Nystatin solution, its preparation method and application

Abstract

The application discloses a nystatin solution and a preparation method and application thereof, which is prepared from the following raw materials in parts by weight: nystatin 20-50 parts, dimethyl sulfoxide 110-220 parts, preservative 1.5-2.0 parts, antioxidant 0.5-1 part and 1,2-propylene glycol 737-880 parts. The application creatively adopts a composite solvent system of dimethyl sulfoxide and propylene glycol, utilizes the extremely strong dissolving capacity of dimethyl sulfoxide and the auxiliary solubilization and dilution effect of propylene glycol, and produces a significant synergistic effect. The system can completely dissolve up to 50 parts by weight of nystatin, forms a clear, transparent and uniform stable solution, fundamentally solves the technical bottleneck that nystatin cannot be prepared into a high-content solution due to poor water solubility, and lays a foundation for poultry group water medication.

Description

Technical Field

[0001] This invention relates to the field of poultry medicine technology, and in particular to a nystatin solution, its preparation method, and its application. Background Technology

[0002] The information disclosed in this background section is intended only to enhance some understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art.

[0003] Aspergillosis is a common disease in poultry, primarily affecting the respiratory and digestive organs. All types of poultry are susceptible, but it is most prevalent in young birds. It often presents as an acute, widespread outbreak with high morbidity and mortality. There is currently no specific treatment for this disease. For infected birds, antifungal medications should be administered as early as possible, while simultaneously improving the environment to eliminate the underlying cause. Nystatin is a first-line drug for treating aspergillosis in poultry, and farmers currently often use nystatin mixed with feed to treat the disease. There are several cases of nystatin product development both domestically and internationally. According to the FDA search results, there are currently few veterinary drug products containing nystatin from abroad. Zoetis' Pharmastatin-20® Type A is the only poultry antifungal drug that uses nystatin as the sole active ingredient and is registered as a feed additive. This product is mainly used to control crop fungal diseases and fungal diarrhea in turkeys. It is mixed with feed when used, but this method is very inconvenient for farmers. Some farmers do not have mixing equipment, and if the feed and drug are not mixed evenly, it may cause drug poisoning or the intake may not achieve the therapeutic effect of the drug. Other products containing nystatin are all veterinary drugs for pets. For example, Dechra's Canaural® ear drops are an oily suspension made from prednisolone, nystatin, etc., primarily used for external ear canal inflammation in cats and dogs; Zoetis' Panolog® ointment is mainly used for skin diseases caused by fungal infections in cats and dogs; Med-Pharmex's DERMA-VET® ointment is mainly used for acute and chronic otitis media in pets, interdigital cysts in cats and dogs, and anal gland infections in dogs, as well as dermatitis caused by fungal infections; Fougera Pharmaceuticals' Animax® ointment is mainly used for skin diseases caused by bacterial or fungal infections in animals, and also has some therapeutic effect on eczematous dermatitis and seborrheic dermatitis. These products are either not intended for treating fungal diseases in poultry, or their administration methods are time-consuming and laborious, resulting in poor therapeutic effects and delaying treatment, causing economic losses for farmers. Summary of the Invention

[0004] The present invention aims to overcome the shortcomings of the prior art and provide a solution for treating mycotic diseases in poultry and a method for preparing the same.

[0005] The technical solution adopted in this invention is as follows:

[0006] In a first aspect of the invention, a nystatin solution is provided, which is made from the following raw materials in parts by weight: 20-50 parts of nystatin, 110-220 parts of dimethyl sulfoxide, 1.5-2.0 parts of preservative, 0.5-1 part of antioxidant, and 737-880 parts of 1,2-propanediol.

[0007] In one or more embodiments of the present invention, the preservative is a compound paraben; a compound paraben refers to a preservative formulation made by mixing two or more different parabens together in a set ratio, including methylparaben, ethylparaben, propylparaben, butylparaben, or their sodium salts.

[0008] In one or more embodiments of the present invention, the antioxidant is vitamin E.

