Cerclage pessary containing progesterone of prolonged, sustained, and continuous release useful for prevention of preterm birth

Abstract

Cerclage pessary containing progesterone homogeneously distributed in the pessary body providing a prolonged, sustained and continuous release for a period of at least 6 months, wherein the pessary consists of dimethylsiloxane elastomer with RTV (Room Temperature Vulcanization) mechanism, the progesterone amount is from 20% to 30% w/w, relative to pessary weight and the ratios of the polymers forming the matrix is from 6:1 to 14 1. The cerclage pessary is useful for the prevention of preterm birth. Progesterone diffuses through the polymer continuously, without altering the shape and integrity of the pessary, since the elastomer forming the polymeric matrix used herein is not biodegradable. This guarantees that the form of pessary remains intact until the end of treatment.

Claims

1. A cervical pessary consisting of 20% to 30% w/w of progesterone homogenously distributed throughout 70% to 80% w/w of a dimethylsiloxane elastomer, wherein the dimethylsiloxane elastomer consists of: (A) a polydimethylsiloxane-vinyl polymer containing amorphous silica, and (B) a copolymer of dimethyl methylhydrogensiloxane and polydimethylsiloxane; having an A:B ratio ranging from 6:1 to 14:1, wherein the cervical pessary has a prolonged, sustained and continuous release of progesterone for a period of at least 6 months, and maintains its intact form all the time.

2. A cervical pessary according to claim 1, wherein the amount of progesterone in the pessary is from 5.0 g to 10.5 g.

3. A cervical pessary according to claim 1, having a weight between 25 and 35 grams.

4. A cervical pessary according to claim 1, wherein the amount of progesterone sustained and continuously released from the pessary is of 15 mg to 65 mg daily, for a period of at least 6 months.

5. A cervical pessary according to claim 1, wherein the A:B ratio is 6:1, 8:1, 10:1, 12:1 or 14:1.

6. A method for preventing preterm birth comprising administering the cervical pessary according to claim 1 to a patient in need thereof.

7. A cervical pessary according to claim 1, wherein: the polydimethylsiloxane-vinyl polymer (A) contains amorphous silica in an amount of 25% w/w of the polymer (A), and the copolymer (B) is a copolymer of 20% dimethyl methylhydrogensiloxane with polydimethylsiloxane.

8. A cervical pessary according to claim 7, wherein the amount of progesterone in the pessary is from 5.0 g to 10.5 g.

9. A cervical pessary according to claim 7, having a weight between 25 and 35 grams.

10. A cervical pessary according to claim 7, wherein the amount of progesterone initially released from the pessary is of 15 mg to 65 mg daily, for a period of at least 6 months.

11. A cervical pessary according to claim 7, wherein the A:B ratio is 6:1, 8:1, 10:1, 12:1 or 14:1.

12. A method for preventing preterm birth comprising administering the cervical pessary according to claim 7 to a patient in need thereof.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1. Layout of the matrix designed and used for making the pessaries of this application. In cross sectional view can be seen location of the pins that perforate the pessary.

(2) FIG. 2. Digital photograph of a bronze matrix used to produce the pessaries of the present invention, connected with the heating system.

(3) FIG. 3. Digital photograph of a bronze matrix used to produce the pessaries of the present invention, at rest, and a pessary obtained in this matrix.

(4) FIG. 4. Digital photographs of a pessary of the present invention Table A: View from the top end, which is installed in the cervix towards the uterus Table B: Side view which shows the holes in the curved surface of the pessary Table C: View from the lower end of the pessary, where their rounded ends can be seen.

(5) FIG. 5. Layout of the medicated cerclage pessary of the present invention. The locations of the main dimensions of the pessary are indicated. D1: Larger outer diameter; D2: Larger Inner Diameter; D3: Smaller diameter; H1: Height.

(6) FIG. 6. In vitro release profile of progesterone from cerclage pessaries comprising 22.5%, 28% and 30% of progesterone. Pessaries comprise Polymer A and B in a ratio 8:1 (R=8:1).

(7) FIG. 7. In vitro release profile of progesterone from cerclage pessaries comprising 22.5% of progesterone. Pessaries comprise Polymer A and B in a ratio (R) of 6:1, 8:1, 10:1, 12:1 and 14:1.

