WO2000019997A1 - Forme posologique a liberation controlee renfermant de l'oxybutynine - Google Patents

Forme posologique a liberation controlee renfermant de l'oxybutynine Download PDF

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Publication number
WO2000019997A1
WO2000019997A1 PCT/IB1998/001982 IB9801982W WO0019997A1 WO 2000019997 A1 WO2000019997 A1 WO 2000019997A1 IB 9801982 W IB9801982 W IB 9801982W WO 0019997 A1 WO0019997 A1 WO 0019997A1
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WIPO (PCT)
Prior art keywords
oxybutynin
dosage form
molecular weight
composition
release
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PCT/IB1998/001982
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English (en)
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WO2000019997A8 (fr
Inventor
David J. Kidney
George V. Guittard
Francisco Jao
Susan M. Marks
Fernando Gumucio
Original Assignee
Alza Corporation
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Application filed by Alza Corporation filed Critical Alza Corporation
Priority to PCT/IB1998/001982 priority Critical patent/WO2000019997A1/fr
Priority to AU12563/99A priority patent/AU1256399A/en
Publication of WO2000019997A1 publication Critical patent/WO2000019997A1/fr
Publication of WO2000019997A8 publication Critical patent/WO2000019997A8/fr

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    • 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
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • This invention pertains to a novel dosage form comprising oxybutynin and to the manufacture of a sustained release dosage form for managing the concentration of oxybutynin and its metabolite,
  • urinary incontinence is particularly common in the elderly; urinary incontinence is present in approximately fifty percent of nursing home patients, and urinary incontinence is a well known urologic problem in women. It will affect nearly all women in some form during their lifetime, and it is of significant social concern to ail humans who experience it.
  • Urinary incontinence arises from the anatomy and the physiology of the urinary tract, which is composed of a bladder and a sphincter.
  • the bladder consists of the bladder musculature, also known as detrusor, and the trigone.
  • the sphincter includes the bladder neck and the proximal urethra.
  • the detrusor muscle is innervated by the pelvic nerve through the parasympathetic nervous system, and the bladder neck and proximal urethra are innervated by the sympathetic nervous system.
  • the major functions of the bladder are the storage and expulsion of urine.
  • the bladder is responsible for accommodating increasing volumes of urine at low pressures. Normally, the bladder remains closed during bladder filling and continence is maintained as long as the bladder neck and urethra! pressure exceeds intravesical pressure. Voluntary voiding occurs when intravesical pressure exceeds bladder neck and urethral pressure, and involuntary voiding occurs when the intravesical pressure exceeds the bladder neck and urethral pressure.
  • Involuntary incontinence also known as urge incontinence, occurs with a loss of a large volume of urine accompanied by symptoms of urgency, frequency and nocturia caused by an unstable bladder or detrusor instability.
  • the patient may lose urine with a change in position or with auditory stimulation.
  • the loss of small volumes of urine usually occurs because of bladder overdistension by a large amount of residual urine referred to as overflow incontinence.
  • the management of incontinence consists in administering a smooth muscle relaxant, such as oxybutynin, which acts directly on the smooth muscle at the site distal to the cholinergic receptor.
  • a smooth muscle relaxant such as oxybutynin
  • the usual dose in the pharmacologic management is repeated doses from two-to-four times a day for oxybutynin. This is difficult to achieve as it requires rigid compliance and it is cost ineffective.
  • oxybutynin is adversely affected by light and it needs protection from air, which properties do not lend the drug to formulation into a dosage form that can administer oxybutynin at a controlled and known rate per unit time to produce the intended therapy.
  • oxybutynin administration is converted at least in part to its desethyl metabolite (Desoxy) in the plasma.
  • Desoxy desethyl metabolite
  • a controlled release dosage form comprising oxybutynin or a pharmaceutically acceptable biologically active salt thereof adapted to release oxybutynin or its salt at a biologically effective rate over time to an environment of use.
  • the invention is characterized in this aspect in that the oxybutynin or active salt is adapted to be partially converted to desethyl metabolite in the environment of use and in that the rate of release of oxybutynin or salt thereof from the dosage form is adapted to provide a controlled release up to 30 hours to provide a higher oxybutynin/desethyl metabolite ratio then 0.18:1.
  • a controlled release dosage form comprising oxybutynin or a pharmaceutically acceptable biologically active salt thereof adapted to release the oxybutynin or salt thereof at a biologically effective rate over time to an environment of use.
  • the invention in this aspect is characterized in that the oxybutynin or salt thereof is adapted to be partially converted to a desethyl metabolite in the environment of use and in that the rate of discharge of the oxybutynin or salt thereof from the dosage form is adapted to be controlled so that the plasma levels of the desethyl metabolite do not exceed 350 ng.h/ml.
  • the dosage form may be adapted to reduce peak levels of the metabolite to 300 ng.
  • Another object of the present invention is to provide a pharmacologic composition comprising oxybutynin, its racemate, its R-enantiomer and its S-enantiomer, administrable to a human, for lessening the incidence of incontinence.
  • Another object of the present invention is to provide a sustained release dosage form that administers oxybutynin at a controlled rate over twenty-four or even 30 hours for its therapeutic benefit accompanied by a lessening of unwanted side effects.
  • Another object of the present invention is to provide a dosage form adapted for the oral administration of ⁇ -cyclohexyl- -hydroxy-benzeneacetic acid-4 (diethylamino) - 2-butynyl ester salt in a first composition in contacting, layered arrangement with a second, force-generating composition that operates in combination for the administration of the beneficial ester salt.
  • Another object of the invention is to provide a dosage form for administering oxybutynin in a sustained-release profile to lessen side effects.
  • the invention thus pertains to a dosage form for the above therapeutic compositions adapted to deliver oxybutynin orally to a warm-blooded animal, including a human patient, in need of oxybutynin therapy.
