Sustained release estrogen vaginal ring pessary for treatment of atrophy, cystitis and uterovaginal prolapse

Abstract

The present invention relates to devices and methods for treating prolapsed pelvic organ, cystitis and Atrophy in women. Particularly, the invention relates to drug loaded vaginal support devices and methods wherein the device is inserted in vagina to support as well as release the drug. Specifically the invention relates to a Vaginal Ring Pessary comprising Estrogen in Silicone rubber polymer matrix, which releases drug over a prolonged period of about 180 days. Additionally the invention relates to the method of fabrication of the device and its use in treatment of vaginal atrophy, cystitis and uterovaginal prolapse.

Claims

1. A vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse, comprising: an annular rigid structure of estrogen homogenously distributed in polymer matrix; wherein the polymer comprises of silicone elastomer and the pessary when inserted in the vagina has a sustained and continuous release of the estrogen hormone for over a period of 6 months; and wherein a ratio of the estrogen to the polymer matrix is 1-15 mg: 100 mg.

2. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the polymer matrix is formed from a liquid silicone rubber.

3. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the amount of Estrogen in the vaginal pessary is in the range of 175-2400 mg.

4. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the annular or ring structure of the pessary comprises of a dimension 50-110 mm outer diameter.

5. The vaginal ring pessary for alleviating pelvic organ prolapse as claimed in claim 4, wherein the annular or ring structure of the pessary has an outer diameter of 63 mm.

6. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the inner diameter of the ring is in the range of 20-110 mm.

7. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the width of the ring, defined as one-half of a difference between the inside diameter of the ring and the outside diameter of the ring, is in the range of 9-11 mm.

8. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the pessary has a durometer of 60-80.

9. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the pessary has a Tensile strength of 1300-1600 psi, and mechanical strengths in the range of 3490-4946 g.

10. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the estrogen comprises of estrogen, estrone, estriol or estradiol.

11. The vaginal ring pessary for alleviating atrophy, cystitis and uterovaginal prolapse as claimed in claim 1, wherein the estrogen is estradiol.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: A 63 mm pessary manufactured by 3D printed molding processing.

(2) FIG. 2: Illustrating the Shore Hardness of the Vaginal Ring pessary

(3) FIG. 3: Compression test in texture analyzer for the silicone rings

(4) FIG. 4: MED-4830 silicone films released in simulated vaginal fluid (SVF) of pH 4.2.

(5) FIG. 5: MED-4830 silicone films released in SVF of pH 4.5.

(6) FIG. 6: MED-4870 silicone films released in SVF of pH 4.2. and

(7) FIG. 7: MED-4870 silicone films released in SVF of pH 4.5;

(8) FIG. 8: Illustrates graph for EST release in mg Vs time in days upto 180 days for device with 1% EST in SVF pH 4.5.

(9) FIG. 9: Illustrates graph for % EST release Vs time in days upto 180 days for device with 1% EST in SVF pH 4.5.

(10) FIG. 10: Illustrates graph for EST release in mg Vs time in days upto 180 days for device with 10% EST in SVF pH 4.5.

(11) FIG. 11: Illustrates graph for % EST release Vs time in days upto 180 days for device with 10% EST in SVF pH 4.5.

(12) FIG. 12: Illustrates graph for EST release in mg Vs time in days upto 180 days for device with 15% EST in SVF pH 4.5.

(13) FIG. 13: Illustrates graph for % EST release Vs time in days upto 180 days for device with 15% EST in SVF pH 4.5.

(14) FIG. 14: Illustrates comparative graph of % EST release from vaginal ring device comprising 1%, 10% and 15% EST drug load.

(15) FIG. 15: Illustrates comparative graph of drug release in mg from the vaginal ring device comprising 1%, 10% and 15% EST drug load.

DETAILED DESCRIPTION OF THE INVENTION

(16) The present invention in an embodiment discloses a vaginal ring pessary for treatment of Pelvic Organ Prolapse or POP. As used herein, a “vaginal ring pessary” refers to a rigid body made up of polymeric material, which on insertion delivers drug or active agent to the vaginal and/or urogenital tract of a subject or patient at the vagina, cervix, or uterus. The invention is directed to the formulation and method of manufacture of a vaginal pessary which has rigidity and shore hardness and is inert in the physiological condition, and releases in a controlled and programmed manner the drug in the vaginal area.

