Method for treating overactive bladders and a device for storage and administration of topical oxybutynin compositions

Abstract

The invention relates to a method for treating overactive bladders and a device for storing and administering non-occluded oxybutynin topical compositions.

Claims

1. A packaging system consisting of: a) 0.25 g to 5 g of a non-occluded oxybutynin topical composition comprising: i) 2 wt % to 20 wt % of the topical composition of oxybutynin; ii) 0.05 wt % to 10 wt % of the topical composition of a thickening agent; iii) 60 wt % or more of the topical composition of an alcohol selected from the group consisting of methanol, ethanol, isopropyl alcohol, benzyl alcohol, propanol and mixtures thereof; and iv) 5.9 wt % or more of the topical composition of water; b) a reservoir for the non-occluded oxybutynin topical composition; and c) a laminate surrounding the reservoir and non-occluded oxybutynin topical composition comprising: i) a first polymer layer that is in direct contact with the non-occluded oxybutynin topical composition, wherein the first polymer layer is a polyethylene polymer or copolymer or acrylic based polymer or copolymer; and ii) a metal foil bound to the first polymer layer; and d) optionally a notch or partial scoring of the laminate surrounding the reservoir and non-occluded oxybutynin topical composition wherein the notch or partial scoring allows a user to open the packaging system and dispense the non-occluded oxybutynin topical composition from the packaging system; and wherein the packaging system can withstand 30 pounds of pressure without bursting when squeezed between two platens of a motorized test stand and when the packaging system is stored at 25 C. and 60% relative humidity for twenty-six weeks the non-occluded oxybutynin topical composition contains not more than 0.2% of phenylcyclohexyl glycolic acid ethyl ester (PCGE); not more than 2.0% phenylcyclohexylglycolic acid (PCGA) and there is not more than a 20% change in the alcohol content.

2. The packaging system of claim 1 wherein the notch or partial scoring of the laminate surrounding the reservoir and non-occluded oxybutynin topical composition is not optional.

3. The packaging system of claim 1 wherein the laminate further comprises an adhesive layer between the first polymer layer and the metal foil for bonding the metal foil to the first polymer layer.

4. The packaging system of claim 1 wherein the laminate further comprises an additional layer for embossing or printing descriptive information.

5. The packaging system of claim 1 wherein the metal foil is aluminum foil with a thickness of 0.2 mil to 0.5 mil.

6. The packaging system of claim 1 wherein the first polymer layer is a polyethylene polymer selected from the group consisting of low density polyethylene and linear low density polyethylene, with a thickness of 0.5 mil to 2.5 mil.

7. The packaging system of claim 3 wherein the adhesive layer comprises a urethane or ethylene/acrylic acid copolymer with a thickness of 0.3 mil to 0.75 mil.

8. The packaging system of claim 1 wherein the non-occluded oxybutynin topical composition is a gel, cream or lotion.

9. The packaging system of claim 8 wherein the non-occluded oxybutynin topical composition is a gel.

10. The packaging system of claim 1 that can withstand 50 pounds of pressure without bursting.

11. The packaging system of claim 1 wherein after storage at 40 C. and 75% relative humidity for thirteen weeks, the non-occluded oxybutynin topical composition contains not more than 0.15% of PCGE; not more than 1.0% of PCGA and there is not more than a 15% change in the alcohol content.

12. The packaging system of claim 11 wherein after storage at 40 C. and 75% relative humidity for thirteen weeks, the non-occluded oxybutynin topical composition contains not more than 0.10% of PCGE; not more than 0.50% of PCGA and there is not more than a 10% change in the alcohol content.

13. The packaging system of claim 1 wherein after storage at 40 C. and 75% relative humidity for twenty-six weeks, the non-occluded oxybutynin topical composition contains not more than 0.17% of PCGE; not more than 1.7% of PCGA and there is not more than a 15% change in the alcohol content.

14. The packaging system of claim 13 wherein after storage at 40 C. and 75% relative humidity for twenty-six weeks, the non-occluded oxybutynin topical composition contains not more than 0.15% of PCGE; not more than 1.0% of PCGA and there is not more than a 10% change in the alcohol content.

15. The packaging system of claim 1 wherein the non-occluded oxybutynin topical composition has a pH of 4.5 to 9.

16. A method for treating human patients suffering from overactive bladder comprising the steps of: a) providing a packaging system as defined in claim 1 to a human; b) dispensing a single or daily dose of the oxybutynin composition from the system; and c) applying the single or daily dose of the oxybutynin composition to a skin surface of the human patient.

17. The method of claim 16 wherein the skin surface is selected from the group consisting of abdomen skin surface, thigh skin surface, arm skin surface and combinations thereof.

18. The packaging system of claim 1 wherein the non-occluded oxybutynin topical composition comprises: i) 2 wt % to 20 wt % of the topical composition of oxybutynin; ii) 0.1 wt % to 5 wt % of the topical composition of the thickening agent; iii) 65 wt % or more of the topical composition of the alcohol selected from the group consisting of methanol, ethanol, isopropyl alcohol, benzyl alcohol, propanol, and mixtures thereof; and iv) 5.9 wt % to 18 wt % of the topical composition of water.

19. The packaging system of claim 1 wherein the first polymer layer is an acrylonitrile-methyl acrylate copolymer with a thickness of 0.5 mil to 2.5 mil.