[0009] Another factor restricting the development and utilization of nystatin is its poor chemical stability. It is particularly susceptible to degradation in solution due to oxidation and hydrolysis, leading to decreased biological activity. Furthermore, the higher-order structure of nystatin molecules is maintained by intramolecular and intermolecular interactions (including hydrogen bonds). Unsuitable formulation environments can disrupt these interactions, thereby affecting its stability and activity. This invention discovers that adding the antioxidant vitamin E to the specific solvent system can effectively inhibit the oxidative degradation of nystatin. Working synergistically with the solvent system, vitamin E effectively ensures the chemical stability and biological activity of nystatin in solution.

[0010] In a second aspect of the invention, a method for preparing the nystatin solution is provided, the method comprising the following steps:

[0011] (1) Place the prescribed amount of dimethyl sulfoxide in the dispensing tank;

[0012] (2) Add the prescribed amount of nystatin and stir thoroughly for 30-50 minutes to fully dissolve the nystatin and obtain solution A;

[0013] (3) Take another portion of the prescribed amount of 1,2-propanediol, stir to dissolve the prescribed amount of preservative and antioxidant, and obtain solution B;

[0014] (4) Mix solution B with solution A and stir for 20-30 minutes. Then add the remaining 1,2-propanediol and stir until homogeneous.

[0015] (5) The solution obtained in step (4) is filtered, filled and dispensed to obtain the nystatin solution.

[0016] In a third aspect of the invention, the use of the nystatin solution in the preparation of a drug for the prevention and treatment of mycosis in poultry is provided.

[0017] In one or more embodiments of the present invention, the poultry is pigeon, chicken, duck, goose, etc.

[0018] Compared with the related technologies known to the inventors, one of the technical solutions of the present invention has the following beneficial effects:

[0019] This invention creatively employs a composite solvent system of dimethyl sulfoxide and propylene glycol. Utilizing the extremely strong dissolving power of dimethyl sulfoxide and the auxiliary solubilizing and diluting effects of propylene glycol, a significant synergistic effect is achieved. This system can completely dissolve up to 50 parts by weight of nystatin, forming a clear, transparent, homogeneous, and stable solution. This fundamentally solves the technical bottleneck of nystatin's poor water solubility, which prevents the preparation of high-concentration solutions, thus laying the foundation for administering medication to poultry through drinking water.

[0020] This invention relates to a solution in which the drug is highly dispersed at the molecular level. When administered to poultry via drinking water, the drug does not require slow processes such as disintegration and dissolution; it can be rapidly absorbed directly through the digestive tract mucosa, resulting in a fast onset of action, high bioavailability, and rapid attainment of effective blood drug concentrations. This allows for timely control of the disease and improved cure rates.

[0021] By optimizing the ratio of the compound solvent, the amount of DMSO and its potential irritation were significantly reduced while ensuring solubility. The addition of propylene glycol improved the viscosity and palatability of the solution, avoiding the problem of reduced water consumption in poultry due to drug odor or solvent irritation, and ensuring that poultry could drink enough water during administration, thereby ingesting the full dose of the drug.

[0022] This invention enables group-based drug administration via drinking water. Compared to traditional methods that require individual administration of medication (tablets) or uneven mixing with feed (premixes), this invention allows for direct administration via drinking water, saving time and effort, ensuring accurate dosage, minimizing stress response, and perfectly adapting to modern, intensive poultry farming models, thus doubling the efficiency of disease prevention and control. Detailed Implementation

[0023] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0024] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments of the present invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, and / or combinations thereof.

[0025] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0026] Example 1

[0027] A nystatin solution, by weight, is made from the following raw materials: 20 parts nystatin, 110 parts dimethyl sulfoxide, 1.5 parts compound parabens, 0.5 parts vitamin E, and 868 parts 1,2-propanediol; the compound parabens are obtained by mixing methylparaben and ethylparaben in a 1:1 mass ratio.

[0028] Preparation process: (1) Place 110 parts of dimethyl sulfoxide in a mixing tank.

[0029] (2) Add 20 parts of nystatin and stir thoroughly for 30 minutes to dissolve the nystatin completely, to obtain solution A.

[0030] (3) Take another 200 parts of 1,2-propanediol and stir to dissolve 1.5 parts of compound parabens and 0.5 parts of vitamin E to obtain solution B.

[0031] (4) Mix solution B with solution A and stir for 20 minutes. Add the remaining 1,2-propanediol, mix well, and filter for later use.

[0032] (5) The solution obtained in step (4) is filled and dispensed to obtain nystatin solution.