(17) The vaginal ring pessary is a vaginal device, particularly annular in structure. The annular ring may be prepared by a polymeric substance that provides enough rigidity, hardness and also provides drug release at the required release rate. Particular embodiment of the present invention provides a ring of dimensions appropriate for insertion into a female vaginal for controlled release of the dispersed active drug formulation. The API or active pharmaceutical ingredient may be dispersed or it may form the core of the device surrounded by the matrix for drug release by erosion.

(18) Preferable embodiment of the present invention discloses a vaginal ring device [20] wherein the drug or the API is dispersed in the polymeric matrix which controls the release of the drug from the device to the subject over a selected prolonged period of time. Optionally an embodiment of the present invention may have the ring device [20] of shapes ring, an oval, an ellipse, a toroid, and the like.

(19) The polymeric matrix according to an embodiment of the present invention comprises of an inert polymer. In some embodiments the matrix is an elastomer which is an amorphous polymer network formed when a polymer or a mixture of polymers undergo cross-linking. In further embodiments the matrix may be 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 combinations thereof. In another embodiment of the present invention the polymeric matrix is silicone polymers. Particular embodiment of the present invention discloses the polymeric matrix as a matrix comprising Liquid silicone rubbers, or LSRs, which are elastomer systems reinforced with silica. Exemplary embodiments of the present invention comprises of silicone rubbers of Graded MED 4830 and MED 4870. Exemplary embodiments further discuss the choice of polymer based on the necessary hardness, tensile strength and Durometer values and their Fabrication methodology is discussed below.

(20) Fabrication of Vaginal Ring Pessary for Controlled Release of Estrogen Over a Period of 6 Months or 180 Days.

(21) Polymers chosen are NuSil MED-4830 and NuSil-4870. The polymers are liquid silicone rubber, specifically NuSil MED-4870 Liquid Silicone Rubber. They are specific for human implantation. Liquid silicone rubbers, or LSRs, are elastomer systems reinforced with silica. They contain functional polymers of lower average molecular weight and viscosity when compared to high consistency rubbers (HCRs). They are typically supplied as two-component systems Part A and Part B and formulated in a 1:1 mix ratio. Because their consistency is akin to petroleum jelly, they are often pumped with injection molding equipment to form molded components such as o-rings, gaskets, valves, seals, and other precision molded parts. The vaginal rings [20] are manufactured by 3D printing using moulds [10, 30] printed by nylon material.

(22) Novel medicated and customised vaginal pessary rings [20] with different drug loadings were developed by using 3D printed moulds [10, 30]. Estriol was loaded in silicone solution and dispersed uniformly in the silicone matrix of the pessary device. That said, the specific aims of this study were: i) to incorporate estriol drug in silicone matrix; ii) to establish customised pessary device by 3D printed mould [10, 30]. iii) to analyse the interactions between drug and silicone polymers; and iv) to characterize and optimise the devices by studying the in vitro release profiles and morphology characters.

(23) Materials and Methods

(24) Materials

(25) Estriol was purchased from Flem Pharma (Shanghai, China). Silicone (MED-4830 and MED-4870) was kindly gifted by Nusil™ (Carpinteria, United State). Potassium hydroxide (ACS reagent, >85%), calcium hydroxide (ACS reagent, ≥95.0%), urea (ACS reagent, 99.0-100.5%), D-(+)-Glucose (ACS reagent), glycerol (ACS reagent, ≥99.5%), lactic acid (meets USP testing specifications), acetic acid (ACS reagent, ≥99.7%), and hydrochloric acid (ACS reagent, 37%) were obtained from Sigma-Aldrich (Auckland, New Zealand). Bovine serum albumin (BSA, fatty acid free) was purchased from MP Biomedicals (Auckland, New Zealand). Simulated vaginal fluid (SVF) was prepared with two pH values (pH 4.2 for normal vaginal condition and pH 4.5 for menopause condition).

(26) Physical Characteristics or Properties of the Polymer

(27) MED-4870

(28) Specific gravity—1.16 g/cc

(29) Hardness—Shore A value—70

(30) Tensile strength—5.17 MPa @ Strain 200%

(31) Mix ratio of Part A:Part B is 1:1.

