CA2230314C - Pharmaceutical formulations - Google Patents

Pharmaceutical formulations Download PDF

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Publication number
CA2230314C
CA2230314C CA002230314A CA2230314A CA2230314C CA 2230314 C CA2230314 C CA 2230314C CA 002230314 A CA002230314 A CA 002230314A CA 2230314 A CA2230314 A CA 2230314A CA 2230314 C CA2230314 C CA 2230314C
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Prior art keywords
darifenacin
pharmaceutically acceptable
dosage form
acceptable salt
released
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CA002230314A
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CA2230314A1 (en
Inventor
Thomas Francis Dolan
Michael John Humphrey
Donald John Nichols
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Merus Labs Luxco SARL
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Pfizer Research and Development Co NV SA
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    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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
    • 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
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • 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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

There is provided a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, characterized in that the dosage form is adapted to deliver at least 10 % by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient. The formulation minimizes unwanted side-effects and increases the bioavailability of darifenacin.</SDO AB>

Description

PHARMACEUTICAL FORMULATIONS CONTAINING DARIFENACIN
~ This invention relates to pharmaceutical dosage forms of darifenacin and its pharmaceuti-cally acceptable salts.
Darifenacin is (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl)-
2,2-diphenyl-acetamide and is disclosed in European Patent N° 0388054, Examples 1B
and 8, and is' referred to therein as 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydro-benzofuran-5-yl)ethyl]pyrrolidine. It is indicated in the treatment of urinary incontinence and irritable bowel syndrome and has the following structure:
coNHZ i o ~N
Clinical investigations have shown a major metabolite of darifenacin to be the following 3'-hydroxy derivative:

N
OH
It appears that the metabolite is 6-fold less selective for muscarinic M3 receptors over M1 receptors in comparison with darifenacin, and so the metabolite is more likely than darifenacin to produce unwanted side-effects such as dry mouth, confusion and blurred vision.
2 0 It has now been found that delivering darifenacin and its pharmaceutically acceptable salts to the lower gastrointestinal tract (e.g. in a sustained release formulation) gives rise ' to a greater ratio of darifenacin to metabolite in the systemic circulation.
This increases the bioavailability of darifenacin, which is likely to minimize any unwanted side-effects.
This is surprising because a slower release rate normally leads to a slower delivery to liver enzymes and a greater degree of metabolism of an administered drug.
Thus, according to the present invention, there is provided a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier;
characterized in that the dosage form is adapted to deliver at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient.
According to another aspect of the present invention, there is provided a pharmaceutical dosage form adapted for oral administration, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the darifenacin, or the pharmaceutically acceptable salt thereof, in said dosage form is: (a) embedded in a matrix form from which it is released by diffusion or erosion; (b) present in a multiparticulate core; (c) released through an aperture provided in an impermeable coating; (d) released through a coating of low aqueous solubility; (e) released through a semipermeable coating;
(f) present as an ion exchange resin; or (g) released at specific points in the gastrointestinal tract by a pulsatile device; characterized in that the dosage form is adapted to deliver at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient.
According to still another aspect of the present invention, there is provided a pharmaceutical dosage form adapted for oral administration, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the darifenacin, or the pharmaceutically acceptable salt thereof, in said dosage form is: (h) embedded in a matrix form from which it is released by diffusion or 2a erosion; (i) present in a multiparticulate core;
(j) released through an aperture provided in an impermeable coating; (k) released through a coating of low aqueous solubility; (1) released through a semipermeable coating;
(m) present as an ion exchange resin; or (n) released at specific points in the gastrointestinal tract by a pulsatile device; characterized in that the dosage form is adapted to release the darifenacin, or the pharmaceutically acceptable salt thereof, in an in vitro model reproducing the conditions in the gastrointestinal tract over a sustained period of time.
According to yet another aspect of the present invention, there is provided an oral tablet formulation consisting essentially of darifenacin hydrobromide in a high molecular weight hydroxypropyl methylcellulose matrix together with anhydrous dibasic calcium phosphate and magnesium stearate.
The dosage forms of the invention may be of the sustained or delayed release type, and so release the darifenacin, or the pharmaceutically acceptable salt thereof, to the gastrointestinal tract of the patient over or after a sustained period of time following administration of the dosage form to the patient. However, when the dosage forms are administered rectally, conventional rectal formulations may be used.
By "lower gastrointestinal tract" is meant the portion of the gastrointestinal tract between the region of the ileo-caecal junction and the rectum inclusive.
"Patient" means primarily a human patient, although the formulations of the present invention may be useful in the treatment of non-human animals.

