Desalqualinium chloride cavitary administration preparation and preparation method thereof

Abstract

The invention discloses a dequalinium chloride cavitary administration preparation and a preparation method thereof. The dequalinium chloride cavitary administration preparation is prepared from the following components in parts by weight: 0.08 to 0.25 part of dequalinium chloride, 30.5 to 68.7 parts of an auxiliary material system and 25 to 50 parts of a matrix, and the auxiliary material system is prepared from a solubilizing combination and a pH adjusting combination; the method has the advantages that high-concentration dissolution of dequalinium chloride in a system is realized; compared with the prior art, the preparation disclosed by the invention has the advantages of excellent residence performance, high safety and good stability, and has a wide application prospect in the field of medicines for treating vaginal infections such as bacterial vaginosis and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a dequalinium chloride intracavitary administration preparation and a preparation method thereof. BACKGROUND

[0002] Dequalinium chloride (also known as chlorhexidine) has the chemical name of 1,1'-decamethylene bis(4-aminoquinoline chloride). The chemical structural formula is as follows:

[0003]

[0004] Dequalinium chloride is a broad-spectrum antibacterial drug with antibacterial, anti-inflammatory and bacteriostatic effects. It has good inhibitory effect on common pathogenic bacteria in the oral cavity and throat, such as staphylococcus and streptococcus, and can effectively relieve local infection symptoms such as acute and chronic pharyngitis, oral ulcer and gingivitis. It has been widely used in the field of throat disease treatment, and common dosage forms are lozenges, sprays and mouthwashes.

[0005] However, the research and application of dequalinium chloride in vaginal and rectal administration preparations are relatively less. Although a small amount of research has shown that dequalinium chloride can be administered in the vagina to treat some vaginal infections, the dosage form is generally a tablet or a suppository, but the types and application range of related products are very limited, and there is a lack of systematic and in-depth research.

[0006] Dequalinium chloride is a weakly basic and moderately hydrophobic drug with a solubility in water of only about 0.05 g / 100 mL. In conventional intracavitary administration preparations (such as suppositories and gels), problems such as drug crystallization and slow dissolution often occur, resulting in low bioavailability and affecting efficacy. In the prior art, the schemes for improving the solubility of dequalinium chloride mostly rely on a single solubilizing agent (such as polyethylene glycol 400) or a strong irritant surfactant (such as sodium dodecyl sulfate). The former has limited solubilizing effect and is difficult to meet the clinical drug concentration requirements, and the latter can improve the solubility but will damage the intracavitary mucosal barrier, causing redness, stinging and other adverse reactions. In addition, intracavitary administration preparations need to match the physiological pH (vaginal pH 3.8-4.5), and the existing pH adjustment schemes (such as a single citric acid buffer pair) are prone to pH fluctuations, further affecting the solubility and stability of the drug. Therefore, developing a dequalinium chloride intracavitary administration preparation with high solubilizing effect, mucosal safety and pH stability has become a problem to be solved in the field. SUMMARY

[0007] The main purpose of the present application is to provide an efficient, safe and convenient use of dequadin vaginal and rectal administration preparation to overcome the shortcomings of the existing drugs for treating vaginal and rectal diseases. Specifically, by optimizing the dosage form and administration method of dequadin, through the synergistic pH adjustment system of "polyethylene glycol-polyol" complex solubilization system and "buffer pair-lactic acid", the solubility and dissolution of dequadin are improved, and the safety of the cavity mucosa is ensured, and the defects of the prior art are solved.

[0008] In order to achieve the above-mentioned purpose, the present application provides the following technical scheme:

[0009] The present application provides a dequadin cavity administration preparation, which comprises the following components by weight fraction: 0.08-0.25 parts of dequadin, 30.5-68.7 parts of auxiliary system, 25-50 parts of matrix;

[0010] The auxiliary system is composed of a solubilization combination and a pH adjustment combination; the solubilization combination is composed of 20-40 parts of polyethylene glycol and 10-25 parts of polyhydric alcohol; and the pH adjustment combination is composed of 0.5-2.5 parts of buffer pair and 0.01-1.20 parts of lactic acid.

[0011] The total weight fraction of the auxiliary system is preferably 55-60 parts.

[0012] The polyethylene glycol is selected from at least one of PEG400 and PEG600; and the polyhydric alcohol is selected from at least one of glycerol and 1,2-propanediol.

