AU2015264960A1 - Intravaginal Device Comprising Anticholinergic Agents, And Methods Of Making Thereof - Google Patents
Intravaginal Device Comprising Anticholinergic Agents, And Methods Of Making Thereof Download PDFInfo
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- AU2015264960A1 AU2015264960A1 AU2015264960A AU2015264960A AU2015264960A1 AU 2015264960 A1 AU2015264960 A1 AU 2015264960A1 AU 2015264960 A AU2015264960 A AU 2015264960A AU 2015264960 A AU2015264960 A AU 2015264960A AU 2015264960 A1 AU2015264960 A1 AU 2015264960A1
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- 230000035699 permeability Effects 0.000 description 1
- 238000000016 photochemical curing Methods 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940100640 transdermal system Drugs 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 206010046901 vaginal discharge Diseases 0.000 description 1
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Abstract
The present invention is directed to an intravaginal device comprising: (a) an annular first matrix comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; and (b) a second matrix comprising an 5 anticholinergic agent, wherein the second matrix is located in the pocket. The present invention is also directed to a method of making an intravaginal device, the method comprising: (a) placing a first matrix into a mold, the mold, being shaped so as to form an annular intravaginal device comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; (b) curing the first matrix; (c) placing a 10 second matrix comprising an anticholinergic agent in the pocket; and (d) curing the second matrix.
Description
WO 2011/163358 PCT/US2011/041447 INTRAVAGINAL DEVICES COMPRISING ANTICHOLINERGIC AGENTS, AND METHODS OF MAKING THEREOF Field of the Invention [0001] The present invention relates to intravaginal devices comprising: (a) an annular first matrix comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; and (b) a second matrix comprising an anticholinergic agent located in the pocket. [00021 The present invention also relates to methods of making intravaginal devices, the methods comprising: (a) placing a first matrix into a mold, the mold being shaped so as to form an annular intravaginal device comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; (b) curing the first matrix; (c) placing a second matrix comprising an anticholinergic agent in the pocket; and (d) curing the second matrix. BACKGROUND OF THE INVENTION [0003] Overactive bladder ('OAB") affects millions of individuals worldwide, a majority of those being women. In individuals with OAB, the detrusor muscle that controls the voluntary relaxation of the bladder during urination contracts spontaneously and involuntarily leading to a variety of symptoms such as urinary incontinence, urinary urgency, and increased urinary frequency. [00041 Currently, OAB is treated by administration of the anticholinergic agent oxybutynin. Oxybutynin is believed to affect the detrusor muscle, leading to relaxation of the bladder and subsequent reduction of spontaneous involuntary contractions. [0005] Currently marketed modes of oxybutynin administration include both oral (syrup or tablets), marketed under the tradenames DITROPAN* (syrup and tablets, Ortho-McNeil Janssen Pharmaceutical, Inc., Titusville, New Jersey) and LYRINEL XL* (tablets, Janssen Cilag EMEA, Beerse, Belgium), and transdermal patches, marketed under the tradename OXYTROL* (Watson Pharmaceutical, Inc., Morristown, New Jersey). Deleterious side WO 2011/163358 PCT/US2011/041447 -2 effects can occur upon oral and transdermal administration of oxybutynin, e.g., dry eyes, dizziness, blurred vision, constipation, and/or headaches. BRIEF SUMMARY OF THE INVENTION [0006] The present invention is directed to an intravaginal device comprising: (a) an annular first matrix comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; and (b) a second matrix comprising an anticholinergic agent, wherein the second matrix is located in the pocket. 10007] In some embodiments, the first matrix comprises an optionally substituted polymer selected from the group consisting of polysiloxane polymers, polyalkylene polymers, polystyrene polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyester polymers, polyurethane polymers, acrylic polymers, nylon polymers, dacron polymers, teflon polymers, and combinations thereof [0008] In some embodiments, the optionally substituted polymer is a polysiloxane polymer of Formula (I): R1. R1, R3 R1 I I I I Ra-S O Si O Si- 0--i R R2 R2 R4 R2 X y wherein X is I to 200; Y is I to 200; Z is 1 to 300; and R 1 , R 2 , R 3 , R4, and R 5 are independently selected from the group consisting of (C 1 6 )alkyl, amino(C 1 .)alkyl, hydroxy(CI- 6 )alkyl, haloalkyl, cyano(C >)alkyl, thio(C -)alkyl, carboxy(CI 4alkyl, aryl(CI 6 )alkyl, (CI 6 )alkoxy(C alkyll, (Csaikenyl, amino(C3_ 1 0 jalkenyi, hydroxv(C3.io)alkenyl, hao(C2-)alkenvl, cyano(C2-)alkenvl, thio(C3_ 13 )alkenyl, carboxy(C 31 o)alkenyl, aryl(C2_6)alkenyl, (C2.) alkynyl, (C 1 )heteroalkyl, (C2_ 6 )heteroalkenyl, (C2_6)heteroalkynyl, (( )alkoxy, (C 3 :o)alkenyloxy, WO 2011/163358 PCT/US2011/041447 -3 (C' - 6 )alkylenedioxv, amino(C2_ 6 )alkoxy, hydroxy(C2_ 6 )alkoxy, halo(C 6 salkoxy, cvano(Ci .)alkoxy, thio(CI-6)alkoxy, carboxv(C2_ 6 )alkoxy, arvi(C I)alkoxy, (C1 )alkoxy(C 2
_
6 )alkoxy, halo(C 1 -)alkoxy(C 2 .J)alkoxy, inono(C Q)alkylamino, di(C -)alkylamino., (C I)alkylearbonylamino, (C2-)alkenylearbonylamino,
(C
6 4)arylcarbonvlairno, (CI alkoxycarbonylamino, (C 6 1 o)aryloxycarbonylamino, (C1.
6 )alkylcarbonyl, (C 2
.
6 )alkenylcarbonyl, (C 6 -io)arvlcarbonyl, (C-Oalkoxycarbonyl,
(C
6 1 4 )aryloxycarbonyl, (C 1 4aikylsulfonylamino, (C 2 .alkenylsulfonyamino, and (C6 1 4 )aryisulfonylamino. In some embodiments, at least one of R 1 , R2? , R,, and R4 is a haloalkyl. In some embodiments, X is I to 2; Y is I to 2; Z is 100 to 200; R 1 is trifluoropropyl; R, R 3 , and R 4 are independently C 1
-C
3 alkyl; and R 5 is vinyl, In some embodiments, the optionally substituted polymer is 3,3,3 -trifluoropropyl methyldimethyl polysiloxane. [0009] In some embodiments, the first matrix comprises 50% to 100% by weight halogenated siloxane polymer. [0010] In some embodiments, the first matrix comprises 80% to 95% by volume of the device. In some embodiments, the first matrix comprises 80% to 95% by weight of the device. [0011] i some embodiments, the pocket extends from 100 to 180' around the perimeter of the first matrix. In some embodiments, the pocket extends from 80' to 1200 around the perimeter of the first matrix. In some embodiments, the pocket has a cross-sectional diameter of 3 mm to 8 mm. In some embodiments, the pocket wall has a uniform thickness of I mi to 4 mm. hi some embodiments, the pocket has a volume of 0.7 cm3 to 1.5 cm3. [0012] In sonre embodiments, the second matrix comprises an optionally substituted polymer selected from the group consisting of polysiloxane polymers, polyalkylene polymers, polystyrene polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyester polyiers, polyurethane polymers, acrylic polymers, nylon polymers, dacron polymers, teflon polymers, and combinations thereof In some embodiments, the second matrix comprises a polysiloxane polymer. [00131 In some embodiments, the second matrix comprises a polysiloxane polymer of Formula (II): WO 2011/163358 PCT/US2011/041447 -4 R, R, Ri. I I I R3 Sii-: R2 2 R2 N (1 vherein R 1 , R 2 and R 3 are independently selected from the group consisting of alkoxy, alkyl, alkynyl, alkynyl, alkenyl, alkylacryloyloxy, acryloyloxy, alkenylalkyl, aryl, and hydrogen; and N is 50 to 300. In some embodiments, R 1 and R2 are independently alkyl or hydrogen. [00141 In some embodiments, the second matrix comprises 30% to 80% by weight polysiloxane polymer. 10015] In some embodiments, the second matrix comprises 5% to 50% by volume of the device. In some embodiments, the second matrix comprises 5% to 50% by weight of the device, [00161 In some embodiments, the anticholinergic agent is homogenously dispersed throughout the second matrix. In some embodiments, the anticholinergic agent is selected from the group consisting of oxybutynin, tolterodine, trospium, solifenacin, darifenacin, dicyclomine, propantheline, propiverine, bethanechol, methylbenactyzium, scopolamine, and pharmaceutically acceptable salts thereof In some embodiments, the anticholinergic agent is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the anticholinergic agent comprises 20% to 70% by weight of the second matrix. [00171 In some embodiments, the first matrix further comprises a slit, wherein the slit extends a length of the pocket. [0018] The present invention is also directed to a method of making an intravaginal device, the method comprising: (a) placing a first matrix into a mold, the mold being shaped so as to form an annular intravaginal device comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; (b) curing the first matrix; (c) placing a second matrix comprising an anticholinergic agent in the pocket; and (d) curing the second matrix. [0019] In some embodiments, the mold is shaped so as to form an annular intravaginal device comprising a pocket and a pocket wall, wherein the pocket wall has a uniform WO 2011/163358 PCT/US2011/041447 -5 thickness, wherein the pocket wall encompasses the pocket, and wherein a slit extends a length of the pocket. In some embodiments, the anticholinergic agent is homogenously dispersed in the second matrix. In some embodiments, the anticholinergic agent is selected from the group consisting of oxybutynin, tolterodine, trospium, solifenacin, darifenacin, dicyclomine, propantheline, propiverine, bethanechol, methylbenactyzium, scopolamine, and pharnmaceutically acceptable salts thereof. In some embodiments, the anticholinergic agent is oxybutynin or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE FIGURES 10020] FIG. 1 depicts a top view of an intravaginal ring having a first matrix (101) comprising a pocket (102), and a second matrix (103) located in the pocket, wherein the pocket is encompassed by a pocket wall (104). The length of the pocket around the perimeter of the first matrix is denoted by the variable (y). The pocket wall has a uniform thickness, i.e., 105a, 105b, and 105c are substantially the same length. [0021] FIG. 2 depicts a top view of an intravaginal ring having an inner perimeter (201), an outer perimeter (202), an inner diameter (203), and outer diameter (204). 10022] FIG. 3A depicts a side view of an intravaginal ring showing a cross-section having a first matrix (301) comprising a pocket (303) and a pocket wall (302), wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket. [00231 FIG. 3B depicts a side view of an intravaginal ring showing a cross-section of a vaginal ring having a first matrix (301) comprising a pocket (302) and a pocket wall (303), and a second matrix (304) comprising an anticholinergic agent located in the pocket. [0024] FIG. 4 depicts a side view of an intravaginal ring having a first matrix (401) having a pocket (402), and a slit (403), wherein the slit extends a length of the pocket. DETAILED DESCRIPTION OF THE INVENTION 10025] The present invention is directed to intravaginal devices comprising: (a) an annular first niatrix comprising a pocket and a pocket wall, wherein the pocket wall has a WO 2011/163358 PCT/US2011/041447 uniform thickness, and wherein the pocket wall encompasses the pocket; and (b) a second matrix comprising an anticholinergic agent located in the pocket. [0026] As used herein, an "intravaginal device" refers to an object suitable for placement in the vaginal tract. In some embodiments, the intravaginal device provides for administration or application of an anticholinergic agent to the vaginal and/or urogenital tract of a subject, including, e.g., the vagina, cervix, or uterus of a female. As used herein, "female" refers to any animal classified as a mammnal, including humans and non humans, such as, but not limited to, domestic and farm animals, zoo animals, sports animals, and pets. In some embodiments, female refers to a human female. In some embodiments, the female is a menopausal woman. In some embodiments, the female is a peri-menopausal woman. 10027] In some embodiments, the female refers to a human female, wherein the female meets one or more criteria selected from (1) predominant or pure urge incontinence consisting of >10 pure or predominant discrete urge incontinence episodes per week, (2) an average urinary frequency of > 8 voids per 24 hours, and (3) an average total void volume of < 3.0 L per 24 hours. In some embodiments, the female is a human female having all three criteria described above. In some embodiments, the female is a human menopausal or peri-menopausal woman having all three criteria described above. [0028] The intravaginal devices of the present invention comprise an anticholinergic agent. As used herein, an "anticholinergic agent" refers to a compound that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. Anticholinergic agents suitable for use with the present invention comprise agents that have a localized effect, as well as systemically acting anticholinergic agents that act at a point remote from the vaginal or urogenital tract. Anticholinergic agents suitable for use with the present invention include, but are not limited to, oxybutynin, tolterodine, trospium, solifenacin, darifenacin, dicyclomine, propantheline, propiverine, bethanechol, methylbenactyzium, scopolamine, combinations thereof, and pharmaceutically acceptable salts thereof. [00291 In some embodiments, the anticholinergic agent is oxybutynin, tolterodine, trospiumn, solifenacin, darifenacin, dicyclomnine, propantheline, propiverine, or pharmaceutically acceptable salts thereof WO 2011/163358 PCT/US2011/041447 [00301 In some embodiments, the anticholinergic agent is oxybutynin or a pharmaceutical acceptable salt thereof, such as, e.g., oxybutynin hydrochloride. Oxybutynin is represented by the chemical formula C22HnNO 3 , the International Union of Pure and Applied Chemistry (1UPAC) name 4-diethylaminobut-2-yiiyl2-cyclohexyl-2 hydroxy-2-phenyl-ethanoate, Chemical Abstracts Service, (CAS) number 5633-20-5, and the PubChem Compound identification number 4634. As used herein, the term "oxybutynin" refers to oxybutynin as well as its pharmaceutically acceptable salts, esters, hydrates, prodrugs, or derivatives thereof unless otherwise noted. [00311 In some embodiments, the intravaginal devices are annular in shape. As used herein, "annular" refers to a shape of, relating to, or forming a ring. Annular shapes suitable for use with the present invention include a ring, an oval, an ellipse, a toroid, and the like. In some embodiments, the intravaginal devices of the present invention are a vaginal ring. [00321 Materials used in the intravaginal devices of the present invention can include any materials suitable for placement in the vaginal tract. In some embodiments, the materials used in the intravaginal device are nontoxic, physiologically suitable, and/or non absorbable in a subject, i.e., they are not absorbed in the vaginal tract. The materials used in the present invention are compatible with an anticholinergic agent. Compatible materials include those materials that are inert, chemically stable, do not chemically interact with, or otherwise affect and/or alter the anticholinergic agent. In some embodiments, the materials are pliable, malleable, and/or capable of being suitably shaped for intravaginal administration. [00331 The intravaginal devices of the present invention can be flexible. As used herein, "flexible" refers to the ability of a solid or semi-solid to bend or withstand stress and strain without being damaged or broken. For example, the device of the present invention can be deformed or flexed, such as, for example, using finger pressure (e.g., applying pressure from opposite external sides of the device using the fingers), and upon removal of the pressure, substantially return to its original shape. The flexible properties of the intravaginal device of the present invention are useful for enhancing user comfort, and also for ease of administration to the vaginal tract and/or removal of the device from the vaginal tract.