[0033] Example 2

[0034] A nystatin solution, by weight, is made from the following raw materials: 50 parts nystatin, 220 parts dimethyl sulfoxide, 2.0 parts compound parabens, 1 part vitamin E, and 727 parts 1,2-propanediol; the compound parabens are obtained by mixing methylparaben and ethylparaben in a 1:1 mass ratio.

[0035] Preparation process:

[0036] (1) Place 220 parts of dimethyl sulfoxide in a dispensing tank.

[0037] (2) Add 50 parts of nystatin and stir thoroughly for 40 minutes to dissolve the nystatin completely.

[0038] (3) Take another 200 parts of 1,2-propanediol and stir to dissolve 2 parts of compound parabens and 1 part of vitamin E.

[0039] (4) Mix solution B with solution A and stir for 20 minutes. Add the remaining 1,2-propanediol, mix well, and filter for later use.

[0040] (5) The solution obtained in step (4) is filled and packaged to obtain nystatin solution.

[0041] Comparative Example 1: Using only 1,2-propanediol

[0042] Compared with Example 2, the difference is that: a nystatin solution, by weight, is made from the following raw materials: 50 parts nystatin, 2.0 parts compound parabens, 1 part vitamin E, and 947 parts 1,2-propanediol.

[0043] Preparation process:

[0044] (1) Place 220 parts of 1,2-propanediol in a mixing tank.

[0045] (2) Add 50 parts of nystatin and stir thoroughly for 40 minutes to dissolve the nystatin completely.

[0046] (3) Take another 200 parts of 1,2-propanediol and stir to dissolve 2 parts of compound parabens and 1 part of vitamin E.

[0047] (4) Mix solution B with solution A and stir for 20 minutes. Add the remaining 1,2-propanediol, mix well, and filter for later use.

[0048] (5) The solution obtained in step (4) is filled and packaged to obtain nystatin solution.

[0049] The resulting solution contained almost no nystatin, appearing cloudy and suspended with a large amount of insoluble matter. It exhibited extremely poor stability and quickly crystallized.

[0050] Comparative Example 2: Dimethyl sulfoxide only

[0051] Compared with Example 2, the difference is that: a nystatin solution, by weight, is made from the following raw materials: 50 parts nystatin, 947 parts dimethyl sulfoxide, 2.0 parts compound parabens, and 1 part vitamin E.

[0052] Preparation process:

[0053] (1) Place 220 parts of dimethyl sulfoxide in a dispensing tank.

[0054] (2) Add 50 parts of nystatin and stir thoroughly for 40 minutes to dissolve the nystatin completely.

[0055] (3) Take another 200 parts of dimethyl sulfoxide and stir to dissolve 2 parts of compound parabens and 1 part of vitamin E.

[0056] (4) Mix solution B with solution A and stir for 20 minutes. Add the remaining dimethyl sulfoxide, mix well, and filter for later use.

[0057] (5) The solution obtained in step (4) is filled and packaged to obtain nystatin solution.

[0058] If only dimethyl sulfoxide is used as a solvent, the resulting nystatin solution is highly toxic and irritating.

[0059] Comparative Example 3 used an alternative organic solvent system (1-propanol-dimethyl sulfoxide).

[0060] The difference from Example 2 is that "1,1-propanediol" is used instead of "1,2-propanediol". The other steps and methods are the same as in Example 2.

[0061] The prepared nystatin solution has lower safety and stability than 1,2-propanediol.

[0062] Comparative Example 4: Low DMSO Ratio

[0063] The difference from Example 2 is: 50 parts nystatin, 80 parts dimethyl sulfoxide, 2.0 parts compound parabens, 1 part vitamin E, and 867 parts 1,2-propanediol. Other steps and methods are the same as in Example 2.

[0064] Insufficient DMSO content cannot completely dissolve nystatin, resulting in poor solution clarity and easy precipitation after standing.

[0065] Comparative Example 5: High DMSO Ratio

[0066] The difference from Example 2 is that: 50 parts nystatin, 280 parts dimethyl sulfoxide, 2.0 parts compound parabens, 1 part vitamin E, and 667 parts 1,2-propanediol. Other steps and methods are the same as in Example 2.

