Intravaginal devices comprising anticholinergic agents, and methods of making thereof

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 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 second matrix comprising an anticholinergic agent in the pocket; and (d) curing the second matrix.

Description

field of invention

[0001] The present invention relates 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 surrounds the pocket; Secondary substrate for anticholinergic agents.

[0002] The present invention also relates to a method of making an intravaginal device comprising: (a) placing a first matrix into a mold which is shaped to form a ring-shaped intravaginal device comprising a bag and a bag wall, wherein the bag wall has a uniform and wherein the bag wall surrounds the bag; (b) curing the first matrix; (c) placing a second matrix comprising an anticholinergic agent into the bag; and (d) curing the second matrix. Background of the invention

[0003] Overactive bladder ("OAB") affects millions of people worldwide, the majority of whom are women. In people with OAB, the voluntary relaxation of the detrusor muscle, which controls the bladde...

Examples

Embodiment 1

[0095] Preparation of the first stromal vaginal ring

[0096] A vaginal ring comprising a first matrix is ​​prepared as follows. The first matrix was prepared using trifluoropropylmethyl / dimethylsiloxane. In a 100 g capacity Hauschild mixing cup, weigh 40 g of part A and 40 g of part B of trifluoropropylmethyl / dimethylsiloxane elastomeric rubber formation (NuSil Technology, Grade CF2-3521, Toms River, NJ), It was then mixed for 10 seconds in a Hauschild model 501T speed mixer. A metal spatula is then used to scrape down the sides of the jar and further mix the two starting components. Finally, a 14-second accelerated mixing cycle was applied to ensure uniformity of mixing.

[0097]The two halves of the insert mold, which will form the bag and have a bag wall of uniform thickness, are lightly coated in an ethanol / water solution of DARVAN WAQ (R.T. Vanderbilt Co., Norwalk, CT) and air dried. Between 12-15 grams of a 1:1 Part A:Part B mixture was placed into the mold half con...

Embodiment 2

[0103] Preparation of two-matrix vaginal rings

[0104] The pockets of the annular primary matrix of the trifluoropropylmethyl / dimethylsiloxane synthetic rubber prepared according to Example 1 were filled with the silicone / oxybutynin secondary matrix.

[0105] To form the second matrix, a mixture of 55% silicone and 45% oxybutynin was weighed into a Hauschild mixing cup and mixed in a Hauschild AM 501 Model T speed mixer. The resulting silicone / oxybutynin paste was injected ample amount into the ring pocket of Example 1 using a syringe. In order to obtain a vaginal ring releasing oxybutynin 4 mg / day, a vaginal ring was used containing a first matrix with an outer diameter of 58.3 mm and a pocket extending 80° around the periphery of the ring. The bag is 5.3 mm in diameter and is syringe filled with a silicone / oxybutynin mixture. In order to obtain a vaginal ring releasing 6 mg / day oxybutynin, a vaginal ring was used containing a first matrix with an outer diameter of 58.3 mm...

Embodiment 3

[0108] Pharmacokinetics and Drug Metabolism in Animals

[0109] A study was performed in dogs to determine the levels of oxybutynin and its active metabolite N-desethyloxybutynin in plasma following oral and intravaginal administration of oxybutynin. The results of this study are shown in Table 1.

[0110] Table 1 Oxybutynin vaginal ring and Oxybutynin hydrochloride oral tablet: C max and T max dose comparison of

[0111]

[0112] A 14-day study was conducted in which 8 adult females were randomly assigned to 4 groups of 2 dogs each. Two dogs received 10 mg of oxybutynin hydrochloride orally per day (2 x 5 mg / day tablets) for 14 consecutive days. The remaining 6 dogs received vaginal rings as described in Example 2 designed for sustained release of oxybutynin at doses of 0, 2.5 or 6 mg / day for 14 days.