20. A packaging system consisting of: a) 0.25 g to 5 g of a non-occluded oxybutynin topical gel, cream or lotion comprising: i) 2 wt % to 20 wt % of the topical gel, cream or lotion of oxybutynin; ii) 0.05 wt % to 10 wt % of the topical gel, cream or lotion of a thickening agent; iii) 65 wt % or more of the topical gel, cream or lotion of an alcohol selected from the group consisting of methanol, ethanol, isopropyl alcohol, benzyl alcohol, propanol and mixtures thereof; and iv) 5.9 wt % to 18 wt % of the topical gel, cream or lotion of water; b) a reservoir for the non-occluded oxybutynin topical gel, cream or lotion; and c) a laminate surrounding the reservoir and non-occluded oxybutynin topical gel, cream or lotion comprising: i) a first polymer layer that is in direct contact with the non-occluded oxybutynin topical gel, cream or lotion, wherein the first polymer layer is a linear low density polyethylene or an acrylonitrile-methyl acrylate copolymer, with a thickness of 0.5 mil to 2.5 mil; ii) a metal foil with a thickness of 0.2 mil to 0.5 mil bound to the first polymer layer; and iii) optionally an additional layer for embossing or printing descriptive information; and d) optionally a notch or partial scoring of the laminate surrounding the reservoir and non-occluded oxybutynin topical gel, cream or lotion wherein the notch or partial scoring allows a user to open the packaging system and dispense the non-occluded oxybutynin topical gel, cream or lotion from the packaging system; and wherein the packaging system can withstand 30 pounds of pressure without bursting when squeezed between two platens of a motorized test stand and when the packaging system is stored at 25 C. and 60% relative humidity for twenty-six weeks the non-occluded oxybutynin topical gel, cream or lotion contains not more than 0.2% of phenylcyclohexyl glycolic acid ethyl ester (PCGE); not more than 2.0% phenylcyclohexylglycolic acid (PCGA) and there is not more than a 20% change in the alcohol content.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a top planar view of one embodiment of the present invention.

(2) FIG. 2 is cross sectional view of the embodiment of the present shown in FIG. 1 taken along line 2-2 of FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

(3) As used herein, the terms device and container are used interchangeably and are broadly defined to refer to any flexible packaging system such as a sachet or pouch that is designed to hold, store and transport an accurate and reproducible amount of a non-occluded oxybutynin topical composition. In one embodiment of the present invention, the device or container should contain an amount of a non-occluded topical oxybutynin composition that will provide a single daily therapeutic dose or a multiple therapeutic dose of oxybutynin. For example, in one embodiment of the present invention the device or container may contain 0.25 g to about 5 grams of a non-occluded topical oxybutynin gel wherein about 3% to about 15% based upon the total weight of the gel is oxybutynin.

(4) As used herein, the term oxybutynin refers to oxybutynin in its free base form as well as pharmaceutically acceptable salts thereof. It also includes racemic mixtures or purified isomeric forms of the free base and pharmaceutically acceptable salts thereof.

(5) The term topical means a composition suitable for direct application to a skin surface and from which a therapeutically effective amount of the oxybutynin is released for transdermal administration to a patient in need of oxybutynin therapy. Examples of topical compositions include, but are not limited to, gels, lotions and creams.

(6) The term non-occluded as used herein refers to a composition applied to the skin without the use of a supporting structure. In other words, a non-occluded topical composition is directly applied to the skin in a free form, which is sufficient to effect transdermal delivery of oxybutynin without the use of a support structure such as a backing member typically used for transdermal patches.

(7) Referring to FIGS. 1 and 2, the device 1, in accordance with the present invention, comprises a laminate that is processed to form a reservoir 3 for the non-occluded oxybutynin composition 5. The reservoir 3 may be prepared by joining or sealing two sheets of opposing laminate material along all its edges 4 or from a single sheet of the laminate that has been folded into an opposing structure and sealed along its edges 4. The device 1 may be in any design, shape or form, irregular or uniform. Uniform shapes such as squares, rectangles, circles and ovals are preferred in order to facilitate the sealing and manufacturing processes. The dimensions of the device 1 will be designed so the reservoir 3 can easily accommodate the desired amount of the non-occluded oxybutynin composition 5.

(8) As shown in FIG. 1, the reservoir 3 may be formed with a narrowed or conical region to allow the dispensing of the non-occluded oxybutynin composition 5 from the device is a uniform, narrow and consolidated stream. The device 1 may also contain one or more notches 20 that will allow the user to open the device 1 and dispense the non-occluded oxybutynin composition 5 from the device 1 for application to a patient's skin. The notch 20 may be a horizontal or angular slit formed into one or more of the edges of the device. The notch 20 may also be formed by removing a portion of the laminate along the sealed edges.

(9) The sealing of the edges of the device 1 can be accomplished by heat, ultrasound, laser, or adhesive and the like. One embodiment of the present invention employs a self-sealing mechanism (i.e., able to form a stable bond between two facing surfaces of the same material without the use of an adhesive). An example of an acceptable self-sealing mechanism is heat sealing. The seal may be a destructive seal which means the seal should form a bond whose strength equals or exceeds the bond strength of the bond joining the layers of the laminated.

(10) The seal strength can be determined by use of a motorized test stand which slowly squeezes the finished device between two platens. An inadequate seal will be evident if the non-occluded oxybutynin composition 5 is forced out of the sealed or finished device 1 at a pressure lower than 20 pounds. An acceptable seal should with stand pressure of at least 20 pounds, preferably at least 30 pounds and most preferably at least 50 pounds without bursting. One embodiment of the present invention is able to withstand 20 to 100 pounds of pressure without bursting, preferably 25 to 80 pounds of pressure without bursting and most preferably 30 to 75 pounds of pressure without bursting. These pressures simulate the effect of pressures experienced during routine handling in packaging and patient use.