(32) NuSil-4830

(33) Specific gravity—1.13 g/cc

(34) Hardness—Shore A value—30

(35) Tensile strength—1,350 psi (9.31 MPa)

(36) Cure time −5 minutes/150° C.

(37) Mix ratio of Part A:Part B is 1:1.

(38) Formulation of Ring:

(39) The vaginal ring [20] is formulated by mixing of the part A and part B (1:1 by weight) of Polymers MED-4870 and MED-4830 by spread mixing. The polymers contain part A and part B that are blended together. Estrogen in powder form is gradually added to the polymer composition to yield estrogen polymer blend.

(40) Curing of the estrogen polymer blend is performed at room temperature following exposure to temperature 160° C. for 10 minutes.

(41) 3D Printing:

(42) The silicone blend was extruded through spreading mixing and then loaded into the 3D printed nylon mould by a metal spatula. The mould [10, 30] with silicone were placed in 160° C. oven for 10-20 min for curing resulting in the silicone was mixed well.

(43) The molds [10, 30] were printed by nylon material.

(44) Curing: The silicone blend extruded into the mold of the 3D printer and allowed a curing at 160° C. for 10-20 min.

(45) Particularly the invention discloses in a preferred embodiment of the present invention a vaginal ring pessary [20] of Estrogen for sustained release of drug for up to 180 days or 6 months.

(46) The invention is a vaginal pessary [20] as illustrated in FIG. 1 shows the view of a vaginal ring/pessary according to an embodiment of the present invention. The annular ring [20] is fabricated with dimensions in the range of 50-110 mm, preferably 60-80 mm and most preferably about 63 mm outer diameter. The range of inner diameter is in the range 20-110 mm and preferably 43 mm. The range of the cross sectional diameter is about 10 mm and the range is about 9-11 mm.

(47) Exemplary embodiment of the present invention discloses a vaginal ring device [20] comprising an annular in structure with an outer diameter 63 mm, 43 mm inner diameter, 10 mm ring diameter (cross section).

(48) Route of Administration

(49) The vaginal ring is configured to be inserted into the vaginal cavity of a mammal, a human, particularly in the vaginal region of a female user or a patient and its fit and physical properties are evaluated to provide the necessary rigidity, and compliance to the patient to whom it is inserted in.

(50) The present invention also includes a method of delivering one or more pharmaceutically active ingredients, according to an embodiment of the present invention to estrogens comprising estradiol, estrogen, estrone, estriol or estradiol. Inserting a ring pessary described herein into the vaginal cavity of a mammal, wherein the ring is retained for time sufficient to deliver the pharmaceutically active ingredient(s) to the mammal.

(51) Exemplary embodiment discloses a vaginal ring pessary [20] which is a homogenous matrix comprising drug distributed in the polymer matrix. Here the drug is estrogen which is homogenously blended in the Liquid silicone polymer, selected from Nusil 4830 and Nusil 4870.

(52) An embodiment of the present invention provides method of optimization of the Polymer for the fabrication of Vaginal Ring Devices.

(53) Polymer Optimization

(54) Preparation of Vaginal Ring Pessary [20] with Polymer MED-4830 comprising of steps:

(55) Mixing of the polymer part A and part B (1:1 by weight) of Polymer MED-4830 by spread mixing;

(56) gradual addition of the Estrogen in powder form to the blended polymer mixer to yield an estrogen-polymer blend; and curing of the estrogen polymer blend by exposure to temperature 160° C. for 10-20 minutes, wherein the ratio of weight of estrogen to polymer is 0.1 mg:100 mg by weight or 0.1% drug content.

(57) Preparation of Vaginal Ring Pessary with Polymer MED-4870 comprising of steps:

(58) Mixing of the polymer part A and part B (1:1 by weight) of Polymer MED-4870 by spread mixing;

(59) gradual addition of the Estrogen in powder form to the blended polymer mixer to yield a estrogen polymer blend; and curing of the estrogen polymer blend at room temperature following exposure to temperature 160° C. for 10 minutes, wherein the ratio of weight of estrogen to polymer is in the range of 0.1 mg:100 mg of 0.1% by weight.