  • the dosage forms of the invention may be administered orally to a patient for oxybutynin therapy.
  • the administration may comprise: (a) admitting orally into the patient a dosage form comprising (b) a semipermeable wall that surrounds (c) a therapeutic composition comprising (a) oxybutynin.
  • the dosage form imbibes fluid through the wall into the dosage form in response to the concentration gradient across the semipermeable wall.
  • the therapeutic composition in the dosage form develops osmotic energy that causes the therapeutic composition to be administered through the exit (d) from the dosage form over a prolonged period of time up to 24 hours (or even in some cases up to 30 hours) to provide controlled and sustained oxybutynin therapy.
  • the dosage form of the invention may be used by (a) admitting into the warm-blooded animal a dosage form comprising: (1) a wall surrounding a compartment, the wall comprising a semipermeable polymeric composition permeable to the passage of fluid and substantially impermeable to the passage of oxybutynin ; (2) an oxybutynin drug layer in the compartment comprising oxybutynin ; (3) a hydrogel push layer in the compartment comprising an osmotic formulation for imbibing and absorbing fluid for expanding in size for pushing the oxybutynin composition from the delivery device; and (4) at least one passageway in the wall for releasing the oxybutynin; (B) imbibing fluid through the semipermeable wall at a fluid imbibing rate determined by the permeability of the semipermeable wall and the osmotic pressure across the semipermeable wall causing the push layer to expand; and (C) delivering the therapeutically active oxybutynin from the delivery device through the exit passageway to
  • the oxybutynin administered by the dosage form of the invention is in the therapeutic range that avoids a toxic dose and avoids an ineffective dose for antispasmodic therapy.
  • the oxybutynin may thus be administered to patients with uninhibited neurogenic and reflex neurogenic bladder for increased vessel capacity which diminishes the frequency of uninhibited contractions of the detrusor muscle and delays the desire to void.
  • the dosage form is indicated for the relief of symptoms associated with voiding such as urgency, urge incontinence, frequency, nocturia and incontinence in patients in neurogenic bladder.
  • FIGURES Figure 1 illustrates the cumulative amount of the dose released in percent for a dosage form provided by the invention.
  • Figure 2 illustrates the average release rate in percent per hour for a dosage form provided by the invention.
  • the dosage form of the invention contains a therapeutic composition comprising 240 ng to 650 mg (nanogram to milligrams) of oxybutynin or an oxybutynin therapeutically acceptable salt.
  • the pharmaceutically acceptable salt is selected from the group consisting of acetate, bitartrate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, hydrobromide, hydrochloride, lactate, malate, aleate, mandelate, mesylate, methylnitrate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate, salicylate, stearate, succinate, sulfate, tannate and tartrate.
  • the drug oxybutynin can be present as the racemate, as the R- enantio er or as the S-enantiomer.
  • the dosage form may further contain 20 mg to 250 mg of a hydrogel, such as 20 mg to 250 mg of a polyalkylene oxide of 75,000 to 600,000 weight-average molecular weight.
  • Representative polyalkylenes are a polyethylene oxide of 100,000 weight- average molecular weight, of 200,000 weight average molecular weight or a polyethylene oxide of 300,000 weight- average molecular weight.
  • the dosage form may also comprise 1 mg to 50 mg of a hydroxypropylalkylcellulose of 9,000 to 150,000 average-number molecular weight selected from the group consisting of hydroxypropyimethylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylceliulose, and hydroxypropyl- pentylcellulose; 1 mg to 40 mg of an osmotic solute selected from the osmotically effective compounds consisting of sodium chloride, potassium chloride, potassium acid phosphate, tartaric acid, citric acid, raffinose, magnesium sulfate, magnesium chloride, urea, inositol, sucrose, glucose and sorbitol; and 0.01 mg to 5 mg of a lubricant, such as calcium stearate, zinc stearate, magnesium stearate, magnesium oleate, calcium palmitate, sodium suberate, potassium laureate, salts of fatty acids, salts of alicyclic acids, salts of aromatic acids
  • the invention provides for the therapeutic composition comprising the drug oxybutynin to be administered as the composition neat, that is, oxybutynin alone, for increasing the urinary bladder capacity, for diminishing the frequency of uninhibited contractions of the detrusor muscles and its accompanying delay of the desire to void.
  • the invention provides for the therapeutic oxybutynin composition to be surrounded by a wall comprising a semipermeable composition with an exit for delivering the therapeutic composition to a human patient in need of oxybutynin therapy.
  • the invention provides, in an additional embodiment, the therapeutic composition comprising oxybutynin as a therapeutic layer in layered, contacting arrangement with a hydrogel composition manufactured as a layer that supports the therapeutic composition to yield a bilayered matrix.
  • the hydrogel layer may comprise 40 mg to 250 mg of a hydrogel, such as a member selected from the group consisting of 40 mg to 250 mg of a polyalkylene oxide of 1,000,000 to 8,000,000 weight-average molecular weight which are selected from the group consisting of polyethylene oxide and polypropylene oxide; or 40 mg to 250 mg of an alkali carboxymethylcelluiose of 10,000 to 6,000,000 weight-average molecular weight such as sodium carboxymethylcelluiose or potassium carboxymethylcelluiose; or 0.1 mg to 250 mg of a hydroxyalkylcellulose of 7,500 to 4,500,000 weight-average molecular weight, represented by hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl- cellulose, hydroxybutylcellulose, and hydroxypentylcellulose; 1 mg to 50 mg of an osmagent selected from the group consisting of sodium chloride, potassium chloride, potassium acid phosphate, tartaric acid, citric acid, raffinose.