(11) The laminate used in preparing the present invention should comprise a first polymer layer 14 that will contact the non-occluded oxybutynin composition and a metal foil layer 10 bonded to the first polymer layer 14. The first polymer layer 14 may be a thermoplastic polymer that does not substantially absorb, react with, or otherwise adversely affect the oxybutynin or other excipients or components used in the non-occluded oxybutynin composition 5. Examples of a thermoplastic material that can be used for the first polymer layer 14 are nitrile rubber modified acrylonitrile-methyl acrylate copolymers. Such materials are disclosed, for example, in U.S. Pat. No. 3,426,102, and are commercially sold under the trademark BAREX. Another thermoplastic polymer that may be used as the first polymer layer is a polyethylene polymer or copolymer. Examples of suitable polyethylene polymers include, but are not limited to, low density polyethylene (LDPE) and linear low density polyethylene (LLDPE).

(12) The thickness of first polymer layer 14 may be about 0.5 mil to about 2.5 mil, more preferably from about 0.75 mil to about 1.5 mil, and even more preferably from about 1.0 mil to about 1.5 mil. While thinner and thicker widths may be employed, the first polymer layer 14 should not be so thin so as to compromise its permeation and stabilizing properties, nor so thick so as to adversely affect its self-sealing and packaging properties.

(13) The first polymer layer 14 is adhered or attached to the metal foil layer 10, such as aluminum foil, by any technique known in the art. Attachment by means of heat fusion or an adhesive layer 12, are preferred. Use of an adhesive layer 12 is preferred in order to achieve greater tear resistance properties which are desirable in creating child resistant/proof packaging.

(14) Suitable adhesives that may be used to adhere or bind the first polymer layer 14 to the metal foil layer 10 include, but are not limited to, urethanes and ethylene/acrylic acid copolymers. Other examples of suitable adhesive materials are described in U.S. Pat. Nos. 4,359,506 and 5,268,209. The adhesive 12 should be selected so it creates a destructive bond between the metal foil layer 10 and the first polymer layer 14. The adhesive may be applied to metal foil and dried to a thickness that should preferably not exceed about 1 mil, and is preferably in a range from about 0.3 mil to about 0.75 mil.

(15) The metal foil layer 10 may be a thickness of about 0.20 mil to about 0.50 mil, preferably about 0.25 mil to about 0.40 mil.

(16) The laminate employed in the present invention may comprise additional layers between the first polymer layer 14 and the metal foil layer 10 and/or on outer or external surface of the metal foil layer 10. The additional layers may provide additional strength and stability to the device 1. One embodiment of the present invention includes an additional external layer such as a paper or polymeric layer that will allow printing or embossing of indicia onto the outer most surface of the device.

(17) Examples of non-occluded oxybutynin composition 5 that may be used in the present invention are described in U.S. Pat. No. 7,179,483, and in particular examples 3-21, which are incorporated herein by reference. Additional examples of non-occluded oxybutynin compositions that may be used in the present invention are described in U.S. Pat. No. 7,425,340.

(18) One embodiment of the present invention is designed for use with a non-occluded oxybutynin gel composition, preferably an oxybutynin chloride gel. The gel comprises oxybutynin or a pharmaceutically acceptable salt thereof, a solvent and a thickening agent.

(19) The oxybutynin is present in the gel in an amount of about 2% to about 20% based upon the total weight of the gel, preferably about 4% to about 15% based upon the total weight of the gel and most preferably about 8% to about 12% based upon the total weight of the gel.

(20) The solvent should comprise at least 50% of the total weight of the gel, preferably at least 60% or more of the total weight of the gel and most preferably at least 70% or more based upon the total weight of the gel. The solvent preferably is an organic solvent or a mixture of water and an organic solvent. The organic solvent should be safe when applied to the human skin and have a relatively low boiling point, i.e., less than 100 C., to allow the quick evaporation when the gel is applied to a patient's skin. Examples of organic solvents that are useful in creating gels for use with the present invention include C1 to C6 hydrocarbons, preferably C1 to C6 alcohols such as methanol, ethanol, isopropyl alcohol, benzyl alcohol, propanol and mixtures thereof. If a water:organic solvent mixture is employed as the solvent for the oxybutynin gel, the ratio of water to organic solvent should range from about 1:2 to about 1:20, preferably about 1:3 to about 1:12 and most preferably about 1:5 to about 1:10.

(21) One embodiment of the present invention employs a non-occluded oxybutynin gel composition that comprises at least 50% of the total weight of the gel of a volatile organic solvent, preferably at least 60% or more of the total weight of the gel of a volatile organic solvent and most preferably at least 65% or more based upon the total weight of the gel of a volatile organic solvent.

(22) The thickening agent may be a compound of high molecular weight which acts to produce a semisolid, viscous solution or suspension-type formulation. The thickening agent may be hydrophobic or hydrophilic and is generally a polymer. Examples of suitable thickening agents for use in the present invention may include synthetic polymers, vinyl polymers, cellulose polymers, natural occurring gelling agents and mixtures of the foregoing. In one embodiment of the present invention, the thickening agent should exhibit a viscosity of about 1,000 cps to 500,000 cps, preferably 5,000 cps to 250 cps and most preferably about 10,000 cps to 100,000 cps when a 2% aqueous solution of the thickening agent is prepared.

(23) Examples of synthetic polymers that may be used as thickening agents include polyacrylic acids or poly(l-carboxyethylene), carboxypolymethylenes prepared from acrylic acid cross-linked with allyl ethers of (polyalkyl) sucrose or pentaerythritol (e.g. CARBOPOL 940/941/980/981/1342/1382 and carbamer polymers such as carbomer 934P/974P), sodium acrylate polymers (e.g. AQUAKEEP J-550/J-400), other polycarboxylic acids and alkyl acrylate polymers (e.g. PEMULEN).

(24) Examples of the vinyl polymers that may be used as thickening agents include carboxyvinyl polymers, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl ether and polyvinyl sulfonates.

(25) Examples of cellulose polymers that may be used as thickening agents include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, hydroxypropylbutyl cellulose, hydroxypropylpentyl cellulose, hydroxyethyl cellulose, ethylcellulose, carboxymethyl cellulose and cellulose acetate.