WO 2011/163358 PCT/US2011/041447 [00341 The intravaginal devices of the present invention comprise a first matrix. As used herein, a "first matrix" refers to any solid, semi-solid, or gel medium. In some embodiments, the first matrix is an amorphous polymer network formed when a polymer or a mixture of polymers undergo cross-linking. Each polymer is comprised of monomeric units, which are linked together to form the polymer. The monomeric units can comprise carbon, hydrogen, oxygen, silicon, halogen, and combinations thereof. The first matrix can be shaped by molding, extrusion, coextrusion, compression, or combinations thereof [00351 In some embodiments, the first matrix is permeable to the anticholinergic agent. In some embodiments, the first matrix is permeable to oxybutynin and/or water. In some embodiments, the first matrix can be chosen due to its mechanical and physical properties (e.g., solubility or permeability of an anticholinergic agent in the material). [00361 In some embodiments, the first matrix comprises various polymers that are compatible with the vaginal tract. In some embodiments, the first matrix comprises a polysiloxane, a polyalkylene, a polystyrene, a polyvinyl acetate, a polyvinyl chloride, a polyester, a polyurethane, an acrylic, a nylon, a dacron, a teflon, or a combination thereof. [0037] As used herein, a "polysiloxane polymer" refers to any of various compounds containing alternate silicon and oxygen atoms in either a linear or cyclic arrangement usually with one or two organic groups attached to each silicon atom. For example, polysiloxane polymers can include substituted polysiloxanes, and diorganopolysiloxanes such as diarylpolysiloxanes and dialkylpolysiloxanes. [00381 In some embodiments, the first matrix comprises an optionally substituted polymer selected from the group consisting of polysiloxane polymers, polyalkylene polymers, polystyrene polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyester polymers, polyurethane polymers, acrylic polymers, nylon polymers, dacron polymers, teflon polymers, and combinations thereof, [0039] In some embodiments, the optionally substituted polymer is a polysiloxane polymer of Formula (I): WO 2011/163358 PCT/US2011/041447 -9 R1 R1 R3 R1 I I I I _ RS - Si O) Si 0 i R I I I | R2 2 K R 2 X Y z wherein X is I to 200; Y is I to 200; Z is 1 to 300; and R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of (C6)alkvL amino(CJ- 6 )alkyl, hydroxy(C p)alkyl, haloalkyl, cyano(Cp 6 )alkyl, thio(C Q)alkyl, carboxy(CIA alkyl, aryl(C> 6 )alkyl, (C]-)alkoxv(Ci )aikyl, (C2_)alkenyi, amino((- )alkenyl, hydroxy(C2Jo)alkenvl, ha lo(C- 6 )alkenyl, cyano(C2_)akenyi, thio(C3)aikenyi, carboxy(C 3 4 o)alkenyl, aryl(C2.)alkenyl, (C2) alkynyl, (CIfheteroalkyl, (C%2_0heteroalkenyl, (C2_s)heteroalkynyli, (C" )alkoxy, (C 3 4)akenyoxy, (C 1 -6alkyl enedioxy, amino(C 2
.
6 )alkoxy, hydroxy(C 2
_
6 )alkoxy, halo(CI-> 6 alkoxy, cyano(C -)alkoxy, thio(C 16 )alkoxy, carboxy(C2_ 6 )alkoxy, aryl(C 1 )alkoxy,
(C
1 6 )alkoxy(C2_6)alkoxy, halo(C - 6 )alkoxy(C 2
_
6 )alkoxy, mono(C - 6 )alkylamino, di(C - 6 )alkyl amino, (Cialkylcarbonylamino, ('C2 6 )alkenvlcarbonyl amino, (C 61.)arylcarbonylamino, (C 1 )aikoxycarbonyiamino, (C 6 1 )aryloxycarbonylamino, (C jsalkyicarbonyl, (C 2
.
6 )alkenylcarbonyl, (C 6 1 o)arylcarbonyl, (C )alkoxycarbonyl, (C614 )aryloxycarbonyl, (C 1 6 )alkylsulfonylamino, (C2_ 6 )alkenylsulfonviamino, and (C 1 4)arylsulfonylamino. In some embodiments, at least one of R 1 , R2, R, and R-4 is a haloalkyl, 10040] In some embodiments, the first matrix is a halogenated siloxane polymer, wherein at least one of RI, R 2 , R 3 , and R 4 is a mono-haloalkyl, di-haloalkyl, or tri-haloalkyl. In some embodiments, the haloalkyl is a bromoalkyl, chloroalkyl, fluoroalkyl, or iodoalkyl. In some embodiments, the haloalkyl is a trifluoroalkyl. In some embodiments, the haloalkyl is a trifluoroethyl, trifluoropropyl, or trifluorobutyl. In some embodiments, the haloalkyl is a difluoroethyl, difluoropropyl, or difluorobutyl. 10041] i some embodiments, X is 1 to 90, 10 to 80, or 20 to 70. Ir some embodiments., X is I to 10, 1 to 5, or I to 3. In some embodiments, Y is I to 90, 10 to 80, or 20 to 70. In some embodiments, Y is 1 to 10, 1 to 5, or I to 3. In some embodiments, Z is 10 to WO 2011/163358 PCT/US2011/041447 - 10 250, 50 to 200, or 75 to 150. As one of skill in the art would recognize, the values of X and Y can vary in each Z subunit. Thus, e.g., X is 3 and Y is 4 in a first Z subunit, and X is 10 and Y is 2 in a second Z subunit. [0042] In some embodiments, R 1 is a trifluoropropyl; R-, R, and R4 are independently
C
1
C
3 alkyl; R 5 is vinyl; X is I to 2; Y is 1 to 2; and Z is 100 to 200. [0043] In sonie embodiments, the first matrix comprises 3,3,3-trifluoropropyl methyldimethyl polysiloxane, e.g., the trifluoropropylmethyl polymer sold. by NuSil Technology (Carpinteria, CA). [00441 Throughout the disclosure, all expressions of percentage, ratio, and the like are "by weight" unless otherwise indicated. As used herein, "by weight" is synonymous with the term "by mass," and. indicates that a ratio or percentage defined herein is according to weight rather than volume, thickness, or some other measure. [0045] In some embodiments, the first matrix is 50% to 100% by weight halogenated siloxane polymer. In some embodiments, the first matrix is 75% to 95% by weight halogenated siloxane polymer. In some embodiments, the first matrix is 80% to 90% by weight halogenated siloxane polymer. [0046] In some embodiments, the first matrix is 80% to 95% by weight of the intravaginal device. In some embodiments, the first matrix is 80% to 95% by volume of the intravaginal device. [0047] The first matrix comprises a pocket and. a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket. As used herein, "pocket" refers to an indentation, groove, furrow, cut, impression, notch, recess, or likewise depression along the surface of the first matrix, which is encompassed by a pocket wall, and wherein the pocket wall has a uniform thickness. See, e.g., FIGS. 1, 2, 3A, and 3B. In some embodiments, a "pocket" as defined herein can be exposed to the exterior of the device via a slit which extends a length of the pocket. Thus, the term "pocket" does not include a bore or other type of cavity that extends any length through the device, since (a) a bore contains at least one distinct entrance from the surface into the first matrix, and (b) a bore does not have a pocket wall of uniform thickness. In some embodiments a pocket of the present invention can be beneficial since anticholinergic agents in a second matrix can be released without having to pass through a separate matrix, e.g., the first matrix.
WO 2011/163358 PCT/US2011/041447 - ii [0048] As used herein, "pocket wall" refers to a portion of the first matrix that defines the lateral boundaries of the pocket. See, e.g., FIGS. 3A and 3B. Thus, the volume defined by the pocket wall comprises the pocket. The pocket wall has a uniform thickness, wherein the distance from the pocket to the lateral outer surface of the device is the same. In some embodiments, the pocket wall has a uniform thickness of 0.5 mm to 5 mm. In some embodiments, the pocket wall has a uniform thickness of 1 mm to 4 mm. In some embodiments, the pocket wall has a uniform thickness of 1.5 mm to 3 mm. In some embodiments, the pocket wall has a uniform thickness of I nun to 2 nun. A pocket wall of uniform thickness can allow the anticholinergic agent in the second matrix to be uniformly released from the intravaginal device through the pocket wall. [0049] As used herein, "encompass" or "encompasses the pocket" refers to the degree by which the pocket wall covers the lateral surface area of the pocket. Thus, the pocket wall encompasses the pocket when the pocket wall covers 95% or more of the lateral surface area of the pocket. In some embodiments, the pocket wall encompasses the pocket when the pocket wall covers 90% or more of the lateral surface area of the pocket. In some embodiments, the pocket wall encompasses the pocket when the pocket wall covers 85% or more of the lateral surface area of the pocket. In some embodiments, the pocket wall encompasses the pocket when the pocket wall covers 80% or more of the lateral surface area of the pocket. By way of example, in some embodiments, the pocket can be tubular in shape, wherein 95% or more of the lateral surface area of the tubular pocket comprises the pocket wall. [0050] In some embodiments, the length of the pocket can vary. For example, in some embodiments, the first matrix is annular in shape and the pocket of the first matrix can extend around a portion of the entire perimeter of the annular matrix. See, e.g., FIG. 1. In some embodiments the pocket extends from 10' to 180' around the perimeter of the first matrix. In some embodiments, the pocket extends from 80' to 120' around the perimeter of the first matrix. In some embodiments, the pocket extends 180', 150, 120, 100", 90", 80, 70', 60', 45", 30', or 10' around the perimeter of the annular first matrix. These variables are represented by the variable "y" in FIG. 1. In some embodiments, the pocket has a cross-sectional diameter of 3 mm to 8 mm, 4 mm to 7 mm, or 5 mm to 6 mm. In some embodiments, the pocket has a total volume of 7 cm3 to 15 cm 3 , 8 cm3 to WO 2011/163358 PCT/US2011/041447 - 12 14 cm 3 , 9 cm 3 to 13 cm 3 , or 10 cm 3 to 12 cm 3 . In some embodiments, the first matrix comprises one or more pockets, e.g., two, three, four, or five pockets. [0051] In some embodiments, the first matrix further comprises a slit on the outer perimeter of the first matrix, wherein the slit extends a length of the pocket. As used herein "slit" refers to any narrow opening, incision, fissure, aperture, breach, cleavage, crack, crevice, gash, split, chasm, or cut in the outer perimeter of the first matrix. In some embodiments, the slit has a uniform width. In some embodiments., the width of the slit is 0.1 mm to 2 mm. In some embodiments, the width of the slit is 0.2 mm to 1 mm. In some embodiments, the width of the slit is 0.4 mm to 0.6 mn. In some embodiments, the width of the slit is 0.5 mm. A slit extending a length of the pocket can allow for a uniform release of active agent from the device without having to pass through a separate matrix, e.g., the first matrix. [0052] The intravaginal devices of the present invention further comprise a second matrix. As used herein, "second matrix" refers to any solid, semi-solid, or gel medium. In some embodiments, the second matrix is an amorphous polymer network formed when a polymer or a mixture of polymers undergo cross-linking. Each polymer is comprised of monomeric units, which are linked together to form the polymer. The monomeric units can comprise carbon, hydrogen, oxygen, silicon, halogen, or a combination thereof. The second matrix can be shaped by flow, molding, or extrusion. In some embodiments, the second. matrix can be flexible. In some embodiments, the second matrix can be chosen due to its mechanical and physical properties (e.g., solubility of an anticholinergic agent in the material). In some embodiments, the second matrix is placed within the pocket of the first matrix as a liquid or gel (i.e., a low viscosity state) and the second matrix is polymerized, cured, or solidified. 10053] In sonie embodiments, the devices comprise more than two matrices, e.g., three or four matrices. In some embodiments, when two or more matrices are present, an anticholinergic agent is in each matrix, or optionally in only one matrix. [00541 In some embodiments, the anticholingeric agent can be homogeneously dispersed in the second matrix. As used herein, homogeneousu" refers to a matrix that has a substantially uniform distribution of the anticholinergic agent throughout the matrix. In some embodiments, the anticholinergic is present in a uniform concentration throughout the second matrix.
WO 2011/163358 PCT/US2011/041447 - 13 [00551 In some embodiments, the anticholinergic agent is heterogeneously dispersed in the second matrix. As used herein, "heterogeneous" refers to a matrix that does not have a substantially uniform distribution of the anticholinergic agent throughout the matrix. For example, there can be segments, regions, or areas of the matrix with varying amounts of the anticholinergic agent located throughout the matrix. [0056] In some embodiments, the second matrix comprises the same material as the first matrix. i some embodiments., the second matrix comprises a different material than that of the first matrix. For example, in some embodiments, the second matrix comprises a siloxane polymer and the first matrix comprises a halogenated siloxane polymer. In some embodiments, the siloxane polymer comprises a polymer of Formula II,
R
1 R, R, R--Sii__ 0 SiFR'
R
2
R
2 R 2 N wherein R1, R, and R 3 are independently selected from the group consisting of alkoxy, alkyl, alkynyl, alkynyl, alkenyl, alkylacryloyloxy, acryloyloxy, alkenylalkyl, aryl, and hydrogen; and N is 50 to 300. in some embodiments, R, and 12 are independently alkyl or hydrogen. As one of skill in the art can appreciate, in a single polymer chain, the R 1 and/or R2 substituents can vary. For example, in a single polymer chain, the R 1 and R2 substituents can include various different alkyl substituents, e.g., methyl, ethyl, propyl, butyl, and the like. [00571 The amount of the anticholinergic agent in the intravaginal device can vary. For example, in some embodiments, the second matrix comprises 20% to 70% by weight anticholingeric agent. In some embodiments, the second matrix comprises 30% to 60% by weight anticholingeric agent. In some embodiments, the second matrix comprises 40% to 50% by weight anticholingeric agent. In some embodiments, the second matrix comprises 50% by weight anticholingeric agent. [00581 The amount of oxybutynin or a pharmaceutically acceptable salt thereof in the intravaginal device can vary. For example, in some embodiments, the second matrix comprises 20% to 70% by weight oxybutynin or a pharmaceutically acceptable salt WO 2011/163358 PCT/US2011/041447 - 14 thereof. In some embodiments, the second matrix comprises 30% to 60% by weight oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the second matrix comprises 40% to 50% by weight oxybutynin or a pharmaceutically acceptable salt thereof In some embodiments, the second matrix comprises 50% by weight oxybutynin or a pharmaceutically acceptable salt thereof [0059] In some embodiments, the second matrix is 30% to 80% by weight siloxane polymer. In some embodiments, the second matrix is 40% to 70% by weight siloxane polymer. In some embodiments, the second matrix is 50% to 60% by weight siloxane polymer. [0060] In some embodiments, the second matrix is 5% to 50% by volume of the device, In some embodiments, the second matrix is 5% to 25%, 8% to 20%, 10% to 18%, or 12% to 15% by volume of the device. [0061] In some embodiments, the second matrix is 5% to 50% by weight of the device. In some embodiments, the second matrix is 5% to 25%, 8% to 20%, 10% to 18%, or 12% to 15% by weight of the device. [00621 The device of the present invention is of aiy size suitable for placement in a vaginal tract of the subject for which it is administered. In some embodiments, the device of the present invention has a cross-sectional diameter of 1 mm to 10 mm. As used herein, a "cross-sectional diameter" refers to the longest straight line segment that passes through the center of a cross-section of the intravaginal device. See, e.g., FIG. 3A. in some embodiments, the device has a cross-sectional diameter of 1 mm to 10 mm, 2 mm to 9 mm, 3 mm to 7 mm, 4 mm to 6.5 mm, 5 mm to 6 mm, or 6 mm. [00631 In some embodiments, the device of the invention has an outer diameter of 40 mm to 80 mm, As used herein, an "outer diameter" refers to any straight line segment that passes through the center of the device, the center being viewed from a top view of the intravaginal device, and whose endpoints are each on the outer perimeter of the device. See, e.g., FIG. 2 (204). In some embodiments, the device has an outer diameter of 40 mm to 80 mm, 45 mm to 65 mm, or 50 mm to 60 mm. [00641 In some embodiments, the device of the invention has an inner diameter of 10 mm to 60 mm, As used herein, an "inner diameter" refers to any straight line segment that passes through the center of the device, the center being viewed from a top view of the intravaginal device, and whose endpoints are on the inner perimeter of the device. See, WO 2011/163358 PCT/US2011/041447 - 15 e.g., FIG. 2 (203). In some embodiments, the device has an inner diameter of 10 nun to 60 mm, 10 mnn to 50 nm, 10 mm to 40 rnm, 20 nm to 40 nm, 10 mm to 30 rnm, or 10 mm to 20 mm. [0065] In some embodiments, the intravaginal device of the present invention further comprises an excipient. Where two or more matrices are present in the device, an excipient is present in each matrix, or optionally in only one matrix, i.e., in either the first or the second matrix. As used herein, an "excipient" refers to a substance that is used in the fornulation of the intravaginal device of the present invention, and, by itself, generally has little or no therapeutic value. One of skill in the art will recognize that a wide variety of pharmaceutically acceptable excipients is used including those listed. in the Handbook of Pharnaceutical Excipients, Pharmaceutical Press 4th Ed. (2003) and Renington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st Ed. (2005), which are incorporated herein by reference in their entirety. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, and/or compositions which are, within the scope of sound medical judgment, suitable for contact with the tissues of hunan beings and animals without excessive toxicity, irritation, allergic response, or other possible complications commensurate with a reasonable benefit/risk ratio. In some embodiments, the excipient can enhance perneabilization of the matrix and the release rate of the anticholinergic agent from the intravaginal vaginal ring. Examples of such excipients include, but are not limited to, a saturated polyglycolyzed glyceride, a block copolymer surfactant., an emulsifier, glyceryl monolaurate, microcrystalline cellulose, hydroxyethylcellulose, ethylcellulose, hydroxypropyl methylcell ulose, polym ethylimethacrylate, polyvinylpyrollidone, and mixtures thereof. The intravaginal device of the invention can also include excipients that enhance and/or promote absorption of the anticholinergic agent across the vaginal mucosa. Absorption promoters include but are not limited to nonionic surface active agents, bile salts, organic solvents, interesterified stone oil, and ethoxydiglycol. Other excipients, such as water, saline, additives, fillers, or other pharmaceutically acceptable and/or therapeutically effective compounds, can also be added to the device of the present invention. [0066] In some embodiments, the present invention is also directed. to a method of making an intravaginal device, the method comprising: (a) placing a first matrix into a WO 2011/163358 PCT/US2011/041447 - 16 mold, the mold being shaped so as to form an intravaginal device comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; (b) curing the first matrix; (c) placing a second matrix comprising an anticholinergic agent in the pocket; and (d) curing the second matrix. [0067] In some embodiments, the method of the present invention further comprises curing the first matrix, the second matrix. and/or all of the matrices of the intravaginal device. As used herein, "curing" refers to a process useful to solidify, harden, or cross link a substantially homogeneous composition of the present invention. Curing can comprise heating, drying, cooling, crystallizing, cross-linking, photo-curing (e.g., exposing to monochromatic or broad-band ultraviolet, visible, or infrared light), or combinations thereof. In some embodiments, the matrix can be cured at 0" to 200C. In other embodiments, the matrix is cured at 120 C to 180"C, or 150'C. In some embodiments, the matrix is cured at room temperature. In some embodiments, the matrix is cured in a mold press. In some embodiments [00681 The present invention is also directed to an intravaginal device made by the method of the present invention. Various methods can be used to make the intravaginal devices of the present invention. Various means of producing intravaginal devices are known in the art. See, e.g., U.S. Patent Nos. 6,544,546; 6,394,094; and 4,155,991 of which the disclosure of each is incorporated herein by reference. [00691 In some embodiments, compression molding is used to form the device of the present invention. Compression molding generally involves compressing a substantially homogeneous mixture to forn a compressed matrix and can be achieved by, e.g., the use of a die press. As used herein, "compressed." refers to a mixture that has been compacted or fused under pressure. A compressed mixture has a density that is greater than the mixture prior to compression, [0070] In some embodiments, the matrix is in a heated liquid state prior to being placed. in the mold. The heated liquid matrix can then solidify upon cooling. In some embodiments, the matrix in a liquid state solidifies with the addition of a catalyst. [00711 In some embodiments, the intravaginal device of the present invention is a flexible, opaque, or molded silicone product with a cross-sectional diameter of 9 mm to 10 mm and an outer diameter of 55 mnim to 60 mm. In some embodiments, the WO 2011/163358 PCT/US2011/041447 - 17 intravaginal device is an intravaginal ring having a pocket having a cross-sectional diameter of 4 nun to 6 nn. [0072] In some embodiments, the pocket of the oxybutynin intravaginal ring can be filled with a paste-like mixture comprising 50% to 60% silicone and 40% to 50% oxybutynin. In some embodiments, the silicone/oxybutynin mixture can cured into a solid, achieving the shape and form of the pocket. [00731 The present invention is also directed to an intravaginal device for administering an anticholinergic agent, the device comprising: (a) an annular first matrix comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; and (b) a second matrix comprising an anticholinergic agent located in the pocket. 10074] In some embodiments, the anticholinergic agent is released from the intravaginal device at a rate of 0.1 mg/day to 20 mg/day. As used herein, the "rate of release" or "release rate" refers to an amount of anticholinergic agent that is released from the intravaginal device over a defined period of time. In other embodiments, the anticholinergic agent is released from the intravaginal device at a rate of 0.1 mg/day to 20 mg/day, 0.5 mg/day to 15 mg/day, I mg/day to 10 mg/day, 2 mg/day to 8 mg/day, 4 mg/day to 6 mg/day, or 5 mg/day. In some embodiments, the anticholinergic agent is released from the intravaginal device at an average rate of 6 mg/day. In some embodiments, the anticholinergic agent is released from the intravaginal device at an average rate of 4 mg/day. In some embodiments, the anticholinergic agent is released from the intravaginal device at an average rate of 2 mg/day. [00751 In some embodiments, the first matrix of the intravaginal device of the present invention determines or controls the rate of release of an anticholinergic agent contained therein. In some embodiments, the second matrix of the intravaginal device determines or controls the rate of release of the anticholinergic agent. In some embodiments, both the first and second matrices determine or control the rate of release of the anticholinergic agent. [00761 In some embodiments, the rate of release of the anticholinergic agent is dependent on the amount of halogenated siloxane polymer in the first matrix. In some embodiments, the release rate of the anticholinergic agent from the device is controlled by controlling the degree of cross-linking present in the polymer material of the first matrix. While not WO 2011/163358 PCT/US2011/041447 - 18 being bound to any particular theory, a high degree of cross-linking would be expected to result in a lower rate of release of the anticholinergic agent from the polymer matrix. The degree of crosslinking is controlled by the amount of crosslinker or catalyst used during production of the intravaginal device. See, c.g., U.S. Patent No. 6,394,094. 10077] In some embodiments, the release rate of the anticholinergic agent is controlled by the amount of siloxane polymer in the second matrix. In some embodiments, the release rate is controlled by both the amount of halogenated siloxane polymer in the first matrix and the amount siloxane polymer in the second matrix, wherein the siloxane polymer of the second matrix is a different polymer than the polymer of the first matrix. [0078] In some embodiments, the release rate of the anticholinergic agent from the intravaginal device can also be controlled or modulated. through the inclusion of additional agents or excipients in the polymer matrix, such as, for example, mineral oil, or fatty acid esters. In some embodiments, the release rate of the anticholinergic agent is controlled by the concentration of the anticholinergic agent in the second matrix. [00791 In some embodiments, the release rate of the anticholinergic agent from the device is controlled by the volume of the pocket, the shape of the pocket, the thickness of the pocket wall, the degree by which the pocket wall encompasses the pocket, and/or the width of the slit in the first matrix. [0080] In some embodiments, the invention is directed to a intravaginal device for decreasing the severity or the frequency of urinary urgency. In some embodiments, urinary urgency is characterized as the sudden, difficult to deter, and/or compelling desire to void urine. [00811 In some embodiments, the device of the present invention allows for elimination of first-pass metabolism of the anti-cholinergie agent, e.g., oxybutyiin, in the liver, thereby providing an advantage of the vaginal delivery of the present invention. Vaginal delivery can reduce the production of first-pass oxybutynin metabolite N desethyloxybutynin. In some embodiments, reduction in the plasma concentration of this metabolite using the device of the present invention can reduce the severity of anticholinergic side effects, e.g., dry mouth, constipation, and/or blurred vision. [00821 In some embodiments, the present invention provides a device for long-term delivery of a constant level of an anticholinergic agent, e.g., oxybutynin, from a single treatment.
WO 2011/163358 PCT/US2011/041447 - 19 [00831 In some embodiments, vaginal delivery device of the anticholinergic agent, e.g., oxybutynin, may allow accumulation of the anticholinergic agent at the bladder at lower doses than is achievable by oral dosing. While not being bound by any particular theory, the bladder and the vaginal tract are anatomically proximal to each other, and the vascular and lymphatic networks of the two organs are shared to a high degree, raising the possibility of accumulation of the anticholinergic agent at the bladder. During intravascular delivery, such accumulation in the bladder may enhance and/or prolong the therapeutic effects of the anticholinergic agent, allowing for decreased overall dosing of the anticholinergic agent. [0084] The present invention is further illustrated by the following Examples. These Examples are provided to aid in the understanding of the invention and are not to be construed as a limitation thereof. EXAMPLES Example I PRODUCTION OF A FIRST MATRIX VAGINAL RING 10085] A vaginal ring comprising a first matrix was prepared as follows. The first matrix was prepared using trifluoropropylmetiyl/dimethyl siloxane. 40 g part A and 40 g part B trifluoropropylme thyl/dimethyl siloxane elastomer formation (NuSil Technology, CF2-3521 grade, Toms River, NJ) were weighed into a 100 g capacity Hauschild mixing cup and subsequently mixed for 10 seconds in a Hauschild Model 501 T speed mixer. A metal spatula was then used to scrape down the sides of the mixing cup and further blend the two starting components. A final 14-second speed mixer cycle was supplied to ensure blend unifonnity. [0086] Two halves of an insert mold capable of forming a pocket and a pocket wall having a uniform thickness, were lightly coated in an ethanol/water solution of DARVAN WAQ (R.T. Vanderbilt Co., Norwalk, CT) and allowed to air dry. Between 12-15 grams of the 1:1 part A:part B blend were placed into the pin containing half of the mold. The insert pins were positioned in the filled portion of the mold and matched unfilled mold half was mated into place.
WO 2011/163358 PCT/US2011/041447 - 20 [00871 The filled mold assembly was then compressed between the unheated platens of a Kuntz injection molding machine in order to discharge excess polymer blend from the mold. During this compression step, the insert pins were held in place to avoid ejection by the applied air pressure. The discharged blend material was removed from the outside of the mold assembly and discarded. [00881 The compressed, filled mold assembly was then placed between the preheated platens of a model 3912 Carver press. A pressure of 5,000 psi was applied and heating of the assembly for 15 minutes at 150 'C was performed to affect elastomer cure. During approximately the first 5 minutes of this curing step, the insert pins were held in place to avoid section from the mold. [0089] After 15 minutes at 150 'C, the mold was removed from the Carver press and cooled on the Kuntz machine's chiller for a sufficient time to allow easy separation of the mold halves and facilitate handling. The cured ring was separated from the mold. The insert pins were then carefully removed from the molded part by gently pulling them out without tearing or otherwise deforming the pocket. [00901 This process resulted in a vaginal ring formed by mold compression having an annular first matrix comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket. Example 2 PRODUCTION OF A TWO-MATRIX VAGINAL RING [0091] The pocket of the annular first matrix of a trifluoropropylmethyl/dimethyl siloxane elastomer prepared according to Example I was filled with a silicone/oxybutynin second. matrix. [00921 To form the second matrix, a mixture of 55% silicone and 45% oxybutynin was weighed in a Hauschild mixing cup and mixed in a Hauschild model AM 501 T speed mixer. A sufficient amount of the resulting silicone/oxybutynin paste was injected via syringe into the pocket of the ring of Example I. In order to achieve a vaginal ring which released 4 mg/day oxybutynin, a vaginal ring comprising a first matrix having an outer diameter of 58.3 mm with a pocket that extended 80' around the exterior perimeter of the WO 2011/163358 PCT/US2011/041447 -21 ring was used. The pocket had a diameter of 5.3 mm and was filled via syringe with the silicone/oxybutynin mixture. In order to achieve a vaginal ring which released 6 mg/day oxybutynin, a vaginal ring comprising a first matrix having an outer diameter of 58.3 mm with a pocket that extended 120' around the exterior perimeter of the ring was used. The pocket had a diameter of 5.3 mm. The ring was cured for 24 hours at ambient conditions to allow the silicon e/oxybutynin polymer paste to solidify. The second matrix was held in the pocket of the first matrix by the pocket wall extending over the lateral surface area of the pocket. The silicone/oxybutynin mixture cured into a white cylindrically shaped solid, following the shape of either the 80' or 120' pocket. [0093] This process resulted in an intravaginal ring having an annular first matrix comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket and a second matrix comprising an oxybutynin/silicone mixture contained int the pocket. Example 3 PHARMACOKINETICS AND DRUG METABOLISM IN ANIMALS [00941 A study was conducted to determine the levels of oxybutynin and its active metabolite, N-desethyloxybutynin, present in plasma following oral and intravaginal administration of oxybutynin in dogs. Results from this study are presented in Table 1. Table 1. Oxybutynin Vaginal Ring vs Oxybutynin Chloride oral Tablet: Dose Comparison of Cmax and Tmax Dosage Form Dose Cma (ng/mL) Oxybutvnin 8 x 5 mg/day 25.6 Chloride tablet 9 - 5 mg/day--7.90 x 5 mg/day 13.90 Oxybutynin 2.5 mg/day 13.95 vaginal ring 6.0 ig/day 18.75 [00951 A 14 day study was conducted, where 8 young adult females were randomly assigned to 4 groups of 2 dogs each. Two dogs received an oral 10 mg dose of oxybutynin chloride daily (2 x 5 ig/day tablets) for 14 consecutive days. The remaining WO 2011/163358 PCT/US2011/041447 6 dogs received an intravaginal ring as described in Example 2, designed to continuously release oxybutynin at a dose of 0, 2.5 or 6 mg/day for 14 consecutive days. [0096] Oxybutynin was detected in the plasma of dogs who were administered oxybutynin either orally or vaginally at all intervals tested. The average maximum (Cmax) plasma levels of oxybutynin were slightly higher and were achieved sooner in dogs with the 6 mg/day vaginal rings (approximately 18.75 ng/mL at 1.5 hours (h) after dosing) than in dogs given oxybutynin orally (approximately 17.9 ng/mL at 3 h after dosing). The Cmax values achieved for the 2.5 mg/day vaginal rings were slightly lower (approximately 13.95 ng/mL at 1 5 h after dosing). [0097] Plasma levels of oxybutynin were sustained for up to 96 h after insertion of the vaginal ring (approximately 4.4 ng/mL and 11.6 ng/mL for dogs with 2.5 and 6.0 mg/day vaginal ring, respectively), but decreased rapidly when administered orally (to <2.75 ng/mL at 8 h or more after dosing). This data suggests that the area under the curve ("AUC") values achieved with the 6 mg/day oxybutynin vaginal rings are slightly higher than those achieved after oral administration of 10 mg/day of oxybutynin chloride. [00981 The amount of N-desethyioxybutynin detected in the plasma was consistently low (less than 1 ng/mL) for dogs given either concentration of oxybutynin vaginal rings. Ir contrast, the amount of N-desethyloxybutynin detected in plasma of dogs given oxybutynin chloride orally was generally similar to the amount of oxybutynin that was measured. [00991 These findings suggest that the 6 mg/day oxybutynin vaginal rings delivered. similar, but more sustained amounts of oxybutynin to the plasma than oral administration of 10 mg/day oxybutynin chloride, while plasma levels of N-desethyloxybutynin were consistently lower in the vaginal ring relative to the oral administration. Example 4 Pharmacokinetics and Drug Metabolism in Humans [001001 Two studies were conducted to measure plasma oxybutynir and N-desethyloxybutynin concentrations over 7 days after insertion of oxybutynin vaginal rings releasing oxybutynin 2 mg/day, 4 mg/day, and 6 mg/day (as described in Example WO 2011/163358 PCT/US2011/041447 2) in 8 healthy women, aged 45 to 62 years. Results of these studies are shown in Table 2 and Table 3, respectively. Table 2, Pharmacokinetic Parameters for Oxybutynin: 2 mg/day Oxybutynin Vaginal Ring Treatment Group: Pharmacokinetic Evaluable Patients Parameters N Mean SD [Median Min-Max Observed Cmia x (ng/mL) 8 4 10 1.13 3.87 2.67-6.42 T, mx (h) 8 84 00 18.14 96.00 48.00-96.00 Estimated C,, (ng/mL) 8 .562 1.017 3.58 2.03-5.02 t, () 8 46.64 18.29 46.37 26.97-86.02 AUC,,(24 h) (h x ng/nL) 8 85.48 24.41 86.04 48.71-120.49 rate 5 | 0.0 0.02 0.06 0.04-0.08 Tma- time to maximum concentration C, concentration at steady state; ts,- time to reach steady slate; AUC_,- area under the c ure at steady slate. Table 3, Pharmacokinetic Parameters for Oxvybutynin: 4 mgidav Oxybutvnin Vaginal Ring Treatment Group: Pharmacokinetic Evaluable Patients Parameters N Mean SD Median Min-Max Observed Cmax (ng/mL) 7 10.66 10.26 7.61 4.95-3380 Tma x (h) 7 75.43 25.66 72.00 24.00-96.00 Estimated CS (n/mL) 9.29 7.26 7.24 4.54-25. 6 t+ (h) 89.35 64 84 71 29 15 0- 18.28 AUCs (24 h) (h x ng/mL) 7 222.89 174.25 173.74 108.99-608 2 rate 5 0.05 0 06 0.03 0 01 0 15 Tmar time to maximum concentration C,,- concentration at steady state; t- tine to reach steady state; AUjC,,- area under the cure at steady state.J [00101] Blood samples were drawn at designated time points over a period of 96 h1 and on Day 7. Pharmacokinetics data used in the analysis include values obtained through the 96 h time point. As indicated in Tables 2 and 3, the mean Cm..ax for oxybutynin was 4.1 ng/mL (median 3.9 ng/mL) in the 2 mg/day oxybutynin vaginal ring treatment group and 10.7 ng/mL (median 7.6 ng/mL) in the 4 mg/day oxybutynin vaginal ring treatment WO 2011/163358 PCT/US2011/041447 - 24 group. All patients in both treatment groups experienced an initial peak in their plasma oxybutynin concentrations between 1.5 h and 6 h. [00102] For N-desethyloxybutrynin, pharmacokinetic analysis identical to that completed for oxybutynin was undertaken. Results for the 2 mg/day oxybutynin vaginal ring and 4 mg/day oxybutynin vaginal ring treatment groups are presented in Tables 4 and 5, respectively. Table 4. Pharmacokinetic Parameters for N-desethyloxybutynin: 2 mg/day Oxybutynin Vaginal Ring Treatment Group: Pharmacokinetic Evaluable Patients Parameters N Mean SD Median Min-Max Observed C (ng/mL) 8 6.60 2.47 678 2.10-10.05 T ma (h1) 8 75.00 15.38 72,00 48.00-96,00 Estimated C', (ng/mIL) 6.26 2.13 6.88 L.68-8A7 8 66601 492 1 50.49 18.11-17332 A UC, (24 h) (h x na/mL) 8 150 21 55.88 165.05 40.3 5-203 16 rate 0.05 0.040 0,04 0.01-0.13 T mb- time to maximum concentration CS.- concentration at steady state; t,- time to Icaah steady state AU Cs,- area under the cure at steady state Table 5. Pharmacokinetic Parameters for N-desethyloxybutynin: 4 mg/day Oxybutynin Vaginal Ring Treatment Group: Pharmacokinetic Evaluable Patients Parameters N Mean SD Median Min-Max IObserved 1 a (h) [ 82 29 18.88 96.00 48.00-96.00 Estimated C, (ng/mL) 7 7.48 3.48 645 3.72-14.33 *,, 7J63, 39 32.44 57 71 J31.08-128.791 A UC., (24 h) (h x n/mL) 7 179.49 83.46 154.90 89.26-343.84 rate 7 0.04 0.02 0.04 0.02-0.07 T m,- time to maximum concentration C's,- concentration at steady state; t,- time to I each steady state; AU C,,- area under the cure at steady state.