  • a hydrogel such as
  • magnesium sulfate magnesium chloride, urea, inositol, sucrose, glucose and sorbitol; 0 to 5 mg of a colorant, such as ferric oxide; 0.1 mg to 30 mg of a hydroxypropylalkylcellulose of 9,000 to 225,000 average-number molecular weight, selected from the group consisting of hydroxypropyl- ethylcellulose, hydroxypropypentylcellulose, hydroxypropylmethylceliulose, and hydropropylbutylcellulose; 0.00 to 1.5 mg of an antioxidant selected from the group consisting of ascorbic acid, butylated hydroxyanisole, butylatedhydroxyquinone, butylhydroxyanisol, hydroxycomarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate, trihydroxybutylrophenone, dimethylphenol, diterlbuty
  • the invention also provides for a dosage form as a therapeutic bilayer comprising an oxybutynin layer, and an osmopolymer hydrogel layer to be administered as the bilayer per se; that is, as the bilayer for increasing the urinary bladder capacity, for diminishing the frequency of uninhibited
  • the invention provides additionally for the compositional bilayer to be surrounded by a wall comprising a semipermeable composition with an exit for delivering the therapeutic composition to a human patient in need of oxybutynin therapy.
  • the invention also provides for a subcoat to surround the therapeutic composition or to surround the bilayer, which subcoat in either embodiment is surrounded by a outer semipermeable wall.
  • the invention provides a dosage form for the delivery of the therapeutic composition comprising oxybutynin.
  • the dosage form comprises up to 650 mg, and in one manufacture 240 ng to 650 mg of oxybutynin or its salt.
  • the dosage form can provide a sustained release at a controlled rate up to 25 mg, and in one controlled release rate 24 ng to 25 mg of oxybutynin or its salt up to 30 hours.
  • the dosage form comprises a wall, which wall surrounds an internal lumen or compartment.
  • the wall comprises a semipermeable composition that is permeable to the passage of fluid and impermeable to the passage of oxybutynin.
  • the wall is nontoxic and it comprises a polymer selected from the group consisting of a cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate.
  • the wall comprises 75 wt% (weight percent) to 100 wt% of the cellulosic wall-forming polymer; or, the wall can comprise additionally 0.01 wt% to 10 wt% of polyethylene glycol, or 1 wt% to 25 wt% of a cellulose, either selected from the group consisting of hydroxypropylcellulose or hydroxypropylalkycellulose such as hydroxypropylmethylcellulose.
  • the total weight percent of all components comprising the wall is equal to 100 wt%.
  • the internal compartment comprises the therapeutic oxybutynin composition in layered position with an expandable hydrogel composition.
  • the expandable hydrogel composition in the compartment increases in dimension by imbibing the fluid through the semipermeable wall, causing the hydrogel to imbibe the fluid, expand and occupy space in the compartment, whereby the drug composition is pushed from the dosage form.
  • the therapeutic layer and the expandable layer act together during the operation of the dosage form for the release of oxybutynin to a patient over time.
  • the dosage form comprises a passageway in the wall that connects the exterior of the dosage form with the internal compartment.
  • the dosage form provided by the invention delivers oxybutynin from the dosage form to the patient at a zero order rate of release over a period of 24 hours.
  • the expression "passageway" as used herein comprises means and methods suitable for the metered release of the therapeutic drug from the compartment of the dosage form.
  • the exit means comprises at least one passageway, including orifice, bore, aperture, pore, porous element, hollow fiber, capillary tube, porous overlay, or porous element that provides for the osmotic controlled release of oxybutynin.
  • the passageway includes a material that erodes or is leached from the wall in a fluid environment of use to produce at least one dimensioned passageway.
  • Representative materials suitable for forming a passageway, or a multiplicity of passageways comprise a leachable poly(glycolic) acid or poly(lactic) acid polymer in the wall, a gelatinous filament, poiy(vinyi alcohol), leachable polysaccharides, salts and oxides.
  • a pore passageway, or more than one pore passageway can be formed by leaching a leachable compound, such as sorbitol, from the wall.
  • the passageway possesses controlled-release dimensions, such as round, triangular, square and elliptical, for the metered release of oxybutynin from the dosage form.
  • the dosage form can be constructed with one or more passageways in spaced apart relationship on a single surface or on more than one surface of the wall.
  • fluid environment denotes an aqueous or biological fluid as in a human patient, including the gastrointestinal tract.
  • Passageways and equipment for forming passageways are disclosed in U.S. Patent Nos. 3,845,770; 3,916,899; 4,063,064; 4,088,864 and 4,816,263.
  • Passageways formed by leaching are disclosed in U.S. Patent Nos. 4,200,098 and 4,285,987.
  • the wall of the dosage form can be formed by using an air suspension procedure. This procedure consists in suspending and tumbling the composition or the layers in a current of air and wall-forming composition until a wall is applied to the oxybutynin forming compartment.
  • the air suspension procedure is well suited for independently forming the wall. The air suspension procedure is described in U.S. Patent No. 2,799,241 ; J. Am. Pharm. Assoc. Vol. 48, pp. 451-459 (1959); and ibid, Vol. 49, pp. 82-84 (1960).
  • the wall can be formed with a wall-forming composition in a Wurster ® air suspension coater using an organic solvent, such as acetone-water cosolvent 90:10 (wt:wt) with 2.5 wt% to 7 wt% polymer solids.
  • An Aeromatic ® air suspension coater using, for example, a methylene dichloride methanol cosolvent comprising 87:13 (v:v) can be used for applying the wall.
  • Other wall-forming techniques such as pan coating system, wall forming compositions are deposited by successive spraying of the composition or the bilayered arrangement, accompanied by tumbling in a rotating pan. A larger volume of cosolvent can be used to reduce the concentration of polymer solids to produce a thinner wall.
  • the wail of the coated compartments are laser or mechanically drilled, and then dried in a forced air or humidity oven for 1 to 3 days or longer to free the solvent.
  • the walls formed by these techniques have a thickness of 2 to 20 mils (0.051 to 0.510 mm) with a preferred thickness of 2 to 6 mils (0.051 to 0.150 mm).