(8) FIG. 8. Images of Transvaginal Ultrasound (EcoTV), Nuclear Magnetic Resonance (NMR) and Digital Photography Table A: EcoTV in a woman at risk of preterm birth, which has the pessary of the present invention installed surrounding the cervix Table B: NMR image of the same woman, wherein the pessary containing and affirming the cervix is displayed Table C. Digital photography of the woman having a short cervix, with the pessary of the present invention located in the cervix.

MANUFACTURING PROCESS OF MEDICATED PESSARY

(9) For the manufacture of medicated pessary of the present invention, the design and construction of a matrix was performed by injection. The matrix was made from bronze SAE 640 material for the formation of medicated pessary according to specifications and layout shown in FIG. 1. The matrix has six perforation pins, a temperature control system, which contains heaters, thermocouple, board for electronic temperature control and a board base incorporated, as shown in FIGS. 2 and 3. To obtain the pessary, the blend of active ingredient with polymers is injected through a hole located on top of the matrix, filling indicator is located to one side at the upper end.

(10) Steps of Manufacturing Process:

(11) 1. Weighing of Raw Materials

(12) In a pharmaceutical grade stainless steel vessel of suitable capacity the required amounts of each ingredient according to the formulations to be used as described in Table 1 are weighted. Transferred then to the mixer. Weighing of micronized progesterone in a polybag according to formulations to be tested as indicated in Table 1.
2. Mixing Procedure Slowly adding micronized progesterone to base polymer A with manual stirring, avoiding adding air; date of incorporation of the micronized progesterone to polymer must be recorded. Performing quality control to assess blend uniformity.
3. Polymerization Process Extracting, weighing and transferring an aliquot of the blend obtained in section 2 to a stainless steel vessel, according to the ratio of polymer A and B to be used, as indicated for each formulation in Table 1. Mixing immediately after polymer addition until the mixture is homogeneous (uniform and brilliant appearance), recording date and time of the preparation for each aliquot in a timesheet. Filling the stainless steel injector of suitable capacity with this final blend, and introducing to the mold inlet hole. Keeping the blend injected into the cast for 15-20 minutes at a temperature of 80±10° C., recording time and temperature in the timesheet. Once the process has been completed, open the matrix and remove the pessary.

(13) Physical Characteristics of Progesterone Cerclage Pessary of the Present Invention

(14) Cerclage pessary of the present invention is made with dimethylsiloxane elastomer with RTV reaction mechanism.

(15) It is a white, flexible, conically circular device, with a firm consistency, with a centered hole and six holes distributed on its surface, as shown in FIG. 4.

(16) It have been reported the occurrence of an increased vaginal discharge with the use of pessaries and vaginal rings, so in the present invention, to facilitate drainage, a pessary having holes distributed throughout the section is preferably used. The holes have a diameter of 3.0 mm±0.2 mm.

(17) In the scheme shown in FIG. 5, the locations of the following dimensions for the pessary of the present invention are shown: Larger outer diameter (D1): 65 mm±5 mm Larger Inner Diameter (D2): 50 mm±5 Height (H1): 25 mm±2 mm Smaller diameter (D3): 33.5 mm±1.5 mm

(18) Weight of the medicated pessary is 30 g±5 g.

(19) Exemplary Formulations

(20) Cerclage pessaries comprising different amounts of progesterone, homogeneously distributed throughout the body of the device, in quantities from 20% to 30% w/w were made. These formulations comprise different proportions of RTV silicone elastomer.

(21) In Table 1 General Formulations (GF) of the present invention are described. Different ratios of polymers used are specified.

(22) TABLE-US-00001 TABLE 1 Formulations of cerclage pessaries containing progesterone with different ratios between Polymer A and Polymer B. Each formulation was expressed as General Formula (GF) in % w/w. % v/v Ingredient GF-1 GF-2 GF-3 GF-4 GF-5 GF-6 GF-7 GF-8 GF-9 Micronized 20.0-30.0 20.0-30.0   20.0-30.0 20.0-30.0 20.0-30.0 20.0-30.0 20.0-30.0 20.0-30.0 20.0-30.0  progesterone Polymer A: 58.33-66.67 60.0-68.57 61.25-70.0 62.22-71.11 63.0-72.0 63.64-72.73 64.17-73.33 64.62-73.85 65.0-74.29 polydimethylsiloxane- vinyl polymer + amorphous silica (25%) + platinum catalyst Polymer B: 11.67-13.33 10.0-11.43  8.75-10.0 7.78-8.89 7.0-8.0 6.36-7.27 5.83-6.67 5.38-6.15 5.0-5.71 Copolymer of Dimethyl methylhydrogen siloxane (20%) + polydimethylsiloxane Total content 100 100 100 100 100 100 100 100 100 (Polymer A:Polymer B) 5:1 7:1 8:1 9:1 10:1 11:1 12:1 13:1 14:1 ratio
Specific Formulations of Medicated Cervical Pessary:

(23) Pessaries containing 20 to 30% of progesterone formed by dimethylsiloxane polymers, containing a variable ratio of Polymer A and Polymer B were made, wherein the first one is polydimethylsiloxane-vinyl polymer with 25% amorphous silica and a platinum catalyst, and the second one is a copolymer of 20% dimethyl methylhydrogen siloxane with polydimethylsiloxane.

(24) In following Tables 2 to 6 pessary formulations of the present invention are shown. All comprising the same elastomer but formed with different proportions of the starting polymers.

(25) TABLE-US-00002 TABLE 2 Formulations of pessary medicated with progesterone in Polymer A:Polymer B = 6:1 and 7:1 ratios Ratio A:B = 6:1 Ratio A:B = 7:1 Ingredient % W/W % W/W Micronized 20 22.5 25 28 30 20 22.5 25 28 30 progesterone Polymer A: 66.67 64.58 62.50 60.00 58.33 68.57 66.43 64.29 61.71 60.00 polydimethylsiloxane- vinyl polymer + amorphous silica (25%) + platinum catalyst Polymer B: 13.33 12.92 12.50 12.00 11.67 11.43 11.07 10.71 10.29 10.00 Copolymer of Dimethyl methylhydrogen siloxane (20%) + polydimethylsiloxane Total content 100 100 100 100 100 100 100 100 100 100

(26) TABLE-US-00003 TABLE 3 Formulations of pessary medicated with progesterone in a Polymer A:Polymer B = 8:1 and 9:1 ratios Ratio A:B = 8:1 Ratio A:B = 9:1 Ingredient % W/W % W/W Micronized 20 22.5 25 28 30 20 22.5 25 28 30 progesterone Polymer A: 70.00 67.81 65.63 63.00 61.25 71.11 68.89 66.67 64.00 62.22 polydimethylsiloxane- vinyl polymer + amorphous silica (25%) + platinum catalyst Polymer B: 10.00 9.69 9.38 9.00 8.75 8.89 8.61 8.33 8.00 7.78 Copolymer of Dimethyl methylhydrogen siloxane (20%) + polydimethylsiloxane Total content 100 100 100 100 100 100 100 100 100 100

(27) TABLE-US-00004 TABLE 4 Formulations of pessary medicated with progesterone in Polymer A:Polymer B = 10:1 and 11:1 ratios Ratio A:B = 10.1:1 Ratio A:B = 11:1 Ingredient % W/W % W/W Micronized 20 22.5 25 28 30 20 22.5 25 28 30 progesterone Polymer A: 72.00 69.75 67.50 64.80 63.00 72.73 70.45 68.18 65.45 63.64 polydimethylsiloxane- vinyl polymer + amorphous silica (25%) + platinum catalyst Polymer B: 8.00 7.75 7.50 7.20 7.00 7.27 7.05 6.82 6.55 6.36 Copolymer of Dimethyl methylhydrogen siloxane (20%) + polydimethylsiloxane Total content 100 100 100 100 100 100 100 100 100 100

(28) TABLE-US-00005 TABLE 5 Formulations of pessary medicated with progesterone in Polymer A:Polymer B = 12:1 and 13:1 ratios Ratio A:B = 12:1 Ratio A:B = 13:1 Ingredient % W/W % W/W Micronized 20 22.5 25 28 30 20 22.5 25 28 30 progesterone Polymer A: 73.33 71.04 68.75 66.00 64.17 73.85 71.54 69.23 66.46 64.62 polydimethylsiloxane- vinyl polymer + amorphous silica (25%) + platinum catalyst Polymer B: 6.67 6.46 6.25 6.00 5.86 6.15 5.96 5.77 5.54 5.38 Copolymer of Dimethyl methylhydrogen siloxane (20%) + polydimethylsiloxane Total content 100 100 100 100 100 100 100 100 100 100

(29) TABLE-US-00006 TABLE 6 Formulations of pessary medicated with progesterone in Polymer A:Polymer B = 14:1 ratio Ratio A:B = 14:1 Ingredient % W/W Micronized 20 22.5 25 28 30 progesterone Polymer A: 74.29 71.96 69.64 66.86 65.00 polydimethylsiloxane- vinyl polymer + amorphous silica (25%) + platinum catalyst Polymer B: 5.71 5.54 5.36 5.14 5.00 Copolymer of Dimethyl methylhydrogen siloxane (20%) + polydimethylsiloxane Total content 100 100 100 100 100

(30) Cervical pessaries were prepared containing 5 g to 10.5 g of progesterone, with ratios of polymer A to B as shown in Tables 1 to 6.