2b Preferably, the dosage forms of the invention are adapted to deliver at least 25%, and more preferably 50% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract.
Preferably, no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 4 hours after dosing; more preferably no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 8 hours after dosing; and most preferably, no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 16 hours after dosing.
The conditions in the gastrointestinal tract are thought to be reproduced in an in vitro model using Apparatus 1 described in USP XXII at page 1578, having baskets of 40 mesh (381~m apertures), a rotation speed of 100 rpm and a dissolution medium of water at 37°C.
Therefore, the sustained release formulations of the invention may be defined alternatively as a pharmaceutical dosage form adapted for administration to the Bast--rointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier;
characterized in that the
3 dosage. form is adapted to release the darifenacin, or the pharmaceutically acceptable salt thereof, in Apparatus 1 described in USP XXI;I at page 1578, having baskets of 40 ~ mesh (381 p.m apertures), a rotation speed of 100 rpm and a dissolution medium of water at 37°C, over a sustained period of time.
Particular oral dosage forms include:
(a) those in which the darifenacin, or the pharmaceutically acceptable salt thereof, is embedded in a matrix from which it is released by diffusion or erosion;
(b) those in which the darifenacin, or the pharmaceutically acceptable salt thereof, is 1 o present in a multiparticulate core;
(c) those in which there is an impermeable coating provided with an aperture through which the darifenacin, or the pharmaceutically acceptable salt thereof, is released;
(d) those in which there is a coating of low aqueous solubility;
(e) those in which there is a semipermeable coating;
(f) those in which the darifenacin is present as an ion exchange resin complex; and (g) pulsatile devices from which the darifenacin i s released at specific points in the gastrointestinal tract.
It will be apparent to those skilled in the art that some of the above means of achieving 2 o sustained release may be combined: for example a matrix containing the active com-pound may be formed into a multiparticulate and/or coated with an impermeable coating provided with an aperture.
Dealing with each category in turn:
(a) In matrix systems, which are preferred, the active compound is embedded or dispersed in a matrix of another material which serves to retard the release of the active compound into an aqueous environment. Suitable matrix materials include hydroxypropyl methylcellulose and hydroxypropyl cellulose. Matrix formulations according to the present ' invention preferably comprise high molecular weight (i.e. 85,000-95,000 mass units) 3 o hydroxypropyl methylcellulose.
(b) In multiparticulate cores, the active compound is present in a number of particles which also contain adjuvants, diluents or carriers. Suitable adjuvants, diluents and carriers include microcrystalline cellulose (preferably having a particle size of 50um) and lactose (preferably having a particle size equivalent to 110 mesh (137.5~.m apertures)).
4 Typically, the blended ingredients are formed into a wet mass which is extruded and spheronized to form beads which are then dried.
(c) Impermeable coatings are applied to tablets containing the active compound.
"Impermeable" means that no significant transport of the active compound can take place across the coating during the intended release period of the formulation.
Suitable ~~
materials include film-forming polymers and waxes [e.g. thermoplastic polymers such as polyethylene-covinyl acetate), polyvinyl chloride), ethyl cellulose and cellulose acetate]
and the coating thickness is preferably greater than 100p.m. The aperture may be formed by drilling, or if the coated formulation is conical, by cutting off the tip.
