Instant compound nystatin liniment for oral cavity

Abstract

The invention discloses an oral instant compound nystatin liniment and a preparation method thereof, the oral instant compound nystatin liniment comprises a powder agent and a mixed solvent which are separately packaged, and the powder agent comprises nystatin, vitamin B2, a diluent and an antioxidant; the mixed solvent comprises glycerol, a thickening agent, water or a phosphate buffer solution. The liniment is prepared by adopting a dry-wet separation method, one part of the liniment is mixture powder containing nystatin, the other part of the liniment is a mixed solvent capable of enabling medicine powder to be quickly dispersed and stably stored, and the mixture powder and the mixed solvent are respectively sealed and packaged and are automatically mixed before being used, so that long-term stable storage of the main component nystatin is facilitated; the alkalescent phosphate buffer solution is adopted, so that the stability after the suspension coating agent is prepared is improved. The liniment is simple in formula, convenient to use, capable of being stably stored for a long time and easy to convert and industrially produce.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a ready-to-prepare compound nystatin liniment for oral use. Background Art

[0002] Oral candidosis is an acute, subacute or chronic fungal disease of the oral mucosa, also known as "thrush". It is mainly caused by Candida infection and is the most common oral fungal infection. Candida is a conditionally pathogenic fungus that can cause local infection of the lips, skin, mucosa and other parts. It is easy to relapse and cause great pain to patients. The treatment options include systemic administration and local administration. Systemic treatment drugs include ketoconazole, miconazole, fluconazole, amphotericin B, etc., but systemic medication has many side effects; local treatment drugs include nystatin, fluconazole, miconazole, sodium bicarbonate, cetylpyridinium chloride, chlorhexidine, etc. Among them, the efficacy of nystatin when applied topically is better than other drugs, and nystatin or fluconazole combined with sodium bicarbonate or other drugs is better than single use.

[0003] Nystatin, also known as nystatin, is a polyene antifungal drug with a conjugated polyene macrolide structure and a broad-spectrum antifungal effect. It has high antibacterial activity against Candida species, Cryptococcus neoformans, Aspergillus, Mucor, Microsporum, Histoplasma capsulatum, Blastomyces dermatitidis and dermatophytes. The pure product of nystatin is yellow crystal, which is easily decomposed by light and heat, is hygroscopic, insoluble in acetone and chloroform, very slightly soluble in water, slightly soluble in lower alcohols, soluble in N, N-dimethylformamide, unstable to acid and alkali, and the solution state is also unstable, and relatively stable in a neutral or weakly alkaline environment.

[0004] At present, there is no commercially available oral nystatin finished preparation for clinical use, and no finished preparation has been found in the authorized patents, which is inconvenient to use. In the clinical treatment of oral candidiasis, nystatin tablets are usually ground into powder and added to glycerin and other media for external use, which is extremely inconvenient and difficult to grind evenly. The prepared coating has large particles, uneven content, and cannot be guaranteed to be clean and hygienic; it can only be stored for a short time after preparation, which seriously affects the clinical use and treatment effect.

[0005] CN 111870611 discloses a topical single-dose nystatin composition for treating thrush and its preparation method. The preparation encapsulates nystatin, oil, cosolvent, vitamin A and vitamin E in a soft capsule with a nozzle and is equipped with a sterile smear. When used, the liquid medicine is squeezed out from the nozzle of the capsule, and the sterile smear is used to safely, quickly and accurately complete the administration, which greatly improves the compliance of thrush drug treatment. The patent uses a soft capsule to encapsulate the nystatin solution, but nystatin is dissolved in an oily solvent and is not easily absorbed by the human body. In addition, the capsule can only accommodate a single dose, and the packaging cost is relatively high. It is not suitable for clinical situations where a large amount of use is required. Summary of the invention

[0006] The object of the present invention is to provide a nystatin preparation which is easy to use, has a long shelf life, high stability and low packaging cost. The present invention separates the solid and liquid preparations, and then mixes the solid preparation and the liquid preparation when used, thereby improving the stability of nystatin and facilitating use.

[0007] The technical solution adopted by the present invention is:

[0008] A ready-to-use compound nystatin liniment for oral use, the liniment comprising a powder and a mixed solvent which are separately packaged, the powder comprising nystatin, vitamin B2, a diluent and an antioxidant;

[0009] The mixed solvent includes glycerol, a thickener, water or a phosphate buffer.