(31) Identity and assessment of active principle in the medicated pessary of the present invention:

(32) To determine the identity and assessment of progesterone contained in pessaries, the following conditions and procedures were used:

(33) Chromatographic Conditions:

(34) Column: Agilent Eclipse XDB C-18 (4.6×150 mm) (5 μM)

(35) Mobile phase: acetonitrile: 60%

(36) Water: 40%

(37) Flow rate: 1.0 mL/min

(38) Wavelength: 240 nm

(39) Injection volume: 50 μL

(40) Approximate Retention time: 8.0 min

(41) Standard Solution:

(42) Weighing accurately about 50 mg±1 mg progesterone secondary standard in a volumetric flask of 100 mL. Adding 60 mL of methanol, sonicating 2 minutes, diluting to volume with methanol. Taking an aliquot of 2.0 mL and transferring to a 100 mL flask with mobile phase. Homogenizing. Filtering through a membrane filter of 0.45 μm (C=0.01 mg/mL).

(43) Sample Solution:

(44) Weighing 10 pessaries and determining their average weight: Taking a pessary and make a cut to open it. Carefully longitudinally cutting into pieces of about 2 mm and put the pieces in a clean dry vessel. Weighing the equivalent of a pessary and bringing to a 250 mL Erlenmeyer flask with tight-fitting lid, adding 150 mL of dichloroethane, covering, placing on a magnetic stirrer and stirring for 18 hours. Quantitatively transferring the extract obtained to a 200 mL volumetric flask rinsing the pessary residue with small amounts of dichloroethane, bringing to volume with dichloroethane, homogenizing.

(45) Taking a 2.0 mL aliquot of this solution and transferring to a 200 mL beaker, carefully evaporating to dryness under nitrogen stream, dissolving the residue with 25 mL of methanol, gently sonicating 2 minutes and quantitatively transferring to a 50 ml volumetric flask rinsing with small amounts of methanol, bringing to volume with methanol, homogenizing. From this solution taking an aliquot of 5.0 mL volumetric and bringing to a 100 mL volumetric flask with mobile phase. Homogenizing. Filtering through a membrane filter of 0.45 μm (C=0.01 mg/mL).

(46) Adjusting Dilutions for the Pessary, as Needed

(47) Procedure:

(48) Separately injecting 50 mL of standard and sample solutions, obtaining the corresponding chromatograms and determining the area under the peak.

(49) Calculations:

(50) $g\text{/}\mathrm{pessary}=\frac{\mathrm{As}}{\mathrm{Ast}}\times \frac{\mathrm{Wst}}{100}\times \frac{2}{100}\times \frac{\%R}{100}\times \frac{200}{\mathrm{Wspl}}\times \frac{50}{2}\times \frac{100}{5}\times \frac{1}{1000}\times \mathrm{PAW}$$\%\mathrm{VD}=g\text{/}\mathrm{pessary}\times 100$
Wherein:
As=Average area under the peak of progesterone in the sample solution
Ast=Average area under the peak of progesterone in the standard solution
Wst=Weight of standard of progesterone, mg
% R=Purity of Standard, in %
Wspl=Weight of sample in mg
PAW=Pessary average weight in mg.

(51) Using the implemented and validated analytical method, the above tests were subjected to physical-chemical analysis, complying with the established product specifications based on design requirements.

(52) Studies of In Vitro Release

(53) It was developed an experimental protocol for the study of in vitro hormonal release for a period of at least five months in order to evaluate the release profile, quantifying mg of released progesterone per day within the indicated period of time.

