Oral solution capable of obviously improving palatability of cats and good in stability and preparation method of oral solution

Abstract

The invention provides an oral solution capable of obviously improving the palatability of cats and good in stability and a preparation method of the oral solution. The oral solution comprises the following raw materials: 1%-2% of itraconazole, 35%-45% of hydroxypropyl beta-cyclodextrin, 10%-15% of propylene glycol, 20%-30% of an amorphous sorbitol solution, 1%-1.5% of vitamin C, 0.1%-1% of essence, 0.01%-0.025% of sucralose, a proper amount of a pH regulator and the balance of purified water; the traditional cognition that cats do not have sweetness perception, so that sweeteners are invalid is broken through, the bitterness of itraconazole and the acerbity of a solution are remarkably covered through compounding of specific components, the adverse reaction rate after the cats take the itraconazole is reduced, and the medication compliance is improved to 90% or above; components with dual functions are introduced, so that the flavoring is assisted, the hydrolysis and oxidative degradation of itraconazole can be inhibited, the solution is ensured to keep high quality under the conditions of high temperature and accelerated storage, and the validity period is prolonged.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of veterinary medicine, in particular to an oral solution with improved palatability and good stability for cats and a preparation method thereof. BACKGROUND

[0002] Itraconazole is a broad-spectrum triazole antifungal drug, its mechanism of action is to inhibit the synthesis of ergosterol, a key component of fungal cell membrane, thereby destroying the integrity of fungal cell membrane and achieving strong bactericidal effect. Due to its unique lipophilic structure, it has significant effect on deep fungal infections in cats (such as aspergillosis, candidiasis) and dermatophytosis, and has become the first-line drug for the treatment of fungal diseases in cats.

[0003] Currently, there are two major core pain points in the clinical application of itraconazole oral solution, which seriously restricts the treatment effect:

[0004] Poor palatability, low compliance of cats taking medicine, itraconazole molecules have strong inherent bitterness, and the number of bitter taste receptor genes in cats is several times that of humans, and the sensitivity of bitter taste perception is much higher than that of humans, direct oral administration can easily cause cats to salivate, scratch their mouths, shake their heads, and even vomit and other rejection reactions;

[0005] In order to solve the extremely low water solubility of itraconazole, the existing preparation needs to add high-concentration hydrochloric acid to improve its solubility to ≥10mg / ml required for treatment through protonation, and the pH value of the finished product needs to be controlled at 1.5-2.5 to maintain the solubility. The strong acid environment not only intensifies the release of itraconazole bitterness, but also produces a sharp sour taste, and the double taste stimulation further worsens the cat's medication experience;

[0006] Traditional flavoring strategies have limitations: it is generally believed in the industry that cats cannot perceive sweetness due to the absence of Tas1r2 gene, so umami agents, flavor agents or lipid carriers are preferred in cat drugs, and sweeteners are deliberately avoided, resulting in the inability to effectively mask the bitterness and sourness of itraconazole solution, and the medication compliance of cats in the clinic is less than 65%.

[0007] Insufficient stability, quality fluctuation within the effective period, the existing itraconazole oral solution is prone to problems such as degradation of active ingredients and increase of impurities during storage; itraconazole molecules are prone to hydrolysis under acidic conditions to generate degradation impurities with no drug effect; there are no targeted stabilizing ingredients in the solution to inhibit the aggregation and precipitation of drug molecules; improper selection or dosage of antioxidants leads to oxidative degradation of the drug.

[0008] Therefore, it is an urgent need in the field of veterinary medicine to develop an itraconazole oral solution that can improve the palatability of cats and improve the stability of the solution. SUMMARY

[0009] The present application provides an oral solution with improved palatability for cats and good stability and a preparation method thereof, aiming at solving the problems in the background art.

[0010] The present application is implemented as an oral solution with improved palatability for cats and good stability, the raw material composition of the oral solution includes, in mass percentage: itraconazole 1%-2%, hydroxypropyl betacyclodextrin 35%-45%, propylene glycol 10%-15%, non-crystalline sorbitol solution 20%-30%, vitamin C 1%-1.5%, essence 0.1%-1%, sucralose 0.01%-0.025%, pH adjuster in proper amount, and the balance is purified water.

[0011] Preferably, the raw material composition of the oral solution includes, in mass percentage: itraconazole 1%,

[0012] hydroxypropyl betacyclodextrin 39%, propylene glycol 10%, non-crystalline sorbitol solution 24%, vitamin C 1%, essence 0.5%, sucralose 0.015%, pH adjuster in proper amount, and the balance is purified water.