[0013] The buffer pair is selected from at least one of citric acid-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate, and acetic acid-sodium acetate.

[0014] The auxiliary system further comprises a stabilizer, which is composed of 0.01-0.03 parts of antioxidant and 0.04-0.06 parts of preservative by weight fraction.

[0015] The pH of the preparation is maintained at 3.5-4.5; and after the synergistic action of the solubilization combination and the pH adjustment combination, the solubility of dequadin is ≥0.4 g / 100 mL; and the osmotic pressure is 350-450 mOsm / kg.

[0016] The preparation does not contain sodium lauryl sulfate (SLS) and cetyltrimethylammonium bromide (CTAB).

[0017] The dodecylguanidinium chloride cavity administration preparation, wherein the preparation is a gel, and the components thereof include, by weight fraction: 0.1 part dodecylguanidinium chloride, 30 parts PEG400, 15 parts glycerol, 10 parts 1,2-propanediol, 1.2 parts citric acid-sodium citrate buffer pair, 0.05 parts lactic acid, 1.5 parts carbomer, and a suitable amount of neutralizing agent as a base, 0.08-0.12 parts non-ionic surfactant; and the balance is purified water.

[0018] The dodecylguanidinium chloride cavity administration preparation, wherein the preparation is a suppository, and the base thereof includes, by weight fraction:

[0019] 35-45 parts high-molecular polyethylene glycol, selected from at least one of PEG6000 and PEG4000;

[0020] 25-35 parts low-molecular polyethylene glycol, selected from at least one of PEG400 and PEG300, and the low-molecular polyethylene glycol is simultaneously used as a polyethylene glycol in a solubilizing combination.

[0021] The preparation method of the dodecylguanidinium chloride cavity administration preparation, wherein the method includes the following steps:

[0022] Step 1: mixing the polyethylene glycols and polyols by weight fraction, adding dodecylguanidinium chloride, and stirring at a constant temperature of 45-60°C to dissolve the drug, to obtain a drug solution;

[0023] Step 2: adding a pH adjusting combination to the drug solution and stirring until the system is uniform;

[0024] Step 3: mixing the mixture of Step 2 with the base uniformly.

[0025] The dodecylguanidinium chloride cavity administration preparation in the preparation of a drug for preventing or treating vaginal infections.

[0026] Therefore, the present application has the following beneficial effects:

[0027] (1) Significant solubilization effect: the complex solubilization system has a synergistic effect, and the solubility of dodecylguanidinium chloride is increased to more than 0.4 g / 100 mL, meeting the clinical drug concentration requirements;

[0028] (2) Strong pH stability: the “buffer pair-lactic acid” combination can stabilize the pH of the preparation at 3.5-4.5, control the osmotic pressure in the range of 350-450 mOsm / kg, perfectly adapt to the physiological environment of the vagina, greatly reduce the mucous membrane irritation, and at the same time avoid the influence of pH fluctuation on drug dissolution;

[0029] (3) Excellent stability: the preparation shows excellent chemical stability (the content decreases by only about 1.8%) under accelerated conditions at 40°C, and can effectively prevent the crystallization and precipitation of the drug in a simulated physiological environment.

[0030] The preparation of the present application not only has excellent residence performance, but also has high safety and good stability, and has a broad application prospect in the field of drugs for treating vaginal infections such as bacterial vaginosis. DETAILED DESCRIPTION

[0031] The present application will be further described below through specific embodiments.

[0032] Example 1: 100g of dequ Chim chloride vaginal gel

[0033] Composition: dequ Chim chloride 0.1g, PEG400 30g, glycerol 15g, 1,2-propanediol 10g, 0.05mol / L citric acid-sodium citrate buffer pair, lactic acid 0.05g, carbomer 940 1.5g, triethanolamine (appropriate amount, neutralize carbomer), Tween 80 0.1g, vitamin E 0.02g, nipagin ethyl 0.05g, purified water (make up to 100g);

[0034] Preparation method:

[0035] Step 1: Mix PEG400 with 1,2-propanediol, stir uniformly, then add dequ Chim chloride, stir at 50℃ constant temperature for 30min to dissolve, make the drug completely dissolved, get the drug solution;

[0036] Step 2: Add glycerol, Tween 80, citric acid-sodium citrate buffer pair and lactic acid to the drug solution of step 1, stir until the system is uniform, adjust the pH to 4.0 with lactic acid aqueous solution;

[0037] Step 3: Take another appropriate amount of purified water, slowly sprinkle carbomer 940, swell at room temperature for 24h, neutralize with triethanolamine until the gel is transparent, add vitamin E, nipagin ethyl, stir uniformly, get the blank gel matrix;

[0038] Step 4: Slowly add the mixture solution obtained in step 2 to the blank gel matrix of step 3, stir at high speed for 18min to make it uniformly mixed, vacuum degassing, then fill in single dose packaging, get the product.

