CN103585712A - Pessulum containing hydrophilic lipophilic carrier - Google Patents

Abstract

The present invention relates to vaginal rings comprising a hydrophilic-lipophilic carrier. Specifically, the present invention provides a vaginal ring, which comprises a silicone rubber tube and a mixture containing medicine and glyceryl monostearate filled therein, and the weight ratio of the medicine to glyceryl monostearate is 1:50-50:1, the mixture accounts for 5-30% by weight of the silicone rubber tube. The invention also provides a preparation method of the vaginal ring. The technical problem to be solved by the present invention is to provide a special carrier for precisely controlling drug release. The special carrier disclosed in the present invention that can accurately control drug release is glyceryl monostearate. This hydrophilic and lipophilic carrier promotes drug penetration through the silicone rubber tube wall, and the controlled release characteristics of silicone rubber itself achieve double precision. purpose of controlled release.

Description

Vaginal ring comprising a hydrophilic lipophilic carrier

technical field

The invention relates to a controlled-release vaginal ring containing a hydrophilic and lipophilic carrier.

Background technique

Some water-soluble or fat-soluble drugs or drugs with certain structural properties are simply put into the silicone rubber tube, and it is difficult to directly penetrate the tube wall of the silicone rubber tube, which may be caused by the basic properties of silicone rubber. Therefore, it is necessary to add a hydrophilic and lipophilic carrier to promote drug penetration through the silicone rubber, which has special properties of the controlled release tube wall.

Glyceryl monostearate is an emulsifier and additive for food; it is used as an emulsifier in cosmetics and pharmaceutical ointments to make the paste delicate and smooth; it is used as an emulsifier for industrial silk oils and a lubricant for textiles; it is used in plastic films It can be used as dripping agent and anti-fogging agent; it can be used as lubricant and antistatic agent in plastic processing, and it can be used as defoamer, dispersant, thickener, wetting agent, etc. in other aspects. It is not mentioned in the prior art that it can be used as a special drug carrier, so that it can work together with the silicone rubber as the matrix of the vaginal ring to achieve double precise controlled release.

Contents of the invention

The present invention aims to provide a vaginal ring capable of precisely controlling drug release.

Another object of the present invention is to provide a preparation method of the vaginal ring.

The object of the present invention is achieved by following design: a kind of vaginal ring, it comprises silicone rubber tube 1 and the mixture 2 that comprises medicine and glyceryl monostearate filled therein, described medicine and monostearic acid The weight ratio of glyceride is 1:50-50:1, preferably 1:10-10:1, and the mixture accounts for 5-30% by weight of the silicone rubber tube, preferably 10-20% by weight.

In one embodiment, the mixture is composed of the drug and glyceryl monostearate, and the weight ratio of the drug to glyceryl monostearate is 1:50-50:1, preferably 1:10 -10:1.

In a preferred embodiment, the mixture is in the form of a solid dispersion, emulsion or cream.

Described medicine is selected from: norethindrone, desogestrel, nomegestone, dienogest, anordrin, medrgestrol, megestrol, mifepristone etc., or their Combination; flavoxate hydrochloride, oxybutynin hydrochloride, tolterodine tartrate, trospium chloride, darfenacin, midodrine, vinpocetine, etc., or their combination; danazol, tamoxifen , anastrozole, letrozole, etc., or their combination; or other classes of drugs suitable for vaginal ring or intrauterine device administration.

The molecular weight of the silicone rubber is 500,000 to 600,000.

The present invention also provides a kind of preparation method of vaginal ring, it comprises the following steps:

(a) mixing the drug and glyceryl monostearate in a weight ratio of 1:50-50:1 to obtain a mixture;

(b) Optionally, prepare the mixture obtained in step (1a) into a solid dispersion, emulsion or cream according to conventional formulation techniques in the prior art;

(c) Take a silicone rubber tube with a length of 12.6-13.8cm and an inner diameter of 2.5-3.5mm, and put the mixture obtained in step (a) or the solid dispersion, emulsion or cream obtained in step (b) into the vaginal ring, The two ends are butted to form a ring, and put into a mold for hot press vulcanization.

