Sodium prasterone sulfate spray as well as preparation method and application thereof

Abstract

The invention provides a prasterone sodium sulfate spray and a preparation method and application thereof.The preparation method comprises the steps that S1, prasterone sodium sulfate, threonine and arginine are added into a mixed solvent, magnetic stirring and vacuum drying are conducted, and a prasterone sodium sulfate medicine eutectic is obtained; s2, adding the SiO2 powder and sodium dihydrogen phosphate into absolute ethyl alcohol, performing ultrasonic treatment, and performing centrifugal washing and drying to obtain modified SiO2; mixing the sodium prasterone sulfate pharmaceutical eutecticum with the modified SiO2 powder, adding the mixture into deionized water, and carrying out rotary evaporation to obtain a sodium prasterone sulfate-SiO2 compound; s3, adding the prasterone sodium sulfate-SiO2 compound, butanediol and glycerol into water, and performing ultrasonic stirring to obtain the prasterone sodium sulfate spray. The prasterone sodium sulfate spray is applied to the vagina, the first-pass effect of the liver is avoided, the bioavailability is improved, the higher local drug concentration is achieved, the plasma concentration is stable, the compliance of a patient is improved, the side effect is reduced, and the good vaginal atrophy treatment effect is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a sodium prasterone sulfate spray and a preparation method and application thereof. Background Art

[0002] Vaginal atrophy is a symptom of aging, especially after menopause, when estrogen levels in women decrease and tissues such as the reproductive and urinary tract age, resulting in a series of symptoms, including vaginal dryness, stinging, dyspareunia, and repeated urinary tract infections. In clinical examinations, the typical manifestations of vaginal atrophy are reduced vaginal folds; the mucosa becomes pale and dry; the epithelial tissue is fragile, and submucosal punctate bleeding can be seen. Laboratory tests show that the vaginal pH value is greater than 5.0, the vaginal cell maturation index changes, tending to be dominated by bottom cells, and vaginal bacterial culture can reveal some rare pathogens. Treatments for vaginal atrophy include lifestyle adjustments, non-hormonal treatments (vaginal lubricants or moisturizers), and systemic and local hormone therapy. At present, estrogen replacement therapy, that is, supplementation with exogenous estrogen, is considered the standard treatment for moderate to severe vaginal atrophy at home and abroad.

[0003] Prasterone Sodium Sulfate, chemical name 3β-hydroxy-5-androsten-17-one sodium sulfate. After entering the peripheral target tissue, prasterone sodium sulfate is converted into prasterone, and under the action of multiple specific enzymes, it is converted into active androgens and / or estrogens. The converted androgens and / or estrogens bind to the specific receptors of target cells to produce biological effects. In the vaginal target cells, the androgens produced increase the production of vaginal epithelial cells from the bottom layer to the middle layer, and the vaginal cell maturation index increases; part of the estrogen produced by the conversion of androgens causes the vaginal mucosa to proliferate and thicken, and the symptoms of pale and dry vaginal mucosa, sexual intercourse pain, and sexual intercourse difficulties are significantly improved.

[0004] However, prasterone sodium sulfate is a steroid compound and a water-insoluble substance with poor solubility. Ordinary preparations are difficult to exert good therapeutic effects. At the same time, the current dosage form requires multiple and frequent administrations, and patient compliance is poor. The drug plasma concentration fluctuates greatly, and a "peak and valley" phenomenon may occur, resulting in greater toxic side effects. Summary of the invention

[0005] In view of this, the present invention provides a sodium prasterone sulfate spray and a preparation method and application thereof.

[0006] The technical solution of the present invention is achieved in this way:

[0007] A method for preparing sodium prasterone sulfate spray, the specific steps comprising:

[0008] S1. Preparation of prasterone sodium sulfate drug co-crystal

[0009] Adding prasterone sodium sulfate, threonine and arginine into a mixed solvent, stirring magnetically, and vacuum drying to obtain prasterone sodium sulfate drug co-crystals;

[0010] S2. Preparation of prasterone sulfate sodium-SiO2 complex

[0011] (1) adding SiO2 powder and sodium dihydrogen phosphate into anhydrous ethanol, ultrasonically treating, centrifuging, washing and drying to obtain modified SiO2;

[0012] (2) mixing the sodium prasterone sulfate drug co-crystal and the modified SiO2 powder, adding them into deionized water, and performing rotary evaporation to obtain a sodium prasterone sulfate-SiO2 complex;

[0013] S3. Preparation of prasterone sodium sulfate spray

[0014] The sodium prasterone sulfate-SiO2 complex, butanediol and glycerol are added into water and ultrasonically stirred to obtain the sodium prasterone sulfate spray.

