Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention pertains to a novel dosage form comprising oxybutynin.
• the invention relates also to a therapeutic composition comprising oxybutynin, to a therapeutic bilayer comprising oxybutynin, and to a method for administering oxybutynin to a patient in need of oxybutynin.
• 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. 2
• 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 urethral 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.
• overflow incontinence The loss of small volumes of urine usually occurs because of bladder overdistention 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.
• oxybutynin a smooth muscle relaxant
• 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.
• a pressing need exists for a dosage form and for a therapeutic composition that can deliver the valuable drug oxybutynin in a controlled, extended dose to a patient in clinical need of incontinence management.
• the pressing need exists for an oral dosage form, for a therapeutic composition 3
• a dosage form and a therapeutic composition that can deliver oxybutynin protected from light to insure that a complete dose of oxybutynin is administered to the patient and still remains substantially independent of the changing environment of the gastrointestinal tract.
• a dosage form for delivering oxybutynin in a rate- controlled dose and which dosage form substantially overcomes the deficiencies and omissions associated with the prior art.
• Another object of the present invention is to provide a dosage form for orally administering oxybutynin in a controlled dose for the nonsurgical treatment of incontinence in a human afflicted with incontinence.
• Another object of the invention is to provide a pharmacologic composition comprising oxybutynin indicated for the pharmacologic management of incontinence. 4
• 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 invention is to provide a dosage form comprising a homogenous drug core for dispensing oxybutynin to a human patient.
• Another object of this invention is to provide a novel composition that makes available oxybutynin therapeutic activity to a patient in need of oxybutynin therapy.
• Another object of the invention is to provide a once-a-day oral sustained release dosage form that delivers a member selected from the group consisting of oxybutynin and its pharmaceutically acceptable salt at a controlled rate over 24 hours.
• Another object of the invention is to provide a dosage form manufactured as an osmotic dosage form that can administer oxybutynin to a biological receptor to produce the desired oxybutynin effects.
• Another object of the present invention is to provide a dosage form manufactured as an osmotic dosage form that maintains oxybutynin and oxybutynin therapeutically acceptable salts in the dosage form, and thereby provides protection from light until the oxybutynin is released from the dosage form, thereby reducing and/or eliminating the unwanted influences of the gastrointestinal environment of use and still provide controlled administration of oxybutynin over time.
• Another objective of the invention is to provide a sustained release dosage form that administers oxybutynin at a sustained release rate accompanied by a lessening of adverse reaction dry mouth.
• Another object of the present invention is to provide a dosage form that administers oxybutynin at a controlled rate over time for its therapeutic benefit accompanied by a lessening of possible unwanted side effects. 5
• Another object of the present invention is to provide a dosage form that contains initially crystalline oxybutynin salt protected by a light resistant, semipermeable polymeric wall which oxybutynin can be administered in a controlled dose over time.
• 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 objective of the invention is to provide a delivery system for a member selected from the group consisting of oxybutynin and its pharmaceutically acceptable salt that achieves an increase in the bioavail- ability of the drug, reduces the formation of its active metabolites, and achieves a flat drug and metabolite concentration profile as compared to an immediate release dosage administered multiple times a day.
• Another object of the present invention is to provide a complete pharmaceutical oxybutynin regimen comprising a composition comprising oxybutynin that can be dispensed from a drug delivery dosage form, the use of which requires intervention only for initiation and possibly for termination of the regimen.
• Another object of the invention is to provide a method for treating incontinence by orally administering oxybutynin from a delivery device in a rate-controlled amount per unit time to a warm-blooded animal in need of incontinence therapy.
• Another object of the invention is to provide a method for lessening the side-effects accompanying the administration of a member selected from the group consisting of oxybutynin and its pharmaceutically acceptable salts by administering the drug from a sustained-release dosage form over twenty-four hours. 6
• Another object of the invention is to provide a method of administering
• Another object of the invention is to provide a method for administering
• Another object of the invention is to decrease dry-mouth in a patient
• Another object of the invention is to provide a method of administering ⁇ oxybutynin in a sustained-release profile to lessen side effects.