(26) Examples of natural gelling agents that may be used as thickening agents include, dextran, gaur-gum, tragacanth, xanthan gum, sodium alginate, sodium pectinate, acacia gum, Irish moss, karaya gum, guaiac gum, locust bean gum, etc., while natural high molecular weight compounds include, among others, various proteins such as casein, gelatin, collagen, albumin (e.g. human serum albumin), globulin, fibrin, etc. and various carbohydrates such as cellulose, dextrin, pectin, starches, agar, mannan, and mixtures of the foregoing.

(27) Additional compounds that may be used as thickening agents are polyethylene compounds (e.g. polyethylene glycol, etc.), polysaccharides (e.g., polysucrose, polyglucose, polylactose, etc.) and salts thereof, acrylic acid esters, alkoxybutyninpolymers (e.g., polyoxyethylene-polyoxypropylene copolymers such as the PLURONIC line of BASF, Parsippany, N.J.), polyethylene oxide polymers, polyethers, gelatin succinate, colloidal magnesium aluminum silicate (which may be useful as a gel stabilizer in conjunction with another gelling agent) and petroleum jelly.

(28) The amount of thickening agent employed in a gel for use with the present invention may vary depending on the specific result to be achieved. However, in one aspect, the amount of gelling agent may be from about 0.05% to about 10%, preferably about 0.1% to about 5 wt % and most preferably about 0.1% to about 3 wt % based upon the total weight of the non-occluded oxybutynin composition.

(29) The amount of thickening agent employed in the non-occluded oxybutynin composition should impart a viscosity to the non-occluded oxybutynin composition of about 1,000 cps to about 200,000 cps, preferably about 2,500 cps to about 100,000 cps and most preferably about 5,000 cps to about 75,000 cps.

(30) A non-occluded oxybutynin gel composition useful in the present invention may also optionally comprise up to about 10 wt % of a lipophilic or hydrophobic agent, which may serve as an emollient or anti-irritant. Emollients and anti-irritants suitable for use in the present invention may include lipophilic agents such as, but not limited to, fatty materials such as fatty alcohols of about 12 to 20 carbon atoms, fatty acid esters having about 12 to 20 carbon atoms in the fatty acid moiety, petrolatum, mineral oils, and plant oils such as soybean oil, sesame oil, almond oil, aloe vera gel, glycerol, and allantoin.

(31) A non-occluded oxybutynin gel composition useful in the present invention may also comprise a pH adjusting agent. The pH adjusting agent may help reduce irritation and/or aid in obtaining proper gelling. Examples of some pH adjusting agents that may be used include, but are not limited to, organic amines (e.g., methylamine, ethylamine, di/trialkylamines, alkanolamines, dialkanolamines, triethanolamine), carbonic acid, acetic acid, oxalic acid, citric acid, tartaric acid, succinic acid or phosphoric acid, sodium or potassium salts thereof, hydrochloric acid, sodium hydroxide, ammonium hydroxide, potassium hydroxide and mixtures thereof. The pH of the non-occluded oxybutynin gel composition should be about 4 to about 11, preferably about 4.5 to about 9 and most preferably about 5 to about 7.

(32) The non-occluded oxybutynin gel composition that may be used in the present invention may further comprise conventional processing and aesthetic aids such as chelating agents, surfactants, permeation enhancers, preservatives, anti-microbial agents, antibacterial agents, antioxidants, lubricants and mixtures of any of the foregoing. A more detailed discussion of these conventional processing and aesthetic aids can be found in U.S. Pat. No. 7,179,483 which is incorporated herein by reference.

(33) The device for storing and administering a non-occluded oxybutynin topical composition prepared in accordance with the present invention should prevent the non-occluded oxybutynin topical composition from degrading when stored for at least one year, preferably two years or longer. For example, the device when filled with the non-occluded oxybutynin composition and sealed can be stored for 26 weeks, 52 weeks, 104 weeks or longer without exhibiting any adverse effect on the non-occluded oxybutynin composition such as a substantially loss of solvent, substantial change in pH or degradation of the oxybutynin. After storage the device should also be able to with stand pressure of at least 20 pounds, preferably at least 30 pounds and most preferably at least 50 pounds without bursting.

(34) One embodiment of the present invention will allow the non-occluded oxybutynin topical composition to be stored at 25 C. and 60% relative humidity for twenty-six (26) weeks. After storage for 26 weeks in the sealed device, the non-occluded oxybutynin composition should exhibit the parameters described in TABLE 1.

(35) TABLE-US-00001 TABLE 1 Parameter Preferred More Preferred Most Preferred Oxybutynin 90-110% of 90-110% of 90-110% of Content labeled claim labeled claim labled claim PCGE NMT 0.2% NMT 0.15% NMT 0.1% PCGA NMT 2.0% NMT 1.0% NMT 0.5% Individual NMT 0.2% NMT 0.175% NMT 0.15% Unknown Total Unknown NMT 1.0% NMT 0.75% NMT 0.5% Solvent NMT 20% NMT 15% NMT 10% change change change pH NMT 1 pH NMT 0.75 pH NMT 0.5 pH change change change

(36) NMT is Not More Than

(37) PCGE is Phenylcyclohexyl glycolic acid ethyl ester, also known as ethylphenyl-cyclohexyl glycolate, cyclohexylphenyl-glycolic acid, and cyclohexyl-mandelic acid ethyl ester.

(38) PCGA is USP Oxybutynin Related Compound A, also known as Phenylcyclohexylglycolic acid, cyclohexylmandelic acid, oxybutacide, CHMA.