[0015] Furthermore, in step S1, the molar ratio of prasterone sodium sulfate to threonine and arginine is 1:0.3-0.5:0.1-0.3.

[0016] Furthermore, in step S1, the mixed solvent is obtained by mixing citric acid, glucose, glycerol and deionized water in a mass ratio of 10-20:10-15:5-8:50-80; the solid-liquid ratio of the sodium prasterone sulfate to the mixed solvent is 1:20-30 g / mL.

[0017] Furthermore, in step S1, the temperature of the magnetic stirring is 50-60°C, and the time is 4-8h; the temperature of the vacuum drying is 30-50°C, and the time is 10-14h.

[0018] Furthermore, in step S2(1), the mass ratio of the SiO2 powder to sodium dihydrogen phosphate is 1:0.15-0.27; the solid-liquid ratio of the SiO2 powder to anhydrous ethanol is 1:8-12 g / mL; and the ultrasonic treatment is carried out at 20-30 kHz and 50-70°C for 2-4 hours.

[0019] Furthermore, in step S2(2), the mass ratio of the sodium prasterone sulfate drug co-crystal to the modified SiO2 powder is 1:4.4-8.8; the solid-liquid ratio of the sodium prasterone sulfate drug co-crystal and the modified SiO2 powder to deionized water is 1:10-20 g / mL; the temperature of the rotary evaporation is 40-50°C, the rotation speed is 200-300 rpm, and the time is 1-3h.

[0020] Furthermore, in step S3, the following raw materials are included in parts by weight: 10-15 parts of sodium prasterone sulfate-SiO2 complex, 2-4 parts of butanediol, 3-5 parts of glycerol, and 80-100 parts of water.

[0021] Furthermore, in step S3, the ultrasonic stirring is carried out at 20-30 kHz, 100-200 W, and 30-40° C. for 8-10 h.

[0022] A sodium prasterone sulfate spray is prepared by any of the above preparation methods.

[0023] Application of prasterone sodium sulfate spray in the preparation of a medicine for treating vaginal atrophy.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The prasterone sodium sulfate spray prepared by the present invention is directly administered vaginally, avoids the first-pass effect of the liver, improves the bioavailability, achieves a higher local drug concentration, has a stable blood drug concentration, improves the patient's compliance, reduces side effects, and has a good effect in treating vaginal atrophy.

[0026] 2. The prasterone sodium sulfate drug co-crystal of the present invention forms a co-crystal with prasterone sodium sulfate, threonine and arginine. Threonine has a polar side chain, which can increase the solubility of prasterone sodium sulfate and reduce precipitation. At the same time, the antioxidant property of threonine can increase the stability of prasterone sodium sulfate. Arginine has an amino group and a carboxyl group, which can improve the overall stability of the prasterone sodium sulfate drug co-crystal. The prasterone sodium sulfate drug co-crystal improves the solubility and bioavailability of prasterone sodium sulfate, thereby enhancing the drug efficacy and being easier to absorb.

[0027] 3. The present invention grafts and modifies SiO2, and some hydroxyl groups on the surface of SiO2 are replaced, which significantly reduces its hygroscopicity and increases stability. At the same time, the reduction of hydroxyl groups can effectively inhibit SiO2 recrystallization or reaggregation, improve the dispersibility of SiO2, and can better and more evenly coat the sodium prasterone sulfate drug co-crystal. The modified SiO2 produces steric hindrance, which prevents sodium prasterone sulfate from flowing out of the mesoporous structure quickly after entering the human body, so that the drug release rate is stable, and the long-term release of the drug is achieved, the drug effect is prolonged, the number of administrations is reduced, and the side effects are reduced. Therefore, the "drug co-crystal + sustained-release body" of the present invention can improve solubility, increase drug stability, long-term release, and prolong drug effect, and has good development prospects. DETAILED DESCRIPTION

[0028] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0029] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0030] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0031] Example 1

[0032] A method for preparing sodium prasterone sulfate spray, the specific steps comprising:

[0033] S1. Preparation of prasterone sodium sulfate drug co-crystal

[0034] Adding sodium prasterone sulfate and threonine and arginine in a molar ratio of 1:0.4:0.2 to a mixed solvent, wherein the solid-liquid ratio of sodium prasterone sulfate to the mixed solvent is 1:25 g / mL, stirring magnetically at a temperature of 55° C. for 6 h, and vacuum drying at 40° C. for 12 h, to obtain sodium prasterone sulfate drug co-crystal;