WO 2011/163358 PCT/US2011/041447 - 25 [00103] Table 6 and Table 7, respectively, summarize the results of the analysis of the mean CIx for oxybutynin was 8.9 ng/mL (median 8.9 ng/mL) in the 6 mg/day oxybutynin vaginal ring treatment group. Table 6. Pharmacokinetic Parameters for Oxybutynin Vaginal Ring 6 mg/day: Pharmacokinetic Evaluable Patients Parameters N Mean SD Median Min-Max Observed Cj. (ng/nL) 8 8.90 1184 S. 94 - )631-11,80 T (h) 8 66.00 24 84 72. 00 24.00-96.00 Estimated C,, (ng/mL) 8 - 59 1.56 7,64 5,28-9,49 t,, (h) 8 23.6 6 9.78 221"5 13A1.61 I t (%/- C") (h) 8 263 4 12 121 0.61-1276 UC (24 h) (h x n/nL) 8 182,06 37,45 118335 126.65-227,76| rate 8 0.11 004 0.11 0.055-0.8 Table 7 Pharmacokinetic Parameters for N-desethloxybutynin Oxvbutynin Vaginal Ring 6 mg/day: Pharinacokinetic Evaluable Patients Parameters N Miemi SD Mledian Mm M-Nax Observed Cj, ingL) 8 16.23 4.7802 16.70 7.719 -2248 T (h) 8 82.50 21.6927 96.00 36.00 96.00 Estimated CE, L) 8 15.21 5.03 15.21 6.70-21.90 tS S (h) 8 5 6, 4 31.30 44.36 25.38-11b5 I4 t(% (h) 8 13.51 8.45 9.27 5.59-25.89 AUC,,(24 h)(h x 8 365.04 120.63 365.10 16078-525.63 n g/mL) ____ ______ rate 8 0.05 0.02 0.05 0.02--009 [001041 In these studies, seven patients experienced an initial peak in their plasma oxybutynin concentrations between 1 and 5 h. Higher concentrations of oxybutynin were reached relative to concentrations of N-desethyloxybutynin for up to approximately 4 hours after vaginal ring insertion. After 6 h, concentrations of N-desethyloxybutynin were higher than oxybutynin concentrations in most cases, and concentrations of WO 2011/163358 PCT/US2011/041447 - 26 N-desethyloxybutynin continued to gradually rise until 72 h, while oxybutynin concentrations stabilized after 48 h. [001051 The combined pharmacokinctics data suggest that 6 mg/day oxybutynin vaginal rings show a modest increase in plasma concentration of oxybutynin (measured by Cm and C,,) over 4 mg/day oxybutynin vaginal rings. The 6 mg/day oxybutynin vaginal rings is further associated with an increase in the plasma concentration of N-desethyloxybutynin over that of the 4 mg/day oxybutynin vaginal rings. Example 5 PLASMA OXYBUTYNIN CONCENTRATIONS FROM VAG NAL AD M INISTRA TION 1001061 A preliminary clinical trial compared median plasma oxybutynin concentrations from 2 mg/day, 4 mg/day, and 6 mg/day oxybutynin vaginal ring treatment groups over a 4 week period. Results are summarized in Table 8. Table 8. Comparative Pharnacokinetics for 2 mg/day, 4 mg/day, and 6 day/mg Oxybutynin Vaginal Ring Treatment Groups 2 mg/day 4 mg/day 6 mg/day oxybutynin oxybutynin oxybutynin vaginal ring vaginal ring vaginal ring Treatment Period 1 Week 1 253 ns!nL 4,67 ng/nL 6 33 ng/mnL Week 3 2.96 ng/mL 4.28 ng/mL 7 02 ng/mL Week 4 2.50 ng/mL 4.29 ng/mL 6 93 ng'mL Treatment Period 2 Week 4 2,51 ri-/m-L 4.26 nig/mi. 700 tig/mit -(Median plasma concentration ofoxyiu yr n) Example 6 COMPARISON OF STEADY STATE OXYBUTYNIN AND METABOLITE PLASMA LEVELS OF VAG NAL ADMINISTRATION VERSUS ORAL AND TRAN SDERMAL ADMINISTRATION WO 2011/163358 PCT/US2011/041447 - 27 [00107] A comparison of the steady state oxybutynin and metabolite plasma levels to those reported for the marketed overactive bladder (OAB) products OxYrRoL 3.9 mg/day (transdermal patch, Watson Pharmaceutical, Inc., Morristown, New Jersey) and DITROPAN XL* 15 mg/day (extended release oral tablet, Ortho-McNeil-Janssen Pharmaceutical, Inc., Titusville, New Jersey) was conducted in order to estimate efficacy and safety parameters. Results are presented in Table 9. Table 9. Comparative Pharinacokinetics for Oxybutynin Vaginal Ring, Extended Release Oxybutynin Chloride Oral Tablets and Transdermal Oxybutynin Oxybutynin N-Desethyloxybutynin Ratio N-Desethyloxybutynin/ Mean C., Alean C, (ng/mL) oxybutynin area under the curve) Vaginal ring 2nig/day 3.6 6.3 1.8 Vaginal rina: 4 maw/day 9.3 75 0,8 Vaginal ring 6 migday 76 15.2 2.0 DITROPAN XL oxybutynin 30 -- 35 13.2 -- 14.2 41 chloride oral tablets OXYTROL' oxybutynin 3.9 mg/day 3.1 -54 3 8 -6.3 12 [001081 Pharmacokinetic data from the oxybutynin vaginal rings was compared to pharmacokinetic data published for DITROPAN XL* extended release oral tablets and the transdernal OXYTROL* system. The oxybutynin vaginal ring produced plasma level of oxybutynin comparable to or slightly higher than those reported for DITROPAN XL* and OXYTROL (depending on the specific oxybutynin release rate for the vaginal ring being evaluated). Plasma levels of N-desethyloxybutynin in vaginal ring-treated patients were generally lower than those reported for DITROPAN XL* extended release tablets but higher than those reported for OXYTROI. For the 4 mg/day oxybutynin vaginal ring, the steady state oxybutynin level was similar to that reported for OXYTROL 4 and DITROPAN XL*. The metabolite N-desethyloxybutynin level of the 4 mg/day oxybutynin vaginal ring was similar to OXYTROLE but substantially lower than the N-desethyloxybutynin level reported for DITROPAN XL*. For the 6 mg/day oxybutynin vaginal ring, the steady state oxybutynin level was higher than that produced by either the Oxytrol* 3.9 ig/day patch or DITROPAN XL* 15 ig/day tablet. The metabolite N-desethyloxybutynin level was higher for the 6 mg/day oxybutynin vaginal ring than WO 2011/163358 PCT/US2011/041447 - 28 OXYTROL' but was still lower than the N-desethyloxybutynin level produced by DITROPAN XL*. These findings are reflected in the area under the curve ratios of N-desethyloxybutynin:oxybutynin, where oxybutynin vaginal ring ratios were similar to the ratios reported for the transdermal system but substantially lower than ratios for the extended release tablets. Example 7 STUDY OF THE SAFETY AND EFFICACY OF 4 MG/DAY and 6 MG/DAY OXYBUTYNIN VAGINAL RING [001091 A randomized, placebo-controlled clinical trial was conducted to study the safety and efficacy of an oxybutynin vaginal ring releasing either 4 mg/day, 6 mg/day (as described in Example 2) or placebo for the treatment of overactive bladder in women who had symptoms of predominant or pure urge incontinence, urinary urgency, or increased urinary frequency. 1001101 445 subjects entered the Treatment Period. The study included four periods: a Screening Period of up to two weeks, a single-blind three-week Placebo Run-In Period, a 12-week double-blind Treatment Period, and a two week Follow-up Period. There was one screening visit followed by 8 other clinic visits: two visits during the Placebo Run-in (Visit I (Placebo Run-In Week 1), Visit 2 (Placebo Run-In Week 3)) and five visits during the Treatment Period (Visit 3 (Baseline), Visit 4 (Treatment Week 1), Visit 5 (Treatment Week 4), Visit 6 (Treatment Week 8) and Visit 7 (Treatment Week 12)) There was a follow-up visit two weeks after the last Treatment Period visit (Visit 8 (Follow-up)). Randomization occurred at Visit I (start of single-blind Placebo Run-In) to ensure that subjects received visually matching Placebo and Treatment period vaginal rings. The subjects were separated into three treatment groups, either the 4 mg/day oxybutynin vaginal ring group, the 6 mg/day oxybutynin vaginal ring group, or a placebo vaginal ring group. [001111 During the study, four vaginal rings were inserted. Each used vaginal ring was replaced by a new vaginal ring at a scheduled time. Ring I was inserted at the start of Placebo Run-In period. Insertion was maintained throughout the three week Placebo WO 2011/163358 PCT/US2011/041447 Run-In period. Ring 2 was inserted at Visit 3 (Baseline). The vaginal ring was replaced one month thereafter: Ring 3 was inserted at Visit 5 (Treatment Week 4) and Ring 4 was inserted at Visit 6 (Treatment Week 8). This final vaginal ring was removed at Visit 7 (Treatment Week 12/Premature Discontinuation). 1001121 384 subjects (132 on the 4 mg/day oxybutynin vaginal ring, 119 on the 6 mg/day oxybutyni vaginal ring, and 133 on placebo vaginal ring) were included in the intention to-treat (ITT) cohort, having provided baseline data and at least one valid post-baseline assessment of the number of incontinence episodes. The modified intent-to- treat cohort (MITT) consisted of ITT patients who met all three criteria for the definition of overactive bladder at baseline (Visit 3), i.e., predominant or pure urge incontinence consisting of >10 pure or predominant discrete urge incontinence episodes per week, and average urinary frequency of >8 voids per 24 hours and average total void of < 3.9 L per 24 hours. The MITT cohort included 323 subjects. The PPC cohort further excluded patients with significant protocol deviations. Among the 384 ITT patients, 61 patients were excluded from the MITT cohort because they failed to meet at least one of the criteria at baseline. [001131 Dose selection for this study was established by pharmacokinetic studies conducted with the oxybutynin vaginal ring at doses of 2 mg/day, 4 mg/day, and 6 ing/day. See Examples 4 and 5. [001141 The primary measure of efficacy was the change from Visit 3 (Baseline) to Visit 7 (Treatment Week 12 Premature Discontinuation) in the total weekly number of incontinence episodes (stress plus urge), calculated by converting the total number of incontinence episodes (stress plus urge) occurring during the 3 consecutive OAB diary days prior to Visits 3 and 7 to a weekly-based number of episodes. Secondary efficacy measurements included the change from Visit 3 (Baseline) to Visit 7 (Treatment Week 12 /Premature Discontinuation) for the following: average daily urinary frequency, the proportion of subjects with no incontinence episodes recorded in the final 3-day diary, the average void volume, and average severity of urgency. [001151 The baseline characteristics number and percentage of subjects assigned to each of the analysis cohorts by treatment group are shown in Table 10.
WO 2011/163358 PCT/US2011/041447 - 30 Table 10. Subject Baseline Characteristics Placebo Oxy 4 ng Oxy 6 ng Total Intent-to-Treat (ITT) 133 132 119 384 Modified ITT (MITT) 112 115 96 323 Exclusion from MITT* 21 17 23 61 Baseline Incontinence 10 7 8 25 Baseline Urinary Frequency 5 8 8 21 Bas,-eline Void Volume 728 1 Per-Protocol Completers (PPC) 71 81 64 216 Exclusion from PPC* 41 34 32 107 Did Not Complete Study 7 5 6 18 Visit 7 Occurred Before 3 1 0 4 Day 74 Use of Prohibited 34 28 24 86 Medications** Protocol Deviations 2 7 5 14 *A subject may be excluded due to more than one deviation. ** Based on verified list of prohibited medications. [00116] Among the 384 ITT subjects, 61 subjects (15.9%) were excluded from the MITT cohort because they failed to meet at least one of the following criteria at baseline: > 10 incontinence episodes per week, an average urinary frequency < 8 voids per day, and an average total void volume < 3.0 liters per day. A total of 25 of the 61 excluded subjects (41%) had < 10 incontinence episodes at baseline, 21 subjects (34.4%) had urinary frequency of < 8 voids per day, and 17 subjects (27.9%) had void volume > 3.0 liters per day. [00117] The Per-Protocol Completers (PPC) cohort consisted of 56.3% of the number of subjects included in the ITT cohort (216 PPC compared to 384 ITT subjects) and 66,.9% of the number of MITT subjects (216 of 323 MITT subjects). Subjects excluded from the PPC Cohort (86 subjects) included those who violated study procedures. [00118] Table 11 sunmarizes the results of the analysis of the mean reduction in the number of incontinence episodes from baseline to the end of treatment for the ITT cohort.