(54) Methodology:

(55) Method: UV spectrophotometry

(56) Wavelength: 262.4 nm (Diffusion Medium)

(57) 240 nm (Samples)

(58) Quartz cuvettes: 1 cm depth

(59) Diffusion Medium:

(60) Adding about 64.26 mL of 50% benzalkonium chloride in a precipitate vessel, adding about 200 mL of double distilled water, dissolving until is completely dissolved. Transfer quantitatively the benzalkonium chloride solution to a 1.0 L flask and dilute to volume with bidistilled water. The resulting solution is then transferred to a polyethylene drum with a tap containing 23 L of double-distilled water inside, stirring until homogenization. The concentration obtained is 1:750.

(61) Measuring the absorbance of the diffusion medium at 262.4 nm in cells of 1 cm using distilled water as a blank. The absorbance must range from 1.3 to 1.6, otherwise the solution should be discarded.

(62) Stock of Standard Solution:

(63) Weighing accurately about 25 mg of standard progesterone, transferring to a 50 mL volumetric flask, adding 25 mL of ethanol, dissolving and bringing to volume with ethanol. Dividing into 5 mL tubes with screw cap, labeling with a name, concentration and date. Keeping refrigerated.

(64) Diluted Standard Solution:

(65) From the stock of standard solution, previously heated to room temperature, an aliquot of 200 μL is taken and transferred to a 10 mL volumetric flask and brought to volume with diffusion medium (C=0.01 mg/mL). Repeating the procedure four times.

(66) Sample Solutions:

(67) Adding 900 mL of diffusion medium to six 1000 mL polyethylene wide-mouth screw top bottles. Individually weighing 6 pessaries, recording their weight and assigning a number to each one of them. Tying each pessary with a suitable length polyethylene yarn to completely immerse in diffusion medium, introducing the pessaries into the bottles and then fixing the yarn on the outer surface thereof with tape.

(68) Pessaries must be positioned at 2±0.2 cm from the base of the bottle.

(69) Labeling each bottle with the weight and number of the corresponding pessary. Covering each bottle, and placing them in a suitable water bath at 37±0.5° C. and stirring at 100 rpm±5 rpm.

(70) Checking and recording temperature and stirring speed of the bathroom daily.

(71) Every 24 hours, at the same time, changing diffusion medium of each bottle. Taking an aliquot of 20 mL of each bottle and discarding the rest of the diffusion medium on weekdays. Taking an aliquot of 10 mL and transferring to a 50 mL volumetric flask, bringing to volume with diffusion medium from the same batch. Absorbance readings of 0.3 to 0.7 must be obtained or otherwise it must be adjusted with diffusion medium of the same batch, as needed.

(72) Measuring absorbance of aliquots and diluted standard solutions in 1 cm quartz cells at 240 nm and using diffusion medium as a blank.

(73) Carrying on the test in the same manner until completion of 150 days.

(74) When calculating the average absorbance of diluted standard solutions, the coefficient of variation should not exceed 2.0%. If this requirement is not met, dilutions must be repeated. Calculating mg progesterone released per day, according to the following formula:
mg of Progesterone=Absorbance Factor×As
Wherein:
As=Absorbance of the sample

(75) $\mathrm{Absorbance}\mathrm{Factor}=\frac{\mathrm{Cds}\times \mathrm{Vt}\times \mathrm{Vds}}{\mathrm{AAs}\times \mathrm{Vs}}$
wherein:
Cds: Concentration of diluted standard solution.
Vt: total volume of diffusion medium 900 mL
Vds: Final Dilution Volume of sample.
AAs: Average Absorbance of diluted standard solution.
Vs: volume of the sample taken for dilution.

(76) In vitro release studies were performed with medicated pessaries described in Tables 2-6, using the described analytical procedure.

(77) In FIG. 6 it is observed progesterone release from three pessaries prepared with a polymer ratio of A:B=8:1 (R=8:1) containing different amounts of progesterone, 22.5%, 28% and 30%, corresponding to 6.75 g, 8.4 g and 9 g of progesterone in each pessary, respectively. Even though the release of progesterone from 22.5% pessaries tends to be low, no significant differences between the three curves are observed. Initial release (day 1) was 59, 62.1 and 63.1 mg, respectively, reaching 21.4, 22.4 and 23 mg on day 150 (5 months progesterone release), and 17, 9, 18.8 and 22.3 mg on day 182 (6 months progesterone release). The average amount of progesterone released between 120 to 150 days was 22.4, 18.8 and 22.3 mg, respectively.

(78) These results revealed no significant differences in progesterone release from pessaries containing 22.5% 28% and 30% of hormone, probably this is due to the fact that saturation was reached in both pessary loading and active ingredient release.