[0013] Preferably, the essence is selected from one or more combinations of water peach essence, strawberry essence, lemon essence, and cherry essence.

[0014] Preferably, the preparation method of the oral solution with improved palatability for cats and good stability includes the following steps:

[0015] S1: preparing a basic dissolution system

[0016] Take the prescribed amount of 40%-50% purified water and add it to the liquid preparation tank, turn on the constant temperature heating device to raise the water temperature to 65-75°C, turn on the stirring, and then add the prescribed amount of propylene glycol and hydroxypropyl betacyclodextrin in sequence, stir for 25-30 min until completely dissolved, and form a clear and transparent basic solution;

[0017] S2: dissolving itraconazole

[0018] Keep the temperature of the liquid preparation tank at 65-75°C and keep the stirring rate unchanged, add the prescribed amount of hydrochloric acid to the basic solution of S1 at a rate of 1.5-2 ml / min, stir for 10 min after the addition is completed, then add the prescribed amount of itraconazole, and continue to stir for 35-40 min until completely dissolved, forming an itraconazole acidic solution; at this time, the solution pH is 1.2-1.4, and the itraconazole is completely dissolved without precipitation;

[0019] S3: adding flavoring and antioxidant ingredients

[0020] Turn off the heating device, and let the itraconazole acid solution of S2 cool naturally to 30-32℃. At this temperature, add the prescribed amount of non-crystalline sorbitol solution, essence, sucralose, and vitamin C in sequence, and stir for 15-20 min after each addition until complete dissolution, and then add the next component;

[0021] S4: pH adjustment and volume adjustment

[0022] To the mixed solution of S3, add the prescribed amount of sodium hydroxide solution at a rate of 0.8-1 ml / min, and monitor the pH in real time with a precision pH meter until the pH reaches 1.5-2.5. Add the remaining purified water to the prescribed total mass, and stir for 25-30 min to mix the solution uniformly to obtain the crude oral solution;

[0023] S5: filtration and sub-packaging

[0024] Filter the crude oral solution through a 0.22 μm microporous filter to remove trace amounts of insoluble impurities, and then sub-packaging into brown sterile glass bottles, which are sealed and stored in the dark.

[0025] Preferably, in step S2, the rate of hydrochloric acid addition is controlled at 1.8 ml / min, and the rate of sodium hydroxide addition is controlled at 0.9 ml / min. This rate of addition can avoid the temporary precipitation of itraconazole caused by the sudden change in local pH.

[0026] Due to the use of the above scheme, the present application has the following advantages:

[0027] 1. Breaking the traditional understanding that "cats have no sweet taste perception, so sweeteners are ineffective", by compounding specific ingredients, the bitterness of itraconazole and the sour taste of the solution are significantly masked, the adverse reaction rate after taking medicine by cats is reduced, and the medication compliance is improved to more than 90%;

[0028] 2. Introducing ingredients with dual functions, which not only assist in flavoring, but also inhibit the hydrolysis and oxidative degradation of itraconazole, ensuring that the solution still maintains high quality under high temperature and accelerated storage conditions, and prolonging the shelf life;

[0029] 3. Providing a preparation method with stable process and strong repeatability, which ensures uniform product quality in batch production. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solutions and advantages of the present application clearer and more apparent, the following embodiments are used to further illustrate the present application. It should be understood that the specific embodiments described herein are only used to explain the present application, and are not used to limit the present application.

[0031] Example 1

[0032] An oral solution with improved palatability and good stability for cats, the raw material composition of the oral solution comprises, by mass percentage: itraconazole 1%, propylene glycol 10%, hydroxypropyl-beta-cyclodextrin 39%, non-crystalline sorbitol solution 24%, hydrochloric acid 0.9%, vitamin C 1%, peach essence 0.1%, sucralose 0.01%, sodium hydroxide, and purified water.

[0033] The preparation method of the oral solution with improved palatability and good stability for cats, comprising the following steps, by 100g of the oral solution: S1: preparing a basic dissolution system

[0034] Take the prescribed amount of 45% purified water (about 10.8g) into the solution tank, turn on the constant temperature heating device to raise the water temperature to 70℃ (temperature fluctuation ±1℃), turn on the stirring (speed 280r / min), add 10.0g of propylene glycol, 39.0g of hydroxypropyl-beta-cyclodextrin in turn, continue stirring for 28min until the material is completely dissolved to form a clear and transparent base solution (no visible particles, turbidity ≤1NTU).