(60) TABLE-US-00001 TABLE 1 Drug release over a period of 56 days in Simulated Vaginal Fluid Result ** % drug Weight of S. NO Polymer Drug SVF pH release drug in mg Trial 1 MED-4830 Estrogen 4.2 0.679% 0.116 mg (0.1% w/w) MED-4830 Estrogen 4.5 0.533% 0.091 mg (0.1% w/w) Trial 2 MED-4870 Estrogen 4.2 0.850% 0.152 mg (0.1% w/w) MED-4870 Estrogen 4.5 0.840% 0.170 mg (0.1% w/w)
Polymer Optimization.

(61) Exemplary embodiment of the present invention has studied a 0.1% Estrogen drug content vaginal ring pessary fabricated with both MED 4830 and MED 4870 silicone rubber polymers.

(62) Initial study was performed with both grades of Nusil silicone polymers. The table no. 1 provided above shows trial data for 56 days with the device weighing in the range of 16-21 g.

(63) Drug Content in the Vaginal Ring Pessary:

(64) Estrogen is loaded at a drug content/device of 0.1% w/w, equal to 17.0 mg (MED-4830) and 18.7 mg (MED-4870) per vaginal ring device.

(65) Weight of the vaginal ring pessary: 17.0 g (MED-4830) and 18.7 g (MED-4870).

(66) Drug content=0.1% by weight=17 mg to 18 mg for MED 4870.

(67) Exemplary embodiment disclosed Estriol as the drug, the scope of the present invention should not be understood to be confined to Estriol alone but is applicable to estrogens in general.

(68) TABLE-US-00002 TABLE 2 Comparative study for Drug Release of Nusil 4830 and Nusil 4870 Part A: Part B: Estriol (weight Drug content S. No Silicone in mg)*** (%)* Results 30-free MED-4830 1:1:— — — Trial 1 MED-4830 1:1:0.002 0.1% Over a period of 56 days, cumulatively released 0.679% (0.116 mg) and 0.533% (0.091 mg) in SVF of pH 4.2 and pH 4.5 respectively. 70-free MED-4870 1:1:— — — Trial 2 MED-4870 1:1:0.002 0.1% Over a period of 56 days, cumulatively released 0.850% (0.152 mg) and 0.840% (0.170 mg) in SVF of pH 4.2 and pH 4.5 respectively. $*:\mathrm{drug}=\frac{\mathrm{Mass}\mathrm{of}\mathrm{drug}}{\mathrm{Mass}\mathrm{of}\mathrm{silicone}}\%.$**: SVF: simulated vaginal fluid ***: Part A and Part B: silicone materials which should be mixed at a fix ratio of Part A: Part B = 1:1.

(69) An embodiment of the present invention discloses a comparative study of vaginal ring pessary comprising of 0.1% drug content for drug release. The vaginal rings fabricated from the two silicone polymers of grades MED 4830 and 4870 were studied for the release of the drug estrogen from the ring over a period of 56 days. The Control was fabricated without the drug.

(70) In reference to FIGS. 4, 5, 6, 7 and Table 2 Cumulative Drug Release was studied using both the Polymers.

(71) a) MED-4830 silicone films released in simulated vaginal fluid (SVF) of pH 4.2,

(72) b) MED-4830 silicone films released in SVF of pH 4.5,

(73) c) MED-4870 silicone films released in SVF of pH 4.2, and

(74) d) MED-4870 silicone films released in SVF of pH 4.5;

(75) Solid line represents 0.1% drug content (Code A), dotted line represents 0.5% drug content (Code B) and dashed line represents 0.1% drug content (Code C).

(76) Trial Samples as illustrated in FIGS. 4, 5, 6, and 7.

(77) Analytical Method

(78) Estriol was analysed by high performance liquid chromatography (HPLC) using LC-20AT liquid chromatography LC-20AT HT auto sampler, DGU-20A5 degasser, RF-10A XL UV/VIS detector (Shimadzu USA manufacturing Inc, USA) equipped with a Phenomenex Synergi polar-RP 80A, 4.6×250 mm, 4 μm column. A mixture of acetonitrile: 0.1% formic acid in water (50:50) was used as mobile phase at a flow rate of 1 mL/min and injection volume of 10 μL with UV detection at 225 nm.