  • the dosage form of the invention is manufactured by standard manufacturing techniques. For example, in one manufacture the beneficial drug oxybutynin and other ingredients comprising a therapeutic composition or comprising the first layer facing the exit means are blended, or they are blended then pressed, into a solid layer.
  • the oxybutynin and other ingredients can be blended with a solvent and formed into a solid or semisolid formed by conventional methods such as ball-milling, calendaring, stirring * or roll-milling and then pressed into a selected shape.
  • the layer posses dimensions that correspond to the internal dimensions of the area the layer is to occupy in the dosage form.
  • the bilayer compositions possess dimensions corresponding to the internal lumen of the dosage form.
  • the oxybutynin hydrogel layer is placed in contact with the oxybutynin drug layer.
  • the layering of the oxybutynin layer and the hydrogel layer can be fabricated by conventional press-layering techniques.
  • the two-layer compartment forming members are surrounded and coated with an outer wall. A passageway is laser drilled or mechanically drilled through the wall to contact the oxybutynin layer, with the dosage form optically oriented automatically by the laser equipment for forming the passageway on the preselected drug surface.
  • the dosage form is manufactured by the wet granulation technique.
  • the oxybutynin and the ingredients comprising the first layer are blended using an organic or inorganic solvent, such as isopropyl alcohol-methylene dichloride 80:20 (v:v) as the granulation fluid.
  • Other granulating fluid such as water, isopropyl alcohol, or denatured alcohol 100% can be used for this purpose.
  • the ingredients forming the first layer are individually passed through a 40 mesh screen and then thoroughly blended in a mixer. Next, other ingredients comprising the first layer are dissolved in a portion of the granulation fluid, such as the cosolvent described above.
  • the latter prepared wet blend is slowly added to the oxybutynin blend with continual mixing in the blender.
  • the granulating fluid is added until a wet blend mass is produced, which wet mass is then forced through a 20 mesh screen onto oven trays.
  • the blend is dried for 18 to 24 hours at 25°C to 40°C.
  • the dry granules are then screened with a 16 mesh screen.
  • a lubricant is passed through an 60 mesh screen and added to the dry screened granule blend.
  • the granulation is put into milling jars and mixed on a jar mill for 2 to 10 minutes.
  • the first and second layer compositions are pressed into a layered tablet, for example, in a Manesty ® layer press.
  • Another manufacturing process that can be used for providing the oxybutynin and hydrogel composition comprises blending their powdered ingredients in a fluid bed granulator. After the powdered ingredients are dry blended in the granulator, a granulating fluid, for example, poly(vinylpyrrolidone) in a solvent, such as in water, is sprayed onto the respective powders. The coated powders are then dried in a granulator. This process coats the ingredients present therein while spraying the granulating fluid. After the granules are dried, a lubricant, such as stearic acid or magnesium stearate, is blended as above into the mixture. The granules are then pressed in the manner described above.
  • a granulating fluid for example, poly(vinylpyrrolidone) in a solvent, such as in water
  • the antioxidant present in the polyalkylene oxide can be removed during the processing step. If antioxidant is desired it can be added to the hydrogel formulation; this can be accomplished during the fluid bed granulation described above.
  • the dosage form of this invention is manufactured in another embodiment by mixing the oxybutynin with composition-forming ingredients and pressing the composition into a solid layer possessing dimensions that correspond to the internal dimensions of the compartment space adjacent to a passageway.
  • the oxybutynin and other drug composition forming ingredients and a solvent are mixed into a solid, or semi- solid, by conventional methods such as bail-milling, calendaring, stirring or roll-milling, and then pressed into a preselected, layer-forming shape.
  • the invention provides further a method of manufacturing a sustained release ' dosage form adapted for managing oxybutynin and its desethylmetabolite in plasma by incorporating an effective amount of oxybutynin or its salt in a controlled release dosage form that releases oxybutynin continuously at a controlled rate to provide a higher oxybutynin concentration and a lower desethylmetabolite concentration than provided by an immediate release dosage form dose-dumps.
  • An immediate release dosage form dumps its drug in an hour or less.
  • the manufacture comprising a composition or comprising a layer of a composition comprising a hydrogel osmopolymer and an optional osmagent are placed in contact with the layer comprising the drug oxybutynin, and the two layers comprising the layers are surrounded with a semipermeable wall.
  • the layering of the first drug oxybutynin composition and the second hydrogel osmopolymer and optional osmagent composition can be accomplished by using a conventional two- layer tablet press technique.
  • the wall can be applied by molding, spraying or dipping the pressed shapes into wall-forming materials. Another technique that can be used for applying the wall is the air suspension coating procedure.
  • the dissolution of a drug indicates the drug entering into solution upon its delivery from a dosage form provided by this invention is measured by the following procedure.
  • a drug receiving solution such as, gastrointestinal fluid, hydrochloride acid, or an aqueous sodium dodecyl suifate, 1 % (w/v) (weight/volume) solution is used as the dissolution media.
  • a dosage form prepared by this invention is placed into the dissolution media and the drug released by the dosage form into the dissolution media is sampled at a constant time interval over the time period of dissolution.
  • the filtered samples are assayed by a reversed high pressure liquid chromatography, or detection by UV.
  • the concentration of the samples is measured against a standard curve containing, for example, at least five standard points.
  • the release rate of drug from a dosage form manufactured by this invention can be ascertained by the following procedure.
  • the procedure comprises placing the dosage form in a solution, usually water, and taking aliquots of the release rate solution, followed by their injection into a chromatographic system to quantify the amount of drug released during specified test intervals.
  • the drug for example, is resolved on a column and detected by UV absorption. Quantitation is performed by linear regression analysis of peak areas from a standard curve containing at least five standard points.