(d) Coatings of low aqueous solubility include polymers. The solubility of such polymers may be pH-dependent, for example substantially insoluble at pH<5 (so that dissolution does not take part in the stomach) and water soluble at pH>5.
Preferred pH
sensitive polymers include shellac, phthalate derivatives (including cellulose acetate phthalate, polyvinylacetate phthalate), polyacrylic acid derivatives, and vinyl acetate and crotonic acid copolymers.
(e) Semipermeable membrane coatings allow the active compound to diffuse across the membrane or through liquid filled pores within the membrane. Suitable coating materials include polymers such as cellulose ester or ether, and acrylic polymers.
Preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate 2 o butyrate.
(f) Darifenacin resinates may be prepared by treating anionic ion exchange resin beads (for example sodium polystyrene sulphonate) with an acid addition salt of darifenacin.
(g) Pulsatile devices have the capacity to release drug at various points of the gastrointestinal tract. They may depend on osmotic potential to trigger release (see US
Patent N° 3,952,741) or erosion of polymeric material due to changes in pH or microbial degradation. Suitable polymeric materials include pectin [Rubinstein et al, 1991, Pectic salt as a colonic delivery system, Proceed. Intern. Symp. Control. Rel.
Bioact. Mater.], methacrylate-galactomannan (Lehman et al, 1991, Methacrylate-galactomannan coating 3 o for colonic specific drug delivery, ibiclj, matter containing azobonds [Kopeckova et al, 1991, Bioadhesive polymers for colon specific drug delivery, ibid], chondroitin [Sintov et al, 1991, Colonic administration of indomethacin using modified chondroitin in a cannu-laced dog model, ibid], dextran hydrogels [Bronsted et al, 1993, A novel hydrogel system designed for controlled drug delivery to the colon, ibid], methacrylic acid copolymers [Siefke et al, 1993, (i-Cyclodextrin matrix films for colon specific drug delivery, ibid], and amylose [Milojevik et al, In vitro and in vivo evaluation of amylose coated pellets for colon specific drug delivery, ibidj. Delivery to specific points of the gastrointestinal tract may also be achieved using multilayered tablets [Gazzaniga et al, 1993, Time dependent oral delivery system for colon specific release, ibidj, or hydrogel plugs in a capsule jBinns et
5 al, Application of a pH-independent PEG-based hydrogel to afford pulsatile drug delivery].
Preferably, in the dosage forms of the present invention, the darifenacin is in the form of its hydrobromide salt (except when the darifenacin is present as an ion exchange resin complex).
A preferred oral formulation is a tablet consisting essentially of darifenacin hydrobromide in a high molecular weight hydroxypropyl methylcellulose matrix together with anhydrous dibasic calcium phosphate and magnesium stearate. The tablet may be colour coated by conventional methods. Preferably, hydroxypropyl methylcellulose makes up 56-58% w/w of the tablet, magnesium stearate makes up approximately 1 % of the tablet, and darifenacin hydrobromide and anhydrous dibasic calcium phosphate make up the balance. The darifenacin hydrobromide content may range from 4mg-54mg per tablet, depending on the dose to be delivered. Such tablets would be suitable for administration once daily.
Preferably, the dosage forms of the present invention are adapted for oral administration, but they may also be adpated for rectal administration. Rectal suppository formulations may be prepared by dispersing the active ingredient in hardened oils or waxes using conventional methods.
According to another aspect of the invention, there is provided a method of treatment of irritable bowel syndrome or urinary incontinence, whi<;h comprises delivering darifenacin, or a pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of a patient in need of such treatment. The method may be performed by administering a 3 o dosage form of the invention to the gastrointestinal tract of a patient in need of such ' treatment.
The invention is illustrated by the following examples in which the following materials are used:

693,,87-242
6 MethocelT"" K4M - a high molecular weight hydroxypropyl methylcellulose with a number average in molecular weight of 89,000. It is classified in the USP as 2208 and a 2%
solution in water has a nominal viscosity of 4000cps. It has a methoxy content of 19-24%
and a hydroxypropcxy content of 7-12%;
MethocelT"" E4M - a high molecular weight hydroxypropyl methylcellulose with a number average molecular weight of 93,000. It is classified in the USP as 2910 and a 2%
solution in water has a nominal viscosity of 4000cps. It has a methoxy content of 28-30%
and a hydroxypropoxy content of 7-12%;
MethocelT"" K100LV - a low molecular weight hydroxypropyl methylcellulose. It is classified in the USP as 2208 and a 2% solution in water has a nominal viscosity of 100cps. It has a methoxy content of 19-24% and a hydroxypropoxy content of 7-12%;
Klucel EFT"" - hydroxy propyl cellulose with a number average molecular weight of 60,000:
EthocelT"" - ethyl cellulose;
AviceIT"" PH101 - microcrystalline cellulose with an average particle size of 50um;
Lactose regular - lactose with a particle size equivalent to 110 mesh (137.5pm apertures);
Lactose Fast FIoT"" - spray dried lactose; and EmcomPressT"" - dibasic calcium phosphate (anhydrous).
Aerosil 200~colloidal anhydrous silica Example 1,~comparative~
Fast release matrix tablet Ingredient Specificationmglunit (theory)glbatch (actual) Darifenacin hydrobromidePfizer 23.810 30.19 Methocel K4M Ph Eur 12.000 15.00 Methocel K100LV PremiumUSP 28.000 35.00 Fast flo Lactose Ph Eur 134.190 167.70 Magnesium Stearate Ph Eur 2.000 2.50 TOTAL 200.OOOmg The Methocel K4M, K100LV premium, darifenacin and Fast-flo lactose were blended in a Turbula blender for 10 minutes. The mixture was then screened using a 30 mesh (500um apertures) screen and reblended for a further 10 minutes. Magnesium stearate was screened through a 30 mesh (500pm apertures) screen and added to the mixture before
7 blending, for a further 5 minutes. The blend was Then subjected to compression ors a tabletting machine using Smm round normal convex tooling to make 1250 tablets.
i Exam I~e 2 ' 5 ~!!edium release rr,atriY t~hmt Ingredient Specificationmg/unit (theory)g/batch (actual) Darifenacin hydrobromidePfizer 23.810 30.19 Methocel K4M Ph Eur 30.000 37.50 Methocel E4M Ph Eur 30.000 37.50 Fast flo Lactose Ph Eur 114.190 142.70 Magnesium Stearate Ph Eur 2.000 2.50 TOTAL 200.000mg The Methocel K4M, E4M, darifenacin and Fast-flo lactose were blended in a suitable blender for 10 minutes. The mixture was then screened using a 30 mesh (500~.m apertures) screen and reblended for a further 10 minutes. Magnesium stearate was l0 screened through a 30 mesh (500pm apertures) screen and added to the mixture before blending for a further 5 minutes. The blend was then subjected to compression on a tabletting machine using 8mm round normal convex tooling to make 1250 tablets.
15 Slovr release matrix tabl t Ingredient Specificationmglunit (theory)glB~atch (actual) Darifenacin hydrobromidePfizer 23.810 30.19 Anhydrous dibasic calcium USP
phosphate 9.790 4.70 Methocel K4M Ph Eur 114.400 143.00 Magnesium Stearate Ph Eur 2.000 2.50 TOTAL 200.000 The Methocel K4M, darifenacin and anhydrous dibasic calcium phosphate were blended in a Turbula blender for 10 minutes. The mixture was then screened using a 30 mesh
8 (500p.m apertures) screen and reblended for a further 10 minutes. Magnesium stearate was screened through a 30 mesh (500pm apertures) screen and added to the mixture before blending for a further 5 minutes. The blend was then subjected to compression on ' a tabletting machine using 8mm round normal convex tooling to make 1250 tablets.
Examlhe 44 Enca~t~sulated coated core multiparticulates (a) Preparation of uncoated cores Ingredient Specificationglkg (theory) g/batch (actual) Darifenacin hydrobromidePfizer 119.048 119.76 Avicel PH101 Ph Eur 359.499 359.50 Lactose Regular Ph Eur 359.499 359.50 Fumaric acid NF 161.954 161.95 Purified water Ph Eur (500.000) 500.0 TOTAL 1000.000g 1000.71 The Avicel PH101, lactose regular, darifenacin and fumaric acid were blended in an Apex Y
cone for minutes.
The mixture was then screened using a mesh (500pm apertures) screen and re-blended for minutes.
Purified water was added to form a wet mass amenable to extrusion.
The resultant wet mass was extruded using an Nica E

