Therapeutic dosage form for delivering oxybutynin

A dosage form, a therapeutic composition, and the use thereof is disclosed for administering a therapeutic agent accompanied by a pharmaceutically acceptable means administered for an indicated therapy.

EXAMPLES PROVIDED BY THE INVENTION The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art in the light of the present disclosure and the accompanying claims. 
 Example 1 A therapeutic composition comprising oxybutynin hydrochloride provided by the invention is prepared as follows: first, 103 grams of oxybutynin hydrochloride is dissolved in 1200 ml (milliliters) of anhydrous ethanol. Separately, 2,280 g of polyethylene of 200,000 weight-average molecular weight, 150 g of hydroxypropylmethylcellulose of 9,200 average-number molecular weight and 450 g of sodium chloride are dry blended in a conventional blender for 10 minutes to yield a homogenous blend. Next, the oxybutynin ethanol solution is added slowly to the blend, with the blender continuously blending until all the ingredients are added to the three component dry blend, with the blending continued for another 8 to 10 minutes. The blended wet composition is passed through a 16 mesh screen and dried overnight at a room temperature of 72° F. (22.2° C.). Then, the dry granules are passed through a 20 mesh screen 18 g of magnesium stearate is added, and all the ingredients 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 % 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 therapeutic composition for its intended oxybutynin therapy. The oxybutynin exhibits antispasmodic activity and it can be used for the management of bladder instability associated with incontinence, often referred to as overactive bladder. 
 Example 2 A therapeutic composition comprising oxybutynin is prepared according to Example 1, wherein the therapeutic composition comprises 3.4 wt % oxybutynin hydrochloride, 75 wt % polyethylene oxide of 200,000 weight-average molecular weight, 1 wt % polyoxyethylene sorbitan mono-oleate comprising 20 moles of ethylene oxide, 5 wt % hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 15 wt % sodium chloride, and 0.6 wt % magnesium stearate, for administering oxybutynin over twenty four hours for the nonsurgical treatment of urge incontinence in a patient in need of therapy. 
 Example 3 A therapeutic composition for the extended and controlled delivery of oxybutynin is prepared by following the procedure of Example 1. The therapeutic comprises 3.4 wt % of oxybutynin or 3.4 wt % oxybutynin pharmaceutically acceptable salt, a pharmaceutically acceptable carrier comprising 75 wt % polyethylene oxide of 100,000 weight-average molecular weight, 1 wt % polyoxyethylene sorbitan monolaurate comprising 20 moles of ethylene oxide, 5 wt % hydroxypropylethylcellulose of 11,200 average-number molecular weight, 15 wt % sodium citrate, and 0.6 wt % magnesium oleate. The therapeutic composition provides a sustained-release dose profile for treating urge incontinence in a patient. 
 Example 4 A sustained-release dosage form is provided by the invention as follows: first, a push-displacement composition is prepared comprising 1274 g of polyethylene oxide of 7,500,000 weight-average molecular weight, 600 g of sodium chloride, and 20 g of ferric oxide are separately screened through a 40 mesh screen. Then, all the ingredients are 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 is added slowly to the blend with continuous mixing for 5 minutes. Then, 1.6 g of butylated hydroxytoluene is added, followed by more blending, with 5 g of magnesium stearate added with 5 minutes of blending, to yield a homogenous blend. The freshly prepared granulation is passed through a 20 mesh screen and allowed to dry for 20 hours at 22.2° C. The push-displacement produced comprises 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 of magnesium stearate. 