(79) In vitro estriol release from silicone rings (IVIED-4830 and MED-4870) were studied in a simulated vaginal fluids (SVF) in pH 4.2 (normal vaginal pH) and pH 4.5 (post menopause vaginal pH) under sink conditions. Samples were accurately weighed and then placed in a screw top container containing 200 mL (for rings) SFV. All samples were shaken at 60 rpm at 35±2° C. At predetermined time intervals, 100 mL (for rings) of the incubation media from each sample was collected and an equal amount of fresh media was added into each release system to maintain the total volume and sink conditions. The concentration of estriol in the release media was determined by HPLC as described in the previous paragraph. The cumulative amount of estriol released was plotted against time for each sample. Estriol-free rings were used as controls. The experiment performed in triplicate with data presented as mean±SD.

(80) As illustrated in FIGS. 4, 5, 6, and 7, cumulative release of silicone rings was presented in FIG. 3 (above), indicating that all formulations showed sustained release over a period of 56 days. The release behaviors were discriminated between different silicone materials and release conditions with different pH values. Over a period of 56 days, 0.68 and 0.53% of estriol (equal to 0.12 and 0.09 mg) were released from MED-4830 rings under pH 4.2 and 4.5 respectively; 0.85 and 0.84% of estriol (equal to 0.15 and 0.17 mg) were released from MED-4870 rings under pH 4.2 and 4.5 respectively.

(81) Mechanical Test for Evaluation of the Ring Pessary

(82) An embodiment of the present invention discloses the Mechanical Evaluation of the Vaginal Ring Pessaries [20] comprising two different Silicone Rubber Polymers of Grade MED 4830 and MED 4870.

(83) TABLE-US-00003 TABLE 3 Trial Samples for Shore Hardness Test. Part A:Part B:Estriol Drug content Code Silicone (weight) (%)* 30-free MED-4830  1:1:— — 30-A MED-4830 01:00.0 0.10% 30-B MED-4830 01:00.0 0.50% 30-C MED-4830 01:00.0   1% 70-free MED-4870  1:1:— — 70-A MED-4870 01:00.0 0.10% 70-B MED-4870 01:00.0 0.50% 70-C MED-4870 01:00.0   1% 70-D MED-4870 01:00.2 .sup. 10% 70-E MED-4870 01:00.3 .sup. 15%
Shore Hardness Test: (FIG. 2, Table 3)

(84) Compression test of the silicone rings were performed using a texture analyser (TA.XT2, Stable Micro System, Haslemere, Surrey, UK) by compression the ring for a distance of 10 mm (n≥3 compressions at different sites per ring) and the maximum compression force in each test was recorded (McCoy et al., 2019). Drug-free and drug-loaded rings were compared to identify if drug incorporation and its concentration can affect the mechanical property of the rings, illustrated in Table no. 3. Considering the rings are designed for long-term application, the rings treated with SVF for a period of 4-month at 35±2° C. were assessed to evaluate the change of mechanical strength during treatment. A commercial ring (brand/manufacturer) similar to the samples was also tested as a reference. Each ring was placed vertically on a ring holder fixed to the platform of the texture analyzer (as shown in FIG. 3). A probe attached to the movable arm was used to compress the ring at a distance of 10 mm at a speed of 2.0 mm/s and the maximum compression forces were recorded. Based on the results Polymer 4870 is chosen for the further vaginal ring pessary [20] device polymer optimization. Further embodiment of the present invention performed tests of mechanical strength on Ring fabricated with Polymer MED 4870 and results indicate the vaginal ring pessary has a durometer of 60-80, most preferably 70 and Tensile strength of 1300-1600 psi, preferably 1500 psi and mechanical strengths in the range of 3490-4946 g.

(85) Final Ring Study

(86) Example 1, 2 and 3 are the exemplary embodiments of the present invention with Vaginal Ring Pessaries [20] of different drug content and evaluated for the release of the drug after fabrication. Different Vaginal Rings with Drug Content 1% Estrogen, 10% Estrogen, and 15% Estrogen were studied for Drug release over a period 180 days.