WO 2011/163358 PCT/US2011/041447 -31 Table 11 Primary Outcome Analysis - ITT Cohort: Total Weekly Number of Incontinence Episodes: Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** OXY 4 mg 132 26.34 -15.38 16.12 0.0613 OXY 6 nig 119 25.12 -15.18 16.24 -2.02 0.1850 Placebo 133 26.44 -13,16 14.65 Treated * Change = Change in Total Weekly Number of Incontinence Episodes (Visit 3 to Visit 7 (or End-of TDireren)ce = Difference between active treatment group and placebo. * P-Value: Significance between active treatment groups and placeo was tested on raw data analysis. [001191 Results show both the 4 mg/day oxybutynin vaginal ring and 6 mg/day oxybutynin vaginal ring groups had greater mean reductions in the total weekly number of incontinence episodes than the placebo vaginal ring group; for the 4 tug/day oxybutynin vaginal ring group, this result approached significance (p=0.0613). The treatment effect observed for the 6 mg/day oxybutynin vaginal ring was approximately the same as the 4 mg/day oxybutynin vaginal ring. [001201 Any subject with qualifying values at baseline for all three principal inclusion criteria (> 10 incontinence episodes per week, an average urinary frequency > 8 voids per day, and an average total void volume < 3.0 liters per day) could have been considered as presenting with an etiology of pure urgency. Therefore, in an additional evaluation of the number of incontinence episodes, defined prior to breaking the blind and before finalizing the study database, an MITT (Modified Intent-to-Treat) cohort, that included this specific group of subjects, was defined. Although not considered the principal cohort for the evaluation of efficacy, the MITT cohort could be viewed as the most representative sample of subjects with OAB since it encompassed that group with the most well-defined set of attributes associated with a clinical presentation of OAB for clinical trials of new treatments. [001211 Table 12 highlights the efficacy analysis of the reduction in the number of incontinence episodes from baseline to the end of treatment for the MITT cohort.
WO 2011/163358 PCT/US2011/041447 - 32 Table 12. Primary Outcome Analysis - Modified MITT Group Cohort: Total Weekly Number of Incontinence Episodes: Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4mg 115 28.34 -16 76 16.45 -2.99 0.0364 Oxy 6 mg 96 26.52 -16.70 1430 -2.93 0.0176 Placebo 112 28.25 13.77 14.50 * Change = Change in Total Weekly Nurnber of incontinence Etpisoces (Visit 3 to Visit 7(o End-of Treatment)). ** Difference = Difference between active treatment group and placebo. ***' P -Value: Significance between active treatment groups and placebo was tested on raw data analysis. [001221 Results suggest statistically significant treatment effects favoring the 4 mg/day and 6 mg/day oxybutynin vaginal rings over placebo in this highly symptomatic group of subjects, with the 6 mg/day oxybutynin vaginal ring exhibiting an effect that is the same as that observed for the 4 mg/day oxybutynin vaginal ring group. Thus, the lower dose of 4 mg/day was sufficient to reduce the number of total weekly incontinence episodes. The MITT cohort results may represent the most clinically meaningful outcome associated with the oxybutynin vaginal ring because subjects in this cohort met the protocol specified definition of clinical signs and symptoms of primarily urge incontinence, i.e., at baseline (Visit 3), all MITT subjects met the required criteria for the weekly number of incontinence episodes, urinary frequency, and void volume. 1001231 The PPC cohort summary statistics support the observed treatment effects for both active oxybutynin rings doses, with the observation that the 6 ig/day ring vaginal ring appears to provide no incremental benefit above that seen for the 4 mg/day vaginal ring. [001241 Table 13 and 14 present descriptive statistics for the ITT cohort by menopausal status. The randomization was stratified by menopausal status, but subset analysis of each group was not planned. Therefore, although p-values were calculated, they were not based on any pre-specified hypothesis. The number of pre-menopausal patients in the study was substantially fewer than the number of menopausal patients. [001251 For pre-menopausal patients, the patients in the 6 mg/day oxybutynin vaginal ring group and placebo group responded similarly, while patients in the 4 mg/day oxybutynin WO 2011/163358 PCT/US2011/041447 - 33 vaginal ring group did not see as great a decrease in total number of incontinence episodes. Table 13: Primary Outcome Analysis (Pre-menopausal Patients) - ITT Cohort: Total Weekly Number of Incontinence Episodes: Change from Baseline (Visit 3) to End of Treatment (Visit 7) Treatments N Baseline Mean Standard Difference** Change* Deviation 4 mg/day oxybutynin ring 35 30.53 -14.73 19.49 2.38 6 mg/day oxybutynin ring 25 28.00 -17.55 | 18.00 -0.44 ------------------------------------------------------------------------------------------- ----------------------------------- Placebo 30 27.84 -17.11 | 15.88 *Change = Change in total weekly ntIber of incontinence Episodes (Visits 3 to Visit 7). ** Difference = Difference between active treatment group and placebo. [001261 Menopausal patients demonstrated a larger reduction in total number of incontinence episodes when randomized to 4 mg/day and 6 mg/day oxybutynin vaginal rings as opposed to placebo. Table 14: Primary Outcome Analysis (Menopausal Patients) - ITT Cohort: Total Weekly Number of Incontinence Episodes: Change from Baseline (Visit 3) to End of Treatment (Visit 7) Treatments N Baseline Mean - Standard Difference** Change* Deviation 4 mg/day oxybutynin ring 97 24.82 -15.61 14.8 -3.60 6 mg/day oxybutynin ring 94 24.35 -14.55 15.78 -2.54 Placebo 103 26.03 -12.01 14.14 *Change = Change in total weekly number of Incontinence Episodes (Visits 3 to Visit 7). ** Difference = Difference between active treatment group and placebo [001271 For MITT and PPC cohorts, pre-menopausal patients did not show any additional reduction in total number of incontinence episodes for the 4 mg/ml and 6 mg/day groups compared to placebo. Menopausal patients in the MITT and PPC cohorts continued to show differences in the reduction of total number of incontinence episodes for the 4 mg/day and 6 mg/day groups compared to placebo. See Tables 15 and 16.
WO 2011/163358 PCT/US2011/041447 - 34 Table 15: Primary Outcome Analysis (Pre-menopausal Patients) - MITT Cohort: Total Number of Incontinence Episodes: Change from Baseline (Visit 3) to End of Treatment (Visit 7) 'Treatments N Base line Mean Standard Difference** Change* Deviation 4 mg/day oxybutynin ring 28 33.75 -16.33 1i 10 1.40 6 mg/day oxybutynin ring 21 29.44 -17,89 19.46 -0,16 Placebo 25 29.96 -17.73 16,68 *Change = Change in total number of Incontinence Episodes (Visits 3 to Visit 7). ** Difference = Difference between active treatment group and placebo. Table 16: Primary Outcome Analysis (Menopausal Patients) - MITT Cohort: Total Number of Incontinence Episodes: Change from Baseline (Visit 3) to End of Treatment (Visit 7) Treatments N Baseline Mean Standard Difference** Change* Deviation 4 mg/day oxybutynin ring 87 26.61 -16.90 14 79 -4.27 6 mg/day oxybutynin ring 75 25.70 -16,36 12. 64 -3 73 Placebo 87 27. 76 -12.63 13 71 *Change = Change in total number of Incontinence Episodes (Visits 3 to Visit 7). ** Difference = Difference between active treatment group and placebo [001281 Table 17 sumnmarizes the findings associated with analysis for the total weekly number of incontinence episodes in the ITT cohort at each individual study visit. For the 4 mg/day oxybutynin vaginal ring, an observable treatment effect at day 28 (Visit 5) is slightly increasing at day 56 (Visit 6). This effect decreases somewhat at day 84 (Visit 7), A similar result was observed fro MITT cohort. For 6 mg/day oxybutynin vaginal ring, the initial treatment effect at day 28 was somewhat smaller at day 56, but then increased substantially at the end of treatment, for both ITT and MITT cohorts.
WO 2011/163358 PCT/US2011/041447 - 35 Table 17: Secondary Outcome Analysis -- ITT Cohort: Total Weekly Number of Incontinence Episodes (stress plus urge): Change from Baseline (Visit 3) to Subsequence Visit Change Treatments N Mean Standard Difference- F from Change, Deviation . Ivalue*... Baseline to Day 28/ 4 mg/day 119 -12.33 13.964 -2.43 0.2553 Visit 5 oxybutynin ring 6 mg/day 101 -13.01 13.406 -3.11 0.0824 oxybutynin ring Placebo 115 -9.90 13.406 Day 56/ 4 mg/day 118 -14.83 14.816 -2.67 0.0997 Visit 6 oxybutynin ring 6 mg/day 107 -13.26 15.208 -1.10 0. 1252 oxybutynin ring Placebo 118 -12.16 13.540 *Change Ch range in total Weekly nurnber of incontinence Episodes (Visits 3 to subsequent visits). ** Dii-ffernce = Difference between active treatment group and placebo. * P-value = Significance between active treatment group and placebo was tested on raw data analysts. [001291 Table 18 and Table 19 summarize the findings of the total ntimber of urge incontinence episodes for the ITT and MITT cohorts, respectively. Table 18. Secondary Outcome Analysis - ITT Cohort: Total Number of Urge Incontinence Episodes: Change ftom Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** OXY 4mg 132 24 18 -15.13 15.393 -2.80 0.0558 OXY 6 ig 119 23.06 -14.90 14.950 -2.57 0 1803 Placebo 133 23.88 -12.43 14.311 Treated * Change = Change in Totai Number of Urge Incontinence Episodes (Visit 3 to Visi 7 (or End of-Treatnient)). ** Difference= Difference between active treatment group and placebo. SP-Valiue: Sinificance between active treatment groups and placebo was tested on rw data analysis.
WO 2011/163358 PCT/US2011/041447 - 36 Table 19. Secondary Outcome Analysis - MITT Cohort: Total Number of Urge Incontinence Episodes: Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference* P-Value*** Oxy 4 mg 115 25.99 -16.37 15.753 -3.29 0.0544 Oxy 6 ng 96 24.28 -16.38 13.380 -3.30 0.0223 Placebo 112 2563 -13.08 14,439 * Change = Change in Total Number of Urge Incontinence Episodes (Visit 3 to Visit 7 (or bnd-of Treatment)). ** Difference Difference between active treatment group and placebo. * P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. [00130] Both tre. atment groups demonstrated a reduction in the weekly number of urge only incontinence episodes to a greater extent than the placebo group. Compared to placebo, the 4 mg/day oxybutynin vaginal ring (p=0.0558 for the ITT and p=0.0544 for the MITT cohort) experienced fewer urge-only incontinence episodes while the 6 mg/day oxybutynin vaginal ring in the MITT cohort (p=0.0223) experienced fewer urge-only incontinence episodes. As indicated for the total incontinence episode endpoint, the 6 mg/day oxybutynin vaginal ring provided no additive treatment effect compared to the 4 mg/day oxybutynin vaginal ring, but both oxybutynin vaginal rings demonstrated a greater magnitude of reduction of urge-only episodes compared to placebo for the MITT cohort (a differential reduction of 3.3 episodes greater than what was observed for placebo). [001311 The analysis of urge incontinence episodes was investigated by menopausal status and is presented in Tables 20 and 21 for the MITT cohort. Results were consistent with what was observed when considering the primary efficacy endpoint, the total weekly number of incontinence episodes. The magnitude of the difference in the mean reduction of urge-only incontinence episodes was greater for both oxybutynin vaginal rings groups in the MITT cohort compared to the ITT cohort.
WO 2011/163358 PCT/US2011/041447 - 37 Table 20. Secondary Outcome Analysis (Pre-Menopausal Patients) MITT CohortTotal Number of Urge Incontinence Episodes: Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** Oxy 4 rmg 28 30.17 -1 583 19.864 -0,06 Oxy 6 mg 21 27.33 -744 18.893 -1.67 Placebo 25 27.16 -15.77 16.92 4 * Change = Change in Total Number of Urge Incontinence Episodes (Visit3 to Visit 7 (or End-of Treatment)). ** Difference = Difference between active treatment group and placebo. Table 21. Secondary Outcome Analysis (Menopausal Patients) MITT Cohort:Total Number of Urge Incontinence Episodes: Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** Oxy 4 tmg 87 24.65 -16.55 1.316 -4.24 Oxv 6 mg 75 23,43 -1608 11,531 -3,77 Placebo 87 25.18 -12 31 13655 * Change = Change in Total Number of Urge Incontinence Episodes (Visit 3 to Visit 7 (or End-of Trealtment)) ** Differen-ce = Diffrence between active r"atgi oup gmd placebo. [001321 Tables 22 and 23 summarize the findings associated with analysis for the total weekly number of urge incontinence episodes in the ITT and MITT cohorts, respectively, at individual study visits. In both cohort analyses, 4 mg/day oxybutynin vaginal rings were shown to provide a relatively consistent reduction in the weekly number of urge only episodes compared to placebo that continued through to the end of treatment. For 6 mg/day oxybutynin vaginal ring, an initial larger differential effect was observed at day 28 then diminished at day 56, which then rebounded somewhat at the end of treatment. The 6 mg/day reduction overall, however, was no greater than that observed for the 4 mg/day group. Table 22: Secondary Outcome Analysis - ITT Cohort: Total Weekly Number of Incontinence Episodes (urge only): Change from Baseline (Visit 3) to subsequence visits Change Treatments N Mean Standard Difference** P Change* Deviation value*** Baseline to Day 28/ 4 mg/day 119 -11.90 14.178 -2.87 0.2926 Visit 5 oxybutynin ring WO 2011/163358 PCT/US2011/041447 - 38 6 mg/day 101 -13.65 | 12,947 -4.62 0,0286 oxybutynin ring Placebo 115 -9.03 13.27 Day 56/ 4 mg/day 118 -14.47 14005 -3.08 0.0501 Visit 6 oxybutynin ring 6mg/day 107 -13.69 13.27 -2.30 0.0221 oxybutynin ring Placebo 118 -11,39 13.080 *Change = Change in total weekly number of Incontinence Episodes (urge only) (Visits 3 to subsequent visits). * Difference = Difference between active treatment group and placebo. *** P-value = Significance between active treatment group and placebo was tested on raw data analysts. Table 23: Secondary Outcome Analysis - MITT Cohort: Total Weekly Number of Incontinence Episodes (urge only): Change from Baseline (Visit 3) to subsequence visits Change Treatments N Mean Standard Difference** P from Change* Deviation value*** Baseline to Day 28/ 4 mg/day 103 -12.57 148 -3.09 0,0669 Visit 5 oxybutynin ring 6 mg/day 83 -14.56 12.804 -5.08 0.0042 oxybutynin ring Placebo 98 -9,48 13.530 Day 56/ 4 mg/day 103 -15.50 14.346 -3.28 0.0359 Visit 6 oxybutymn ring 6 mg/day 87 -14.43 13 091 -2.21 0.0144 oxybutynin ring Placebo 101 -12.22 12 ,734 *Change = Change in total weekly number of incontinence Episodes (urge only) (Visits 3 to subsequent visits). ** Difference = Difference between active treatment group and placebo. * P-vahie = Significance between active treatment group and placebo was tested on raw data analysts. [001331 Table 24 summarizes the findings associated with the analysis of the change from baseline to end-of-treatment for the average daily urinary frequency in the subjects who were treated.