(39) With respect to the change in solvent, the above TABLE 1 indicates the change in solvent after storage should not vary by more than 20%, 15% or 10% of the initial amount of solvent. This means, if the initial amount of solvent was 100 mg of ethanol, after storage under the appropriate time and conditions, the amount of solvent should not be less than 80 mg, 85 mg or 90 mg respectively. Similarly, with respect to the change in pH, if the initial pH of the non-occluded oxybutynin topical composition is 6, after storage, the pH should be no lower than 5 and no higher than 7 for the NMT 1 pH criteria and should not be lower than 5.5 or higher than 6.5 for the NMT 0.5 pH criteria.

(40) Another embodiment of the present invention will allow the non-occluded oxybutynin topical composition to be stored at 25 C. and 60% relative humidity for fifty-two (52) weeks. After storage for 52 weeks in the sealed device, the non-occluded oxybutynin composition should exhibit the parameters described in TABLE 2.

(41) TABLE-US-00002 TABLE 2 Parameter Preferred More Preferred Most Preferred Oxybutynin 90-110% of 90-110% of 90-110% of Content labeled claim labeled claim labled claim PCGE NMT 0.2% NMT 0.17% NMT 0.15% PCGA NMT 2.0% NMT 1.7% NMT 1.0% Individual NMT 0.2% NMT 0.18% NMT 0.16% Unknown Total Unknown NMT 1.0% NMT 0.80% NMT 0.65% Solvent NMT 20% NMT 15% NMT 10% change change change pH NMT 1 pH NMT 0.75 pH NMT 0.5 pH change change change

(42) A further embodiment of the present invention will allow the non-occluded oxybutynin topical composition to be stored at 25 C. and 60% relative humidity for one hundred four (104) weeks. After storage for 104 weeks in the sealed device, the non-occluded oxybutynin composition should exhibit the parameters described in TABLE 2.

(43) A still further embodiment of the present invention will allow the non-occluded oxybutynin topical composition to be stored at 40 C. and 75% relative humidity for thirteen (13) weeks. After storage for 13 weeks in the sealed device, the non-occluded oxybutynin composition should exhibit the parameters described in TABLE 3.

(44) TABLE-US-00003 TABLE 3 Parameter Preferred More Preferred Most Preferred Oxybutynin 90-110% of 90-110% of 90-110% of Content labeled claim labeled claim labled claim PCGE NMT 0.2% NMT 0.15% NMT 0.1% PCGA NMT 2.0% NMT 1.0% NMT 0.5% Individual NMT 0.2% NMT 0.175% NMT 0.15% Unknown Total Unknown NMT 1.0% NMT 0.75% NMT 0.5% Solvent NMT 20% NMT 15% NMT 10% change change change pH NMT 1 pH NMT 0.75 pH NMT 0.5 pH change change change

(45) An additional embodiment of the present invention will allow the non-occluded oxybutynin topical composition to be stored at 40 C. and 75% relative humidity for twenty-six (26 weeks). After storage for 26 weeks in the sealed device, the non-occluded oxybutynin composition should exhibit the parameters described in TABLE 4.

(46) TABLE-US-00004 TABLE 4 Parameter Preferred More Preferred Most Preferred Oxybutynin 90-110% of 90-110% of 90-110% of Content labeled claim labeled claim labeled claim PCGE NMT 0.2% NMT 0.17% NMT 0.15% PCGA NMT 2.0% NMT 1.7% NMT 1.0% Individual NMT 0.2% NMT 0.18% NMT 0.16% Unknown Total Unknown NMT 1.0% NMT 0.80% NMT 0.65% Solvent NMT 20% NMT 15% NMT 10% change change change pH NMT 1 pH NMT 0.75 pH NMT 0.5 pH change change change

(47) Due to the high solvent content of the non-occluded oxybutynin compositions used in the present invention there is a chance that material from the laminate forming the device may leach from the laminate into the non-occluded oxybutynin composition. This leaching effect is undesirable and should be kept to a minimum or eliminated completely. In order to avoid the unwanted leaching of laminate compounds into the non-occluded oxybutyinin composition, the laminate should be selected so upon storage of the filled and sealed device, the total amount of leachable materials is not more than 1% of the total weight of the non-occluded oxybutynin composition. More importantly, after storage of the filled and sealed device, no individual leachable material should exceed the acceptable daily intake limits established by the United States Food and Drug Administration.

(48) One embodiment of the present invention, such as an LLDPE device, will allow the total leachable concentration in the non-occluded oxybutynin composition after storage in a filled and sealed device for 52 weeks at 25 C. and 60% relative humidity to be not more than 300 ppm, preferably not more than 200 ppm and most preferably not more than 150 ppm.

(49) Another embodiment of the present invention, such as an LLDPE device, will allow the total leachable concentration in the non-occluded oxybutynin composition after storage in a filled and sealed device for 104 weeks at 25 C. and 60% relative humidity to be not more than 300 ppm, preferably not more than 200 ppm and most preferably not more than 150 ppm.

(50) A further embodiment of the present invention, such as a BAREX device, will allow the total leachable concentration in the non-occluded oxybutynin composition after storage in a filled and sealed device for 52 weeks at 25 C. and 60% relative humidity to be not more than 100 ppm, preferably not more than 50 ppm and most preferably not more than 25 ppm.

(51) A still further embodiment of the present invention, such as a BAREX device, will allow the total leachable concentration in the non-occluded oxybutynin composition after storage in a filled and sealed device for 104 weeks at 25 C. and 60% relative humidity to be not more than 100 ppm, preferably not more than 50 ppm and most preferably not more than 25 ppm.

(52) The leachable materials are determined by first conducting an extraction study on samples of the laminate and samples of the first polymer layer of the laminate (14) to identify potential leachable components. Once the potential leachable components are identified, the storage and administration device is filled with an appropriate dose of the non-occluded oxybutynin composition and sealed. The filled and sealed device is stored at 25 C. and 60% relative humidity for the required time period. After storage, the device is opened and the non-occluded oxybutynin composition is analyzed using an appropriate analytical technique such as high performance liquid chromatography (HPLC).