• Figures 1 to 6 illustrate the clinical benefits for delivering a member
• the present invention provides a therapeutically active compound
• composition comprising 240 ng to 650 mg (nanogram to milligrams) of
• 28 acceptable salts can be present in a dosage form in, for example, 5 mg, 10
• the drug oxybutynin can be present as the
• composition further contains 20 mg to 250 mg of a hydrogel, such as 20 mg
• Representative polyalkylenes are a polyethylene oxide of ⁇ o 100,000 weight-average molecular weight or a polyethylene oxide of 200,000 ⁇ weight-average molecular weight.
• the therapeutic composition comprises 1
• hydroxypropylmethylcelluiose hydroxypropylethyl-cellulose
• hydroxypropylbutylcellulose is hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose; 1 mg to 40 mg
• lubricant such as calcium stearate, zinc stearate, magnesium stearate,
• the invention provides for the therapeutic composition comprising the
• the invention provides for the
• the hydrogel layer comprises 40 mg to 250 mg of a
• hydrogel such as a member selected from the group consisting of 40 mg to s 250 mg of a polyalkylene oxide of 1 ,000,000 to 8,000,000 weight-average
• 9 molecular weight which are selected from the group consisting of o polyethylene oxide and polypropylene oxide; or 40 mg to 250 mg of an alkali 1 carboxymethylcellulose of 10,000 to 6,000,000 weight-average molecular 2 weight such as sodium carboxymethylcellulose or potassium carboxy- 3 methylcellulose; or 0J mg to 250 mg of a hydroxyalkylcellulose of 7,500 to 4 4,500,000 weight-average molecular weight, represented by 5 hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, 6 hydroxybutylcellulose, and hydroxypentylceilulose; 1 mg to 50 mg of an 7 osmagent selected from the group consisting of sodium chloride, potassium s chloride, potassium acid phosphate, tartaric acid, citric acid, raffinose, 9 magnesium sulfate, magnesium chloride, urea, inositol, sucrose, glucose and 0 sorbitol; 0 to 5 mg of a colorant, such as ferric oxide; 0
• the invention provides for the therapeutic oxybutynin composition, the therapeutic bilayer comprising the drug oxybutynin layer, and the osmopolymer hydrogel layer to be administered as the composition or the bilayer per se; that is, as the composition or the bilayer together 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 additionally for the therapeutic composition and 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 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 hydroxypropylalkylcellulose such as hydroxypropyl- 10
• the internal compartment comprises the
• the therapeutic layer and the expandable layer act
• 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
• passageway as used herein comprises means and
• the exit means comprises at least one is passageway, including orifice, bore, aperture, pore, porous element, hollow
• the passageway includes a
• a pore passageway, or more than one pore passageway, can be
• the passageway possesses controlled-release dimensions, such as round,
• the dosage form can be constructed with one or more 11
• passageways in spaced apart relationship on a single surface or on more than one surface of the wall.
• the expression "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 the 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 ⁇ b ⁇ 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 methyiene dichloride methanol cosolvent comprising 87:13 (v:v) can be used for applying the wall.
• Other wall-forming techniques, such as pan coating can be used for providing the dosage form.
• 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 wall of the coated compartments are laser or mechanically drilled, and then dried in a forced air or humidity 12
• 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, calendering, stirring or roll-milling and then pressed into a selected shape.
• the layer possess dimensions that correspond to the internal dimensions of the area the layer is to occupy in the dosage form.
• the bilayer 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.
• organic or inorganic solvent such as isopropyl alcohol-methylene dichloride 80:20 (v:v)
• 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 13
• the first and ⁇ o second layer compositions are pressed into a layered tablet, for example, in a ⁇ Manesty ® layer press.
• oxybutynin and hydrogel composition comprises blending their powdered
• a granulating fluid for example,
• a lubricant such as stearic acid or
• the fluid bed granulating process is used to manufacture the hydrogel layer
• the antioxidant present in the polyalkylene oxide can be removed during the
• antioxidant it can be added to the hydrogel
• the oxybutynin and other drug composition forming ingredients and a solvent are mixed into a solid, or semi- solid, by conventional methods such as ball-milling, calendering, stirring or roll-milling, and then pressed into a preselected, layer-forming shape.
• 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. This procedure consists in suspending and tumbling the two layers in a current of air until the wall forming composition surrounds the layers. Manufacturing procedures are described in Modern Plastics Encyclopedia, Vol. 46, pp. 62-70 (1969); and in Pharmaceutical Sciences, by Remington, 14th Ed., pp. 1626-1648 (1970), published by Mack Publishing Co., Easton, PA.