[0067] While it can dissolve, it increases costs and raises the potential risks of irritation and toxicity associated with DMSO. Stability tests may show no improvement, or even worse results due to the high reactivity of DMSO.

[0068] Comparative Example 6: No antioxidants (Vitamin E)

[0069] The difference from Example 2 is: 50 parts of nystatin, 220 parts of dimethyl sulfoxide, 2.0 parts of compound parabens, and 728 parts of 1,2-propanediol.

[0070] Solutions without added vitamin E cannot guarantee the chemical stability and biological activity of nystatin in solution for a longer period of time, resulting in a decrease in nystatin content of ≥12%, which makes it impossible to maintain an effective therapeutic concentration.

[0071] The table below shows the appearance and performance parameters of the solutions in Examples 1-2 and Comparative Examples 1-6.

[0072]

[0073] Experiment: To test the therapeutic efficacy and recovery rate of the drug of this invention against mycotoxin poisoning in pigeons.

[0074] 1) Subjects: A flock of pigeons poisoned by aspergillosis under the same rearing conditions was selected from a pigeon farm and divided into 5 groups of 20 pigeons each, for a total of 100 pigeons. All groups were provided with the same basic feed and water.

[0075] 2) Method: The control group of pigeons was fed a basal diet;

[0076] In Experiment 1, the nystatin solution prepared in Example 1 was diluted with 1L of water for every 25ml of the solution, and used for 3 consecutive days, based on the control group.

[0077] In Experiment 2, the nystatin solution prepared in Example 2 was diluted with 1L of water for every 10ml of solution, and used for 3 consecutive days, based on the control group.

[0078] The experimental groups used the nystatin solution prepared in Comparative Example 3, and diluted it with 1L of water for every 10ml of solution, based on the control group, and used it for 3 consecutive days.

[0079] Experimental Group 4: The nystatin solution prepared in Comparative Example 5 was used, and diluted with 1L of water for every 10ml of the solution, and used for 3 consecutive days.

[0080] 3) Experimental results:

[0081]

[0082] The table above shows that the cure rate for the control group was 20%, the cure rate for experimental group 3 was 45%, and the cure rate for experimental group 4 was 40%; the cure rate for experimental group 1 was 85%, and the cure rate for experimental group 2 was 90%. The differences between experimental groups 1 and 2 and the control group, as well as experimental groups 3 and 4, were significant (P < 0.01). Furthermore, the cure rate of the experimental groups increased significantly with increasing drug concentration.

[0083] Compared with the control group, the group of this invention had a lower mortality rate, a higher survival rate, and a significant therapeutic effect, demonstrating a clear therapeutic effect on pigeons poisoned by mycotoxins.

[0084] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A nystatin solution, characterized in that, It is made from the following raw materials in parts by weight: 20 parts nystatin, 110 parts dimethyl sulfoxide, 1.5 parts compound parabens, 0.5 parts vitamin E, and 868 parts 1,2-propanediol. The compound parabens are obtained by mixing parabens methylparaben and parabens ethylparaben in a mass ratio of 1:

1.

2. A nystatin solution, characterized in that, It is made from the following raw materials in parts by weight: 50 parts nystatin, 220 parts dimethyl sulfoxide, 2.0 parts compound parabens, 1 part vitamin E, and 727 parts 1,2-propanediol; the compound parabens are obtained by mixing methylparaben and ethylparaben in a mass ratio of 1:

1.

3. The method for preparing the nystatin solution according to claim 1 or 2, characterized in that, The method includes the following steps: (1) Place the prescribed amount of dimethyl sulfoxide into the dispensing tank; (2) Add the prescribed amount of nystatin and stir thoroughly for 30-50 minutes to fully dissolve the nystatin and obtain solution A; (3) Take another portion of the prescribed amount of 1,2-propanediol, stir to dissolve the prescribed amount of compound parabens and vitamin E, and obtain solution B; (4) Mix solution B with solution A and stir for 20-30 minutes. Then add the remaining 1,2-propanediol and stir until homogeneous. (5) The solution obtained in step (4) is filtered, filled and dispensed to obtain the nystatin solution.

4. The use of the nystatin solution according to claim 1 or 2 in the preparation of drugs for the prevention and treatment of mycotic diseases in poultry.

5. The application as described in claim 4, characterized in that, The poultry mentioned are pigeons, chickens, ducks, or geese.

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