(53) The initial extraction study to determine the potential leachable components maybe conducted by placing a sample of the laminate and/or sample of the first polymer layer in a Soxhlet extraction apparatus or an open bottle along with a suitable solvent such as alcohol, water or alcohol and water mixtures. The solvent is then analyzed by gas chromatography/mass spectroscopy (GCMS); high performance liquid chromatography (HPLC) or liquid chromatography/mass spectroscopy (LCMS) to determine the identity of any potential leachable compound.

(54) The present invention also relates to a method for treating human patients suffering from overactive bladder comprising the steps of: a) providing a storage and administration device comprising a single or daily dose of a non-occluded oxybutynin composition to a human; b) dispensing the single or daily dose of the oxybutynin composition from the storage and administration device; and c) applying the single or daily dose of the oxybutynin composition to the skin of the human patient, such as the abdomen, thighs, arms or combination of the foregoing.

(55) The storage and administration device employed in the above described method may be a pouch or sachet as described previously and is prepared from a laminate material comprising, from inside out, a first polymer layer (14), an adhesive (12) and a metal foil layer (10) wherein the adhesive layer (12) adheres the first polymer layer (14) to the metal foil layer (10).

(56) The non-occluded oxybutynin composition is dispensed from the storage and administration device by opening or unsealing at least a portion of one of the device's sealed edges and applying pressure to an end of the device that is opposite of the opened or unsealed portion to force the contents of the reservoir from the device. Once the non-occluded oxybutynin composition is dispensed from the reservoir of the device, the device should be disposed.

(57) The non-occluded oxybutynin composition 5 employed in the above described method may be a gel, cream or lotion as previously described. One embodiment of the method of the present invention employs an oxybutynin gel that comprises oxybutynin or a pharmaceutically acceptable salt thereof, a solvent and a thickening agent as described previously. The amount of non-occluded oxybutynin composition in the device for the single or daily dose should comprise about 0.25 grams to about 5 grams of which about 3% to about 15% based upon total weight of the composition is oxybutynin.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(58) The following are provided by way of example only and are by no means intended to be limiting.

Example 1 (Oxybutynin 10% Gel)

(59) A non-occluded oxybutynin chloride gel was prepared with the following composition:

(60) TABLE-US-00005 Component % by Weight Grams per dose Oxybutynin chloride 10.0 0.100 Purified Water, USP 10.5 0.105 Alcohol, USP 73.3 0.733 Glycerin, USP 1.0 0.010 Sodium Hydroxide 3.2 0.032 Solution, 2N Hydroxypropyl 2.0 0.020 Cellulose, NF (KLUCEL HF) Total 100 1.0

(61) The above composition was prepared by mixing the alcohol, oxybutynin chloride and glycerin in a jacketed mixer for about 5 minutes. The KLUCEL HF was slowly added while continuing to mix. The water and sodium hydroxide solution are added to obtain a pH of about 6. After all ingredients were added, the mixing continued for 1.5 to 3 hours. The temperature of the mixer was maintained between 15-35 C.

Example 2 (Oxybutynin 4.4% Gel)

(62) A non-occluded oxybutynin chloride gel was prepared according to the procedure described in Example 1 to produce the following composition:

(63) TABLE-US-00006 Component % by Weight Grams per dose Oxybutynin chloride 4.40 0.132 Purified Water, USP 18.0 0.540 Alcohol, USP 73.3 2.199 Glycerin, USP 1.0 0.030 Sodium Hydroxide 1.3 0.039 Solution, 2N Hydroxypropyl 2.0 0.060 Cellulose, NF (KLUCEL HF) Total 100 3.0

Example 3 (Oxybutynin 13.2% Gel)

(64) A non-occluded oxybutynin hydrochloride gel was prepared according to the procedure described in Example 1 to produce the following composition:

(65) TABLE-US-00007 Component % by Weight Grams per dose Oxybutynin chloride 13.2 0.132 Purified Water, USP 5.90 0.059 Alcohol, USP 73.3 0.733 Glycerin, USP 1.0 0.010 Sodium Hydroxide 4.6 0.046 Solution, 2N Hydroxypropyl 2.0 0.020 Cellulose, NF (KLUCEL HF) Total 100 1.0

Example 4

(66) A device in accordance with the present invention was prepared using a BAREX laminate that had the following composition from inside (oxybutynin contact) the device to outside: 1.5 mil BAREX/adhesive/0.35 mil aluminum foil/81b LDPE/white 261b C1S paper. The BAREX resin is an acrylonitrile-methyl acrylate copolymer. The BAREX lamiante was commercially available from Graphic Packaging International, Inc. of Shaumburg, Ill., USA under the designation LC FLEX No. 81920 (formerly S-6037).

(67) A Klockner LA-160 Packager machine was set up using a single roll of the BAREX laminate. The laminate was 12 inches wide and slit into two halves. The two halves were guided together such that the BAREX resin sides of the two halves opposed each other. The two 6 inch webs were then heat sealed together to form three lanes of 3-sided sachets.

(68) The oxybutynin chloride gel of Example 1 was delivered into each sachet using individually-adjustable, precision metering pumps (one for each lane). The pumps were primed by applying nitrogen pressure to the pressure/storage vessel. After priming, each pump delivered approximately 1 gram of the oxybutynin chloride gel of Example 1 to each reservoir of the 3-sided sachets. The final side of each sachet was then heat sealed. The three sachets were then split apart and cut into individual sachets.

(69) The cycle or web speed and sealing temperatures will depend upon the machines and equipment employed. In this Example, a longitudinal heat seal temperature of about 150 C. (145-155 C.), a cross heat seal temperature of about 150 (145-155 C.) and a cycle speed of 30-50 cycles per minute were employed.