[0039] Example 2: 100g of dequ Chim chloride vaginal gel

[0040] Composition: dequ Chim chloride 0.2g, PEG600 25g, glycerol 20g, 0.03mol / L sodium dihydrogen phosphate-sodium hydrogen phosphate buffer pair, lactic acid 0.5g, carbomer 934 2.0g, sodium hydroxide (appropriate amount), Tween 60 0.12g, sodium bisulfite 0.03g, benzalkonium chloride 0.04g, purified water (make up to 100g);

[0041] Preparation method:

[0042] Step 1: Mix the prescribed amount of PEG600 with glycerol, stir until uniform, then add dequalinium chloride, stir at 55°C for 30 min to completely dissolve the drug, obtaining a drug solution;

[0043] Step 2: Add Tween 60, sodium dihydrogen phosphate-sodium hydrogen phosphate buffer pair, and lactic acid to the drug solution from Step 1, stir until uniform, adjust the pH to 4.2 with aqueous lactic acid solution;

[0044] Step 3: Take another appropriate amount of purified water, slowly sprinkle carbomer 934, swell at room temperature for 24 h, then add sodium hydroxide solution to neutralize until the gel is transparent, then add sodium bisulfite and benzalkonium chloride, stir until uniform, obtaining a blank gel base;

[0045] Step 4: Slowly add the mixture from Step 2 to the blank gel base from Step 3, stir at high speed for 20 min to mix uniformly, vacuum degassing, then fill into single-dose packaging, obtaining the product.

[0046] Example 3: Dequalinium chloride vaginal gel 100g

[0047] Composition: dequalinium chloride 0.08g, PEG400 20g, 1,2-propanediol 25g, 0.08mol / L citric acid-sodium citrate buffer pair, lactic acid 0.01g, carbomer 940 1.0g, triethanolamine (appropriate amount), Tween 80 0.08g, vitamin E 0.01g, nipagin ethyl ester 0.06g, purified water (make up to 100g);

[0048] Preparation method:

[0049] Step 1: Mix the prescribed amount of PEG400 with 1,2-propanediol, stir until uniform, then add dequalinium chloride, stir at 45°C for 30 min to completely dissolve the drug, obtaining a drug solution;

[0050] Step 2: Add Tween 80, citric acid-sodium citrate buffer pair, and lactic acid to the drug solution from Step 1, stir until uniform, adjust the pH to 3.5 with aqueous lactic acid solution;

[0051] Step 3: Take another appropriate amount of purified water, slowly sprinkle carbomer 940, swell at room temperature for 24 h, then add triethanolamine to neutralize until the gel is transparent, then add vitamin E and nipagin ethyl ester, stir until uniform, obtaining a blank gel base;

[0052] Step 4: Slowly add the mixture from Step 2 to the blank gel base from Step 3, stir at high speed for 18 min to mix uniformly, vacuum degassing, then fill into single-dose packaging, obtaining the product.

[0053] Example 4: Dequalinium chloride rectal suppositories 100g

[0054] Composition: dequalinium chloride 0.15g, PEG6000 40g, PEG400 30g, glycerol 12g, 0.05 mol / L citric acid-sodium citrate buffer pair, lactic acid 0.2g, vitamin E 0.02g, nipagin ethyl 0.05g, the rest is supplemented with matrix.