• the dosage form can be manufactured by following the teaching in U.S. Patent Nos. 4,327,725; 4,612,008; 4,783,337; 4,863,456; and 4,902,514.
• Exemplary 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, 15
• a therapeutic oxybutynin composition provided by 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 16
• composition comprises 3.4 wt% oxybutynin hydrochloride, 76 wt%
• the therapeutic ⁇ o composition can be administered as the composition for its intended ⁇ oxybutynin therapy.
• An osmopolymer hydrogel composition provided by the invention was prepared as follows: first 1274 g of pharmaceutically acceptable sodium carboxymethylcellulose comprising a 5,250,000 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 and 100 g of hydroxypropylcellulose of 30,000 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 therapeutic oxybutynin composition and the osmopolymer hydrogel composition 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 18
• hydrogel composition as prepared in Example 3 to produce the tablet comprising two layers.
• the bilayered tablet was manufactured into a sustained-release dosage form that provides a controlled-release of oxybutynin 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 wt: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 walled, 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 comprises 95 wt% cellulose acetate comprising 39.8% acetyl content, and 5 wt% polyethylene glycol of 3350 number-average 19
• 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 carboxymethylcellulose 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 delivering the
• 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 0.12 mg 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, 0.08 mg of butylated hydroxytoluene, 0.98 mg of red ferric oxide, and 0.24 mg of magnesium stearate; 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
• 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% hydroxypropyl- methylcellulose 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
• composition comprises 10.6 wt% oxybutynin
• compositions comprises 16 wt% oxybutynin is hydrochloride, 76.67 wt% polyethylene oxide of 200,000 weight-average
• a hydrogel composition was prepared according to the above
• composition comprises 58.75 wt% hydroxyethyl-
• 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% hydroxyethyl- cellulose 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
• 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% hydroxypropylmethylcellulose 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 from 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 23
• a sustained-release dosage form manufactured as a tablet designed ⁇ for oral administration comprising 240 ng to 650 mg of a member selected
• the invention pertains additionally to the use of the therapeutic substance
• composition and the dosage form by providing a method for delivering
• the method comprises administering orally the
• composition to a patient for oxybutynin therapy.
• the method comprises: (A)
• ⁇ develops osmotic energy that causes the therapeutic composition to be
• the method of the invention comprises also: (A) admitting into the
• a dosage form comprising: (1) a wall surrounding a
• the wall comprising a semipermeable polymeric composition
• oxybutynin comprising oxybutynin; (3) a hydrogel push layer in the compartment ⁇ o comprising an osmotic formulation for imbibing and absorbing fluid for ⁇ expanding in size for pushing the oxybutynin composition from the delivery
• the oxybutynin is administered by
• the oxybutynin is
• voiding such as urgency, urge incontinence, frequency, nocturia and
• Oxybutynin is used for treating urinary-
• the present invention provides a sustained-release (SR) dosage form that provides a controlled-release (CR) rate of oral administration of oxybutynin designed to provide a continuous plasma drug concentration and avoid peak and valley concentrations. 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.
• SR sustained-release
• CR controlled-release
• the patients blood was sampled on days 1 and 4 to quantify oxybutynin and its desethyl-metabolite (DESOXY) by liquid chromatography mass spectroscopy (LC/MS).
• the oxybutynin was absorbed rapidly following immediate-release (IR) dosing with mean C MAX of 12 ng/ml.
• C MAX is the maximum concentration after dosing in the plasma.
• the drug release kinetics for the controlled-release (CR) plasma concentration rose slowly, reaching a mean peak-concentration C MAX value of 4.2-6.7 ng/ml.
• the metabolite DESOXY was formed rapidly following immediate release, and its formation paralleled the slow absorption of oxybutynin following controlled release.
• the DESOXY had a shorter t 1/2 life compared to OXY, indicating presystemic metabolite formation assuming it to be true metabolite t 1/2 .
• 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.
• the day 4 OXY and DESOXY AUC and their ratios are presented in the Table, where 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 MAX denotes the maximum concentration.
• 34 of the female patients were administered the sustained release dosage form of the invention, 32 female patients were administered the immediate release dosage form, and 16 were administered placebo.
• the dosing program for the sustained release dosage form comprised of 5 mg/day for 2 weeks, then 10 mg/day for two weeks, and finally 15 mg/day for two weeks, administered once a day.