WO 2011/163358 PCT/US2011/041447 - 39 Table 24. Secondary Outcome Analysis - ITT Cohort:Average Daily Urinary Frequency: Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** OXY 4 mg 132 11.36 -1.70 2,806 -0.60 0.0722 OXY 6 mg 119 10 82 -2.03 2.771 -0.93 0.0004 Placebo 1 1 1. 24 -1.10 2.730 Treated * Chne=Cag n Average DaIs.i Uriary Frequency (Visit 3 to Visit 7 (or End-oT Ireatmnt)f). ** Difference = Difference between active treatment group and placebo. *** P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. [001341 All treatment groups demonstrated a statistically significant reduction in the average daily urinary frequency. In the ITT cohort, the 6 mg/day oxybutynin vaginal ring demonstrated a statistically significant reduction (p=0.0004) in average daily urinary frequency from baseline to end-of-treatment compared to placebo. The 4 mg/day oxybutynin vaginal ring also demonstrated reduction in average daily urinary frequency when compared to placebo that approached significance (p=0.0722). [001351 Analysis for the MITT cohort (Table 25) yielded similar results. Table 25. Secondary Outcome Analysis - MITT Cohort: Average Daily Urinary Frequency: Change from Baseline (Visit 3) to End of-Treatment (Visit 7) Meanti Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 115 11.60 -1.80 2.839 -0.7 0.1039 Oxy 6 mg 96 11.01 -2.10 2.918 -1.0 0.0020 Placebo 112 1132 -1.10 2.746 Change = Change in Average Daily Urinary Frequency (Visit 3 to Visit 7 (or End-of-Treatment)). ** Difference = Difference between active treatment group and placebo. *** P-Vaue: Significance between active treatment groups and placebo was tested on raw daa analysis. [001361 Analysis of average void volume in mL for the ITT and MITT cohorts is presented in Tables 26 and 27, respectively. In both cohorts, all three treatment groups showed very little difference in daily average void. volume from baseline (Visit 3) to End of-treatment. Neither the 4 mg/day nor the 6 mg/day significantly increased daily average void volume compared to placebo.
WO 2011/163358 PCT/US2011/041447 - 40 Table 26. Secondary Outcome Analysis - ITT Cohort: Daily Average Void Volume: Change from Baseline (Visit 3) to End-of Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 tmg 131 1597,89 -73,55 523.862 1977 O6300 Oxy 6 mg 117 1712.96 -10803 632.052 -14,71 0.7 72 Placebo 132 1750.64 -93.32 646.620 * Change = Change in Average Daily Average Void Volume (Visit 3 to Visit 7 (or End-of-Treatment)). ** Diffrence = Difference between active treatment group and placebo. SP -Value: Significance between active treatment groups adpceowsttdenrwnantYSis Table 27. Secondary Outcome Analysis - MITT Cohort: Daily Average Void Volume: Change from Baseline (Visit 3) to End-of Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mug 114 1630.60 -100.75 487.074 -58.86 03969 Oxy 6 mg 94 1632.90 -55.42 587,371 -13,5.3 0.8301 Placebo 111 1627.5 -41.89 564.552 * Change = Change in Average Daily Void Volume (Visit 3 to Visit 7 (or End-of-Treatmtent)). * Difference = Difference between active treatment group and placebo. ** P-Value: Significance between active treatment groups and placebo was tested on raw data anatysis. [00137] Table 28 summarizes the findings associated with analysis of the change from baseline to end-of-treatment for the average void volume per void in the subjects who were treated. Table 28. Secondary Outcome Analysis - ITT Cohort: Average Void Volume Per Void: Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** OXY 4 mg 131 53.06 5.19 15.398 3.44 0.2134 OXY6 mg 117 59.49 7.07 19.821 1 532 0.0126 Placebo 132 58,63 1,75 16,981 Treated WO 2011/163358 PCT/US2011/041447 -41 Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** *Change = Change in Average Void Volume Per Void (Viisit 3 to Visit 7 (or End -of-Treatmient)). Difference = Difference between active treatment group and placebo. ***P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. [001381 The 6 mg/day oxybutynin vaginal ring demonstrated a significantly greater increase in the average volume per void as compared to placebo. The 4 mg/day oxybutynin vaginal ring also demonstrated. a reduction, although not significant, in the average volume per void as compared to placebo. [001391 Tables 29 and 30 summarize the findings associated with analysis of the change from baseline to end-of-treatment for the average severity of urgency in the ITT and MITT cohorts, respectively. Table 29. Secondary Outcome Analysis - ITT Cohort: Average Severity of Urgency: Change from Baseline (Visit 3) to End-of Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** OXY 4 mg 132 18.78 -3.59 6.648 -1.01 0.2234 OXY 6 mg 118 1 .90 -4.38 6.493 -1 80 0.0065 Placebo 133 1 857 -2.58 5.663 Treated * Change = Change in Average Daily Severity of Urgency (Visit 3 to Visit 7 or End-of-Treatment)). ** Difference = Difference between active treatment group and placebo. *** P-Value: Significanec between active treatment groups and placebo was tested on raw data analysis. Table 30. Secondary Outcome Analysis - MITT Cohort: Average Severity of Urgency: Change from Baseline (Visit 3) to End-of Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 rg 115 1926 -3.59 6.505 -1.16 0.2730 Oxy 6 mg 96 18.07 -4.20 6.0 1.7 0.026 Placebo 112 . 18 59 -2.43 5,461 * Change = Change in Average Daily Severity of Urgency (Visit 3 to Visit 7 (or End-of-Treatment)). * difference = Difference between active treatment group and placebo. *** P-Value: Significance between active treatment groups and placebo was tested on raw data analysis.
WO 2011/163358 PCT/US2011/041447 - 42 [00140] In the ITT cohort, both oxybutynin vaginal ring groups showed differentially greater reductions compared to placebo; for 6 mg/day oxybutynin vaginal ring this difference was statistically significant (p=0.
0 06 5 ). The MITT cohort gave similar results to the ITT cohort. 1001411 Tables 31 and 32 summarize the findings associated with analysis of the proportion of subjects with no incontinence episodes recorded in the Final 3-day diary at the end-of treatment visit for the ITT and MITT cohorts., respectively. Table 31. Secondary Outcome Analysis - ITT Cohort: Proportion of Subjects with no Incontinence Episodes Recorded in Final 3 Day Diary Treatments /b P-Vaiue* Oxy 4 mg (35/132) 26.52% 0.1476 Oxy 6 mug (35/119) 29.41% 0.0602 Placebo (25/133) 18.80% * Based on stratified Cochran-Mate-Haense tests between active treatment and placebo. Table 32. Secondary Outcome Analysis - MITT Cohort: Proportion of Subjects with no Incontinence Episodes Recorded in Final 3 Day Diary Treatments %0 P-Vaiue* Oxy 4 mg (29/115) 25.22% 0.0258 Oxy 6 mg (25/96) 26.04% 0.0269 Placebo (15/112) 13.39% * Based on stratified Coehran-MateHaenszei tests between active treatment and placebo. [001421 In the ITT cohort, both 4 mg/day oxybutynin vaginal ring (26.52%) and 6 mg/day oxybutynin vaginal ring (29.41%) had larger proportions of subjects compared to placebo (18.80%) who reported no incontinence episodes at the end-of-treatment Visit. For the MITT cohort, the proportions of subjects reporting no incontinence episodes at the end of treatment was substantially less for subjects receiving placebo (13.39%), leading to statistically significant differences favoring both 4 mg/day oxybutynin vaginal ring (p=0.0258) and 6 mg/day oxybutynin vaginal ring (p=0.0269).
WO 2011/163358 PCT/US2011/041447 - 43 [001431 Visual Analogue Scale (VAS) was recorded using a 100 nm scale, marked off in 10 segments. One end of the scale had the anchor "absence of symptoms" while the other end had. the anchor "unbearable symptoms." The patients were asked to circle a line on the scale indicating the best reflection of her subjective symptoms associated with overactive bladder overlooking the time window of the last 4 weeks, with 1 being the best and 10 being the worst. [001441 Results of the analysis in VAS from baseline (visit 3) to End-of-Treatment for the ITT cohort are present in Table 33. For the ITT cohort, both the 4 mg/day oxybutynin ring (=0.0199) and the 6 mg/day oxybutynin ring (p=0.0012) achieved significance in reducing the VAS compared to placebo. Results were similar for the MITT cohort where both the 4 mg/day oxybutynin ring (p=0.0374) and the 6 mg/day oxybutynin rings (p=0.0045) achieved significance compared to placebo as well. Table 33. Secondary Outcome Analysis - ITT Cohort: VAS: Change ftom Baseline (Visit 3) to End-of-Treatment (Visit 7) * Mean Standard6 Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 131 5.77 -1.79 2901 -0.52 0.0199 Oxy 6 mg 117 6.43 -2.50 2.674 -1.23 0.0012 Placebo 131 6.03 1 27 2605 * Change = Change in VAS (Vii 3 to Vis't 7 (or End-of-Treatment)) * Difference = Difference between active treatment group and placebo. *** P-Value: Significan ce between active teatient groups and placebo was tested on raw data analysis. 1001451 Urinary Distress Inventory (UDI) was a list of 19 symptoms described by people who have bladder problems and/or who experience urine leakage. Patients filled out the UDI, indicating which symptoms they had experienced in the past 4 weeks and, of those, how bothersome they were. The scale to assess how bothersome the symptoms were ranged from 0 to 3, 0 for "not at all," 1 for "slightly", 2 for "moderately", and 3 for "greatly." Analysis results of the change from baseline (Visit 3) to end-of-treatment (Visit 7) for all 19 questions for the ITT cohort are presented below. [001461 For the ITT cohort, statistically significant differences between the treatment groups and placebo were found in the assessment of the 6 different symptoms from the mean change from baseline (Visit 3) to end-of-treatment (Visit 7). Both the 4 mg/day and WO 2011/163358 PCT/US2011/041447 - 44 6 mg/day oxybutynin vaginal rings achieved statistical significance compared to placebo for reducing the experience of frequent urination (4 mg/day p=0.0016, 6 mg/day p = 0.0007), the strong feeling of urgency to empty bladder (4 mg/day p =0.0277, 6 n/day p=0.0028), the experience of urine leakage related to the feeling of urgency (94mg/day p:=0.0091, 6 mg/day p 0.0025), the experience of small amounts of urine leakage (4 mg/day p =0.0056, 6 mg/day p=0.226), and the experience of large amounts of urinary leakage (4 mg/day p=0.0260, 6 mg/day p=0.0030). For the experience of nighttime urination, 4 mg/day (p=0.0100) achieved a significant reduction compared to placebo, whereas 6 mg/day (p=O.07 3 2 ) approached significance. Tables 34-52 show the analysis of each question in the UDI for the ITT cohort. Table 34. Secondary Outcome Analysis - ITT Cohort: UDI - Did you Experience Frequent Urination? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Chanue* Deviation Difference** P-Value*** Oxy 4 mg 130 1.88 -0,76 1,112 -0.31 0.0016 Oxy 6 ng 119 2.14 -0.94 1.122 -0.49 0.0007 Placebo 130 2.00 -0.45 0.943 Change = Change in severity of UDI --- Did you Experience Frequent Urination? (Visit 3 to Visit 7 (or End of-Treatment)). * Difference = Differencc between active reaInent group and placebo. *** P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. Table 35. Secondary Outcome Analysis - ITT Cohort: UDI -A Strong Feeling of Urgency to Empty Bladder? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 131 1.79 -0.55 1.097 -0.2 0.0277 Oxy 6 mg 119 203 077 1.093 -0.42 0.0028 Placebo 132 1.89 -0.35 0.894 Chance = Cange in severity of UI -) A Strong Feeling of Urgency to Empty Bladder? (Visit 3 to Visit 7 (or End-of-Treatment)), ** Difference = Difference between active treatment group and placebo. *** P-Value: Significancelbetween active tratment groups and placebo was tested on raw data analysis.
WO 2011/163358 PCT/US2011/041447 - 45 Table 36. Secondary Outcome Analysis -- ITT Cohort: UDI - Did You Experience Urine Leakage Related to the Feeling of Urgency? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 132 1 76 -0.73 1.173 -0.25 0.0091 Oxy 6 mg 119 1.91 -0.87 1.062 0.39 0.0025 Placebo 133 185 -0,48 1,052 * Change = Change in severity of UDI - Did 'ou Experience Urine Leakage Related to the Feeling of Urgency? (Visit 3 to Visit 7 (or End-of- Tratiment)). * Difference = Difference between active rtnent group and placebo. *** P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. Table 37. Secondary Outcome Analysis -- ITT Cohort: UDI - Did You Experience Urine Leakage Related to Physical Activity, Coughing or Sneezing Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 132 0 76 -0.14 0.898 01 0.5409 Oxy 6 mg 118 0.90 -0.22 0.878 0.02 0.6632 Placebo 133 0U86 -0,24 0,909 * Change = Change in severity of UDI - Did You Experience Urine Leakage Related to Physical Activity, Coughing or Sneezing? (Visit 3 to Visit 7 (or End-of-Treatment)). * Differ-nce = Difference between active trealxtent group and placebo. *** P-Value: Significanee between active treatment groups and placebo was tested on raw data analysis. Table 38. Secondary Outcome Analysis -- ITT Cohort: U DI - Did You Experience Urine Leakage Not Related to Urgency or Activity? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 130 0.68 -0.16 0.922 -0.01 0.8660 Oxy 6 mg 119 0.71 -0.34 1.020 -0.19 0.1151 Placebo 131 0.65 -0.15 0.949 * Change = Change in seventy of UI) -- Did You Experience Urine Leakage Not Related to Urgency or Activity?, (Visit 3 to Visit 7 (or End-of-Treatment)). ** Difference = Difference betw cen active treatment group and placebo. **P.-Vaue: Signiicance between active treatment groups tnd plcbo wads teted ott ra-w daa analysis.
WO 2011/163358 PCT/US2011/041447 - 46 Table 39. Secondary Outcome Analysis -- ITT Cohort: UDI - Did You Experience Small Anounts of Lakage (i.e., Drops)? Change fr Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard 1 Treatments N Baseline Change* Deviation Difference** P-Value* Oxy 4 ng 130 1.42 -0.57 1 .092 -0.34 0.0056 Oxy 6 mg 118 1.46 -0.56 0.966 -0.33 0.0226 Placebo 133 132 0.23 1.016 * Change = Change in severity ofUDI -- Did You Exnerience Smiali Anounts of Leakage (i.e., Drops)? (Visit 3 to Visit 7 (or End-of-Treatnen)). ** Difference = Difference betwen active treatment group and placebo. *' P-Value-7 Significance between active treatment groups Ind placebo wxas testeud on raw d~lta anivls. Table 40. Secondary Outcome Analysis - ITT Cohort: UDI - Did You Experience Large Amounts of Urinary Leakage? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 132 1 .02 -0.46 1.322 -0.06 0.0200 Oxy 6 mg 119 1 25 -0,70 1,219 -0.3 0.0030 Placebo 132 1.3 -0.40 1.043 * Change = Change ir severity of UDI - Did You Experience Large Amounts of Urinary Leakage? (Visit 3 to Visit 7 (or End-o Treaim ient)). * Difference = Difference between active treatment group and placebo. *** P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. Table 41. Secondary Outcome Analysis - ITT Cohort: UDI - Did You Experience Nighttime Urination Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 130 1 .54 -0.55 1.057 -0.25 0.0100 Oxy 6 mg 118 169 -0.54 1.107 -24 0.0732 Placebo 133 1.63 -0.30 0.847 * Change = (hange in severity of UDI -- Did You Experience Nighttime Uriaion (Visit 3 to Visit 7 (or End-of-Treatment)). ** Difference = Difference between active treatment group and placebo. *-** P-Value: Significanice between active treatment groups and placebo was tested on raw data analysis.