[0055] Preparation method:

[0056] Step 1: Mix PEG6000 and PEG400, heat and stir in a 60°C water bath until completely melted into a uniform transparent liquid;

[0057] Step 2: Add glycerol, citric acid-sodium citrate buffer pair, lactic acid to the melted matrix, continue to stir, mix evenly, adjust pH to 4.1 with lactic acid aqueous solution;

[0058] Step 3: Under constant temperature (60°C) stirring, add dequalinium chloride to the above mixture, continue to stir for 20 min until the drug is completely dissolved, add vitamin E, nipagin ethyl, stir evenly;

[0059] Step 4: The drug solution obtained in step 3 is injected into the pre-cooled suppository mold while hot, cooled and solidified, then demolded, and the suppository is obtained.

[0060] Example 5: dequalinium chloride rectal suppository 100g

[0061] Composition: dequalinium chloride 0.25g, PEG4000 45g, PEG300 25g, 1,2-propanediol 15g, 0.06 mol / L sodium phosphate dibasic-sodium phosphate buffer pair, lactic acid 1.0g, sodium bisulfite 0.03g, benzalkonium chloride 0.04g, the rest is supplemented with matrix.

[0062] Preparation method:

[0063] Step 1: Mix PEG6000 and PEG400, heat and stir in a 65°C water bath until completely melted into a uniform transparent liquid;

[0064] Step 2: Add 1,2-propanediol, sodium phosphate dibasic-sodium phosphate buffer pair, lactic acid to the melted matrix, stir evenly, adjust pH to 4.5 with lactic acid aqueous solution;

[0065] Step 3: Under constant temperature (65°C) stirring, add dequalinium chloride, continue to stir for 25 min until the drug is completely dissolved, add sodium bisulfite and benzalkonium chloride, stir evenly;

[0066] Step 4: The drug solution obtained in step 3 is injected into the pre-cooled suppository mold while hot, cooled and solidified, then demolded, and the suppository is obtained.

[0067] Example 6: Dequalinium chloride rectal suppository 100g

[0068] Composition: dequalinium chloride 0.1g, PEG6000 35g, PEG400 35g, glycerol 10g, 0.04mol / L citric acid-sodium citrate buffer pair, lactic acid 0.08g, vitamin E 0.01g, nipagin ethyl ester 0.05g, the rest is made up with the matrix.

[0069] Preparation method:

[0070] Step 1: Mix PEG6000 and PEG400, heat and stir in a 55°C water bath until completely melted into a uniform transparent liquid;

[0071] Step 2: Add glycerol, citric acid-sodium citrate buffer pair, lactic acid to the melted matrix, continue to stir until mixed evenly, adjust the pH to 3.8 with lactic acid solution;

[0072] Step 3: Add dequalinium chloride, constant temperature stirring for 25min until the drug is completely dissolved, add vitamin E, nipagin ethyl ester, stir evenly;

[0073] Step 4: Pour the drug solution obtained in step 3 into pre-cooled suppository mold while hot, cool and solidify after cooling, demold, and get it.

[0074] Example 7: High lactic acid content dequalinium chloride gel 100g

[0075] Composition: dequalinium chloride 0.2g, PEG400 35g, glycerol 18g, 0.05mol / L citric acid-sodium citrate buffer pair, lactic acid 1.2g, carbomer 940 1.8g, triethanolamine (appropriate amount), Tween 80 0.1g, vitamin E 0.02g, nipagin ethyl ester 0.05g, purified water (make up to 100g);

[0076] Preparation method:

[0077] Step 1: Mix the prescribed amount of PEG400 and glycerol, stir evenly, then add dequalinium chloride, constant temperature stirring at 50°C for 30min, until the drug is completely dissolved, get the drug solution;

[0078] Step 2: Add Tween 80, citric acid-sodium citrate buffer pair, lactic acid to the drug solution of step 1, stir evenly, adjust the pH to 4.3 with lactic acid solution;

[0079] Step 3: Take another appropriate amount of purified water, slowly sprinkle in carbomer 940, swell at room temperature for 24h, then neutralize with triethanolamine until the gel is transparent, then add vitamin E, nipagin ethyl ester, stir evenly, get the blank gel matrix;

[0080] Step 4: The mixture obtained in Step 2 was slowly added to the blank gel base of Step 3, and stirred at high speed for 18 min to mix evenly. After vacuum degassing, it was filled into single-dose packaging to obtain the product.