(70) The 1 g sachets prepared in this Example were tested using a motorized test stand which slowly squeezed the sachets between two platens. The 1 g sachets received 30 and 50 pounds of pressure without bursting.

(71) The sachets prepared in this Example were also subjected to stability testing at 25 C. and 60% relatively humidity for at least 26 and 52 weeks and 40 C. and 75% relatively humidity for at least 13 and 26 weeks. The samples exhibited a stability that met the preferred, more preferred and most preferred values contained in TABLES 1-4 above.

Example 5

(72) A device in accordance with the present invention was prepared using a BAREX laminate that had the following composition from inside (oxybutynin contact) the device to outside: 1.5 mil BAREX/adhesive/0.35 mil aluminum foil/81b LDPE/white 261b C1S paper. The BAREX resin is an acrylonitrile-methyl acrylate copolymer. The BAREX lamiante was commercially available from Graphic Packaging International, Inc. of Shaumburg, Ill., USA under the designation LC FLEX No. 81920 (formerly S-6037).

(73) 1 gram sachets using the oxybutynin chloride composition of Example 1 were prepared according to the procedure described in Example 4 with a longitudinal heat seal temperature of 165-180 C., a cross heat seal temperature of 165-180 C. and a cycle speed of 50-60 cycles per minute were employed.

(74) The 1 g sachets prepared in this Example were tested using a motorized test stand which slowly squeezed the sachets between two platens. The 1 g sachets received 30 pounds of pressure without bursting.

Example 6

(75) A device in accordance with the present invention was prepared using an LLDPE laminate that had the following composition from inside (oxybutynin contact) the device to outside: LLDPE/EAA (ethylene/acrylic acid copolymer) resin/0.35 mil aluminum foil/white primacor resin blend/water-base extrusion primer/proprietary treat process/polyester. The LLDPE laminate was commercially available from Alcoa Flexible Packaging of Richmond, Va. under the name PHARMA POUCH PP 1312.

(76) 1 gram sachets using the oxybutynin chloride composition of Example 1 were prepared according to the procedure described in Example 4 with a longitudinal heat seal temperature of about 130 C. (125-135 C.), a cross heat seal temperature of about 130 C. (125-135 C.) and a cycle speed of about 23 (20-26) cycles per minute.

(77) The 1 g sachets prepared in this Example were tested using a motorized test stand which slowly squeezed the sachets between two platens. The 1 g sachets received 50 pounds of pressure without bursting.

(78) The sachets prepared in this Example were also subject to stability testing at 25 C. and 60% relatively humidity for at least 26 and 52 weeks and 40 C. and 75% relatively humidity for at least 13 and 26 weeks. The samples exhibited a stability that met the preferred, more preferred and most preferred values contained in TABLES 1-4 above.

Example 7

(79) A device in accordance with the present invention was prepared using an LLDPE laminate that had the following composition from inside (oxybutynin contact) the device to outside: LLDPE/EAA (ethylene/acrylic acid copolymer) resin/0.35 mil aluminum foil/white primacor resin blend/water-base extrusion primer/proprietary treat process/polyester. The LLDPE laminate was commercially available from Alcoa Flexible Packaging of Richmond, Va. under the name PHARMA POUCH PP 1312.

(80) 3 gram sachets using the oxybutynin chloride composition of Example 2 were prepared according to the procedure described in Example 5 except a longitudinal heat seal temperature of about 185 C. (180-190 C.), a cross heat seal temperature of about 185 C. (180-190 C.) and a cycle speed of about 50 (45-55) cycles per minute were employed.

(81) The 3 g sachets prepared in this Example were tested using a motorized test stand which slowly squeezed the sachets between two platens. The 3 g sachets received 100 pounds of pressure without bursting.

Example 8

(82) A device in accordance with the present invention was prepared using an LLDPE laminate that had the following composition from inside (oxybutynin contact) the device to outside: LLDPE/EAA (ethylene/acrylic acid copolymer) resin/0.35 mil aluminum foil/white primacor resin blend/water-base extrusion primer/proprietary treat process/polyester. The LLDPE laminate was commercially available from Alcoa Flexible Packaging of Richmond, Va. under the name PHARMA POUCH 1312.

(83) 1 gram sachets using the oxybutynin chloride composition of Example 3 were prepared according to the procedure described in Example 5 except a longitudinal heat seal temperature of about 155 C. (150-160 C.), a cross heat seal temperature of about 190 C. (185-195 C.) and a cycle speed of about 23 (20-26) cycles per minute were employed.

(84) The 1 g sachets prepared in this Example were tested using a motorized test stand which slowly squeezed the sachets between two platens. The 1 g sachets received 50 pounds of pressure without bursting.

Comparative Example 1

(85) A device not in accordance with the present invention was prepared using a 2 mil LDPE laminate obtained from Tekni-Plex Inc. of Flemington, N.J. The laminate had the following composition from inside (oxybutynin contact) the device to outside: 2 mil LDPE/10.0# ethylene-acrylic acid copolymer/0.00035 mil aluminum foil/10.0#LDPE/26# C1S Paper. All the attempts to create an oxybutynin chloride topical gel sachet resulted in leaking pouches.

Example 9

(86) A leachable study was conducted on a product as described in Example 4. In the first part of the study samples of the BAREX laminate and samples of acrylonitrile-methyl acrylate copolymer were exposed to aggressive Soxhlet and open bottle extractions using four different solvent systems: 1) 190 proof ethanol (HPLC grade); 2) 85% of 190 proof ethanol (HPLC grade) and 15% nanopure deionized water; 3) isopropanol (HPLC grade) and 4) nanopure deionized water. The extracts of the full laminate and acrylonitrile-methylacrylate copolymer were analyzed by GCMS, HPLC and LC/MS. Based upon the extraction testing the following compounds were identified as potential leachable components: Lauryl alcohol; Lauryl acrylate; Nonylphenol; Di-octyl maleate; Di-octyl fumarate; Butyl stearate; and Tris-nonylphenyl phosphate

(87) The extraction study also identified nonylphenyl phosphate as a potential leachable, however, it was later determined that is compound was generated as an artifact of the hydrolytic oxidation of the tris-nonylphenyl phosphate during the analysis.