(87) Vaginal Ring Pessary Analytical Evaluation

(88) In Vitro Release Studies

(89) Different Vaginal Rings [20] with different Drug Content were studied for Drug release over a period 180 days.

(90) In vitro Estriol release from silicone rings MED-4870 with different drug content (1%, 10% and 15% drug per device) were studied in a simulated vaginal fluids (SVF) in pH 4.2 (normal vaginal pH) and pH 4.5 (post menopause vaginal pH) under sink conditions. Samples were accurately weighed and then placed in a screw top container containing 200 mL SFV. All samples were shaken at 60 rpm at 35±2° C. At predetermined time intervals, 100 mL of the incubation media from each sample was collected and an equal amount of fresh media was added into each release system to maintain the total volume and sink conditions. The concentration of Estriol in the release media was determined by HPLC as described below. The cumulative amount of estriol released was plotted against time for each sample. Estriol-free films/rings were used as controls. The experiment performed in triplicate with data presented as mean±SD.

(91) Analytical Method

(92) 1. HPLC method Estriol (E3) was analysed by high performance liquid chromatography (HPLC) using LC-20AT liquid chromatography LC-20AT HT auto sampler, DGU-20A5 degasser, RF-10A XL UV/VIS detector (Shimadzu USA manufacturing Inc, USA) equipped with a Phenomenex Synergi polar—RP 80A, 4.6×250 mm, 4 μm column. A mixture of acetonitrile: 0.1% formic acid in water (50:50) was used as mobile phase at a flow rate of 1 mL/min and injection volume of 10 μL with UV detection at 225 nm.

Example 1

(93) Vaginal pessary or vaginal ring [20] is made up of Estriol as the drug with drug concentration of 1% w/w or 1 mg in 100 mg of polymer ie., in MED-4870. The drug release data is depicted in Table 4 and FIG. 8 and FIG. 9.

(94) Vaginal ring pessary weight=16.0-18.5 g (Average weight 17.7 g)

(95) Drug content=1% 175.7 mg/device, 10% 1747.7 mg/device and 15% 2361.1 mg.

(96) TABLE-US-00004 TABLE 4 Drug Release from Vaginal Pessary with Estriol (1%) in MED-4870 Daily Weekly release release Days (mg) SD (mg) SD % Release SD 0 0 0 0 0 0 0 1 0.297 0.073 2.076993 0.624198 0.16833 0.038 4 0.116 0.005 0.815212 0.04668 0.380797 0.023 7 0.037 0.001 0.258378 0.005161 0.430795 0.027 14 0.044 0.001 0.310493 0.006401 0.623705 0.014 21 0.035 0.005 0.247287 0.041092 0.723877 0.034 28 0.031 0.002 0.220457 0.016307 0.874757 0.053 35 0.029 0.002 0.205023 0.013318 0.991792 0.062 42 0.029 0.002 0.199573 0.015249 1.105735 0.071 49 0.026 0.002 0.18229 0.01557 1.209959 0.078 82 0.018 0.001 0.122986 0.008711 1.541152 0.106 116 0.008 0.001 0.05366 0.0119 1.69076 0.137 123 0.043 0.002 0.30127 0.013402 1.862353 0.142 131 0.041 0.003 0.286207 0.026926 2.157096 0.067 137 0.039 0.003 0.271126 0.026697 2.182112 0.175 145 0.036 0.002 0.250556 0.014043 2.469305 0.072 153 0.034 0.002 0.238 0.014 2.632 0.078 160 0.032 0.003 0.224 0.025 2.763 0.097 167 0.036 0.004 0.251 0.036 2.918 0.091 174 0.033 0.002 0.232 0.020 3.059 0.095 181 0.032 0.003 0.226 0.028 3.198 0.110

Example 2

(97) Vaginal pessary or vaginal ring [20] is made up of Estriol as the drug with drug content of 10% w/w in MED-4870. The drug release data is depicted in Table 5 and FIG. 10 and FIG. 11.