[0035] The mixed solvent is obtained by mixing citric acid, glucose, glycerol and deionized water in a mass ratio of 15:13:7:60;

[0036] S2. Preparation of prasterone sulfate sodium-SiO2 complex

[0037] (1) SiO2 powder and sodium dihydrogen phosphate in a mass ratio of 1:0.2 were added to anhydrous ethanol, the solid-liquid ratio of SiO2 powder to anhydrous ethanol was 1:10 g / mL, and ultrasonic treatment was performed at 25 kHz and 60°C for 3 h, followed by centrifugation, washing and drying to obtain modified SiO2;

[0038] (2) mixing sodium prasterone sulfate drug cocrystal and modified SiO2 powder in a mass ratio of 1:6.6, adding them into deionized water at a solid-liquid ratio of 1:15 g / mL, and rotary evaporating at 45° C. and 250 rpm for 2 h to obtain a sodium prasterone sulfate-SiO2 complex;

[0039] S3. Preparation of prasterone sodium sulfate spray

[0040] 13 parts of sodium prasterone sulfate-SiO2 complex, 3 parts of butylene glycol and 4 parts of glycerol were added to 90 parts of water, and ultrasonically stirred at 25 kHz, 150 W, and 35° C. for 9 hours to obtain sodium prasterone sulfate spray.

[0041] Example 2

[0042] A method for preparing sodium prasterone sulfate spray, the specific steps comprising:

[0043] S1. Preparation of prasterone sodium sulfate drug co-crystal

[0044] Adding sodium prasterone sulfate and threonine and arginine in a molar ratio of 1:0.3:0.1 to a mixed solvent, wherein the solid-liquid ratio of sodium prasterone sulfate to the mixed solvent is 1:20 g / mL, stirring magnetically at a temperature of 50° C. for 4 hours, and vacuum drying at 30° C. for 10 hours, to obtain sodium prasterone sulfate drug cocrystal;

[0045] The mixed solvent is obtained by mixing citric acid, glucose, glycerol and deionized water in a mass ratio of 10:10:5:50;

[0046] S2. Preparation of prasterone sulfate sodium-SiO2 complex

[0047] (1) SiO2 powder and sodium dihydrogen phosphate in a mass ratio of 1:0.15 were added to anhydrous ethanol, the solid-liquid ratio of SiO2 powder to anhydrous ethanol was 1:8 g / mL, and ultrasonic treatment was performed at 20 kHz and 50°C for 2 h, followed by centrifugation, washing and drying to obtain modified SiO2;

[0048] (2) mixing sodium prasterone sulfate drug cocrystal and modified SiO2 powder in a mass ratio of 1:4.4, adding them into deionized water at a solid-liquid ratio of 1:10 g / mL, and rotary evaporating at 40° C. and 200 rpm for 1 h to obtain a sodium prasterone sulfate-SiO2 complex;

[0049] S3. Preparation of prasterone sodium sulfate spray

[0050] 10 parts of sodium prasterone sulfate-SiO2 complex, 2 parts of butylene glycol and 3 parts of glycerol were added to 80 parts of water, and ultrasonically stirred at 20 kHz, 100 W, 30° C. for 8 hours to obtain sodium prasterone sulfate spray.

[0051] Example 3

[0052] A method for preparing sodium prasterone sulfate spray, the specific steps comprising:

[0053] S1. Preparation of prasterone sodium sulfate drug co-crystal

[0054] Adding sodium prasterone sulfate and threonine and arginine in a molar ratio of 1:0.5:0.3 to a mixed solvent, wherein the solid-liquid ratio of sodium prasterone sulfate to the mixed solvent is 1:30 g / mL, stirring magnetically at a temperature of 60° C. for 8 h, and vacuum drying at 50° C. for 14 h, to obtain sodium prasterone sulfate drug co-crystal;

[0055] The mixed solvent is obtained by mixing citric acid, glucose, glycerol and deionized water in a mass ratio of 20:15:8:80;

[0056] S2. Preparation of prasterone sulfate sodium-SiO2 complex

[0057] (1) SiO2 powder and sodium dihydrogen phosphate in a mass ratio of 1:0.27 were added to anhydrous ethanol, the solid-liquid ratio of SiO2 powder to anhydrous ethanol was 1:12 g / mL, and ultrasonic treatment was performed at 30 kHz and 70°C for 4 h, followed by centrifugation, washing and drying to obtain modified SiO2;