extruder (1 mm screen) and then spheronised using a Caleva spheroniser to form multiparticulate beads.
The beads were then dried using a bed temperature of for hour to remove excess moisture.

(b) Preparation of final formulation Ingredient Specificationmglunit (theory)glbatch (actual) Darifenacin uncoated Pfizer 200.000 150.30 cores Ethyl cellulose N-10 NF 17.750 13.32 Klucel EF NF 7.250 5.44 Ethyl Acetate NF 237.500 178.2 , Isopropyl alcohol NF 237.500 178.1 TOTAL 225.000 Filled into white size 2 gelatine capsule snens.
9 Ethyl acetate and isopropyl alcohol were stirred in .a suitable vessel to ensure thorough mixing. To this mixture the Klucel EF and ethyl cellulose N10 were added and the solution stirred until complete dissolution had taken place. The uncoated beads were added to a fluidised bed coater and using an inlet temperature of 40°C
the beads were coated with the solution containing 'the Klucel EF and ethylcellulose N10. On completion of coating the beads were dried for 10 minutes using a bed temperature of approximately 50°C. The coated beads were filled into capsule shells prior to administration.
Examlhe 55 Ion exchange resin formulation Ingredient glbatch Darifenacin hydrobromide 60.39 Sodium polystyrene sulphonate 187.00 Disodium edetate; dihydrate 1.53 Water 2000.00 The disodium edetate and sodium polystyrene sulphonate were suspended in water. This suspension was then heated to 50°C whilst stirring. The darifenacin hydrobromide was then added to the suspension and the suspension stirred for a further 2 hours at 50°C.
The darifenacin polystyrene sulphonate was then filtered off and washed until free of bromide ions. The darifenacin resinate was then dried under vacuum at 25°C for approximately 16 hours.
exam lia a 6 [com~aarative) Immediate Release Capsule ~ 5rn~
Ingredient Specificationmglunit theoryglbatch (actual) Darifenacin hydrobromidePfzer 8.929 547.46 Lactose t'h Eur 104..453 6267.20 Maize starch Ph Eur 34.818 2089.10 Aerosil 200 Ph Eur 0.300 18.00 Magnesium stearate Ph Eur 1.500 84.88 TOTAL 150.000 1467.28 of the lactose was added to all of the darifenacin hydrobromide and blended in an Apex 8L double cone tumbling blender for 20 minutes. This was then milled using a Fitzmill (hammers forward, high speed) through a 1 mm screen and the mill washed with the remaining lactose (4800.08). This lactose, Aerosil 200 and maize starch were then 5 added to the darifenacin hydrobromide/lactose preblend prepared initially and blended for ' minutes in a Gardner 28L double cone tumbling blender. This blend was then passed through a 1 mm screen using a Fitzmill (knives forward, slow speed) and then blended for a further 20 minutes using the 28L blender. Magnesium stearate (88.888) was then added and blending continued using the 28L blender for 5 minutes. The final blend was
10 then encapsulated into size 2 hard gelatin capsule shells using a Zanasi capsule filling machine.
Measurement of in vitro release rates Dissolution methods Dissolution of the formulations of Examples 1-4 was performed using a rotating basket apparatus (Apparatus 1, USPXXI I, p. 1578). The formulations were placed in baskets (40 mesh, 381 um apertures) using a rotation speed of 1 OOrpm in 900m1 water at 37°C +/-2 0 0.5°C. At specified time intervals, 10m1 aliquots were removed from the dissolution vessel from a zone midway between the surface of the dissolution medium and the top of the basket not less than 1 cm from the vessel wall. The first 7m1 is discarded and the remaining solution transferred to an HPLC vial for subsequent analysis.
The release of darifenacin from the formulation of Example 5 was determined according to USP XXIII Apparatus 4 (page 1794). Using a flow rate of 250m1/hour solutions at 37°C