• the dosing program for the immediate release dosage form comprised of 5 mg/day for 2 weeks, then 10 mg/day for two weeks, and finally 15 mg/day for two weeks, administered in divided doses three times a day.
• decrease in urge urinary incontinence and anticholinergic side effect observations were made for each dose level.
• the mean plasma oxybutynin concentration was maintained flat during a 24 hour period for the sustained release dosage form administered once a day; at steady state (after dosing for 4 days) the mean plasma oxybutynin concentration ranged from 3.2 to 5.5 ng/ml following a 15 mg dose.
• plasma oxybutynin concentration following the immediate release administered three times a day showed peak-through fluctuation; at steady state (after dosing for 4 days) the mean peak plasma concentration following 5 mg three times a day was 12.4 ng/ml and the trough concentration was 1.4 ng/ml.
• the concentrations at other dose levels are proportional to dose.
• the clinical study evaluated the number of urge urinary incontinence at each week. The number of urge urinary incontinence episodes was documented by the patients in weekly study-diaries provided to them. The decrease in urge urinary incontinence episodes from baseline was evaluated for the sustained release dosage form and the immediate release dosage form compared to the placebo and were also compared to each other.
• a therapeutic index was obtained for the clinical study by combining the dose delivered versus the urge urinary incontinence relationship and the dose versus dry mouth relationship.
• Accompanying Figure 4 is a representation of the therapeutic index comparison between the sustained release, SR, dosage form and the immediate release dosage form, evidencing the decrease in urge-urinary incontinence episodes from the baseline and the probability of dry mouth.
• U-UI denotes urge-urinary incontinence
• DM denotes dry mouth
• SR denotes sustained release
• IR denotes immediate release.
• the broad-double pointed arrow denotes the unexpected decrease in dry mouth achieved by the sustained release dosage form compared to the very small decrease in dry mouth seen in the narrow-double pointed arrow.
• the therapeutic index is defined as the dose or concentration range within which optimum therapy with minimum toxicity i.e. successful therapy is achieved. It can be evaluated as the relative position of the dose vs. efficacy (urge urinary incontinence in this case) and dose vs. toxicity (dry mouth in this case) curve. It is also recognized that a drug with wider therapeutic index is better than a drug with a narrow index. 29
• Figure 1 shows the urge urinary incontinence in logarithmic scale for all treatments - the line with the star represents a placebo treatment, the line connected by square represents urge urinary incontinence obtained for an immediate release dosage form, and the line connected with dark circles depicts urge urinary incontinence obtained by the sustained release dosage form of the invention.
• U-UI means urge urinary incontinence
• visit day denotes the days the patient visited the clinic and the dose level denotes the mg of oxybutynin delivered by the dosage form on that day
• SR refers to sustained release dosage form
• IR refers to immediate release dosage form.
• Figure 3 depicts the incidence of dry mouth following the administration of placebo, sustained release oxybutynin dosage forms and immediate release oxybutynin dosage forms.
• SR refers to sustained release dosage form
• IR refers to immediate release dosage form
• clean area denotes the probability of absence of dry mouth relief
• lines slanted left denote the probability of mild dry mouth
• crossed lines denotes the probability 30
• FIG 4 is a representation of the therapeutic index comparison between the sustained release dosage form and the immediate release oxybutynin dosage form.
• the therapeutic index is the dose or concentration range within which optimum therapy with minimum toxicity i.e. successful therapy is achieved. It can be evaluated as the relative position of the dose vs. efficacy (urge urinary incontinence in this case) and dose vs. toxicity (dry mouth in this case) curve. Both the dose vs. urge urinary incontinence curve and the dose vs. dry mouth curve is presented in Figure 4.
• the broad continuous dark line presents the dose vs. urge urinary incontinence relationship for sustained release dosage form and the narrow continuous line presents the dose vs.
• the broken dark line represents the occurrence of dry mouth for the sustained release dosage form and the broken narrow line represents the occurrence of dry mouth for the immediate release dosage form.
• the heavy longer dark double pointed arrow depicts the unexpected greater separation for the dose vs. urge urinary incontinence curve and the dose vs. dry mouth curve for the sustained release dosage form compared to the small double pointed arrow for the immediate release dosage form. This teaches that the therapeutic index is wider for the sustained release dosage form as compared to immediate release dosage form.