[0058] (2) mixing sodium prasterone sulfate drug cocrystal and modified SiO2 powder in a mass ratio of 1:8.8, adding them into deionized water at a solid-liquid ratio of 1:20 g / mL, and rotary evaporating at 50° C. and 300 rpm for 3 h to obtain a sodium prasterone sulfate-SiO2 complex;

[0059] S3. Preparation of prasterone sodium sulfate spray

[0060] 15 parts of sodium prasterone sulfate-SiO2 complex, 4 parts of butylene glycol and 5 parts of glycerol were added to 100 parts of water, and ultrasonically stirred at 30kHz, 200W, 40°C for 10 hours to obtain sodium prasterone sulfate spray.

[0061] Comparative Example 1

[0062] The difference from Example 1 is that the sodium prasterone sulfate drug co-crystal is replaced by sodium prasterone sulfate, and the rest is consistent with Example 1.

[0063] That is, the preparation method of the sodium prasterone sulfate spray of this comparative example, the specific steps include:

[0064] S1. Preparation of sodium prasterone sulfate-SiO2 complex

[0065] (1) SiO2 powder and sodium dihydrogen phosphate in a mass ratio of 1:0.2 were added to anhydrous ethanol, the solid-liquid ratio of SiO2 powder to anhydrous ethanol was 1:10 g / mL, and ultrasonic treatment was performed at 25 kHz and 60°C for 3 h, followed by centrifugation, washing and drying to obtain modified SiO2;

[0066] (2) mixing sodium prasterone sulfate and modified SiO2 powder in a mass ratio of 1:6.6, adding them into deionized water at a solid-liquid ratio of 1:15 g / mL, and rotary evaporating them at 45 ° C and 250 rpm for 2 h to obtain a sodium prasterone sulfate-SiO2 complex;

[0067] S2. Preparation of prasterone sodium sulfate spray

[0068] 13 parts of sodium prasterone sulfate-SiO2 complex, 3 parts of butylene glycol and 4 parts of glycerol were added to 90 parts of water, and ultrasonically stirred at 25 kHz, 150 W, and 35° C. for 9 hours to obtain sodium prasterone sulfate spray.

[0069] Comparative Example 2

[0070] The difference from Example 1 is that SiO2 is not modified, and the rest is the same as Example 1.

[0071] That is, the preparation method of the sodium prasterone sulfate spray of this comparative example, the specific steps include:

[0072] S1. Preparation of prasterone sodium sulfate drug co-crystal

[0073] Adding sodium prasterone sulfate and threonine and arginine in a molar ratio of 1:0.4:0.2 to a mixed solvent, wherein the solid-liquid ratio of sodium prasterone sulfate to the mixed solvent is 1:25 g / mL, stirring magnetically at a temperature of 55° C. for 6 h, and vacuum drying at 40° C. for 12 h, to obtain sodium prasterone sulfate drug co-crystal;

[0074] The mixed solvent is obtained by mixing citric acid, glucose, glycerol and deionized water in a mass ratio of 15:13:7:60;

[0075] S2. Preparation of prasterone sulfate sodium-SiO2 complex

[0076] The sodium prasterone sulfate drug co-crystal and SiO2 powder were mixed at a mass ratio of 1:6.6, added into deionized water at a solid-liquid ratio of 1:15 g / mL, and rotary evaporated at 45°C and 250 rpm for 2 h to obtain a sodium prasterone sulfate-SiO2 complex;

[0077] S3. Preparation of prasterone sodium sulfate spray

[0078] 13 parts of sodium prasterone sulfate-SiO2 complex, 3 parts of butylene glycol and 4 parts of glycerol were added to 90 parts of water, and ultrasonically stirred at 25 kHz, 150 W, and 35° C. for 9 hours to obtain sodium prasterone sulfate spray.

[0079] Test example

[0080] 60 SD female rats (weight 250±20g) were purchased, and the ovariectomized rat model was established: the rats were subjected to bilateral ovariectomy, and the fluid in the rat vagina was taken, and the smear was examined under a microscope, and 5% methylene blue was added for staining and observed under a microscope. Rats with zero keratinized epithelial cells in vaginal smears for ten consecutive days and a cleanliness level of II or above were selected for the following test. The rats for the establishment of the ovariectomized rat model were randomly divided into an ovariectomy control group and an experimental group (Example 1 group, Example 2 group, Example 3 group, Comparative Example 1 group and Comparative Example 2 group), with 10 rats in each group.