The silicone rubber tube is prepared through the following steps: knead the silicone rubber compound until soft, put it in a silicone rubber extruder, and extrude it according to the specified size.

Description of drawings

Figure 1 In vitro release curve of oxybutynin hydrochloride vaginal ring

Figure 2 Silicone rubber vaginal ring with one or several drug carrier solid dispersions, emulsions or creams.

The present invention will be further described in detail based on specific embodiments below.

Detailed ways

Example 1

Vaginal rings containing oxybutynin hydrochloride:

(1) 50 mg of oxybutynin hydrochloride and 150 mg of glyceryl monostearate were mixed, heated to 60° C., and cooled to obtain a solid dispersion.

(2) Preparation of emulsion: add 0.3g of diethanolamine to 10g of water, heat to 100°C, then slowly add 3g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free emulsion. Mix 50 mg of oxybutynin hydrochloride and 150 mg of the emulsion evenly to obtain the drug-containing emulsion.

(3) Preparation of cream: add 0.2 g of poloxamer to 6 g of water, heat to 100°C, then slowly add 3 g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free cream. 50 mg of oxybutynin hydrochloride and 150 mg of cream are uniformly mixed to obtain a drug-containing cream.

Preparation of Silicone Rubber Controlled Release Tube: The silicone rubber compound was mixed 5 times until soft, placed in a silicone rubber extruder, and extruded according to the size of a silicone rubber tube with a length of 12.8 cm and an inner diameter of 2.8 mm.

Take 200 mg of solid dispersion, emulsion or cream obtained in step (1), (2) or (3) and put it into an unvulcanized vaginal ring silicone rubber controlled-release tube, connect the two ends to form a ring, and put it into a mold Hot press vulcanization, the vaginal ring shown in Figure 2 can be obtained, wherein 1 is the outer silicon rubber controlled-release tube, and 2 is the drug carrier mixture.

In vitro release profile determination:

Take one piece of this product, put it in a 125ml jar with a stopper, add 30ml of ultra-pure water precisely, put it in a constant temperature water bath oscillator at 37±0.5°C, oscillate at a frequency of 60 times/min and an amplitude of 3cm, every 24 After 1 hour, take it out to measure the release amount and replace the medium solution, and make 6 rings in parallel.

The test chromatographic conditions are

Chromatographic column: C18, VP-ODS, 5μm, 4.6×250mm

Mobile phase: methanol: phosphate buffer (pH=6.8) = 15:85

Flow rate: 1ml/min

Detection wavelength: 220nm

The vaginal ring oxybutynin hydrochloride released by this method is 100-300 micrograms per day in vitro, and the specific data are shown in Table 1 below:

Table 1

The above results show that the oxybutynin hydrochloride vaginal ring obtained by using the device and method of the present invention has a uniform and stable drug release in vitro.

Example 2

Vaginal ring containing oxybutynin hydrochloride

(1) 50 mg of oxybutynin hydrochloride and 200 mg of glyceryl monostearate were mixed, heated to 60° C., and cooled to obtain a solid dispersion.

(2) Preparation of emulsion: add 0.3g of diethanolamine to 10g of water, heat to 100°C, then slowly add 3g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free emulsion. Mix 50 mg of oxybutynin hydrochloride and 200 mg of the emulsion evenly to obtain the drug-containing emulsion.

(3) Preparation of cream: add 0.2 g of poloxamer to 6 g of water, heat to 100°C, then slowly add 3 g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free cream. Mix 50 mg of oxybutynin hydrochloride and 200 mg of cream evenly to obtain the medicated cream.

Preparation of Silicone Rubber Controlled Release Tube: The silicone rubber compound was mixed 5 times until soft, placed in a silicone rubber extruder, and extruded according to the size of a silicone rubber tube with a length of 12.8 cm and an inner diameter of 2.8 mm.