 Example 5 A medical device with a sustained-release profile is prepared as follows: first, 147 mg of the oxybutynin composition of Example 2 is added to a punch die set and tamped. Then, 98 mg of the push-displacement composition of Example 3 is added and the two layers compressed under a pressure head of 1.0 ton (907.18 kg) into a {fraction (11/32)} inch (0.873 cm) diameter, contacting intimate bilayer matrix. Next, the bilayered matrix is converted into a medical device as follows: first, a semipermeable wall-forming composition is prepared comprising 95 wt % cellulose acetate having a 39.8% acetyl content and 5 wt % polyethylene glycol having a number-average molecular weight of 3,350 by dissolving the ingredients in a cosolvent comprising acetone and water in 90:10, wt:wt, composition to make 4% solid solution. The wall-forming composition is sprayed onto and around the bilayered matrix. Next, the semipermeable walled, bilayered matrix is drilled to provide a 20 mil (0.51 mm) orifice to contact the oxybutynin. The residual solvent is removed by drying for 48 hours at 50° C. and 50% relative humidity. Next, the medical devices are dried further for 1 hour at 50° C. to remove excess moisture. The medical device provided by this example comprises a therapeutic composition comprising 3.4 wt % to 75 wt % polyethylene oxide of 200,000 weight-average molecular weight, 1 wt % polyoxyethylene sorbitan monooleate containing 20 moles of ethylene oxide, 5 wt % hydroxypropylmethylcellulose of 9,200 average-number molecular weight, 0.6 wt % magnesium stearate, and 15 wt % sodium chloride. A push-displacement composition comprising 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 3,350 number-average molecular weight. The medical device comprises an exit passageway of 20 mils (0.50 mm). The medical device had a start-up delivery time of 1.57 hours and delivered 91.6% of oxybutynin. A medical device lacking the nonionic surfactant exhibited a start-up time of 1.86 hours and delivered 89.8% of its drug. The medical device provided by the invention comprising the surfactant unexpectedly had an earlier start-up time by decreasing the start-up time 0.29 hours for providing earlier therapy, and the same medical device oxybutynin an additional 1.8 hours the equivalent to 0.47 mg more oxybutynin therapy. 
 Example 6 A dosage form is provided by following the above examples, wherein the therapeutic composition comprises: (a) 5 mg of oxybutynin hydrochloride, 111.6 mg of polyethylene oxide, 7.35 mg of hydroxypropylmethylcellulose, 1.2 mg of polyoxyethylene sorbitan monolaurate with 20 mol of ethylene oxide, 0.88 mg of magnesium stearate, 22.05 mg of sodium chloride, and 0.12 mg of butylated hydroxytoluene; a wall that surrounds the therapeutic composition permeable to fluid and impermeable to oxybutynin, and an exit in the wall for delivering the oxybutynin. 
 Example 7 A medical device manufactured as an oral dosage form is provided according to the present disclosure, wherein the therapeutic composition comprises 10 mg of oxybutynin hydrochloride, 74.8 mg of polyethylene oxide, 1.88 mg of hydroxypropylmethylcellulose, 1.5 mg of polyoxyethylene sorbitan monostearate with 20 mol of ethylene oxide, 0.24 mg of magnesium stearate, 7.05 mg of sodium chloride, and 0.07 mg of butylated hydroxytoluene; a semipermeable wall that surrounds the internal composition said semipermeable wall permeable to fluid flux and impermeable to oxybutynin flux; and a passageway in the wall for delivering the oxybutynin to a patient with acute urinary incontinence, or chronic urinary incontinence. 
 Example 8 A medical device designed, shaped and adapted as an oral dosage form tablet is prepared according to the mode and the manner of the invention, wherein the medical device comprises a therapeutic drug core comprising 15 mg of oxybutynin hydrochloride, 72.07 mg of polyethylene oxide, 1.88 mg of hydroxypropylmethylcellulose, 1.75 mg of polyoxyethylene oxide sorbitan mono-oleate with 20 moles of ethylene oxide, 0.23 mg of magnesium stearate, 4.7 mg of sodium chloride, and 0.08 mg of butylated hydroxytoluene; a semipermeable wall that surrounds the drug core for comprising an exit for administering the oxybutynin for treating urge incontinence in a patient. 