[0010] Further, the powder comprises the following components in parts by mass:

[0011] 23-46 parts of nystatin, 1-5 parts of vitamin B2, 75-450 parts of diluent, and 2.5-10 parts of antioxidant.

[0012] Furthermore, the powder is packaged into small packets, each packet containing 1-2 million units of nystatin.

[0013] The mixed solvent includes the following components by weight:

[0014] 1000-1500 parts of glycerol, 50-100 parts of thickener, 500-1500 parts of water or phosphate buffer.

[0015] Furthermore, every 10 to 30 mL of the mixed solvent (preferably every 20 mL) corresponds to the powder containing 1 to 2 million units of nystatin.

[0016] The diluent is one or more of pregelatinized starch, xanthan gum, and povidone K30.

[0017] The antioxidant is sodium isoascorbate or anhydrous sodium sulfite, preferably sodium isoascorbate.

[0018] Furthermore, the mesh size of the powder is 80 to 100 meshes.

[0019] Furthermore, the packaging material of the powder is a light-shielding aluminum-plastic film to prevent nystatin from decomposing.

[0020] Preferably, the powder comprises the following components in parts by weight:

[0021] 30-40 parts of nystatin, 3-5 parts of vitamin B2, 110-250 parts of diluent, and 2.5-10 parts of antioxidant.

[0022] In the mixed solvent, the thickener is povidone K90 or xanthan gum.

[0023] The pH value of the phosphate buffer solution is 6.5-8, and the concentration is 0.01-0.1 mol / L.

[0024] Preferably, the pH value of the phosphate buffer is 7-8, and the concentration is 0.05-0.1 mol / L.

[0025] More preferably, the pH value of the phosphate buffer is 7.4 and the concentration is 0.05 mol / L.

[0026] Furthermore, the mixed solvent comprises the following components by weight:

[0027] 1000-1500 parts of glycerol, 50-100 parts of thickener, 500-1500 parts of phosphate buffer.

[0028] Preferably, the mass fraction of glycerol in the mixed solvent is 45-55%, more preferably 50%.

[0029] The instant compound nystatin liniment for oral use can be prepared according to the following method:

[0030] All raw materials of the powder are passed through a 80-100 mesh sieve, nystatin, vitamin B2, a diluent and an antioxidant are mixed and packaged to obtain a powder containing 1 million to 2 million units of nystatin per package;

[0031] The thickener is first dissolved in water or phosphate buffer, then mixed with glycerol, water or phosphate buffer according to the ratio, and packaged to prepare 10-30 mL of mixed solvent (preferably 20 mL). The mixed solvent can be packaged in light-proof materials such as brown glass bottles.

[0032] Preferably, the thickener is dissolved in phosphate buffer, then mixed with glycerol and phosphate buffer according to a ratio, and packaged to prepare 10-30 mL of mixed solvent (preferably 20 mL).

[0033] The present invention also provides a method for preparing the instant compound nystatin liniment for oral use, the method comprising:

[0034] All raw materials of the powder are passed through a 80-100 mesh sieve, nystatin, vitamin B2, a diluent and an antioxidant are mixed and packaged to obtain a powder containing 1 million to 2 million units of nystatin per package;

[0035] The thickener is first dissolved in water or phosphate buffer (preferably phosphate buffer), then mixed with glycerol, water or phosphate buffer (preferably phosphate buffer) according to a ratio, and packaged to prepare 10-30 mL of a mixed solvent.

[0036] The method is carried out in an oxygen-free environment throughout the process. The oxygen-free environment can be a vacuum environment or a nitrogen protection environment.

[0037] The present invention also provides the use of the instant compound nystatin liniment for oral use in preparing the nystatin suspension coating, wherein the method of the use is: adding the powder into the mixed solvent and shaking well to prepare the suspension coating.

[0038] Before using the instant compound nystatin liniment for oral cavity, the powder is added into the mixed solvent and shaken to prepare a suspension coating for oral cavity coating.

[0039] The suspension can be stored stably for more than 3 months.

[0040] The beneficial effects of the present invention are:

[0041] 1. There is no ready-to-use oral nystatin ointment among the approved preparations and patents applied for, which fills the current gap in the ready-to-use oral preparations of nystatin.