[0081] Example 8: Low-concentration oxychloroquine gel 100 g

[0082] Composition: oxychloroquine 0.12 g, PEG600 22 g, 1,2-propanediol 22 g, 0.07 mol / L sodium dihydrogen phosphate-sodium hydrogen phosphate buffer pair, lactic acid 0.3 g, carbomer 934 1.2 g, sodium hydroxide (appropriate amount), Tween 60 0.11 g, sodium bisulfite 0.02 g, benzalkonium chloride 0.05 g, purified water (make up to 100 g);

[0083] Preparation method:

[0084] Step 1: Mix PEG400 with 1,2-propanediol, and then add oxychloroquine. Stir until dissolved at 52°C for 30 min to completely dissolve the drug, and obtain a drug solution;

[0085] Step 2: Add Tween 80, sodium dihydrogen phosphate-sodium hydrogen phosphate buffer pair, and lactic acid to the drug solution of Step 1. Stir until uniform, and adjust the pH to 4.0 with lactic acid solution;

[0086] Step 3: Take an appropriate amount of purified water, slowly add carbomer 934, and swell at room temperature for 24 h. Then neutralize to a transparent gel with sodium hydroxide solution, and then add sodium bisulfite and benzalkonium chloride. Stir until uniform to obtain a blank gel base;

[0087] Step 4: Slowly add the mixture obtained in Step 2 to the blank gel base of Step 3, and stir at high speed for 18 min to mix evenly. After vacuum degassing, it was filled into single-dose packaging to obtain the product.

[0088] Example 9: High-concentration oxychloroquine suppository 100 g

[0089] Composition: oxychloroquine 0.25 g, PEG6000 42 g, PEG400 32 g, 1,2-propanediol 13 g, 0.05 mol / L citric acid-sodium citrate buffer pair, lactic acid 0.8 g, vitamin E 0.03 g, nipagin ethyl ester 0.05 g, and the rest is made up with the base.

[0090] Preparation method:

[0091] Step 1: Mix PEG6000 with PEG400, and heat and stir in a 60°C water bath until completely melted into a uniform transparent liquid;

[0092] Step 2: Add 1,2-propanediol, citric acid-sodium citrate buffer pair, lactic acid into the melted base, continue to stir until mixed evenly, adjust pH to 4.1 with lactic acid aqueous solution;

[0093] Step 3: Under constant temperature (60℃) stirring, add dequalinium chloride into the above mixture, continue to stir for 22 min until the drug is completely dissolved, add vitamin E, nipagin ethyl ester, and stir until mixed evenly;

[0094] Step 4: Pour the hot drug solution obtained in Step 4 into pre-cooled suppository molds, and after cooling and solidification, demold to obtain the suppository.

[0095] Example 10: Low lactic acid content dequalinium chloride suppository 100g

[0096] Composition: dequalinium chloride 0.09g, PEG6000 38g, PEG300 30g, glycerol 11g, 0.03mol / L sodium dihydrogen phosphate-sodium hydrogen phosphate buffer pair, lactic acid 0.02g, sodium bisulfite 0.01g, benzalkonium chloride 0.06g, and the rest is made up with the base.

[0097] Preparation method:

[0098] Step 1: Mix PEG6000 and PEG300, heat and stir in a 58℃ water bath until completely melted into a uniform transparent liquid;

[0099] Step 2: Add glycerol, sodium dihydrogen phosphate-sodium hydrogen phosphate buffer pair, lactic acid into the melted base, continue to stir until mixed evenly, adjust pH to 3.6 with lactic acid aqueous solution;

[0100] Step 3: Under constant temperature (58℃) stirring, add dequalinium chloride into the above mixture, continue to stir for 20 min until dissolved, add sodium bisulfite and benzalkonium chloride, and stir until mixed evenly;

[0101] Step 4: Pour the hot drug solution obtained in Step 4 into pre-cooled suppository molds, and after cooling and solidification, demold to obtain the suppository.

[0102] Test 1: Synergistic protective effect of lactic acid on pH stability of the preparation

[0103] 1.1 Test design

[0104] Test group: gel of Example 1 of the present application (containing 0.05g lactic acid + citric acid-sodium citrate buffer pair);

[0105] Control group: gel without lactic acid (other ingredients are the same as Example 1, only use citric acid-sodium citrate buffer pair to adjust pH to 4.0);

[0106] Method: 2 groups of samples were stored under accelerated conditions (40℃±2℃, relative humidity 75%±5%) for 3 months, and the pH values were measured at 0 days, 30 days, 60 days, and 90 days, respectively.