(79) Additionally, the effect of different ratios of polymer A and B on the hormone release profile was evaluated due to the complexity in the process of the curing of polymers, and the difficulty in polymerization that can occur when the ratios are inadequate.

(80) FIG. 7 shows release from pessaries containing 22.5% of progesterone in polymer ratios (R) of 6:1, 8:1, 10:1, 12:1 and 14:1. The result was surprising, since the release profile is virtually the same and no differences were observed in both initial release (day 1) and the amount of progesterone released in last months (120-150 days) reaching 24.6, 23.3, 23.0, 22.4 and 23.9 mg, respectively.

(81) Thus, the preferred ratios of the present invention are from 6:1 to 14:1 for polymer A relative to polymer B, since it did not significantly affected the amount of progesterone released in the beginning and in last months, as well as it did not modify the hormone release profile from pessaries.

(82) Clinical Studies in Women with Risk of Preterm Birth

(83) Clinical Case 1:

(84) A 26 year old woman with a history of preterm vaginal birth in 2011.

(85) In the current pregnancy she was in control at a High Risk Obstetric Clinic because she had a dichorionic diamniotic twin pregnancy with morphologically normal fetuses. In a pregnancy control at 18 weeks a transvaginal ultrasound to measure cervical length was performed, which results in 35 mm (under 25 percentile for said gestational age). She was hospitalized at 20 weeks and 1 day, because a cervical shortening to 28 mm is detected in the last 2 weeks. Unable to provide some measure for effective prevention of preterm birth, it is proposed to the patient using a pessary medicated with progesterone of the present invention. She willingly agreed to the installation thereof, which is performed without difficulty after signing the informed consent. The pessary was installed when she was 21 weeks 4 days of gestation. Cervical length was 30 mm after pessary installation maintaining at that length in the following controls. In her later controls she did not referred discomforts such as increased vaginal discharge or constipation. She again was hospitalized when she was 32 weeks of gestation for having sensitive uterine contractions. At that time a new cervical length measurement is performed resulting in a 23 mm length with a well positioned pessary. Since the event does not progress to preterm birth, she is discharged at 32 weeks and 4 days.

(86) She again assisted to a medical consultation at 34 weeks and 2 days referring having expelled the pessary the prior night (34 weeks and 1 day). The case is clinically re-evaluated and for exceeding the 34 weeks of gestation is decided not to reinstall the pessary, indicating partial rest.

(87) The patient has her childbirth through an elective cesarean section at 37 weeks and one day. The newborn boys of 2,200 and 2,780 grams were born in good conditions and are discharged on the eighth day of life with his mother.

(88) Clinical Case 2:

(89) A 38 year old multigesta woman with a past history of three previous miscarriages and no delivery.

(90) In a private practice consultation for control of singleton pregnancy, a cervical length of 38 mm at 12 weeks of gestation is detected. In a subsequent control at 24 weeks and 4 days a cervical length of 10 mm with cervical wedge or funnel is found. She is hospitalized for deciding management alternatives. After five days of rest, a new transvaginal ultrasound results in a 20 mm neck. The patient is proposed to use a pessary medicated with progesterone, to which she willingly agreed. After signing the informed consent, the pessary was installed at 25 weeks and 4 days, without difficulty or discomfort for the patient. She is controlled periodically and the patient did not refer discomfort with the pessary (no increased vaginal discharge or constipation). In a control when she was 29 weeks and 4 days, a cervical length of 15.8 mm with a well positioned pessary is found. The patient is clinically and sonographically controlled monthly, no more cervical shortening or discomfort attributable to the use of the pessary is detected. Pessary is removed at 36 weeks and the patient had a spontaneous vaginal delivery at 38 weeks of gestation.

(91) Transvaginal Ultrasound and Magnetic Resonance Imaging

(92) The patient of the clinical case 2 was subjected to a Transvaginal ultrasound (Eco TV) and Nuclear Magnetic Resonance (NMR) to measure and evaluate cervical length, and placement and positioning of medicated pessary of the present invention. As shown in FIG. 8, the Eco TV (Table A) shows the position of the pessary in the cervix and NMR (Table B) clearly shows how the pessary with progesterone of the present invention surrounds the cervix supporting and protecting it from uterus weight. In the digital photography (Table C) the pessary of the present invention installed in the patient is seen and the neck within the pessary is observed. Although this patient initially had a fairly short neck (10 mm), the pessary was very well positioned.

REFERENCES

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