[0042] 2. Through preparation process screening, the dry-wet separation method was used to prepare the ointment. The prepared oral compound nystatin ointment was divided into two parts, one part was a mixture powder containing nystatin, and the other part was a mixed solvent that could quickly disperse the powder and stably preserve it. They were sealed separately and mixed before use, which created objective conditions for the long-term stable preservation of the main drug nystatin.

[0043] 3. By optimizing the formula and using weakly alkaline phosphate buffer, the stability of the prepared suspension coating is improved, and it can be stored for more than 3 months, solving the problem that nystatin cannot be stored stably for a long time after being prepared into a liquid preparation.

[0044] 4. The ointment has a simple formula and is easy to use. Before use, add the mixed powder into the mixed solution and shake it well to make a suspension ointment for oral application. It is convenient and simple, and the suspension ointment can also be stored for a relatively long time. Compared with the temporary grinding of nystatin tablets into powder and then adding a certain amount of solvents such as glycerin, enema, etc., it is more hygienic, uniform, stable, easy to apply and convenient to carry.

[0045] The difference between the present preparation and preparation method and other patented oral nystatin preparations is that the nystatin ointment of the present invention is prepared by dry-wet separation method. The ready-to-mix compound nystatin ointment for oral use of the present invention has a "dry" mixture powder part which is composed of nystatin, vitamin B2, diluent (pregelatinized starch, xanthan gum, povidone K30, etc.), antioxidant (sodium isoascorbate, anhydrous sodium sulfite, etc.), etc. The addition of diluent and antioxidant can ensure that nystatin is stable for a long time and help to mix it into a suspension ointment; vitamin B2 can also play a role in auxiliary treatment and promote ulcer healing.

[0046] The "wet" mixed solvent part is composed of glycerol, thickener (povidone, propylene glycol, povidone K90, etc.), neutral water or weak alkaline buffer solution, etc. On the basis of the traditional glycerol as the main solvent component, the thickener is introduced to increase the adhesion of the preparation, which is conducive to coating on the affected area. The use of near-neutral water or weak alkaline buffer solution is more conducive to the stability of nystatin and makes the therapeutic effect better. Experiments have shown that when the pH value of the phosphate buffer is 7-8 and the concentration of glycerol is about 50%, the combination of the two further improves the stability of nystatin. Compared with glycerol alone, water alone or a mixed solvent of glycerol and water, the present invention finds that in a weakly alkaline phosphate buffer environment, nystatin has better stability. The dry and wet separated preparation of the present invention can be stored stably for a long time, and the suspension coating obtained by mixing can also be used stably for a long time, so it is easy to transform and industrialize production, and has good market potential and promotion and application value. DETAILED DESCRIPTION

[0047] The technical solution of the present invention is further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

[0048] Example 1

[0049] Before preparation, all raw materials are sieved through 80-100 meshes, 35g of nystatin raw material (containing about 150 million units), 5g of vitamin B2, 115g of pregelatinized starch, 40g of povidone K30, and 5g of sodium isoascorbate are weighed, and the mixed powder is uniformly dispersed in the drug by gradual addition method, and then sealed and packaged into 100 packages with a light-shielding aluminum-plastic composite film, each package weighing 2.0g, containing about 1.5 million units of nystatin. The whole process of industrial production should be prepared in an oxygen-free environment. This embodiment is carried out under a nitrogen protection environment.

[0050] Preparation method of 20ml mixed solvent per bottle

[0051] Prepare 1000 ml of phosphate buffer with a pH of 7.4 and 0.05 mol / L for use; weigh 75 g of povidone K90, add an appropriate amount of the above phosphate buffer, stir, and place in a constant temperature box at 60°C until a clear solution becomes; take 1000 ml of glycerol, add it to the above povidone K90 solution, add an appropriate amount of the above phosphate buffer, stir, mix evenly, and make up to 2000 ml with phosphate buffer, use 30 ml brown medicine bottles to package, 20 ml per bottle, each bottle contains about 50% glycerol by volume and about 3.75% povidone K90 by weight by volume.

[0052] The above-mentioned 1 pack of mixed powder and 1 bottle of mixed solvent together constitute the ready-to-use compound nystatin ointment for oral use.