WO 2011/163358 PCT/US2011/041447 - 47 Table 42. Secondary Outcome Analysis -- ITT Cohort: UDI - Did You Experience Bed Wetting? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standd 6 Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 132 0.17 -0.05 0.537 0.01 1.0000 Oxy 6 mg 119 0.18 -0.08 0.5551 0 0.5169 Placebo 133 0.23 -0.08 0.488 Change = Change in severity of UI Did You Experience Bed Wetting? (Visit 3 to Visit 7 (or End-of Treatment)). ** Difference = Difference between active treatment group and placebo. SP-Vaiuec Significance between active treatment groups and placebo was tested on raw data anillvsis. Table 43. Secondary Outcome Analysis - ITT Cohort: UDI - Did You Experience Difficulty Emptying Your Bladder? Change from Baseline (Visit 3) to End-of-Treatnent (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 131 0.29 -0.07 0.647 -0.03 0.5941 Oxy 6 mg 119 0 24 -0,03 0,559 -0.01 0.7669 Placebo 133 0.29 -0.04 0.558 * Change = Change in severity of UDI - Did You Experience Difficulty Emptying Your Bladder? (Visit 3 to Visit 7 (or End-o- Treatment)). * Difference = Difference between active treatment group and placebo. ***' P-Value: Significance between active treatment groups nd placebo was tested on rw data analysis. Table 44. Secondary Outcome Analysis - ITT Cohort: UDI - Did You Experience Feeling of Incomplete Bladder Emptying? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 ng 132 0.70 -0.27 0.839 -0.1 0.9700 Oxy 6 mg 119 066 -0.32 0.712 -0.15 0.2430 Placebo 133 C.55 -0.17 0.746 Change = Change in severity of UDI Did You Experience Feeling of Incomiplete Bladder Emptying? (Visit 3 to Visit 7 (or End-of-Treatment)). ** Difference = Difference between active treatment group and placebo. ~'~'P-Value: Siatti Fiess c belst en active treatitteCnt groups attd placebo wais tested on raw data analysis.
WO 2011/163358 PCT/US2011/041447 - 48 Table 45. Secondary Outcome Analysis -- ITT Cohort: UDI - Did You Experience Lower Abdominal Pressure? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standd 6 Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 130 0.36 -0.19 0.648 0.11 0.6737 Oxy 6 mg 119 0.42 -0.23 0.718 0.09 0.6136 Placebo 133 0.50 -0.32 0.724 * Change = Change in seCven o f UDI [ Did You Experience Lower Abdominal Pressure? (Visit 3 to Visit 7 (or End-of-Treatment)). ** Difference = Difference between active treatment group and placebo. *' P-Vaiuec Significance between aIctive treatment groups inc placebo was tested on raw data anivlsis. Table 46. Secondary Outcome Analysis - ITT Cohort: UDI - Did You Experience Pain When Urinating? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 131 0.02 0.02 0.290 0.02 0.6638 Oxy 6 mg 119 0.07 -0,03 0,389 -0.03 0.8220 Placebo 132 0.03 0.00 0.175 * Change = Change in severity of UDI - Did You Exnerience Pain When Urinating? (Visit 3 to Visit 7 (or End-of-Treat ment)). * Difference = Difference between active treatment group and placebo. * P-Value: Significance between active treatment groups ad pa cebo was tested on raw data analysis. Table 47. Secondary Outcome Analysis - ITT Cohort: UDI - Did You Experience Pain in the Lower Abdominal Area or Genital Area? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 131 0.18 -0.09 0.561 -0.07 0.5503 Oxy 6 mg 119 0.09 0.04 0.458 0.06 0.3151 Placebo 133 H.11 0.02 0.410 Change = (Iange in secverny of UDI -- id You Experience Pain in the Lower Abdominal Area or Genital Area? (Visit 3 to Visit ' (or End-of-Treatnent)). ** Difference = Difference between active treatment group and placebo. *'** P-Value: Significance between active treatnent groups and placebo was tested on raw data analysis.
WO 2011/163358 PCT/US2011/041447 - 49 Table 48. Secondary Outcome Analysis -- ITT Cohort: UDI - Did You Experience Heaviness or Dullness in the Pelvic Area? Change fr Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard6 Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 131 0.24 -0.12 .95 -0.02 0.5703 Oxy 6 mg 119 0.24 -0.07 0.578 0.03 0.5657 Placebo 133 0 24 -0.10 0.64 * Change = Change in severIty of UDI iDid You Experience leiviness or Dullness in the Pelvic Area? (Visit 3 to Visit 7 (or End-of-Treatmen)). ** Difference = Differeice between active treatment group and placebo. SP-Vailue- Significance between active treatment groups inc plw~ebo was tested on raw dala analysis. Table 49. Secondary Outcome Analysis - ITT Cohort: UDI - Did You Experience a Feeling of Buloing or Protrusion in the Vaginal Area? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard6 Treatments N Baseline Change* Deviation Difference* P-Value*** Oxy 4 mg 131 0.13 -0.05 0.398 -0.07 0.0939 Oxy 6 mg 119 0.14 -0.03 0.410 -0.05 0.5616 Placebo 133 0 13 0.02 0.436 * ChanGe = Change in severity of UDI Did You Experience a Feeling of Blgin or Protrusion In the Vaginal Area? (Visit 3 to Visit 7 (or End-of-Treatment)). ** Difference = Differenice between active treatment group and placebo. ***PValie: Signilicance between active treatment groups aind plocebo wasttested on raw daita anal~ysis. Table 50. Secondary Outcome Analysis - ITT Cohort: UDI - Did You Experience Bulging or Protrusion You Can See in the Vaginal Area? Change from Baseline (Visit 3) to End-of-Treatment (Visit Mean Standard Treatments N Baseline Change* Deviation Difference* P-Value*** Oxy 4 mg 130 0.04 0.01 0.197 0.06 0.5211 Oxy 6 mg 119 0.06 -0.02 0.318 0.03 0.9471 Placebo 133 0.12 -0.05 0.324 * Change =- Cha' in seventy of UDI -- Did You Experience uitlging Or Protrusnion You Can See in the Vaginal Area? (Visit 3 to Visit 7 (or End-of-Treatment)). ** Difference = Differeice bettcen active treatment group and placebo. "~P.-Valuec Significance between active treatment groups aind plocebo wat tested on raw daita anal~ysis.
WO 2011/163358 PCT/US2011/041447 - 50 Table 51. Secondary Outcome Analysis -- ITT Cohort: UDI - Did You Experience Pelvic Discomfort when Standing or Physically Exertina Yourself? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) IM ean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 130 0 24 -015 0.611 -0.1 0 9167 Oxy 6 mg 119 1 010 -0.01 0.04 0.6233 Placebo 133 0 13 -0,05 0,377 * Change = Change in severity of TJDI - Did You Experience Pelvic Discomfort when Standing or Physically E xerting Yoursel? (Visit 3 to Visit 7 (or End-o -Treattient)). ** Difference = Difference between active treatment group and placbo, * P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. Table 52. Secondary Outcome Analysis -- ITT Cohort: UDI - Did You Have to Push on the Vaginal Walls to Have a Bowel Movement? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Mean Standard Treatments N Baseline Change* Deviation Difference** P-Value*** Oxy 4 mg 130 0.30 -0.05 0.657 0.03 0.7222 Oxy 6 mg 118 0. 1 -0.07 0.448 0.01 0.4654 Placebo 133 0.44 -0.08 004 * Change = Change in severity of Lt)i Did You Have to Push on the Vagin Walls to Have a Bowel Movement? (Visit 3 to Visit 7 (or End-of-Treatment)). ** Difference = Difference betw een active treatment group and placebo. SP.-V'aiie: Significance betweenriactive treatment groups zind ptocbo wads tested On raw daita anlysis. [001471 An Incontinence Impact Questionnaire (IIQ) was a list of 30 questions that referred to areas in the patient's life, which may have been influenced or changed by their incontinence problem. The questionnaire measured how severe women found accidental urine loss and/or prolapse had affected their activities, relationships, and feelings. The scale to access how severe the activity/relationship/feeling was affected ranged from 0 to 3, 0 for "not at all", I for "slightly". 2 for "moderately", and 3 for "greatly." In addition, 9 for "not applicable" indicated the environment for recording that scale no longer applied, therefore was treated as missing severity. Analysis results of the change from baseline (Visit 3) to end-of-treatment (Visit 7) for all 30 questions for the ITT cohort are presented below. [00148] For the ITT cohort, statistically significant differences between the treatment group and. placebo were found in the assessment of 12 different questions for the mean WO 2011/163358 PCT/US2011/041447 - 51 change from baseline to end-of-study. Both 4 mg/day and 6 mg/day oxybutynin vaginal rings showed a significant reduction in the severity compared to placebo for the affect of incontinence on (1) the patient's ability to travel by car or bus for distances greater than 20 minutes awav from home, and (2) sleep. 6 mg/day Oxybutynin vaginal rings were able to achieve or approach statistical significance, compared to placebo, for further reducing the severity of the effect of incontinence on patient's shopping activities, entertainment activities such as going to a movie or concert, ability to travel by car or bus for distances < 20 minutes away from home, going places if you are not sure about available restrooms, going on vacation, church or temple attendance, participating in social activities outside your home, frustration, depression, and embarrassment. Tables 53-82 show the analysis of each question in the IIQ for the ITT cohort. Table 53. Secondary Outcome Analysis - ITT Cohort: IIQ-- Ability to do Household Chores? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 ig 130 0.7651 Oxy 6 mg 119 0,2236 ***PValue: Significance between active treatment groups and placebo was tested on raw data analysis. Table 54. Secondary Outcome Analysis - ITT Cohort: IQ- Ability to do Usual Maintenance or Repair Work Done in Home or Yard Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 125 0.4769 Oxy 6 mg 112 0.3907 ***PValue: Significance between active treatment groups and placebo was tested on raw data analysis. Table 55. Secondary Outcome Analysis - ITT Cohort: IIQ- Shopping Activities Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 ing 131 0.4450 Oxy 6 mg 119 0.0305 ***P -Value: Significance between active treatment groups and placebo was tested on raw data analysis.
WO 2011/163358 PCT/US2011/041447 - 52 Table 56. Secondary Outcome Analysis -- ITT Cohort: IIQ- Hobbies and Pastime Activities Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 rng 129 0.3783 Oxy 6 mug 118 0.1616 '**P-Valuxe: Significance between active treatment groups and placebo was tested on raw data analysis. Table 57. Secondary Outcome Analysis - ITT Cohort: IIQ- Physical Recreation Activities such as Walking, Swimming, or Other Exercise Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 tmg 128 0.6786 Oxy 6 mg 114 0.1235 P-Value: Significatce between active treatment groups and placebo was tested on raw data analysis. Table 58. Secondary Outcome Analysis - ITT Cohort: IQ- Entertainment Activities such as Going to a Movie or Concert? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 128 0.3367 Oxy 6 tmg 116 0.0326 ***P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. Table 59. Secondary Outcome Analysis - ITT Cohort: IIQ--- Ability to Travel by Car or Bus for Distances <20 Minutes Away from Home Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 130 0.3661 Oxy 6 mg 119 176 ***P-Value: Signincance between active treatment groups and placebo was tested on raw data analysis.
WO 2011/163358 PCT/US2011/041447 - 53 Table 60. Secondary Outcome Analysis -- ITT Cohort: IIQ- Ability to Travel by Car or Bus for Distances >20 Minutes Away from Home Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 129 0.0159 Oxy 6 mg 115 0.0087 ***PValue: Significance between active treatment groupsand placebo was tested on raw data analysis. Table 61. Secondary Outcome Analysis - ITT Cohort: IIQ- Going Places if You Are Not Sure About Available Restroom? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 tng 129 0.1966 Oxy 6 mg 118 0009 ***P -Value: Significance between active treatment groups and placebo was tested on raw data analysis. Table 62. Secondary Outcome Analysis - ITT Cohort: IIQ- Going on Vacation Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 129 0.3876 Oxy 6 tng 115 0.0007 t **PValue: Significance between active treatment groups and placebo was tested on raw data analysis Table 63. Secondary Outcome Analysis - ITT Cohort: IIQ--- Church or Temple Attendance Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 119 0.1848 Oxy 6 mg 104 0.0522 ***PValue: Significance between active treatment groups and placebo was tested on raw data analysis.
WO 2011/163358 PCT/US2011/041447 - 54 Table 64. Secondary Outcome Analysis -- ITT Cohort: IIQ- Volunteer Activities Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 117 0.8591 Oxy 6 ng 104 0.1745 '**P-Value: Significance between active treatment groups and placebo was tested on raw data analysts. Table 65. Secondary Outcome Analysis - ITT Cohort: IIQ- Employment (Work) Outside the Home Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 111 0.9359 Oxy 6 mg 103 0.1618 ***P-VaIue: Significance between active treatment groups and placebo was tested on raw data analysis. Table 66. Secondary Outcome Analysis - ITT Cohort: IIQ--- Having Friends Visit You in Your Home Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mng 128 0.8684 Oxy 6 mg 116 0.2938 ***P-Value: Significance between active treatment groups and placebo was tested on raw data analysis. Table 67. Secondary Outcome Analysis - ITT Cohort: IIQ- Participating in Social Activities Outside Your Home Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatmeiits N P-Value* Oxy 4 mg 129 0.1091 Oxy 6 ng 119 0.0476 *'*P-Value: Significance between active treatments groups and placebo was tested on raw dam analysis.
WO 2011/163358 PCT/US2011/041447 - 55 Table 68. Secondary Outcome Analysis -- ITT Cohort: IIQ- Relationship with Friends Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 129 0.9647 Oxy 6 ng 118 0.1953 ***P-Value: Significance between active treatment groups and placebo was tested on raw data analys s. Table 69. Secondary Outcome Analysis - ITT Cohort: IIQ--- Relationship with Family Excluding Husband/Companion Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 ing 126 0.5875 Oxy 6 mg 118 0.0820 ***P-Valjue: Significance between active treatment groups and placebo was tested on raw daa analysis. Table 70. Secondary Outcome Analysis -- ITT Cohort: IIQ- Ability to Have Sexual Relations Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 100 0.7603 Oxy 6 ng 100 0.4086 ***P-Value: Significane between active iraitment goups and placebo was tested on raw data analysis. Table 71. Secondary Outcome Analysis - ITT Cohort: IIQ- Way You Dress Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatmeiits N P-Value* Oxy 4 mg 130 0.1192 Oxy 6 mg 118 0.0610 ***P-Value: Significance between active treatments groups and placebo was tested on raw da-m analysis.
WO 2011/163358 PCT/US2011/041447 - 56 Table 72. Secondary Outcome Analysis -- ITT Cohort: IIQ- Emotional Health Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 129 0.6604 Oxy 6 ng 119 0.1065 ***P-Value: Significance between active treatment groups and placebo was tested on raw data analys s. Table 73. Secondary Outcome Analysis - ITT Cohort: IIQ- Physical Health Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 128 0.5352 Oxy 6 mg 118 0.1530 ***P-VaIlue: Significance between active treatment groups and placebo was tested on raw data analysis. Table 74. Secondary Outcome Analysis - ITT Cohort: IIQ-- Sleep Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 ing 130 0.017 Oxy 6 mg 119 0.0164 ***P-Value: Significance between active treatment groups and placebo was tested on raw daa analysis. Table 75. Secondary Outcome Analysis -- ITT Cohort: IIQ- Does Fear of Odor Restrict Your Activities? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 ng 128 0.3858 Oxy 6 ng 119 0.0873 ***P-Value: Significance between active treatment groups and placebo was tested on raw data analysts.
WO 2011/163358 PCT/US2011/041447 - 57 Table 76. Secondary Outcome Analysis -- ITT Cohort: IIQ- Does Fear of Embarrassment Restrict Your Activities? Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 130 0.2826 Oxy 6 ng 118 0.4150 ***P-Value: Significance between active treatment groups and placebo was tested on raw data analys s. Table 77. Secondary Outcome Analysis - ITT Cohort: IIQ- Nervousness or Anxiety Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 129 0.7747 Oxy 6 mg 11 0.5468 ***P-VaIue: Significance between active treatment groups and placebo was tested on raw data analysis. Table 78. Secondary Outcome Analysis - ITT Cohort: IIQ-- Fear Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 ing 126 0.8370 Oxy 6 mg 118 0.2871 ***P-Value: Significance between active treatment groups and placebo was tested on raw daa analysis. Table 79. Secondary Outcome Analysis - ITT Cohort: IIQ- Frustration Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatmeiits N P-Value*** Oxy 4 mg 130 0.2598 Oxy 6 mg 119 0.0047 ***P Value: Significance between active treatment groups and placebo was tested on raw da-m analysis.