of the following pH were used to assess release:
0-1hr pH 1.5; 1-2hr pH 2.5; 2-3.5hr pH4.5; 3.5-5hr pH 6.9; 5-24hr pH 7.2.
3 o Dissolution of the formulation of Example 6 was performed using a rotating basket apparatus (Apparatus 1, USPXXII, p 1578). The formulations were placed in baskets (40mesh, 381 um apertures) using a rotation speed of 100rpm in 900m1 water at 37°C +/-0.5°C. At specified time intervals a 20m1 aliquot of dissolution media was removed from a zone midway between the surface of the dissolution media and the top of the basket not 3 5 less than 1 cm from the vessel wall. The aliquots were filtered (0.45p.m, Acrodisc) and the
11 first 5m1 of filtrate discarded. 5m1 of the remaining filtrate was then diluted to 25m1 using a 1:1 (vlv) solution of water/methanol prior to analysis by HPLC.
Analysis ' S For the formulations of Examples 1-5, High Performance Liquid Chromatography (HPLC) was performed using a BDS Hypersil C18 column. The mobile phase used was an aqueous 0.03M potassium dihydrogen orthophosphate at pH 3.5/methanol, (1000:800 v/v) using a flow rate of 1.5mUmin at 37°C and a sample size of 20uL.
Detection was by fluorescence operating at an excitation wavelength of 288nm (slit width 18nm) and an emission wavelength of 320nm (slit width 18nm).
For the formulation of Example 6, High Performance Liquid Chromatography (HPLC) was performed using a Novapack C18 column. The mobile phase was aqueous 0.01 M
sodium acetate containing 0.2%v/v triethylamine at pH
6.0/methanol/acetonitrile (45:54:1, v/v/v) using a flow rate of 1.Oml/min and a sample size of 50p1. Detection was by ultraviolet spectroscopy at 230nm.
Results Example 1 formulation (con 've) 2 0 Time (hl °!o release (ranael 1 65 (52-81 ) 2 80 (72-92) 4 91 (87-96) example 2 formulation 'Time lhl % release 1 41 (38-46) 4 77 (73-81 ) ' 8 95 (94-96) Example 3 formulation Time fhl % release 1 6 (5-7) 8 42 (36-44) 3 5 16 67 (59-70)
12 Examr~le 4 formulation Time (hl % release 1 11 (9-15) 4 58 (50-70) 8 98 (95-103) r Time (h) % release l0 1 11 (10-12) 2 25 (24-27) 6 55 (51-59) 12 79 (77-82) 18 90 (89-91 ) 24 94 (93-95) Examcale 6 formufatior~co~r parative~
Time (hl % release 0.25 94 2 0 0.5 99 0.75 98 ~xam'Ihe 8 Clinical Pharmacokinetics Studx A four way, multiple dose crossover study to investigate the bioavailability of darifenacin and its 3'-hydroxy metabolite when given as a sustained release formulation compared with an immediate release formulation was carried out. Thirteen normal males received the formulations of Examples 1-3 od each for 6 days as well as the formulation of Example 6 three times a day. Plasma samples for drug and metabolite assay were taken 3 0 over 24 hours on the last day of dosing for each period of the study. The pharmacokinetic parameters (area under the concentration-time curve over 24 hours, AUC, maximum concentration and concentration at 24 hours post dose) were obtained for both drug and metabolite. The table below shows the ratio of RUC values for darifenacin and metabolite (AUCda~fenacin~AUCmetabolite) and the relative bioavailability of darifenacin (Feel darifenacin) and 3 5 metabolite (F~, metabolite) for the formulations versus an immediate release capsule.
13 Ratio of AUC of darifenaciw metabolite and re~a+~~~A hin~wail~F,jlItV (Fg,,) versus an immediate release cad s~_yle Formulation: Example 6 Example Example 2 Example (immediate release)1 3 Ratio of 0.66 0.58 0.82 1.03 AUCder/AUCmet Fred dariienacinna 0.88 1.10 1.17 Fret metabortena 0.98 0.82 0.70 na = Not applicable These data indicate that the relative bioavailability of darifenacin over the metabolite is increased when darifenacin is administered in a sustained release formulation according to the invention.