  • the release rate procedure comprises attaching a dosage form to a plastic rod with the orifice exposed to the drug receiving solution. Then, attaching the rod to a release arm, with the arm affixed to an up/down reciprocating shaker, which operates at an amplitude of about 3 cm and 2 seconds per cycie. Then, continuously immersing the dosage form in 50 ml test tubes containing 30 ml of H 2 0, equilibrated in a constant temperature water bath at 37°C ⁇ 0.5°C. Next, at the end of each interval, transfer the dosage form to the next row of new test tubes containing a receiving solution, such as water.
  • a receiving solution such as water.
  • solvents suitable for manufacturing the wall, the composition layers and the dosage form include inert inorganic and organic solvents that do not adversely harm the materials, the wall, the layer, the composition and the drug wall.
  • the solvents broadly include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatics, aromatics, heterocyclic solvents and mixtures thereof.
  • Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethylacetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon chloroform, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclo-octane, toluene, naphtha, 1 ,4-dioxane, tetrahydrofuran, diglyme, aqueous and nonaqueous mixture
  • a therapeutic oxybutynin composition for use in the invention was prepared as follows: first, 103 grams of oxybutynin hydrochloride was dissolved in 1200 ml (milliliters) of anhydrous ethanol. Separately, 2,280 g of polyethylene oxide of 200,000 weight-average molecular weight, 150 g of hydroxypropylmethylcellulose of 9,200 average-number molecular weight and 450 g of sodium chloride were dry blended in a conventional blender for 10 minutes to yield a homogenous blend. Next, the oxybutynin ethanol solution was added slowly to the blend, with the blender continuously blending until all the ingredients were added to the three component dry blend, with the blending continued for another 8 to 10 minutes.
  • the blended wet composition was passed through a 16 mesh screen and dried overnight at a room temperature of 72°F (22.2°). Then, the dry granules were passed through a 20 mesh screen, 18 g of magnesium stearate was added, and all the ingredients blended again for 5 minutes. The fresh granules are ready for formulation into a therapeutic oxybutynin composition.
  • the therapeutic composition comprises 3.4 wt% oxybutynin hydrochloride, 76 wt% polyethylene oxide of 200,000 weight-average molecular weight, 5 wt% of hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 15 wt% sodium chloride, and 0.6 wt% magnesium stearate.
  • the therapeutic composition can be administered as the composition for its intended oxybutynin therapy.
  • An osmopolymer hydrogel composition for use in t h e invention was prepared as follows: first 1274 g of pharmaceutically acceptable polyethylene oxide comprising a 7,500,000 weight-average molecular weight, 600 g of sodium chloride, and 20 g ferric oxide were separately screened through a 40 mesh screen. Then, all the screened ingredients were mixed with 100 g of hydroxypropylmethylcellulose of 11 ,200 average-number molecular weight to produce a homogenous blend. Next, 300 ml of denatured anhydrous alcohol was added slowly to the blend with continuous mixing for 5 minutes.
  • the final composition 5 comprised 63.67 wt% polyethylene oxide of 7,500,000 weight-average molecular weight, 30 wt% sodium chloride, 1 wt% ferric oxide, 5 mg hydroxypropylmethylcellulose of 11 ,200 average-number molecular weight, 0.08 wt% butylated hydroxytoluene, and 0.25 mg magnesium stearate.
  • An osmopolymer hydrogel composition for use in the invention was prepared as follows: first 1274 g of pharmaceutically acceptable sodium carboxymethylcelluiose comprising a 5,250,000 weight-average molecular 5 weight, 600 g of sodium chloride, and 20 g ferric oxide were separately screened through a 40 mesh screen. Then, all the screened ingredients were mixed with 100 g of hydroxypropylmethylcellulose of 11 ,200 average-number molecular weight and 100 g of hydroxypropylcellulose of 30,000 average- number molecular weight to produce a homogenous blend. Next, 300 ml of o denatured anhydrous alcohol was added slowly to the blend with continuous mixing for 5 minutes.
  • Example 1 The therapeutic oxybutynin composition and the osmopolymer hydrogel composition for example as shown in Example 1 were made into a bilayer tablet as follows: first, 147 mg of the oxybutynin composition as prepared in Example 1 was added to a punch die set and tamped. Then, 98 mg of the hydrogel composition as prepared in Example 2 was added and the two layers compressed under a pressure head of 1.0 ton (1000 kg) into a 11/32 inch (0.873 cm) diameter, contacting intimate bilayered tablet. The example was repeated with the hydrogel composition as prepared in Example 3 to produce the tablet comprising two layers.
  • EXAMPLE 5 The bilayered tablet for example as described in Example 4 was manufactured into a dosage form as follows :- first, a semipermeable wall-forming composition was prepared comprising 95 wt% cellulose acetate having a 39.8% acetyl content and 5 wt% polyethylene glycol having a number-average molecular weight of 3350 by dissolving the ingredients in a cosolvent comprising acetone and water in 90:10 w wt composition to make a 4% solid solution. The wall-forming composition was sprayed onto and around the bilayered cores as prepared in Examples 2 and 3 to provide a 26.4 mg semipermeable wall.
  • the semipermeable wailed, bilayered tablet was laser drilled to provide a 20 mil (0.51 mm) orifice to contact the oxybutynin layer and the exterior of the dosage form.
  • the residual solvent was removed by drying for 48 hours at 50°C and 50% relative humidity.
  • the dosage forms were dried further for 1 hour at 50°C to remove excess moisture.
  • the dosage form provided by this manufacture provides 3.4 wt% oxybutynin hydrochloride, 76 wt% polyethylene oxide of 200,000 weight-average molecular weight, 5 wt% hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 0.6 wt% magnesium stearate, and 15 wt% sodium chloride in the therapeutic oxybutynin composition.
  • the osmopolymer hydrogel push composition comprises 63.67 wt% polyethylene oxide of 7,500,000 weight-average molecular weight, 30 wt% sodium chloride, 1 wt% ferric chloride, 5 wt% hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 0.08 wt% butylated hydroxytoluene, and 0.25 wt% magnesium stearate.