[0113] Oxybutynin was detected in the plasma of dogs administered orally or intravaginally with oxybutynin at all intervals tested. mean maximum plasma concentration ...

field of invention

[0001] The present invention relates 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 surrounds the pocket; Secondary substrate for anticholinergic agents.

[0002] The present invention also relates to a method of making an intravaginal device comprising: (a) placing a first matrix into a mold which is shaped to form a ring-shaped intravaginal device comprising a bag and a bag wall, wherein the bag wall has a uniform and wherein the bag wall surrounds the bag; (b) curing the first matrix; (c) placing a second matrix comprising an anticholinergic agent into the bag; and (d) curing the second matrix. Background of the invention

[0003] Overactive bladder ("OAB") affects millions of people worldwide, the majority of whom are women. In people with OAB, the voluntary relaxation of the detrusor muscle, which controls the bladde...

Examples

Embodiment 1

[0095] Preparation of the first stromal vaginal ring

[0096] A vaginal ring comprising a first matrix is ​​prepared as follows. The first matrix was prepared using trifluoropropylmethyl / dimethylsiloxane. In a 100 g capacity Hauschild mixing cup, weigh 40 g of part A and 40 g of part B of trifluoropropylmethyl / dimethylsiloxane elastomeric rubber formation (NuSil Technology, Grade CF2-3521, Toms River, NJ), It was then mixed for 10 seconds in a Hauschild model 501T speed mixer. A metal spatula is then used to scrape down the sides of the jar and further mix the two starting components. Finally, a 14-second accelerated mixing cycle was applied to ensure uniformity of mixing.

[0097]The two halves of the insert mold, which will form the bag and have a bag wall of uniform thickness, are lightly coated in an ethanol / water solution of DARVAN WAQ (R.T. Vanderbilt Co., Norwalk, CT) and air dried. Between 12-15 grams of a 1:1 Part A:Part B mixture was placed into the mold half con...

Embodiment 2

[0103] Preparation of two-matrix vaginal rings

[0104] The pockets of the annular primary matrix of the trifluoropropylmethyl / dimethylsiloxane synthetic rubber prepared according to Example 1 were filled with the silicone / oxybutynin secondary matrix.

[0105] To form the second matrix, a mixture of 55% silicone and 45% oxybutynin was weighed into a Hauschild mixing cup and mixed in a Hauschild AM 501 Model T speed mixer. The resulting silicone / oxybutynin paste was injected ample amount into the ring pocket of Example 1 using a syringe. In order to obtain a vaginal ring releasing oxybutynin 4 mg / day, a vaginal ring was used containing a first matrix with an outer diameter of 58.3 mm and a pocket extending 80° around the periphery of the ring. The bag is 5.3 mm in diameter and is syringe filled with a silicone / oxybutynin mixture. In order to obtain a vaginal ring releasing 6 mg / day oxybutynin, a vaginal ring was used containing a first matrix with an outer diameter of 58.3 mm...

Embodiment 3

[0108] Pharmacokinetics and Drug Metabolism in Animals

[0109] A study was performed in dogs to determine the levels of oxybutynin and its active metabolite N-desethyloxybutynin in plasma following oral and intravaginal administration of oxybutynin. The results of this study are shown in Table 1.

[0110] Table 1 Oxybutynin vaginal ring and Oxybutynin hydrochloride oral tablet: C max and T max dose comparison of

[0111]

[0112] A 14-day study was conducted in which 8 adult females were randomly assigned to 4 groups of 2 dogs each. Two dogs received 10 mg of oxybutynin hydrochloride orally per day (2 x 5 mg / day tablets) for 14 consecutive days. The remaining 6 dogs received vaginal rings as described in Example 2 designed for sustained release of oxybutynin at doses of 0, 2.5 or 6 mg / day for 14 days.

[0113] Oxybutynin was detected in the plasma of dogs administered orally or intravaginally with oxybutynin at all intervals tested. mean maximum plasma concentration ...

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