[0107] 1.2 Test results

[0108] Table 1 Effect of lactic acid on pH stability of the preparation

[0109] Storage time Test group pH Control group pH Test group property Control group property 0 days 4.01 4.02 Clear transparent gel Clear transparent gel 30 days 4.02 3.75 Clear transparent gel Clear transparent gel 60 days 4.05 3.52 Clear transparent gel Slightly turbid 90 days 4.10 3.31 Clear transparent gel Obvious crystallization

[0110] Conclusion: Under the accelerated conditions of high temperature and high humidity, the test group, through the synergy of lactic acid and the buffer pair, has minimal pH fluctuation (±0.1), while the control group has a pH decrease of about 0.7 and drug precipitation occurs. It is proved that lactic acid plays an irreplaceable role in maintaining the stable state of diquafosine in the system.

[0111] Test 2: Comparative test of dissolution of the preparation

[0112] 2.1 Test design

[0113] According to the dissolution determination method (paddle method) in Chinese Pharmacopoeia 2020, with artificial vaginal fluid (pH 4.2) as the dissolution medium (500mL), the rotation speed is 50rpm, the temperature is 37±0.5℃, and the samples are taken at 5min, 10min, 15min, 30min, and 60min. HPLC is used to determine the dissolution amount of the drug, and the dissolution of the following samples is determined:

[0114] Test group: suppository of Example 4 of the application;

[0115] Control group: suppository without lactic acid (other ingredients are the same as Example 4, only the pH is adjusted to 4.1 with the buffer pair).

[0116] 2.2 Test results

[0117] Table 2 Results of the comparative test of the dissolution of the preparation

[0118] Sampling time (min) Test group dissolution (%) (n=3) Control group dissolution (%) (n=3) 5 38 22 10 55 35 15 72 48 30 91 65 60 98 78

[0119] Conclusion: The dissolution of the test group (containing lactic acid) at 30min reaches more than 90%, which is significantly higher than that of the control group (65%), proving that the addition of lactic acid not only stabilizes the pH, but also promotes the release of the drug in the simulated vaginal environment, which is beneficial to the rapid onset of the drug.

[0120] Test 3: Effect of total amount of excipients and surfactant on quality and rheological property

[0121] 3.1 Test design

[0122] Sample A (most preferred): prepared according to Example 1, with a total amount of excipients of about 58g.

[0123] Sample B (with SLS): Sample A with 0.5 g SLS instead of Tween 80.

[0124] Sample C (excipients excess): Total amount of excipients increased to about 95 g (PEG 50 g, glycerol 25 g, etc.).

[0125] Sample D (excipients deficiency): Total amount of excipients decreased to about 25 g (PEG 10 g and no 1,2-propanediol).

[0126] 3.2 Test results

[0127] Table 3: Content uniformity and chemical stability (40°C / 3 months)

[0128]

[0129] Conclusion: Sample A achieves the best balance in uniformity, stability and yield stress (residence). The addition of SLS will destroy the rheology, while the total amount of excipients not in the range of 25% to 65% will cause serious degradation of stability.

[0130] Test 4: Verification of nonlinear synergistic effect of the complex solubilizing system

[0131] 4.1 Test method

[0132] The equilibrium solubility of dequalinium chloride in the following four solvent media (25°C) was determined, respectively:

[0133] Group 1: purified water;

[0134] Group 2: 30 g PEG400 aqueous solution;

[0135] Group 3: 15 g glycerol + 10 g 1,2-propanediol aqueous solution;

[0136] Group 4: 30 g PEG400 + 15 g glycerol + 10 g 1,2-propanediol (solubilizing combination of Example 1 of the present application).

[0137] 4.2 Test results

[0138] Table 4: Equilibrium solubility of dequalinium chloride in different systems

[0139]

[0140]

[0141] Conclusion: The actual solubility of group 4 (0.528) is much higher than the arithmetic sum of the solubility of group 2 and group 3 (0.297). This proves that the combination of polyethylene glycol and polyhydric alcohol is not a simple physical mixture, but through changing the polarity parameter of the solvent system, it produces a significant nonlinear synergistic solubilization effect on dequalinium chloride.