[0035] S2: Dissolve itraconazole

[0036] Keep the temperature of the solution tank at 70℃ and the stirring speed at 280r / min, add 0.9g of hydrochloric acid (1.2mol / L) at a rate of 1.8ml / min, continue stirring for 10min after the addition is completed to ensure uniform dispersion of the hydrochloric acid; then add 1.0g of itraconazole and continue stirring for 38min until the itraconazole is completely dissolved to form an itraconazole acid solution (at this time, the pH is 1.3±0.1 measured by a precision pH meter, and no drug precipitation is observed by sampling observation).

[0037] S3: Add flavoring and antioxidant ingredients

[0038] Turn off the heating device and naturally cool the acid solution of S2 to 31℃ (continue stirring at a speed of 250r / min during the cooling process), then add 24.0g of non-crystalline sorbitol solution (stir for 18min), 0.1g of peach essence (stir for 16min), 0.01g of sucralose (stir for 15min), and 1.0g of vitamin C (stir for 17min) in turn at this temperature, and each step needs to confirm that the material is completely dissolved before proceeding to the next step.

[0039] S4: pH adjustment and constant volume

[0040] The 0.8 mol / L sodium hydroxide solution was added at a rate of 0.9 ml / min, and the pH was monitored in real time with a precision pH meter (accuracy ± 0.01) until the pH stabilized at 2.0 ± 0.1; the remaining purified water (about 13.2 g) was added to a total mass of 100 g, and stirring was maintained at 250 r / min for 27 min to ensure uniform mixing of the solution, obtaining a crude internal solution.

[0041] S5: filtration and sub-packaging

[0042] The crude product was filtered through a 0.22 μm polyether sulfone (PES) microporous filter membrane (filtration pressure 0.2 MPa) to remove trace amounts of insoluble impurities; immediately after filtration, it was sub-packaged into 10 ml brown sterile glass bottles (transmittance ≤ 5%, wavelength 200 nm-400 nm), sealed with a cap, labeled, and stored in the dark at 25°C ± 2°C.

[0043] Example 2

[0044] Compared with Example 1, the preparation raw materials were adjusted to 0.5% peach essence and 0.015% sucralose. In the preparation process, only in step S3, the stirring time of peach essence was extended to 18 min, and the stirring time of sucralose was extended to 17 min to ensure complete dissolution of high-concentration materials. The final pH was adjusted to 2.0 ± 0.1, and the solution was clear and transparent (turbidity ≤ 0.8 NTU) after constant volume.

[0045] Example 3

[0046] Compared with Example 1, the preparation raw materials were adjusted to 1% peach essence and 0.025% sucralose. In the preparation process, the stirring time of peach essence was extended to 20 min, and the stirring time of sucralose was extended to 18 min in step S3. The final pH was stable at 2.0 ± 0.1, and the solution had no stratification and no odor.

[0047] Example 4

[0048] The "peach essence" was replaced with "strawberry essence", and the remaining raw materials and specifications were consistent with Example 2, as follows: strawberry essence 0.5% and sucralose 0.015%; the preparation process was consistent with Example 2, and the strawberry essence stirring time was 17 min in step S3 to ensure uniform dispersion of flavor substances; the final solution was a light brown clear liquid with a faint strawberry aroma.

[0049] Example 5

[0050] Replace "peach flavor" with "lemon flavor", and the rest of the raw materials and specifications are consistent with Example 2, as follows: lemon flavor 0.5% and sucralose 0.015%; the preparation process is consistent with Example 2, and the stirring time of lemon flavor in S3 step is 16 min; the final solution has no irritating sour taste and meets the clarity requirement (turbidity ≤0.9 NTU).

[0051] Example 6

[0052] Replace "peach flavor" with "cherry flavor", and the rest of the raw materials and specifications are consistent with Example 2, as follows: cherry flavor 0.5%; the preparation process is consistent with Example 2, and the stirring time of cherry flavor in S3 step is 18 min; the final solution has cherry characteristic aroma and no odor.

[0053] To verify the effect of "flavor + sucralose complex" and "specific concentration range" on palatability and stability, the following comparative examples are set, and the raw material specifications are consistent with Example 1, and the preparation steps follow the parameters of claims 4 and 5 except for the variables.