WO 2011/163358 PCT/US2011/041447 - 58 Table 80. Secondary Outcome Analysis -- ITT Cohort: IIQ - Anger Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 rng 128 0.1752 Oxy 6 ng 118 0.6365 '**P-Valuxe: Significance between active treatment groups and placebo was tested on raw data anays s. Table 81. Secondary Outcome Analysis - ITT Cohort: IIQ- Depression Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 mg 128 0.7450 Oxy 6 mg 118 0.0095 ***P-Vailue: Significance between active treatment groups and placebo was tested on raw data analysis. Table 82. Secondary Outcome Analysis - ITT Cohort: IIQ--- Embarrassment Change from Baseline (Visit 3) to End-of-Treatment (Visit 7) Treatments N P-Value*** Oxy 4 ing 129 02835 Oxy 6 mg 119 0.0337 ***P-Vaaue: Significance between active treatment groups and placebo was tested on raw data analysis. [001491 In this double-blind study consisting of a two-week placebo run-in followed by 12 weeks of active treatment or placebo, both the 4 mg/day and the 6 mg/day oxybutynin vaginal rings demonstrated greater reductions compared to placebo from baseline to the end-of-treatment in the weekly total number of reported incontinence episodes and in the number of urge-only incontinence episodes. For the ITT cohort, the 4 mg/day vaginal ring demonstrated a reduction relative to placebo of 2.22 total episodes (p=0.0613) and 2.80 urge-only episodes (p=0.558). The 6 mg/day vaginal ring exhibited a reduction of 2.02 total episodes (p=0.1850) and 2.57 urge-only episodes (p=0.1803) compared to placebo. For the MITT cohort, these reductions were, for the 4 mg/day oxybutynin vaginal ring, 2.99 total episodes (p=0.
0 3 64 ) and 3.29 urge-only episodes (p=0.544) and, for 6 mg/day vaginal ring, 2.93 total episodes (p=0.0176) and 3.30 urge-only episodes (p:=0.0223). The proportions of patients in the 4 mg/day and 6 mg/day oxybutynin WO 2011/163358 PCT/US2011/041447 - 59 vaginal ring groups who reported no incontinence episodes at the end of the treatment was also significantly greater for both the ITT and MITT cohorts. [001501 Urinary frequency was reduced by 0.60 voids per 24 hours for 4 mg/day (p=0.0722) and 0.93 voids per 24 hours for 6 mg/day (p=0.0004) compared to placebo for the ITT cohort. For the MITT cohort, these reductions were 0.70 voids per 24 hours for 4 mg/day (p=. 1039) and EQ void per 24 hours for 6 mg/day (p=0.0020). No statistically significant differences between the 4 mg/day and. 6 mg/day vaginal rings and placebo were observed with respect to change in average void volume per 24 hours. As a result of a decrease in urinary frequency and no change in average void volume per 24 hours, both active treatment vaginal rings had an average void volume increase of 5.32 mL. for the ITT cohort (p=0.0126) and 4.94 mL for the MITT cohort (p=0.
0 4 44 ) compared to placebo. [001511 Mean VAS was reduced by 0.52 for the 4 mg/day (p=0.0199) and 1.23 (p=0.0012) for the 6 mg/day vaginal rings compared to placebo for the ITT cohort. For the MITT cohort, these reductions were 0.44 (p=0.0374) for the 4 mg/day vaginal rings and 1.12 (p=0.0045) for the 6 mg/day vaginal rings. [001521 Results showed that the 4 mg/day vaginal rings provided a level of active treatment effect that exceeded the effect of placebo alone and that the 6 mg/day vaginal rings provided similar results compared to placebo, in addition, was associated with greater reduction in urinary frequency compared to placebo than the 4 mg/day vaginal ring. When considering the MITT cohort consisting of patients who met all three criteria for incontinence at baseline (as opposed to the ITT cohort that included all three patients with analyzable data for the total incontinence episode endpoint), the magnitude of the effect for the oxybutynin vaginal ring groups, especially for the 4 mg/day vaginal rings, was even more evident. [001531 The incidence of treatment-emergent adverse events reported with a frequency of 2% or greater, by body system, is provided in Table 75, WO 2011/163358 PCT/US2011/041447 - 60 Table 75. Treatment-Emergent Adverse Events With an Incidence of 2% or Greater in Any Treatment Group During Double-Blind Period - Treated Safety Cohort Placebo Oxy 4 Mg Oxy 6 Mg Total MedDRA System Organ (N=155) (N= 143) (N=:147) (N=143) Class and Preferred Term N % N % N % N % INFECTIONS AND INFESTATIONS URINARY TRACT INFECTION 7 4.52 13 9.09 18 12.24 38 8.54 SINUSITIS 2 129 3 2,10 2 1,36 7 1.57 UPPER RESPIRATORY TRACT 1 0.65 3 2.10 1 0.68 5 1.12 INFECTION VULVOVAGINAL MvYCOTIC 4 258 3 210 6 4.08 13 2.92 INFECTiON GASTROINTESTINAL DISORDERS DRY MOUTH 4 ].58 7 4.90 15 10.20 26 5.84 NAUSEA 1 0.65 4 2.80 2 1.36 7 1.57 ABDOMINAL PAIN 3 1.94 3 210 3 2,04 9 2.02 CONSTIPATION 2 1.29 2 [140 4 2. 7 2 8 1.80 DSIARRHOEA 6 187 2 14A0 5 40 13 2.92 REPRODUCTIVE SYSTEM AND BREAST DISORDERS VAGINAL DISCHARGE 6 3.87 5 3.50 7 4.76 18 4,04 VAGINAL PAIN 0 0.00 3 2,10 0 0,00 3 0.67 VAGINAL HAE MORRHAGE 4 2.58 2 1.40 6 4.08 12 2 70 VAGINAL ERYTHEMA 1.29 0 0 00 3 14 5 1.12 MIJSCUILOSKELETAL AND CONNECTIVE TISSUE DISORDERS BACK PAIN 4 2.58 3 2.10 1 0.68 8 1.80 NERV01S SYSTEM DISORDERS HEAACI 129 3 210 6 .011 2.47 RENAL AND URINARY DISORDERS DYSURIA 0 0,00 3 210 2 1.36 5 1.12 INVESTIGATIONS HEPATIC ENZYME INCREASED 2 1.29 0 0.00 3 2.04 5 1.12 [00154] The incidence of treatment-emergent adverse events was comparable across treatment groups with the exception of urinary tract infection, dry mouth, and headache. The niost conmonly reported adverse events were urinary tract infection (12.24% on 6 mg/day oxybutynin vaginal ring, 9.09% on 4 mg/day oxybutynin vaginal ring, and 4.52% on placebo) and dry mouth (10.20% on 6 mg/day oxybutynin vaginal ring, 4.90% on 4 WO 2011/163358 PCT/US2011/041447 - 61 mg/day oxybutynin vaginal ring, and 2.58% on placebo); both adverse events were associated with incidence rates that increased with dose. The incidence rates of dry mouth compare favorably to the 29-61% rate reported for an oral, extended release formulation of oxybutynin (Ditropan XL*) and are similar to the rates of 4.9-9.6% seen in a twice weekly transdermal oxybutynin product.All of the various embodiments or options described herein can be combined in any and all variations. While the invention has been particularly shown and described with reference to some embodiments thereof, it will be understood by those skilled in the art that they have been presented by way of example only, and not limitation, and various changes in form and details can be made therein without depanring from the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents. [00155] All documents cited herein, including journal articles or abstracts, published or corresponding U.S. or foreign patent applications, issued or foreign patents, or any other documents, are each entirely incorporated by reference herein, including all data, tables, figures, and text presented in the cited documents.
Claims (27)
- 2. The intravaginal device of claim 1, wherein the first matrix comprises an optionally substituted polymer selected from the group consisting of polysiloxane polymers, polyalkylene polymers, polystyrene polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyester polymers, polyurethane polymers, acrylic polymers, nylon polymers, dacron polymers, teflon polymers, and combinations thereof. 3, The intravaginal device of claim 2, wherein the optionally substituted. polymer is a polysiloxane polymer of Formula (I): R1 R1 R3 R1, I I I I R -S-S O Si -O - Si Si -R5 2 R 2 R 4 R 2 XY (I) wherein X is I to 200; Y is I to 200; Z is I to 300; and WO 2011/163358 PCT/US2011/041447 - 63 RI, R2, Ra, R4, and Ra are independently selected from the group consisting of (C- 6 )alkyl, amino(C 6 )alkyl, hydroxy(CI -falkyl, haloalkyl, cyano(Ci- 6 )alkyl, thio(C - 6 )alkyl, carboxy(CI. 6 )alkyl, an(CI )alkyl, (CI. 6 )alkoxy(C alkylyl, (C 2 - 6 )alkenyl, amino(C-A-o)alkenyl, hydroxv(C3 o)alkenyl, halo(C2_ 6 )alkenyi, cyano(C 2 _6)alkenyl, thio(C3- ;)alkenyl, carboxy(C c)alkenyl, aryl(C 2 _salkenyi, (C2_)alkynyl, (C1. 6 )heteroalkyl, (C 2 _6 heteroalkenvi, (C 2 6 )heteroalkynyi, (C s)alkoxy, (Cs 1 I)alkenyloxy, (C pc)alkylenedioxy, amino(C 2 - 6 )alkoxy, hydroxy(C2_)alkoxy, haio(C 6 ~alkoxy, cyano(C 1 6 )aikoxy, thio(C 6 )alkoxy, carboxy(C2_ 6 )alkoxy, arvi(Ca )alkoxy, (Ci> 6 )alkoxy(C 2 _ 6 )alkoxy, haio(Ci )alkoxy(C 2 . 6 )aikoxy, mono(C - 6 )alkylamino, di(C )alkylamno, (C] 6 )alkylcarbonylamino, (C2_ 6 )alkenylcarbonylamino, (C, 1 4)arylcarbonylamino, (C 6 )alkoxycarbonylamino, (C 6 )aryoxycarbonylamino, (C 1 6 )alkylcarbonyl, (C 2 _)alkenyicarbonyl, (C 6 w)arylcarbonyl, (C 1 6 )alkoxycarbonyl, (C 6 1 4)aryloxycarbonyl, (C pjalkylsulfonylamino, (C2_ 6 )alkenylsulfonylamino, and (C 6 4)arlsulfonylamino.
- 4. The intravaginal device of claim 3, wherein at least one of R1, R2, R-, and 14 is a haloalkyl.
- 5. The intravaginal device of claim 3, wherein X is I to 2; Y is I to 2; Z is 100 to 200; and R 1 is trifluoropropyi; R 2 , R3, and R4 are independently C 1 -C 3 alkyl; and R is vinyl.
- 6. The intravaginal device of claim 3, wherein the optionally substituted polymer is 3,3,3 trifluoropropyl methyldimethyl polysiloxane. WO 2011/163358 PCT/US2011/041447 - 64 7. The intravaginal device of any one of claims 3 to 6, wherein the first matrix comprises 50% to 100% by weight halogenated siloxane polymer.
- 8. The intravaginal device of any one of claims 1 to 7, wherein the first matrix comprises 80% to 95% by volume of the device.
- 9. The intravaginal device of any one of claims I to 8, wherein the first matrix comprises 80% to 95% by weight of the device.
- 10. The intravaginal device of any one of claims I to 9, wherein the pocket extends from 10' to 180' around the perimeter of the first matrix.
- 11. The intravaginal device of claim 10, wherein the pocket extends from 80' to 120' around the perimeter of the first matrix.
- 12. The intravaginal device of any one of claims I to 11, wherein the pocket has a cross sectional diameter of 3 mmi to 8 mm.
- 13. The intravaginal device of any one of claims I to 12., wherein the pocket wall has a uniform thickness of I mm to 4 mm,
- 14. The intravaginal device of any one of claims 1 to 13, wherein the pocket has a volume of 0.7 cn3 to 1.5 cm3.
- 15. The intravaginal device of any one of claims I to 14, wherein the second matrix comprises an optionally substituted polymer selected from the group consisting of polysiloxane polymers, polyalkylene polymers, polystyrene polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyester polymers, polyurethane polymers, acrylic polymers, nylon polymers, dacron polymers, teflon polymers, and combinations thereof.
- 16. The intravaginal device of claim 15, wherein the second matrix comprises a polysiloxane polymer.
- 17. The intravaginal device of claim 16, wherein the second matrix comprises a polysiloxane polymer of Formula (II): WO 2011/163358 PCT/US2011/041447 -65 R, R, RI I I I Ra--i-0 Si-O -Si R3 R 2 R 2 R2 N (II) wherein R 1 , R2, and R 3 are independently selected. from the group consisting of alkoxy, alkyl, alkynyl, alkynyl, alkenyl, alkylacryloyloxy, acryloyloxy, alkeniylalkyl, aryl, and hydrogen; and N is 50 to 300.
- 18. The intravaginal device of claim 17, wherein RI and R2 are independently alkyl or hydrogen.
- 19. The intravaginal device of any one of claims 15 to 18, wherein the second matrix comprises 30% to 80% by weight polysiloxane polymer.
- 20. The intravaginal device of any one of claims 1 to 19, wherein the second matrix comprises 5% to 50% by volume of the device.
- 21. The intravaginal device of any one of claims 1 to 20, wherein the second matrix comprises 5% to 50% by weight of the device.
- 22. The intravaginal device of any one of claims I to 21, wherein the anticholinergic agent is homogenously dispersed throughout the second matrix.
- 23. The intravaginal device of any one of claims 1 to 22, wherein the anticholinergic agent is selected from the group consisting of oxybutynin, tolterodine, trospium, solifenacin, darifenacin, dicyclomine, propantheline, propiverine, bethanechol, methylbenactyzium, scopol amine, and pharmaceutically acceptable salts thereof WO 2011/163358 PCT/US2011/041447 - 66 24. The intravaginal device of any one of claims I to 23, wherein the anticholinergic agent is oxybutynin or a pharmaceutically acceptable salt thereof.
- 25. The intravaginal device of any one of claims 1 to 24, wherein the anticholinergic agent comprises 20% to 70% by weight of the second matrix.
- 26. The intravaginal device of any one of claims I to 25, wherein the first matrix further comprises a slit, wherein the slit extends a length of the pocket.
- 27. A method of making an intravaginal device, the method comprising: (a) placing a first matrix into a mold, the mold being shaped so as to form an annular intravaginal device comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, and wherein the pocket wall encompasses the pocket; (b) curing the first matrix; (c) placing a second matrix comprising an anticholinergic agent in the pocket; and (d) curing the second matrix.
- 28. The method of claim 27, wherein the mold is shaped. so as to form an annular intravaginal device comprising a pocket and a pocket wall, wherein the pocket wall has a uniform thickness, wherein the pocket wall encompasses the pocket, and wherein a slit extends a length of the pocket.
- 29. The method of any one of claims 27 and 28, wherein the anticholinergic agent is homogenously dispersed in the second matrix.
- 30. The method of any one of claims 27 to 29, wherein the anticholinergic agent is selected from the group consisting of oxybutynin, tolterodine, trospium, solifenacin, darifenacin, dicyclomine, propantheline, propiverine, bethanechol, methylbenactyzium, scopolamine, and pharnaceutically acceptable salts thereof.
- 31. The method of any one of claims 27 to 30, wherein the anticholinergic agent is oxybutynin or a pharmaceutically acceptable salt thereof.
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| AU2015264960A AU2015264960A1 (en) | 2010-06-22 | 2015-12-07 | Intravaginal Device Comprising Anticholinergic Agents, And Methods Of Making Thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/357,325 | 2010-06-22 | ||
| AU2011270997A AU2011270997A1 (en) | 2010-06-22 | 2011-06-22 | Intravaginal devices comprising anticholinergic agents, and methods of making thereof |
| AU2015264960A AU2015264960A1 (en) | 2010-06-22 | 2015-12-07 | Intravaginal Device Comprising Anticholinergic Agents, And Methods Of Making Thereof |
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| AU2011270997A Division AU2011270997A1 (en) | 2010-06-22 | 2011-06-22 | Intravaginal devices comprising anticholinergic agents, and methods of making thereof |
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| AU2015264960A1 true AU2015264960A1 (en) | 2015-12-24 |
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| AU2015264960A Abandoned AU2015264960A1 (en) | 2010-06-22 | 2015-12-07 | Intravaginal Device Comprising Anticholinergic Agents, And Methods Of Making Thereof |
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