  • the semipermeable wall comp ⁇ ses 95 wt% cellulose acetate comprising 39.8% acetyl content, and 5 wt% polyethylene glycol of 3350 number-average molecular weight.
  • the dosage form comprises an exit passage of 20 mils (0.50 mm) and it has a mean release rate of 0.260 mg/hr for 23.8 hours.
  • the semipermeable wall provides substantial protection from photo (light) degradation of the oxybutynin in the dosage form.
  • a dosage form is prepared according to the above examples, comprising a drug layer consisting of 6.67 wt% oxybutynin hydrochloride, 87.83 wt% polyethylene oxide of 200,000 weight-average molecular weight, 5.00 wt% hydroxypropylmethylcellulose of 9,200 average-number molecular weight, and 0.50 wt% magnesium stearate; in layered contact with a push hydrogel layer comprising 58.75 wt% sodium carboxymethylcelluiose of 6,000,000 weight-average molecular weight, 30 wt% sodium chloride, 5.00 wt% hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 1.00 wt% ferric oxide, 5.00 wt% hydroxypropylcellulose of 75,000 average-number molecular weight and 0.25 wt% magnesium stearate; which bilayered core is surrounded by a semipermeable wall comprising cellulose acetate and polyethylene glycol; and an exit port through the wall for
  • a dosage form was prepared according to the above examples wherein the dosage form of this example comprises a drug oxybutynin layer comprising 5 mg oxybutynin, 111.60 mg polyethylene oxide of 200,000 weight-average molecular weight, 7.35 mg hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 0.88 mg magnesium stearate, 22.05 mg of sodium chloride, and 0.12mg of butylated hydroxytoluene; a hydrogel push layer comprising 62.40 mg of polyethylene oxide of 7,000,000 weight- average molecular weight, 29.40 mg of sodium chloride, 4.90 mg hydroxypropylmethylcellulose of 9,200 average-number molecular weight,
  • a wall comprising cellulose acetate consisting of a 39.8% acetyl content and polyethylene glycol of 3350 number-average molecular weight in the percentage ratio of 95 wt% cellulose acetate to 5 wt% polyethylene glycol, and an exit passageway in the wall.
  • a dosage form was prepared according to the examples provided by this invention wherein the dosage form comprises: a drug oxybutynin layer comprising 5.3 wt% oxybutynin, 82.37 wt% polyethylene oxide of 200,000 weight-average molecular weight, 2 wt% hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 0.25 wt% magnesium stearate, 10 wt% sodium chloride, and 0.08 wt% butylated hydroxytoluene; a push hydrogel layer comprising 63.37 wt% polyethylene oxide of 2,000,000 weight- average molecular weight, 30 wt% sodium chloride, 5 wt% hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 0.08 wt% butylated hydroxytoluene, 1 wt% black ferric oxide and 0.25 wt% magnesium stearate; a wall comprising 99 wt% cellulose acetate comprising a 39
  • An oxybutynin composition was prepared according to the above examples, wherein the composition comprises 10.6 wt% oxybutynin hydrochloride, 79.57 wt% polyethylene oxide of 200,000 weight-average molecular weight, 2 wt% hydroxypropylmethylcellulose of 9,200 average- number molecular weight, 0.25 wt% of magnesium stearate, 7.5 wt% of sodium chloride, and 0.08 wt% butylated hydroxytoluene.
  • An oxybutynin composition was prepared according to the above examples wherein the composition comprises 16 wt% oxybutynin hydrochloride, 76.67 wt% polyethylene oxide of 200,000 weight-average molecular weight, 2 wt% hydroxypropylmethylcellulose of 9,200 average- number molecular weight, 0.25% magnesium stearate, 5 wt% sodium chloride and 0.08 wt% butylated hydroxytoluene.
  • a hydrogel composition was prepared according to the above examples wherein the composition comprises 58.75 wt% hydroxyethylcellulose of 1 ,300,000 molecular weight, 30 wt% sodium chloride, 10 wt% polyvinylpyrrolidone of 42,000 viscosity-average molecular weight, 1 wt% red ferric oxide, and 0.25 wt% magnesium stearate.
  • a dosage form was prepared according to the present invention wherein the dosage form comprises: a drug layer comprising 3.4 wt% oxybutynin hydrochloride, 76 wt% polyethylene oxide of 200,000 weight- average molecular weight, 5 wt% hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 0.6 wt% magnesium stearate, 15 wt% sodium chloride; a push hydrogel layer comprising 58.75 wt% hydroxyethylcellulose of 1 ,300,000 average-number molecular weight, 30 wt% sodium chloride, 10 wt% polyvinylpyrrolidone of 42,000 viscosity-average molecular weight, 1 wt% red ferric oxide, and 0.25 wt% magnesium stearate; a wall comprising 95 wt% cellulose acetate comprising a 39.8% acetyl content, and 5 wt% polyethylene glycol of 3350 number-average molecular weight,
  • a dosage form was manufactured according to the present examples wherein the dosage form comprises: a drug oxybutynin layer comprising 3.4 wt% oxybutynin hydrochloride, 76 wt% polyethylene oxide of 200,000 weight- average molecular weight, 5 wt% hydropropylmethylcellulose of 9,200 average-number molecular weight, 0.6 wt% of magnesium stearate, and 15 wt% sodium chloride; a push hydrogel layer for pushing the drug oxybutynin layer form the dosage form comprising 63.67 wt% polyethylene oxide of 7,000,000 weight-average molecular weight, 30 wt% sodium chloride, 1 wt% red ferric oxide, 5 wt% hydroxypropylmethylcellulose of 9,200 average- number molecular weight, 0.08 wt% butylated hydroxytoluene, and 0.25 wt% magnesium stearate; a subcoat that surrounds the drug oxybutynin layer and push hydrogel layer wherein the
  • a dosage form designed and shaped as a pharmaceutically acceptable tablet for the oral administration of a member selected from the group consisting of oxybutynin and its pharmaceutically acceptable salts was made by following the above examples.