[0054] Comparative Example 1: no flavor, no sucralose (traditional formula)

[0055] Raw material composition (based on 100 g of oral solution)

[0056] Remove "flavor" and "sucralose", and the rest of the raw materials and amounts are consistent with Example 1, and the balance of purified water is adjusted to about 24.1 g. The preparation steps, only non-crystalline sorbitol solution and vitamin C are added in S3 step, and the rest of the steps are consistent with Example 1; the final solution has pH = 2.0 ± 0.1, and is a light brown clear liquid, but has obvious itraconazole bitterness and astringency.

[0057] Comparative Example 2: only add 0.5% peach flavor (no sucralose)

[0058] Raw material composition (based on 100 g of oral solution)

[0059] Remove "sucralose", and the rest of the raw materials and amounts are consistent with Example 2, and the balance of purified water is adjusted to about 23.6 g.

[0060] Preparation steps

[0061] No sucralose is added in S3 step, and the rest of the steps are consistent with Example 2; the final solution has peach aroma, but the bitterness is still obvious.

[0062] Comparative Example 3: only add 0.015% sucralose (no flavor)

[0063] Raw material composition (based on 100 g of oral solution)

[0064] Remove "essence", the rest of the raw materials and dosage is consistent with example 2, the balance of purified water is about 23.6g.

[0065] Preparation steps

[0066] S3 step without adding essence, the rest of the steps are consistent with example 2; the final solution has no obvious aroma, the astringent feeling is relieved, but the bitter taste still exists.

[0067] Comparative example 4: low concentration of compound (0.05% peach essence + 0.005% sucralose)

[0068] Raw material composition (per 100g oral solution)

[0069] Reduce the concentration of essence and sucralose, the rest of the raw materials and dosage is consistent with example 2, as follows:

[0070] Material name dosage mass percentage

[0071] Peach essence 0.05%, sucralose 0.005%, the balance of purified water (about 24.0g);

[0072] Preparation steps

[0073] Consistent with example 2, the stirring time of essence and sucralose in S3 step is 15min; the final solution has weak aroma, and the bitter taste is not obviously relieved.

[0074] Comparative example 5: high concentration of compound (1.5% peach essence + 0.035% sucralose)

[0075] Raw material composition (per 100g oral solution)

[0076] Increase the concentration of essence and sucralose, the rest of the raw materials and dosage is consistent with example 2, as follows:

[0077] Material name, peach essence 1.5% (about 1.5g), sucralose 0.035% (about 0.035g)

[0078] The balance is purified water (about 22.1g);

[0079] Preparation steps

[0080] Consistent with example 2, the stirring time of essence in S3 step is extended to 22min, and the stirring time of sucralose is extended to 20min; the final solution has too strong aroma, and some cats may produce odor rejection.

[0081] Effect example comparison 1

[0082] Palatability test method: 20 healthy adult cats were selected for the experiment, weighing 3-5 kg, and aged 1 year or older. During the experiment, the surrounding environment was kept clean and hygienic, and the cats were placed in separate cages to ensure adequate feeding and drinking of natural light. The cats in each group were fed four kinds of itraconazole oral solution, and the experiment lasted for 3 days. The cats were observed for self-licking behavior and whether vomiting, salivation and other phenomena occurred after feeding. The following is the specific feeding method:

[0083] (1) Take 0.5 ml of each oral solution in an empty bowl and observe whether the cat licks it. If there is no licking behavior within 5 minutes, it is recorded as no

[0084] (2) 30 minutes later, the cats were orally injected with 0.25 ml / kg of body weight of the oral solution, and observed for whether they spit water, spit bubbles, and vomit. If there is no above behavior within 15 minutes, it is recorded as no.

[0085] Table 1 Summary of palatability data for different formulations

[0086]

[0087]

[0088]

[0089] The experimental results of the stability of the drug of the present application are as follows: According to the "Technical Guidelines for Stability Research of Veterinary Chemical Drugs (Trial)", the stability was investigated under high temperature 60℃, accelerated conditions (40℃, 75% RH).

[0090] Table 2 Stability test observation results of Examples 1-3 and Comparative Examples 1-5 and commercially available products

[0091]

[0092]

[0093] According to the results of the comparative experiment of the examples, it can be understood that:

[0094] First, the results of Examples 1-3 and Comparative Example 1 of the present application show that the product indeed has poor palatability for cats. The adverse reaction rate of Comparative Example 1, which does not add fragrance or sweetener, is as high as 14 / 30, while the adverse reaction rate of Comparative Example 2, which only adds fragrance, is 12 / 30, and the adverse reaction rate of Comparative Example 3, which only adds sweetener, is 10 / 30. Examples 1-3, the prescription of the product can greatly reduce the adverse reaction rate of itraconazole oral solution by compounding fragrance and sweetener. The preferred Example 2 (0.5% watermelon fragrance + 0.015% sucralose) has an adverse reaction rate of 2 / 30.