Take 250 mg of solid dispersion, emulsion or cream obtained in step (1), (2) or (3) and put it into an unvulcanized vaginal ring silicone rubber controlled-release tube, connect the two ends to form a ring, and put it into a mold Hot press vulcanization, that is.

The in vitro release curve of the obtained vaginal ring was measured according to the steps in Example 1. As a result, the in vitro release amount of oxybutynin hydrochloride in the vaginal ring in this example was 100-600 micrograms per day.

Example 3

Vaginal ring containing letrozole

(1) Mix 400 mg of letrozole and 150 mg of glyceryl monostearate, heat to 60°C and cool to obtain a solid dispersion.

(2) Preparation of emulsion: add 0.3g of diethanolamine to 10g of water, heat to 100°C, then slowly add 3g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free emulsion. Letrozole 400mg and 150mg emulsion are uniformly mixed to obtain a drug-containing emulsion.

(3) Preparation of cream: add 0.2 g of poloxamer to 6 g of water, heat to 100°C, then slowly add 3 g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free cream. Letrozole 400mg and 150mg cream are evenly mixed to obtain a medicated cream.

Preparation of Silicone Rubber Controlled Release Tube: The silicone rubber compound was kneaded 5 times until soft, placed in a silicone rubber extruder, and extruded according to the size of a silicone rubber tube with a length of 13 cm and an inner diameter of 2.8 mm.

Take 550 mg of solid dispersion, emulsion or cream obtained in step (1), (2) or (3) and put it into an unvulcanized vaginal ring silicone rubber controlled-release tube, connect the two ends to form a ring, and put it into a mold Hot press vulcanization, that is.

The in vitro release curve of the obtained vaginal ring was measured according to the steps of Example 1. As a result, the in vitro release amount of letrozole in the vaginal ring of this example was 800-1000 micrograms per day.

Example 4

vaginal ring with mifepristone

(1) 600 mg of mifepristone and 150 mg of glyceryl monostearate were mixed, heated to 60° C., and cooled to obtain a solid dispersion.

(2) Preparation of emulsion: add 0.3g of diethanolamine to 10g of water, heat to 100°C, then slowly add 3g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free emulsion. 600 mg of mifepristone and 150 mg of emulsion are uniformly mixed to obtain a drug-containing emulsion.

(3) Preparation of cream: add 0.2 g of poloxamer to 6 g of water, heat to 100°C, then slowly add 3 g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free cream. 600 mg of mifepristone and 150 mg of cream are uniformly mixed to obtain the medicated cream.

Preparation of the silicone rubber controlled-release tube: the silicone rubber compound was mixed 5 times until soft, placed in a silicone rubber extruder, and extruded according to the size of a silicone rubber tube with a length of 13 cm and an inner diameter of 3 mm.

Take 750 mg of solid dispersion, emulsion or cream obtained in step (1), (2) or (3) and put it into an unvulcanized vaginal ring silicone rubber controlled-release tube, connect the two ends to form a ring, and put it into a mold Hot press vulcanization, that is.

The in vitro release curve of the obtained vaginal ring was measured according to the steps in Example 1. As a result, the in vitro release amount of mifepristone in the vaginal ring in this embodiment was 800-1000 micrograms per day.

Example 5

Vaginal ring containing danazol

(1) 800 mg of danazol and 150 mg of glyceryl monostearate were mixed, heated to 60°C, and cooled to obtain a solid dispersion.

(2) Preparation of emulsion: add 0.3g of diethanolamine to 10g of water, heat to 100°C, then slowly add 3g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free emulsion. Mix danazol 800 mg and 150 mg emulsion uniformly to obtain drug-containing emulsion.

(3) Preparation of cream: add 0.2 g of poloxamer to 6 g of water, heat to 100°C, then slowly add 3 g of preheated glyceryl monostearate, stir evenly and cool to obtain a drug-free cream. Mix danazol 800 mg and 150 mg cream evenly to obtain the medicated cream.