[0142] Test: 5: Effect of osmotic pressure and microenvironment ionic strength of the preparation on mucosal safety

[0143] 5.1 Test method

[0144] The osmotic pressure molar concentration of samples A, C, and D was determined using an osmometer; and whether drug crystals precipitated within 24 hours after adding an equal amount of artificial vaginal fluid (to simulate the secretory environment) to each sample was observed.

[0145] 5.2 Test results

[0146] Table 5: Osmotic pressure and microenvironment stability test

[0147]

[0148] Conclusion: The osmotic pressure of sample A (392 mOsm / kg) is in the ideal physiological range, avoiding the mucosal dehydration and irritation that sample C (915 mOsm / kg) can cause. The test again proves that by limiting the total amount of excipients (≤65%) and accurately buffering the concentration (0.03-0.08 mol / L), the present application forms a stable charge shielding layer in the microenvironment, preventing the "salting out" phenomenon of dequalinium chloride caused by the dramatic change in ionic strength when it comes into contact with physiological body fluids.

Claims

1. A cavity delivery formulation of dequinoline chloride, characterized in that, By weight, it comprises the following components: 0.08–0.25 parts of dequinoline chloride, 30.5–68.7 parts of excipient system, and 25–50 parts of matrix; The excipient system consists of a solubilizing combination and a pH adjustment combination; The solubilizing composition consists of 20-40 parts of polyethylene glycol and 10-25 parts of polyol; The pH adjustment combination consists of 0.5 to 2.5 parts of buffer pair and 0.01 to 1.20 parts of lactic acid.

2. The dequinoline chloride cavity delivery formulation according to claim 1, characterized in that, The total weight of the excipient system is 55-60 parts.

3. The dequinoline chloride cavity delivery formulation according to claim 1, characterized in that, The polyethylene glycol is selected from at least one of PEG400 and PEG600; the polyol is selected from at least one of glycerol and 1,2-propanediol.

4. The dequinoline chloride cavity delivery formulation according to claim 1, characterized in that, The buffer pair is selected from at least one of citric acid-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate, and acetic acid-sodium acetate.

5. The dequinoline chloride cavity delivery formulation according to claim 1, characterized in that, The auxiliary material system also includes a stabilizer, which, by weight, consists of 0.01 to 0.03 parts antioxidant and 0.04 to 0.06 parts preservative.

6. The dequinoline chloride cavity delivery formulation according to any one of claims 1-5, characterized in that, The pH of the formulation is maintained at 3.5–4.5; and after the synergistic effect of the solubilizing combination and the pH adjusting combination, the solubility of dequinoline chloride is ≥0.4 g / 100 mL.

7. The dequinoline chloride cavity delivery formulation according to any one of claims 1-5, characterized in that, The formulation does not contain sodium dodecyl sulfate or hexadecyltrimethylammonium bromide.

8. The dequinoline chloride cavity delivery formulation according to any one of claims 1-5, characterized in that, The formulation is a gel, and by weight, its components include: 0.1 parts dequinoline chloride, 30 parts PEG400, 15 parts glycerol, 10 parts 1,2-propanediol, 1.2 parts citrate-sodium citrate buffer pair, 0.05 parts lactic acid, 1.5 parts carbomer, and an appropriate amount of neutralizing agent as a matrix, 0.08-0.12 parts nonionic surfactant; the balance is purified water.

9. The dequinoline chloride cavity delivery formulation according to any one of claims 1-5, characterized in that, The formulation is a suppository, and its base, by weight, includes: 35-45 parts of high molecular weight polyethylene glycol, selected from at least one of PEG6000 and PEG4000; 25 to 35 parts of low molecular weight polyethylene glycol, selected from at least one of PEG400 and PEG300, wherein the low molecular weight polyethylene glycol is also used as a polyethylene glycol in the solubilizing composition.

10. A method for preparing the dequinoline chloride cavity delivery formulation according to any one of claims 1-9, characterized in that, Includes the following steps: Step 1: Mix polyethylene glycol and polyols according to the weight ratio, add diquinoline chloride, and stir at a constant temperature of 45-60℃ to dissolve the drug and obtain a drug solution; Step 2: Add the pH adjustment kit to the drug solution and stir until the system is homogeneous; Step 3: Mix the mixture from Step 2 with the matrix until homogeneous.

11. The use of the dequinoline chloride intracavitary administration formulation according to any one of claims 1-9 in the preparation of a medicament for the prevention or treatment of vaginal infections.

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