[0053] Example 2 Preparation Stability Study

[0054] 1. Investigation on the stability of the mixed powder

[0055] The above prescription and the control prescription (without sodium isoascorbate) were used to prepare mixtures, and the nystatin contents of the two prescriptions were determined by high performance liquid chromatography (HPLC), and the results were expressed as percentage of the labeled amount. The results are shown in Table 1.

[0056] Table 1: Stability study of nystatin mixed powder prepared by two prescriptions (n=5)

[0057]

[0058] The test results show that the validity period is calculated based on the content ≥ 80%. The mixture powder prepared by the prescription of Example 1 has a validity period of more than 1 year, while the control prescription without sodium isoascorbate has a validity period of only 6-9 months.

[0059] 2. Investigation of the stability of mixed solvents

[0060] The mixed solvent formula contains glycerol volume ratio ≥50%, which has antibacterial effect. The clarity, color and pH value (measured after diluting 100 times with injection water) of the mixed solvent prepared in Example 1 were investigated, and there was no obvious change within 1 year. The measurement results are shown in Table 2.

[0061] Table 2: Stability study of mixed solvents in Example 1 (n=5)

[0062] Observation Project 0 month January March June December Clarity Clarity Clarity Clarity Clarity Clarity Color colorless colorless colorless colorless colorless pH 7.38±0.04 7.35±0.03 7.39±0.05 7.36±0.04 7.40±0.05

[0063] This indicates that the properties and pH value of the mixed solution prepared according to the prescription of Example 1 have no significant changes within 1 year.

[0064] 3. Stability study of the prepared coating

[0065] Five groups of the instant compound nystatin liniment for oral use prepared according to the prescription of Example 1 were prepared into coatings. It was found that the mixed powder could be evenly dispersed into a suspension after shaking.

[0066] After being placed at room temperature for 3 months, the percentage of the labeled amount of nystatin was determined by high performance liquid chromatography. The results are shown in Table 3.

[0067] Table 3: Stability study of the instant compound nystatin liniment for oral use according to Example 1 after preparation (n=5)

[0068] Measurement time 0 month January March Percentage 98.9±1.2％ 96.8±1.3％ 93.7±1.3％

[0069] The results showed that after preparation, the nystatin content decreased by about 5% after being placed at room temperature for 3 months, which basically met the use requirements.

[0070] Example 3

[0071] Glycerol was used as the solvent, and 20 mL was dispensed into each bottle as solution A. Povidone K90 is difficult to dissolve in glycerol, and glycerol itself has a high viscosity, so no additional thickener is required.

[0072] Weigh 75 g of povidone K90, add appropriate amount of deionized water and stir, put it in a thermostat at 60°C until it becomes a clear solution; take 1000 ml of glycerol, add it to the above povidone K90 solution, add appropriate amount of water and stir, mix well and make up to 2000 ml with water, use 30 ml brown medicine bottles to package, 20 ml per bottle, each bottle contains about 50% glycerol by volume and about 3.75% povidone K90 by weight by volume, as solution B.

[0073] Prepare a phosphate buffer solution with a pH of 7.4 and 0.05 mol / L, dissolve povidone K90 to a weight-to-volume ratio of 3.75%, and dispense 20 mL into each bottle as solution C.

[0074] Prepare a 0.9% sodium chloride aqueous solution, dissolve povidone K90 to make its weight-to-volume ratio 3.75%, and dispense 20 mL into each bottle as solution D.

[0075] One package of the mixed powder of Example 1 was mixed with 20 mL of solvents A, B, C and D, and the mixture was evenly dispersed into a suspension after shaking.

[0076] The viscosity of pure glycerin in solution A is too high. After adding the powder, it cannot be shaken and mixed evenly, and grinding is required to obtain a suspension. This will cause inconvenience in operation, so pure glycerin is not suitable for use as a solvent for dry-wet separation ointment.

[0077] Three portions of each solvent were prepared and placed at room temperature for 3 months. The percentage of the labeled amount of nystatin was determined by high performance liquid chromatography. The results are shown in Table 4.

[0078] Table 4: Stability study of compound nystatin liniment prepared with different solvent formulas (n=3)

[0079] 0 month January March Example 1 Prescription 98.9±1.2％ 96.8±1.3％ 93.7±1.3％ Solution A 97.6±1.4％ 94.5±1.3％ 91.1±1.3％ Solution B 98.2±1.4％ 95.3±1.3％ 91.6±1.4％ Solution C 98.5±1.2％ 96.1±1.4％ 92.5±1.5％ Solution D 97.8±1.5％ 94.1±1.6％ 90.2±1.5％

[0080] The results showed that the stability of solutions A, B, C, and D were not as good as that of the prescription in Example 1.