• the once-daily delivery system provided by this invention maintains an essentially flat concentration throughout the dosing duration of 24 hours, as seen by the absence of peak-to-trough fluctuation, whereas peak-to-trough fluctuation are seen with the multiple daily administration of the immediate release dosage form, as depicted in accompanying Figure 5.
• Figure 5 depicts the mean plasma oxybutynin concentration, in ng/mL, steady state on day 4, for an immediate release, IR, dosage form and a sustained release, SR, dosage form. 31
• the delivery system provided by this invention maintains its chemical and physical integrity in a gastrointestinal environment and generally reaches the colo within 3 to 5 hours after oral administration.
• metabolic activity is higher in the duodendum and jejunum and decreases in the ileum and colon and for some drugs other anti-transport are more prevalent in the colon.
• the physiological disposition of a drug and its metabolites can depend on the gastrointestinal site of absorption.
• the clinical studies made available by this invention demonstrated unexpectedly a decrease in oxybutynin metabolism when administered by the sustained release dosage form of the invention.
• the relative bioavailability is higher for the drug, combined R+S (racemic) oxybutynin (153%) and also for the individual R- and S- enantiomers of oxybutynin (156% and 187%, respectively) compared to immediate release dosage form (base of 100%); the relative bioavailability is lower for the metabolite, combined R+S (racemic) desethyloxybutynin (69%) and also for the individual R- and S- enantiomers of desethyloxybutynin (73% and 92%, respectively) compared to immediate release dosage form (base of 100%).
• the plasma concentration curves are shown in Figure 5 for both sustained release dosage form and the immediate release dosage form.
• the ratio, (drug AUC, nf / metabolite AUC ⁇ nf ) for the sustained release dosage form was more than twice that for the immediate release.
• the plasma concentration for the sustained release dosage form of the invention administered in the fasting state is similar to that observed when taken after a meal as seen in drawing Figure 6.
• Drawing Figure 6 illustrates the mean observed plasma R-oxybutynin concentration following the sustained delivery of oxybutynin hydrochloride by the dosage form tablet of the invention 1 X 10 mg qd, wherein qd denotes once-a-day dose, in the fed and fasting states with 43 patients.
• the data shows food does not affect the manner in which the drug is absorbed from the sustained release dosage form of the invention.
• the relative oxybutynin bioavailability for the product is similar (approximately 103%) to that of the immediate release product (base 100%) and the relative bioavailability of the metabolite desethyloxybutynin is lower (approximately 68%) as compared to immediate release product (base 100%).
• the ratio, (drug AUC / metabolite AUC) for the product was only slightly higher (0.13) as compared to IR oxybutynin (0.09). Additionally, when the prior art product is 33
• the prior art delivery product loses the sustained release property when taken with meals.
• the sustained release dosage form of the invention was further evaluated in safety and efficacy studies and compared to immediate release. The data from this study was modeled and a dose vs. therapeutic effect (urge urinary incontinence) relationship and a dose vs. side effect (dry mouth) relationship was established.
• the results of the urge urinary incontinence modeling analysis shows a trend towards higher decrease in the urge urinary incontinence episodes for the sustained release dosage form compared to immediate release dosage form.
• the dry mouth modeling analysis shows that the probability of dry mouth is higher for the immediate release as compared to the sustained release dosage form of this invention.
• a therapeutic index was obtained for the clinical study by combining the dose versus the urge urinary incontinence relationship and the dose versus dry mouth relationship.
• the therapeutic index is defined as the dose or concentration range within which optimum therapy with minimum toxicity i.e. successful therapy is achieved. It can be evaluated as the relative position of the dose vs. efficacy (urge urinary incontinence in this case) and dose vs. toxicity (dry mouth in this case) curve.
• the sustained release dosage form of this invention was shown to have an increased therapeutic index (wider separation between the dose vs. urge urinary incontinence curve and dose vs. dry mouth curve) as compared to the immediate release dosage form, as seen in Figure 4.
• a SR was administered in doses up to and comprising 30 mg/day which was efficacious in reducing urge urinary incontinence and was well-tolerated with respect to anticholinergic side-effects and especially dry mouth. 34
• the dosage form and the oxybutynin composition of this invention can be used in a method for administering a ⁇ drug by the oral route, and, in another method, the dosage form and
• composition can be sized and shaped for administering a drug by the
• sublingual and buccal routes are 13 sublingual and buccal routes.
• the sublingual and buccal routes can be used

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• 1999
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