[0081] The experimental groups were given correspondingly prepared sodium prasterone sulfate sprays at a daily dose of 200 mL / kg, once a day, for 1 month; the control group was excluded and no drug treatment was given;

[0082] One month later, the fluid was collected from the vagina of the rats, smeared under a microscope, stained with 5% methylene blue, and the vaginal keratinized epithelial cells were observed under a microscope (the number of keratinized epithelial cells in the vaginal smears of each group before administration was zero); blood was collected and the plasma β-endorphin content was determined; the results are shown in Table 1.

[0083] Table 1

[0084]

[0085] Note: * Compared with the removal control group, p<0.01

[0086] As can be seen from Table 1, compared with Comparative Examples 1 and 2, the keratinized epithelial cells of each rat in the Examples 1-3 groups of the present invention increased significantly, and the increase in keratinized cells indicates that menopausal symptoms can be improved and sexual function can be enhanced. The prasterone sulfate sodium spray of the Examples 1-3 groups of the present invention has an increasing effect on the plasma β-endorphin content of the ovariectomized rats, indicating a preventive and therapeutic effect on vaginal atrophy.

[0087] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing prasterone sodium sulfate spray, characterized in that: The specific steps include: S1. Preparation of prasterone sodium sulfate drug co-crystal Adding prasterone sodium sulfate, threonine and arginine into a mixed solvent, stirring magnetically, and vacuum drying to obtain prasterone sodium sulfate drug co-crystals; S2. Preparation of prasterone sulfate sodium-SiO2 complex (1) adding SiO2 powder and sodium dihydrogen phosphate into anhydrous ethanol, ultrasonically treating, centrifuging, washing and drying to obtain modified SiO2; (2) mixing the sodium prasterone sulfate drug co-crystal and the modified SiO2 powder, adding them into deionized water, and performing rotary evaporation to obtain a sodium prasterone sulfate-SiO2 complex; S3. Preparation of prasterone sodium sulfate spray The sodium prasterone sulfate-SiO2 complex, butanediol and glycerol are added into water and ultrasonically stirred to obtain the sodium prasterone sulfate spray.

2. The method for preparing a sodium prasterone sulfate spray according to claim 1, wherein: In step S1, the molar ratio of prasterone sodium sulfate to threonine and arginine is 1:0.3-0.5:0.1-0.

3.

3. The method for preparing a sodium prasterone sulfate spray according to claim 1, wherein: In step S1, the mixed solvent is obtained by mixing citric acid, glucose, glycerol and deionized water in a mass ratio of 10-20:10-15:5-8:50-80; the solid-liquid ratio of the sodium prasterone sulfate to the mixed solvent is 1:20-30 g / mL.

4. The method for preparing a sodium prasterone sulfate spray according to claim 1, characterized in that: In step S1, the temperature of the magnetic stirring is 50-60°C and the time is 4-8h; the temperature of the vacuum drying is 30-50°C and the time is 10-14h.

5. The method for preparing a sodium prasterone sulfate spray according to claim 1, characterized in that: In step S2(1), the mass ratio of the SiO2 powder to sodium dihydrogen phosphate is 1:0.15-0.27; the solid-liquid ratio of the SiO2 powder to anhydrous ethanol is 1:8-12 g / mL; and the ultrasonic treatment is carried out at 20-30 kHz and 50-70°C for 2-4 hours.

6. The method for preparing a sodium prasterone sulfate spray according to claim 1, characterized in that: In step S2(2), the mass ratio of the sodium prasterone sulfate drug co-crystal to the modified SiO2 powder is 1:4.4-8.8; the solid-liquid ratio of the sodium prasterone sulfate drug co-crystal and the modified SiO2 powder to deionized water is 1:10-20 g / mL; the temperature of the rotary evaporation is 40-50°C, the rotation speed is 200-300 rpm, and the time is 1-3 h.

7. The method for preparing a sodium prasterone sulfate spray according to claim 1, characterized in that: In step S3, the following raw materials are included in parts by weight: 10-15 parts of sodium prasterone sulfate-SiO2 complex, 2-4 parts of butanediol, 3-5 parts of glycerol, and 80-100 parts of water.

8. The method for preparing a sodium prasterone sulfate spray according to claim 1, characterized in that: In step S3, the ultrasonic stirring is carried out at 20-30 kHz, 100-200 W, and 30-40° C. for 8-10 h.

9. A prasterone sodium sulfate spray prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the sodium prasterone sulfate spray according to claim 9 in the preparation of a drug for treating vaginal atrophy.

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