  • the dosage form provided by the example comprises a drug composition weighing 92 mg comprising 5.45 wt% of oxybutynin hydrochloride, 9.98 wt% of sodium chloride, 82.16 wt% of polyethylene oxide of 100,000 molecular weight, 2.00 wt% of hydroxypropylmethylcellulose of 11 ,300 molecular weight, 0.25 wt% of magnesium stearate, 0.08 wt% of butylated hydroxytoluene, and 0.05 wt% of green ferric oxide.
  • composition was surrounded by a wall comprising a semipermeable cellulose acetate polymer comprising a 39.8% acetyl content and polyethylene glycol comprising a 3,350 molecular weight.
  • the dosage form comprised can exit for delivering oxybutynin to the gastrointestinal tract of a patient.
  • a dosage form adapted as an orally administrable tablet was made according to the above examples.
  • the dosage form of this example comprises a drug composition weighing 92 mg and comprising 5.45 wt% oxybutynin hydrochloride, 9.98 wt% sodium chloride, 82.19 wt% polyethylene oxide possessing a 200,000 molecular weight, 2.00 wt% hydroxypropylmethylcellulose of 11 ,300 molecular weight, 0.25 wt% magnesium stearate, 0.08 wt% butylated hydroxytoluene, and 0.05 wt% green ferric oxide; a push composition initially in contact with the drug composition, weighing 62 mg and comprising 63.67 wt% polyethylene oxide possessing a 2,000,000 molecular weight, 30.00 wt% sodium chloride, 5.00 wt% hydroxypropylmethylcellulose of 11 ,200 molecular weight, 1.00 wt% of a 95.5 mixture of black iron oxide/lactose, 0.
  • the dosage form exhibited a cumulative release of oxybutynin hydrochloride of greater than zero mg to 1 mg in 0 to 4 hours, 1 mg to 2.5 mg in 0 to 8 hours, 2.75 mg to 4.25 mg in 0 to 14 hours, and 3.75 mg to 5 mg in 0 to 24 hours.
  • a dosage form for the oral administration of oxybutynin was made by following the above examples.
  • the dosage form comprises a 92 mg drug composition comprising 10.90 wt% oxybutynin hydrochloride, 7.48 wt% sodium chloride, 79.25 wt% polyethylene oxide possessing a 200,000 molecular weight, 1.99 wt% hydroxypropylmethylcellulose possessing a 11,300 molecular weight, 0.25 wt% magnesium stearate, 0.08 wt% butylated hydroxytoluene, and 0.05 wt% red ferric oxide; a push composition weighing 62 mg and comprising 63.67 wt% polyethylene oxide possessing a 2,000,000 molecular weight, 30 wt% sodium chloride, 5 wt% hydroxypropylmethylcellulose possessing a 11 ,300 molecular weight, 1.00 wt% black iron oxide/lactose (95:5), 0.25 wt% magnesium stearate, and 0.08
  • the dosage form delivers in 0 to 4 hours up to 20% (up to 2 mg) of oxybutynin hydrochloride, in 0 to 8 hours 20 to 50% (2.0 to 5.0 mg) of oxybutynin salt; in 0 to 14 hours 50 to 85% (5.5 mg to 8.5 mg) of oxybutynin; and 0 to 24 hours greater than 75% (greater than 7.5 mg) of the drug.
  • a dosage form for the oral delivery of a member selected from the group consisting of oxybutynin and its pharmaceutically acceptable salts was made according to the above examples.
  • the dosage form comprised a drug layer weighing 92 mg comprising 16.30 wt% oxybutynin chloride, 4.98 wt% sodium chloride, 76.35 wt% polyethylene oxide of 200,000 molecular weight, 1.99 wt% hydroxypropylmethylcellulose, 0.25 wt% magnesium stearate, 0.08 wt% butylated hydroxytoluene, 0.02 wt% black iron oxide/lactose (95:5); a push composition weighing 62 mg comprising 63.67 wt% polyethylene oxide possessing a 2,000,000 molecular weight, 30.00 wt% sodium chloride, 5.00 hydroxypropylmethylcellulose of 11 ,300 molecular weight, 1.00 wt% black iron oxide/lactose (95:5), 0.25 wt% magnesium ste
  • a dosage form was prepared according to the previous examples comprising an oxybutynin salt, that delivers up to 1.60 mg in 0 to 4 hours, up to 5 mg in 0 to 8 hours, up to 8.5 mg in 0 to 12 hours, up to 11 mg in 0 to 16 hours, and up to 15 mg in 0 to 24 hours.
  • a solid, orally administrable dosage form comprising 1 mg to 100 mg of a drug selected from the group consisting of oxybutynin and its pharmaceutically acceptable sait is prepared by following the previous examples.
  • FIG. 1 depicts the cumulative amount of the dose released normalized to the percent of the dose released from dosage forms comprising 5 mg, 10 mg, and 15 mg of oxybutynin.
  • Figure 2 depicts the average release rate expressed as percent of the total dose per hour for dosage forms comprising 5 mg, 10 mg, and 15 mg of oxybutynin.
  • a method of manufacturing a sustained release dosage form for managing oxybutynin and its desethylmetabolite in plasma comprises the incorporation of an effective amount of oxybutynin or its pharmaceutically acceptable salt in a sustained and controlled release dosage form which release oxybutynin continuously at a controlled zero order rate to provide a relatively higher oxybutynin concentration and a relatively lower desethylmetabolite concentration than provided by an immediate release dosage form profile.
