spray unit.
  • a pharmaceutical active ingredient in this case tolterodine L- tartrate
  • Example 4 Dissolution Study of Formulation Prepared According to Example 3
  • Dissolution was performed using USP apparatus I, paddle speed @ 100 rpm, media volume - 900ml, change over media, lhr, 2hr time points in 0.1N HCL and 3, 4, 6, 8, 9 hrs and an infinity time point in pH 6.8 phosphate buffer. Results are given in the table below.
  • solution #4 40 grams of a pharmaceutical active ingredient, in this case tolterodine L- tartrate, was added to about 3000 grams of purified water. This mixture is continuously mixed until a clear solution is obtained (solution #2). In a separate solution (solution #3), 280 grams of HPC and colloidal silicon dioxide is added to about 1000 grams of purified water. This mixture is continuously mixed until a clear solution is obtained (solution #3). Solution #2 and solution #3 were then mixed together for at least 30 minutes, thereby forming solution #4. Solution #4 was sprayed on about 1000 grams of MCC coated spheres of the first layer using a fluid bed coater equipped with bottom spray unit.
  • a pharmaceutical active ingredient in this case tolterodine L- tartrate
  • HPC 3.90 grams of HPC was added to about 1000 grams of purified water. This mixture was continuously mixed until a clear solution is obtained (solution #5). 26.08 grams of ethylcellulose 20cps, 6.72 grams of colloidal silicon dioxide and 3.308 grams of triethyl citrate was added to solution #5, thereby forming solution #6. This mixture (solution #6) is continuously mixed for at least 30 minutes before undergoing spraying. Solution #6 was then sprayed on to about 500 grams of the coated beads of the second layer using, once again, fluid bed coater equipped with bottom spray unit.
  • Example 6 Dissolution Study of Formulation Prepared According to Example 5

Abstract

La présente invention concerne une bille à libération contrôlée contenant un principe pharmaceutiquement actif. La bille à libération contrôlée comprend un noyau constitué d’un matériau inerte sensiblement insoluble dans l’eau. Une première couche est placée sur le noyau, la première couche comprenant un polymère sensiblement hydrosoluble. Une deuxième couche est placée sur la première couche, la deuxième couche comprenant le principe pharmaceutiquement actif et un polymère. Enfin, une troisième couche est placée sur la deuxième couche, la troisième couche comprenant un système polymère de contrôle de la libération. La présente invention concerne également des formes pharmaceutiques, telles que des comprimés et des gélules, comprenant les billes à libération contrôlée, et des procédés de fabrication des billes à libération contrôlée.
PCT/CA2009/000418 2008-04-01 2009-04-01 Nouvelles formulations pharmaceutiques orales à libération contrôlée WO2009121178A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA2718753A CA2718753A1 (fr) 2008-04-01 2009-04-01 Nouvelles formulations pharmaceutiques orales a liberation controlee

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA2,629,099 2008-04-01
CA002629099A CA2629099A1 (fr) 2008-04-01 2008-04-01 Nouvelles formulations pharmaceutiques orales a liberation controlee

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WO2009121178A1 true WO2009121178A1 (fr) 2009-10-08

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871275B2 (en) 2007-08-08 2014-10-28 Inventia Healthcare Private Limited Extended release compositions comprising tolterodine
US20150086626A1 (en) * 2012-04-17 2015-03-26 Mylan, Inc Stable dosage forms of skeletal muscle relaxants with extended release coating

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2459180A1 (fr) 2009-07-31 2012-06-06 Ranbaxy Laboratories Limited Compositions pharmaceutiques à unités multiples multi-couches

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2170526A1 (fr) * 1994-07-08 1996-01-25 Lars Stubberud Nouvelles perles a liberation lente et preparation pharmaceutique les contenant
CA2350061A1 (fr) * 1998-11-11 2000-05-18 Pharmacia Ab Nouveau comprime a liberation controlee, methode de production, et formulation multicouche comprenant ledit comprime
WO2004105735A1 (fr) * 2003-05-30 2004-12-09 Ranbaxy Laboratories Limited Compositions pharmaceutiques de tolterodine a liberation controlee et leurs procedes de preparation
US20070248670A1 (en) * 2006-04-21 2007-10-25 Van Den Heuvel Dennie J M Tolterodine beads
WO2009003724A1 (fr) * 2007-07-03 2009-01-08 Synthon B.V. Bille de toltérodine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2170526A1 (fr) * 1994-07-08 1996-01-25 Lars Stubberud Nouvelles perles a liberation lente et preparation pharmaceutique les contenant
CA2350061A1 (fr) * 1998-11-11 2000-05-18 Pharmacia Ab Nouveau comprime a liberation controlee, methode de production, et formulation multicouche comprenant ledit comprime
WO2004105735A1 (fr) * 2003-05-30 2004-12-09 Ranbaxy Laboratories Limited Compositions pharmaceutiques de tolterodine a liberation controlee et leurs procedes de preparation
US20070248670A1 (en) * 2006-04-21 2007-10-25 Van Den Heuvel Dennie J M Tolterodine beads
WO2009003724A1 (fr) * 2007-07-03 2009-01-08 Synthon B.V. Bille de toltérodine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871275B2 (en) 2007-08-08 2014-10-28 Inventia Healthcare Private Limited Extended release compositions comprising tolterodine
US20150086626A1 (en) * 2012-04-17 2015-03-26 Mylan, Inc Stable dosage forms of skeletal muscle relaxants with extended release coating

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CA2629099A1 (fr) 2009-10-01
CA2718753A1 (fr) 2009-10-08

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