[0081] Previous studies have shown that at lower concentrations, 50% glycerol, glycerol, and saline as solvents have better stability for nystatin. However, at higher concentrations, nystatin is more susceptible to oxidation and decomposition, so the stability of the suspension prepared with pure glycerol in solution A also decreases.

[0082] In addition, for solutions B and D, the thickener povidone K90 is acidic after being dissolved in water. If conventional deionized water or physiological saline is used as the solvent, the solution will be acidic. Nystatin is unstable in an acidic environment, so the stability of the suspensions prepared by solutions B and D is poor.

[0083] The pH value was adjusted to a weakly alkaline state using a phosphate buffer solution having a pH value of 7.4 and a value of 0.05 mol / L, which was helpful in improving the stability of the nystatin suspension.

[0084] However, the present invention combines glycerol and phosphate buffer to prepare 50% glycerol, which has antibacterial effect and is not easy to mold. The present invention finds that under this prescription, the stability of the suspension is significantly improved compared with the use of phosphate buffer alone. In addition, the viscosity of the suspension is appropriate, easy to apply, and has better adhesion to the mucous membrane.

Claims

1. A ready-to-use compound nystatin liniment for oral use, characterized in that The liniment comprises a powder and a mixed solvent which are separately packaged, and the powder comprises nystatin, vitamin B2, a diluent and an antioxidant; The mixed solvent includes glycerol, a thickener, water or a phosphate buffer.

2. The instant compound nystatin liniment for oral use according to claim 1, characterized in that The powder comprises the following components in parts by weight: 23-46 parts of nystatin, 1-5 parts of vitamin B2, 75-450 parts of diluent, and 2.5-10 parts of antioxidant.

3. The instant compound nystatin liniment for oral use according to claim 2, characterized in that The powder is packaged into small packets, each packet containing 1-2 million units of nystatin; each 10-30 mL of mixed solvent corresponds to the powder containing 1-2 million units of nystatin.

4. The instant compound nystatin liniment for oral use according to claim 1, characterized in that The mixed solvent includes the following components by weight: 1000-1500 parts of glycerol, 50-100 parts of thickener, 500-1500 parts of water or phosphate buffer.

5. The instant compound nystatin liniment for oral use according to claim 1, characterized in that The diluent is one or more of pregelatinized starch, xanthan gum, and povidone K30; the antioxidant is sodium isoascorbate or anhydrous sodium sulfite; and the thickener is povidone K90 or xanthan gum.

6. The instant compound nystatin liniment for oral use according to claim 1, characterized in that The packaging material of the powder is a light-shielding aluminum-plastic film, and the packaging of the mixed solvent adopts a light-shielding material.

7. The instant compound nystatin liniment for oral use according to claim 4, characterized in that The mixed solvent includes the following components by weight: 1000-1500 parts of glycerol, 50-100 parts of thickener, 500-1500 parts of phosphate buffer; The pH value of the phosphate buffer solution is 6.5-8, and the concentration is 0.01-0.1 mol / L.

8. The instant compound nystatin liniment for oral use according to claim 7, characterized in that In the mixed solvent, the pH value of the phosphate buffer is 7-8, and the concentration is 0.05-0.1 mol / L; in the mixed solvent, the mass fraction of the glycerol is 45-55%.

9. The instant compound nystatin liniment for oral use according to claim 1, characterized in that The instant compound nystatin liniment for oral use is prepared according to the following method: All raw materials of the powder are passed through a 80-100 mesh sieve, nystatin, vitamin B2, a diluent and an antioxidant are mixed and packaged to obtain a powder containing 1 million to 2 million units of nystatin per package; The thickener is first dissolved in water or phosphate buffer, then mixed with glycerol, water or phosphate buffer according to a ratio, and dispensed to prepare 10 to 30 mL of a mixed solvent; The method is carried out in an oxygen-free environment throughout the process.

10. Use of the instant compound nystatin liniment for oral use according to any one of claims 1 to 8 in the preparation of a nystatin suspension coating, the method of the use comprising: adding the powder into a mixed solvent and shaking well to prepare the suspension coating.

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