(98) TABLE-US-00005 TABLE 5 Drug Release from Vaginal Pessary with Estriol (10%) in MED-4870 Daily Weekly relaese release Days (mg) SD (mg) SD % Release SD 0 0 0 0 0 0 0 1 1.703 0.078 11.92016 0.664646 0.097447 0.004581 4 0.647 0.023 4.529327 0.197641 0.208533 0.008832 7 0.189 0.009 1.321577 0.076768 0.240945 0.010408 14 0.165 0.004 1.151873 0.034102 0.306865 0.012159 21 0.109 0.002 0.764833 0.013583 0.350635 0.012563 28 0.096 0.003 0.669373 0.028854 0.388937 0.011491 35 0.083 0.004 0.583187 0.03204 0.422304 0.012473 42 0.079 0.002 0.55338 0.016874 0.453974 0.012618 49 0.076 0.001 0.52909 0.011852 0.484254 0.012958 82 0.042 0.001 0.296795 0.006341 0.564309 0.01204 116 0.018 0.001 0.125799 0.006275 0.599283 0.01329 123 0.116 0.003 0.813573 0.027505 0.645835 0.012426 131 0.101 0.002 0.705918 0.017189 0.692004 0.012523 137 0.098 0.001 0.688539 0.011874 0.725775 0.012411 145 0.095 0.003 0.666668 0.023067 0.769375 0.012375 153 0.086 0.001 0.601 0.011 0.809 0.012 160 0.087 0.003 0.607 0.023 0.843 0.013 167 0.086 0.003 0.599 0.022 0.878 0.013 174 0.085 0.003 0.595 0.026 0.912 0.014 181 0.079 0.002 0.554 0.015 0.943 0.014

Example 3

(99) Vaginal pessary or vaginal ring is made up of Estriol as the drug with drug content of 15% w/w in MED-4870. The drug release data is depicted in Table 6 and FIG. 12 and FIG. 13.

(100) TABLE-US-00006 TABLE 6 Drug Release from Vaginal Pessary with Estriol (15%) in MED-4870 Daily Weekly relaese release Days (mg) SD (mg) SD % Release SD 0 0 0 0 0 0 0 1 2.124567 0.194071 14.87197 1.663812 0.090239 0.010261 4 0.781012 0.023345 5.467086 0.200142 0.189673 0.015627 7 0.296129 0.027557 2.072902 0.236254 0.227359 0.01888 14 0.244034 0.010614 1.708237 0.090996 0.299759 0.021501 21 0.159404 0.008146 1.115827 0.06984 0.347009 0.021653 28 0.139904 0.00429 0.979327 0.036781 0.388501 0.022179 35 0.126696 0.003054 0.88687 0.026183 0.426125 0.023923 42 0.117984 0.001151 0.825887 0.009865 0.461135 0.024608 49 0.108698 0.002616 0.760883 0.022431 0.493392 0.02471 82 0.056592 0.004285 0.396147 0.036738 0.572688 0.032467 116 0.022561 0.001596 0.157928 0.013681 0.605149 0.031019 123 0.16542 0.006667 1.157937 0.057154 0.654269 0.033896 131 0.138733 0.002316 0.971127 0.019859 0.701331 0.034586 137 0.138838 0.001306 0.971868 0.011199 0.736652 0.035621 145 0.131821 0.000387 0.922746 0.003317 0.781367 0.036751 153 0.119 0.002 0.832 0.021 0.822 0.039 160 0.123 0.002 0.859 0.020 0.858 0.040 167 0.118 0.005 0.823 0.044 0.893 0.040 174 0.105 0.011 0.737 0.095 0.924 0.042 181 0.114 0.003 0.795 0.023 0.958 0.043
Results:

(101) The vaginal pessary [20] releases the estrogen over a period of 6 months at a steady state release comprising 30-50 μg/day with a 1% drug content in the ring pessary, a 70-200 μg/day with a 10% drug content in the ring pessary and 100-300 μg/day with a 15% drug content per device.

(102) The most preferred drug concentration is 1% and 10% for the vaginal ring pessary based on the results of drug release shown in Tables 4, 5 and 6.

(103) Advantages:

(104) 1. Improved patient experience—considering comfort, ease of use and quality of life. 2. Eliminate risks surrounding non-compliance to Ovestin. 3. Cheaper to produce a pessary device with slow-release oestrogen as opposed to separate manufacturing of the cream and tubing.

(105) At the outset of the description that follows, it is to be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is only an exemplary embodiment and is not intended to be taken restrictively to imply any limitation on the scope of the present invention.