Preparation of Silicone Rubber Controlled Release Tube: The silicone rubber compound was kneaded 5 times until soft, placed in a silicone rubber extruder, and extruded according to the size of a silicone rubber tube with a length of 13.2 cm and an inner diameter of 3 mm.

Take 950 mg of solid dispersion, emulsion or cream obtained in step (1), (2) or (3) and put it into an unvulcanized vaginal ring silicone rubber controlled-release tube, connect the two ends to form a ring, and put it into a mold Hot press vulcanization, that is.

The in vitro release curve of the obtained vaginal ring was measured according to the steps in Example 1. As a result, the in vitro release amount of danazol in the vaginal ring in this example was 800-1000 micrograms per day.

comparative example

Vaginal rings without glyceryl monostearate

Preparation of Silicone Rubber Controlled Release Tube: The silicone rubber compound was kneaded 5 times until soft, placed in a silicone rubber extruder, and extruded according to the size of a silicone rubber tube with a length of 13.2 cm and an inner diameter of 3 mm.

Take 800 mg of danazol and put it into an unvulcanized vaginal ring silicone rubber controlled-release tube, connect the two ends to form a ring, put it into a mold for hot-pressing vulcanization, and obtain the product.

The in vitro release curve of the obtained vaginal ring was measured according to the steps in Example 1. As a result, the release amount of danazol in the vaginal ring in this example was about 50 ug per day in the in vitro release test.

The technical problem to be solved by the present invention is to provide a special carrier for precisely controlling drug release. The special carrier disclosed in the present invention that can accurately control drug release is glyceryl monostearate. This hydrophilic and lipophilic carrier promotes drug penetration through the silicone rubber tube wall, and the controlled release characteristics of silicone rubber itself achieve double precision. purpose of controlled release.

Claims (8)

1. a pessary, it comprises silicone rubber tube and is filled in the mixture that comprises medicine and glyceryl monostearate wherein, described medicine and the part by weight of glyceryl monostearate are 1:50-50:1, and described mixture accounts for the 5-30% weight of silicone rubber tube weight.

2. pessary as claimed in claim 1, the part by weight of wherein said medicine and glyceryl monostearate is 1:10-10:1; Described mixture accounts for the 10-20% weight of silicone rubber tube weight.

3. pessary as claimed in claim 1 or 2, wherein, described mixture is comprised of medicine and glyceryl monostearate.

4. pessary as claimed in claim 1 or 2, wherein, described mixture is solid dispersion, Emulsion or cream.

5. pessary as claimed in claim 1, wherein, described medicine is selected from: norethindrone, desogestrel, nomegestrol, dienogest, anorethindrane dipropionate, medroxyprogesterone, megestrol, mifepristone, flavoxate hydrochloride, ditropan XL, Tolterodine tartrate, trospium chloride, darifenacin, midodrine, vinpocetine, danazol, tamoxifen, Anastrozole, letrozole.

6. pessary as claimed in claim 1, wherein, the molecular weight of described silicone rubber is 500,000 to 600,000.

7. a method of preparing the pessary as described in as arbitrary in claim 1-5, it comprises the following steps:

(a) medicine is mixed according to arbitrary the limited part by weight of claim 1-5 with glyceryl monostearate, obtain mixture;

(c) get the silicone rubber tube of a length 12.6-13.8cm, internal diameter 2.5-3.5mm, the mixture that step (a) is obtained packs in pessary, and two ends docking circularizes, and puts into mould and carries out hot-press vulcanization molding.

8. the preparation method of pessary as claimed in claim 7, it is characterized in that, in step (a) with (c), also comprise step (b): according to conventional formulation technology of the prior art, the mixture that step (a) is obtained is prepared into solid dispersion, Emulsion or cream; Corresponding step (c) is: get the silicone rubber tube of a length 12.6-13.8cm, internal diameter 2.5-3.5mm, solid dispersion, Emulsion or cream that step (b) is obtained pack in pessary, and two ends docking circularizes, and puts into mould and carries out hot-press vulcanization molding.

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