 Example 9 Medical devices sized, shaped and adapted as an oral dosage form are manufactured according to the invention to provide the following: (1) a therapeutic composition comprising 5.3 wt % oxybutynin, 82.37 wt % polyethylene of 200,000 molecular weight, 2 wt % hydroxypropylmethylcellulose of 9,200 molecular weight, 1 wt % polyoxyethylene sorbitan monooleate with 20 mols of ethylene oxide, 0.25 wt % magnesium stearate, 9 wt % sodium chloride, and 0.08 wt % butylated hydroxytoluene; (2) a therapeutic composition comprising 10.6 wt % oxybutynin hydrochloride, 78.57 wt % polyethylene oxide of 200,000 molecular weight, 1 wt % polyoxyethylene sorbitan mono-oleate with 20 mols of ethylene oxide, 2 wt % hydroxypropylmethylcellulose of 9,200 molecular weight, 0.25 wt % magnesium stearate, 7.5 wt % sodium chloride, and 0.08 wt % butylated hydroxytoluene; and, (3) a therapeutic composition comprising 16 wt % oxybutynin hydrochloride, 76.67 wt % polyethylene oxide of 200,000 molecular weight, 1 wt % hydroxypropylmethylcellulose of 9,200 molecular weight, 1 wt % polyoxyethylene sorbitan mono-oleate with 20 mols of ethylene oxide, 0.25 wt % magnesium stearate, 5 wt % sodium chloride, and 0.08 wt % butylated hydroxytoluene; which therapeutic compositions (1), (2), and (3) independently are in laminated arrangement with (4) a push-displacement composition comprising 63.37 wt % of polyethylene oxide of 2,000,000 molecular weight, 30 wt % sodium chloride, 5 wt % hydroxypropylmethylcellulose of 9,200 molecular weight, 0.08 wt % butylated hydroxytoluene, 1 wt % black ferric oxide, and 0.25 wt % magnesium stearate; a wall surrounds the combinations of (1) (4), (2) (4), and (3) (4), said wall comprising 99 wt % cellulose acetate comprising a 39.8% acetyl content and 1 wt % polyethylene glycol of 3,350 molecular weight; and an exit passageway in the wall for providing dosage form with a start-up time of 1½ hours or less and a delivery dose of 91% or greater for treating incontinence in a patient in need of oxybutynin therapy. 
 Examples 10 and 11 A dosage form for the oral administration of oxybutynin chloride is prepared comprising a drug composition consisting of 5 wt % oxybutynin chloride, 5 wt % osmotic salt, 88 wt % polyoxyethylene oxide possessing a 200,000 molecular weight, and 2 wt % binder. The dosage form exhibited a start-up time of 1.6 hours, and it delivered 88.5% of the oxybutynin chloride at a 67% zero order rate. A dosage form for the oral administration of oxybutynin chloride is prepared comprising 5 wt % oxybutynin chloride, 2.5 wt % polyoxyethylene-20-sorbitan monooleate, 10 wt % osmotic salt, 80.5 wt % polyoxyethylene oxide possessing a 200,000 molecular weight and 2 wt % binder. The dosage form exhibited a 1.6 hour start-up time, and it delivered 91.6% of the oxybutynin hydrochloride at 73% zero order rate. 
 METHOD OF USING THE INVENTION The invention pertains additionally to the use of the therapeutic composition and the use of the dosage form by providing a method for delivering oxybutynin orally to a warm-blooded animal, including a human patient, in need of oxybutynin therapy. The method comprises administering orally the therapeutic composition to a patient for oxybutynin therapy. The method also comprises: (A) admitting orally into the patient a dosage form comprising (B) a semipermeable wall that surrounds (C) a therapeutic composition comprising (C) 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 to provide sustained and controlled oxybutynin therapy. The method of the invention comprises also: (A) admitting orally into a warm-blooded animal a dosage form comprising: (B) 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; (C) a therapeutic composition comprising oxybutynin in the compartment (E) a hydrogel push-displacement composition in the compartment comprising an osmotic formulation for imbibing and absorbing fluid for expanding in size for pushing the therapeutic oxybutynin composition from the dosage form; and (D) at least one passageway in the wall for releasing the oxybutynin; (F) 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-displacement composition to expand; and (G) delivering the therapeutically active oxybutynin from the delivery device through the exit passageway to a warm-blooded animal over a prolonged period of time up to 24 hours. The oxybutynin is administered by the method of the invention in the therapeutic range that avoids a toxic dose and avoids an ineffective dose for antispasmodic therapy. The oxybutynin is administered to patients with uninhibited neurogenic and reflex neurogenic bladder for increased vesual 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. The therapeutic compositions and the dosage forms of this invention can be used in methods for administering oxybutynin by the oral route into the gastrointestinal tract, and for delivering oxybutynin through the sublingual and buccal routes. The sublingual and buccal routes can be used for administering a smaller dose for immediate therapy, and as a by-pass of the first pass of hepatic metabolism of oxybutynin. In summary, it will be appreciated that 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. While the invention has been described and pointed out in detail with reference to operative embodiments thereof, it will be understood by those skilled in the art that various changes, modifications, substitutions and omissions can be made without departing from the spirit of the invention. It is intended, therefore, that the invention embrace those equivalents within the scope of the claims which follow.