(88) 1 gram sachets prepared according to the procedure described in Example 4 were stored at 25 C. and 60% relatively humidity for 122 weeks. After storage, the contents of a sachet were transferred to a glass scintillation vial and approximately 2 g of acetonitrile was added to the mixture vortex. Samples were prepared in triplicate and analyzed by GCMS. The GCMS test results indicated the stored gel contained: less than 1 ppm of lauryl alcohol; less than 1 ppm of lauryl acrylate; less than 1 ppm of nonylphenol; less than 1 ppm of di-octyl maleate; less than 1 ppm of di-octyl fumarate; and less than 1 ppm of butyl stearate.

(89) Due to the thermal instability of tris-nonylphenyl phosphate, the vortexed sample was also analyzed by HPLC and found to contain less than 1 ppm of tris-nonylphenyl phosphate.

(90) 1 gram sachets prepared according to the procedure described in Example 4 were stored at 25 C. and 60% relatively humidity for 63 and 65 weeks. After storage, the contents of a sachet were transferred to a glass scintillation vial and approximately 2 g of acetonitrile was added to the mixture vortex. Samples were again prepared in triplicate and analyzed by GCMS. The GCMS test results indicated the stored gel contained: less than 1 ppm of lauryl alcohol; less than 1 ppm of lauryl acrylate; less than 1 ppm of di-octyl maleate; less than 1 ppm of di-octyl fumarate; and less than 1 ppm of butyl stearate.

(91) The GCMS analysis also indicated the gel stored for 63 and 65 weeks contained between less than 1 ppm and 6.46 ppm of nonylphenol. Specifically, the tests on the 63 week sample yielded values of 1.12 ppm, 1.32 ppm and less than 1 ppm for the nonylphenol, and the tests on the 65 week sample yielded values of 6.46 ppm, 4.23 ppm and 4.68 ppm.

(92) The vortexed sample was also analyzed by HPLC and found to contain less than 1 ppm of tris-nonylphenyl phosphate.

Example 10

(93) A leachable study was conducted on a product as described in Example 6. In the first part of the study samples of the PHARMA POUCH PP1312 laminate and samples of the LLDPE polymer were exposed to aggressive Soxhlet and open bottle extractions using four different solvent systems: 1) 190 proof ethanol (HPLC grade); 2) 85% of 190 proof ethanol (HPLC grade) and 15% nanopure deionized water; 3) isopropanol (HPLC grade) and 4) nanopure deionized water. The extracts of the full laminate and LLDPE polymer were analyzed by GCMS, HPLC and LC/MS. Based upon the extraction testing the following compounds were identified as potential leachable components:

(94) Erucamide (Z-docos-13-enamide)(CAS#112-84-5);

(95) tris-2,4-di-tert-butylphenyl phosphate (CAS#6683-19-8) (IGRAFOS 168 phosphate which is an oxidation product of Igrafos 168 known to be used by Alcoa as an antioxidant);

(96) tris-2,4-di-tert-butylphenyl phosphite (CAS#31570-04-4) (IGRAFOS 168); and

(97) Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (CAS#2082-79-3) (IRGANOX 1076 also known to be used by Alcoa as an antioxidant).

(98) 1 gram sachets prepared according to the procedure described in Example 6 were stored at 25 C. and 60% relatively humidity for 121 weeks, 104 weeks and 99 weeks. After storage, the contents of a sachet were transferred to a glass scintillation vial and approximately 2 g of acetonitrile was added to the mixture vortex. Samples were prepared in triplicate and analyzed by HPLC and LCMS and found to contain the following leachables:

(99) TABLE-US-00008 IRGAFOS 168 IRGANOX Sample Erucamide Phosphate 1076 121 weeks 26.0 ppm 102.1 ppm 10.82 ppm 121 weeks 23.1 ppm 60.0 ppm 8.06 ppm 121 weeks 21.1 ppm 104.3 ppm 9.59 ppm 104 weeks 23.2 ppm 109.1 ppm 8.61 ppm 104 weeks 17.1 ppm 102.3 ppm 9.55 ppm 104 weeks 29.1 ppm 121.5 ppm 11.50 ppm 99 weeks 16.3 ppm 100.1 ppm 12.81 ppm 99 weeks 21.3 ppm 85.7 ppm 9.37 ppm 99 weeks 23.6 ppm 95.8 ppm 8.96 ppm average 22.3 ppm 97.9 ppm 9.9 ppm

(100) Although IRGAFOS 168 was reported in the extraction study as a potential leachable only its oxidation product IRGAFOS 168 phosphate was measured due to the poor stability of IRGAFOS 168 in solution and its rapid conversion to IRGAFOS 168 phosphate.

(101) While certain preferred and alternative embodiments of the present invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art. Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof which do not depart from the spirit and scope of the invention.

(102) The term comprising as used in the following claims is an open-ended transitional term that is intended to include additional elements not specifically recited in the claim. The term consisting essentially of as used in the following claims is a partially closed transitional phrase and is intended to include the recited elements plus any unspecified elements that do not materially affect the basic and novel characteristics of the claim. For example, an outermost layer on the disclosed laminates that are embossed or printed with indicia would be included in the meaning of consisting essentially of, even if not specifically recited. The term consists of as used in the following claims is intended to indicate that the claim is restricted to the recited elements.