[0095] Second, the stability observation results of the itraconazole oral solution of the present application are shown in Table 2. The experimental data show that under the influence of high temperature for 30 days, the appearance, content and related substances of Examples 1, 2 and 3 all meet the quality standards, but under the long-term trend of accelerated conditions, the growth trend of related substances and the content decrease trend of Example 2 are significantly better than those of Comparative Examples 1-4.

[0096] The above description of the embodiments is to facilitate the understanding and use of the present application by those of ordinary skill in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without having to go through creative labor. Therefore, the present application is not limited to the above embodiments. Improvements and modifications made by those skilled in the art based on the principles of the present application without departing from the scope of the present application should be within the scope of protection of the present application. The above description is only of the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement and improvement made within the spirit and principles of the present application should be included in the scope of protection of the present application.

Claims

1. An oral solution for internal administration which is significantly improved in palatability and has good stability, characterized in that, The raw material composition of the oral solution comprises, by mass percentage: itraconazole 1%-2%, hydroxypropyl betadex 35%-45%, propylene glycol 10%-15%, non-crystalline sorbitol solution 20%-30%, vitamin C 1%-1.5%, essence 0.1%-1%, sucralose 0.01%-0.025%, a pH regulator in an appropriate amount, and the balance being purified water.

2. The oral solution for cats according to claim 1, wherein The raw material composition of the oral solution comprises, by mass percentage: itraconazole 1%, hydroxypropyl betadex 39%, propylene glycol 10%, non-crystalline sorbitol solution 24%, vitamin C 1%, essence 0.5%, sucralose 0.015%, a pH regulator in an appropriate amount, and the balance being purified water.

3. The oral solution for cats of claim 1, wherein, The essence is selected from one or more combinations of watermelon essence, strawberry essence, lemon essence, and cherry essence.

4. A method for preparing the oral solution for internal use according to any one of claims 1 to 3, which is improved in palatability for cats and is stable, characterized by, The method comprises the following steps: S1: preparing a basic dissolution system A prescription amount of 40%-50% purified water is taken into a liquid preparation tank, a constant temperature heating device is turned on to raise the water temperature to 65-75°C, stirring is started, and a prescription amount of propylene glycol and hydroxypropyl betadex is sequentially added, and stirring is continued for 25-30 min until complete dissolution, forming a clear and transparent base solution; S2: dissolving itraconazole The temperature of the liquid preparation tank is maintained at 65-75°C, and the stirring rate is unchanged, a prescription amount of hydrochloric acid is added to the base solution of S1 at a rate of 1.5-2 ml / min, after the addition is completed, stirring is continued for 10 min, a prescription amount of itraconazole is then added, and stirring is continued for 35-40 min until complete dissolution, forming an itraconazole acid solution; at this time, the solution has a pH of 1.2-1.4, and the itraconazole is completely dissolved without precipitation; S3: adding flavoring and antioxidant components The heating device is turned off, the itraconazole acid solution of S2 is naturally cooled to 30-32°C, and a prescription amount of non-crystalline sorbitol solution, essence, sucralose, and vitamin C is sequentially added at this temperature, and stirring is continued for 15-20 min after each component is added until complete dissolution, and the next component is then added; S4: pH adjustment and volume setting A prescription amount of sodium hydroxide solution is added to the mixed solution of S3 at a rate of 0.8-1 ml / min, and the pH is monitored in real time using a precision pH meter until the pH reaches 1.5-2.5; the balance of purified water is added to reach the total prescription mass, and stirring is continued for 25-30 min to uniformly mix the solution, obtaining a crude oral solution; S5: filtration and sub-packaging The crude oral solution is filtered through a 0.22 μm microporous filter to remove trace amounts of insoluble impurities, and then sub-packaged into brown sterile glass bottles, which are sealed and stored in the dark.

5. The preparation method according to claim 4, characterized in that, In step S2, the hydrochloric acid is added at a rate of 1.8 ml / min, and the sodium hydroxide is added at a rate of 0.9 ml / min; these addition rates can avoid a sudden change in local pH of the solution, which can cause temporary precipitation of itraconazole.

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