  • EXAMPLE 23 The drug oxybutynin, identified as OXY, was administered in a clinical study to a number of patients to treat urinary incontinence. Patients who self-administered oxybutynin often quit or discontinue treatment due to its anti-cholinergic side effects, which appear to be peak- concentration related.
  • the present invention thus provides a sustained release (SR) controlled-release (CR) oral dosage form comprising oxybutynin designed to provide both oxybutynin therapy throughout the entire gastrointestional tract and a continuous plasma drug concentration that avoid peak and valley concentrations.
  • SR sustained release
  • CR controlled-release
  • the sustained release dosage form of this invention continuously delivers oxybutynin throughout the entire gastrointestional tract (Gl), thereby making it therapeutically effective for oxybutynin to be absorbed throughout the entire gastrointestional tract into the blood. That is, the controlled-extended release dosage form of this invention maintains a therapeutic plasma concentration free of an overdose and free of an ineffective underdose of oxybutynin.
  • the drug release kinetics for the controlled-release (CR) plasma concentration rose slowly, reaching a mean C max value of 4.2- 6.7 ng/ml .
  • the metabolite DESOXY was formed rapidly following immediate release, and its formation parallelled the slow absorption of oxybutynin following controlled release.
  • the DESOXY had a shorter t 4 life compared to OXY, indicating presystemic metabolite formation assuming it to be true metabolite t .
  • Single and multiple dose AUC values were similar for both the controlled release and the immediate release suggesting time invariant pharmacokinetics .
  • AUC denotes the area under the plasma concentration profile.
  • OXY and DESOXY AUC and their ratios are presented in the Table below wherein BA denotes the percent bioavailable, that is, BA denotes the relative amount of oxybutynin absorbed from the controlled release (CR) dosage form compared to the immediate release (IR) dosage form, and C ⁇ denotes the maximum concentration.
  • BA denotes the percent bioavailable, that is, BA denotes the relative amount of oxybutynin absorbed from the controlled release (CR) dosage form compared to the immediate release (IR) dosage form
  • C ⁇ denotes the maximum concentration.
  • the higher ratio of OXY-BA following CR compared to IR suggests lower metabolic formation on first pass. This indicates CR could reach the colon within 3-5 hours post dosing. Presystemic cytochrome P450-mediated oxidation may occur in the upper part of the gastrointestinal tract; then, drug release from CR in the colon escapes presystemic metabolism, which could explain the higher OXY/DESOXY ratio and increased OXY BA following CR.
  • the dosage form and the oxybutynin composition of this invention can be used in a method for administering a drug by the oral route, or the dosage form and composition can be sized and shaped for administering a drug by the sublingual and buccal routes.
  • the sublingual and buccal routes can be used for quicker therapy, and they can be used when a smaller dose of drug is needed for immediate therapy.
  • the latter routes can be used as a by-pass of the first pass of heptic metabolism of the drug.
  • the present invention contributes to the art an unobvious dosage form that possesses practical utility, can administer a drug at a dose-metered release rate per unit time.

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Abstract

L'invention concerne un déséthylemétabolite de l'oxybutynine, et sa réduction dans le plasma en circulation. Spécifiquement, l'invention concerne une forme posologique à libération contrôlée renfermant de l'oxybutynine ou un sel biologiquement actif pharmaceutiquement acceptable de cette substance, qui permet de libérer dans le temps l'oxybutynine ou son sel, suivant un taux biologique, à destination du point d'utilisation. Une conversion partielle du produit est prévue au point d'utilisation et le taux de libération est prévu pour répondre aux besoins d'une libération contrôlée durant jusqu'à 30 heures, ce qui donne un rapport oxybutynine/déséthylemétabolite supérieur à 0,18:1 ou une valeur telle que les niveaux de plasma du métabolite n'excèdent pas 350 ng.h/ml à l'utilisation.
PCT/IB1998/001982 1998-10-07 1998-10-07 Forme posologique a liberation controlee renfermant de l'oxybutynine WO2000019997A1 (fr)

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PCT/IB1998/001982 WO2000019997A1 (fr) 1998-10-07 1998-10-07 Forme posologique a liberation controlee renfermant de l'oxybutynine
AU12563/99A AU1256399A (en) 1998-10-07 1998-10-07 Controlled release dosage from comprising oxybutynin

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6436428B1 (en) 2000-03-21 2002-08-20 Enhance Pharmaceuticals, Inc. Device and method for treating urinary incontinence in females
US8241667B2 (en) 2001-11-06 2012-08-14 Osmotica Kereskedelmi és Szolgáltató KFT Dual controlled release osmotic device

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JPH05339151A (ja) * 1992-05-30 1993-12-21 Kodama Kk 持効性塩酸オキシブチニン製剤
JPH069388A (ja) * 1992-06-24 1994-01-18 Kodama Kk 徐放性塩酸オキシブチニン製剤
WO1996012477A1 (fr) * 1994-10-21 1996-05-02 Leiras Oy Systeme d'administration orale a liberation lente contenant de l'oxybutynine
WO1996037202A1 (fr) * 1995-05-22 1996-11-28 Alza Corporation Forme galenique contenant de l'oxybutynine
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JPH05339151A (ja) * 1992-05-30 1993-12-21 Kodama Kk 持効性塩酸オキシブチニン製剤
JPH069388A (ja) * 1992-06-24 1994-01-18 Kodama Kk 徐放性塩酸オキシブチニン製剤
WO1996012477A1 (fr) * 1994-10-21 1996-05-02 Leiras Oy Systeme d'administration orale a liberation lente contenant de l'oxybutynine
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6436428B1 (en) 2000-03-21 2002-08-20 Enhance Pharmaceuticals, Inc. Device and method for treating urinary incontinence in females
US8241667B2 (en) 2001-11-06 2012-08-14 Osmotica Kereskedelmi és Szolgáltató KFT Dual controlled release osmotic device

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AU1256399A (en) 2000-04-26

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