Claims (21)

CLAIMS:
1. A pharmaceutical dosage form adapted for oral administration, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the darifenacin, or the pharmaceutically acceptable salt thereof, in said dosage form is:
(a) embedded in a matrix form from which it is released by diffusion or erosion;
(b) present in a multiparticulate core;
(c) released through an aperture provided in an impermeable coating;
(d) released through a coating of low aqueous solubility;
(e) released through a semipermeable coating;
(f) present as an ion exchange resin; or (g) released at specific points in the gastrointestinal tract by a pulsatile device;
characterized in that the dosage form is adapted to deliver at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient.
2. The dosage form as claimed in claim 1, which is adapted to deliver at least 50% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract.
3. The dosage form as claimed in claim 1 or claim 2, which is adapted to release the darifenacin, or the pharmaceutically acceptable salt thereof, to the gastrointestinal tract of the patient over or after a sustained period of time following administration of the dosage form to the patient.
4. The dosage form as claimed in claim 3, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 4 hours after dosing.
5. The dosage form as claimed in claim 4, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 8 hours after dosing.
6. The dosage form as claimed in claim 5, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 16 hours after dosing.
7. A pharmaceutical dosage form adapted for oral administration, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the darifenacin, or the pharmaceutically acceptable salt thereof, in said dosage form is:
(h) embedded in a matrix form from which it is released by diffusion or erosion;
(i) present in a multiparticulate core;
(j) released through an aperture provided in an impermeable coating;
(k) released through a coating of low aqueous solubility;

(l) released through a semipermeable coating;
(m) present as an ion exchange resin; or (n) released at specific points in the gastrointestinal tract by a pulsatile device;
characterized in that the dosage form is adapted to release the darifenacin, or the pharmaceutically acceptable salt thereof, in an in vitro model reproducing the conditions in the gastrointestinal tract over a sustained period of time.
8. The dosage form as claimed in claim 7, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 4 hours.
9. The dosage form as claimed in claim 7, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 8 hours.
10. The dosage form as claimed in claim 7, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 16 hours.
11. The dosage form as claimed in any one of claims 1 to 10, wherein the darifenacin is in the form of its hydrobromide salt.
12. The dosage form as claimed in any one of claims 1 to 11, wherein the matrix material is high molecular weight hydroxypropyl methylcellulose.
13. A process for the production of a dosage form as defined in claim 12, which comprises mixing darifenacin, or a pharmaceutically acceptable salt thereof, with high molecular weight hydroxypropyl methylcellulose.
14. A use of darifenacin, or a pharmaceutically acceptable salt thereof, for delivery to the lower gastrointestinal tract of a patient, to treat irritable bowel syndrome or urinary incontinence.
15. The use as claimed in claim 14, wherein the darifenacin, or a pharmaceutically acceptable salt thereof, is present in a dosage form as defined in any one of claims 1 to 12.
16. An oral tablet formulation consisting essentially of darifenacin hydrobromide in a high molecular weight hydroxypropyl methylcellulose matrix together with anhydrous dibasic calcium phosphate and magnesium stearate.
17. A formulation as claimed in claim 16, wherein the hydroxypropyl methylcellulose has a molecular weight of 85,000-95,000 mass units.
18. A formulation as claimed in claim 16 or claim 17, wherein the hydroxypropyl methylcellulose makes up 56-58% w/w of the tablet.
19. A formulation as claimed in any one of claims 16 to 18, wherein the magnesium stearate makes up approximately 1% w/w of the tablet.
20. A formulation as claimed in any one of claims 16 to 19, wherein the darifenacin hydrobromide content of the tablet is in the range 4-54mg.
21. A formulation as claimed in any one of claims 16 to 20, which is additionally provided with a colour coating.
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