Fluralan soft chewable tablet for pets and preparation method of fluralan soft chewable tablet

Abstract

The invention relates to a fluralan soft chewable tablet for pets and a preparation method of the fluralan soft chewable tablet. The fluralan soft chewable tablet comprises the following raw materials: 14.0% of fluralan, 0.3%-1.0% of lauryl sodium sulfate, 1.0%-3.0% of magnesium stearate, 5.0%-10.0% of polyethylene glycol, 3.0%-5.0% of cane sugar, 0.05%-0.5% of a preservative, 10.0%-22.0% of a phagostimulant, 4.0%-10.0% of a release agent, 11.0% of glycerol, 13.8% of soybean oil and the balance of corn starch. The chewable tablet soft material disclosed by the invention is obviously improved in the aspects of state, wall sticking condition, demolding condition and forming, conventional existing equipment is adopted, the process is simple and feasible, and a sample is stable in microbial limit level in a long-term placement process and meets standard requirements.

Description

Technical Field

[0001] The invention relates to a flurellana soft chewable tablet for pets and a preparation method thereof, belonging to the technical field of animal medicine. Background Art

[0002] Flurella is a systemic antiparasitic drug that covers the entire life cycle of fleas and ticks. It has a fast onset and long duration of effect on adult fleas, and can also prevent fleas from laying eggs, thereby completely killing fleas. It also has a complete killing effect on various ticks. The once-three-month dosing method can effectively improve the medication compliance of pet owners, is easily accepted by pet owners, and has a high market recognition. Flurella was approved for marketing in Europe and the United States in 2014 as a chewable tablet under the trade name Bravecto TM ). Oral solution products were approved in Europe in 2017, and drops were approved in Europe and the United States in 2016 and 2018, respectively.

[0003] Soft chewable tablets are a popular dosage form in the field of pet medicine tablets and have high market recognition. However, this type of dosage form often has the following problems during the development process: the soft material of soft chewable tablets is oily and sticky, and it is not easy to get out of the mold during tableting, which affects the molding effect; in order to increase palatability, attractants such as meat or organ extracts are generally added during preparation, but bacteria are easily bred during the production process and storage process, resulting in excessive microbial limits and affecting product quality.

[0004] Patent document CN104203214A discloses a flurellan soft chewable composition and a preparation method thereof. In the preparation process, pamoic acid or a pharmaceutically acceptable salt thereof is added to a soft chewable dough, and the lubricity of the chewable cookie dough-like soft material and the mold is improved to improve the processability of the chewable dough in a processing equipment. The processing equipment includes a horizontal plowshare or planetary mixer and a molding machine for manufacturing a block shape. Among them, the horizontal plowshare mixer is relatively less popular in China and has a higher price. The molding machine needs to be customized, which increases the product cost.

[0005] Patent document CN116637078A discloses a flurellan soft chewable composition, a soft chewable tablet, and a preparation method and application thereof. The soft chewable composition contains auxiliary materials such as chicken liver powder that are prone to breeding bacteria, and the microbial limit level cannot be effectively guaranteed during the preparation production or storage process.

[0006] The use of a release agent that is different from the original and easily available can improve the soft material state, wall adhesion, and demoulding ability, thereby improving the formability, while ensuring that the product's microbial limits meet the regulations during long-term storage, which is of great significance to the industrial and commercial production of flurella soft chewable tablets. Summary of the invention

[0007] In view of the shortcomings of the prior art, the present invention provides a soft chewable tablet of flurellana for pets and a preparation method thereof. The soft chewable tablet material of the present invention has obvious improvements in state, wall adhesion, demolding and molding. Conventional existing equipment is used, the process is simple and feasible, and the microbial limit level of the sample is stable during long-term storage, which meets the standard requirements.

[0008] The present invention is achieved through the following technical solutions:

[0009] A soft chewable tablet of flurellana for pets, comprising the following raw materials by weight percentage:

[0010] Flurellan 14.0%, sodium lauryl sulfate 0.3%-1.0%, magnesium stearate 1.0%-3.0%, polyethylene glycol 5.0%-10.0%, sucrose 3.0%-5.0%, preservatives 0.05%-0.5%, attractants 10.0%-22.0%, release agents 4.0%-10.0%, glycerin 11.0%, soybean oil 13.8%, corn starch supplemented 100%.

[0011] Preferably according to the present invention, the preservative is one or a combination of sodium benzoate, methylparaben, and propylparaben.

[0012] More preferably, the preservative is sodium benzoate or a mixture of methylparaben and propylparaben.

[0013] Preferably according to the present invention, the attractant is pig liver powder or chicken liver powder.

[0014] Further preferably, the appetite attractant is pig liver powder.

[0015] According to the preferred embodiment of the present invention, the pig liver powder is prepared by fluidized bed spray drying process. After being prepared by the process, its microbial load is reduced to the lowest level, which ensures that the microbial limit of the product meets the standard to the greatest extent. The pig liver powder has good palatability for pet dogs and is added in a conventional amount, 10.0% to 22.0%.

[0016] According to the present invention, the release agent is preferably microcrystalline cellulose and / or carnauba wax.

[0017] A soft chewable tablet of flurellana for pets, comprising the following raw materials by weight percentage:

[0018] Flurellan 14.0%, sodium lauryl sulfate 0.3%-1.0%, magnesium stearate 2.0%-3.0%, polyethylene glycol 8.0%-10.0%, sucrose 4.0%-5.0%, preservatives 0.05%-0.2%, attractants 15.0%-20.0%, release agents 5.0%-8.0%, glycerin 11.0%, soybean oil 13.8%, corn starch supplemented 100%.

[0019] The preparation method of the above-mentioned flurellana soft chewable tablet for pets comprises the following steps:

[0020] (1) Flurellanine, corn starch, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, sucrose, preservatives, food attractants, and release agents are crushed and sieved for later use;

[0021] (2) adding flurellanil, corn starch, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, sucrose, preservatives, phagostimulants, and release agents into a wet granulator according to the proportion, stirring and mixing until uniform, to obtain a premixed powder;

[0022] (3) transferring the obtained premixed powder to a mixer, starting stirring, and adding a mixed liquid of glycerin and soybean oil according to a ratio to prepare a soft chewable tablet soft material;

[0023] (4) Adding the soft chewable tablet material into a fully automatic forming machine to prepare a soft chewable tablet.

[0024] Preferably, in step (1), flurellana, corn starch, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, sucrose, preservatives, attractants and release agents are crushed and sieved respectively, and the particle size range is: 60 mesh pass rate 100%, 80 mesh pass rate greater than or equal to 80%, 100 mesh pass rate greater than or equal to 60%, and the flurellana raw material is finely powdered by a jet mill, and the light scattering method is used for detection, and the D90 is less than 25μm.

[0025] The method for preparing the flurellana soft chewable tablets of the present invention has no special requirements on equipment, adopts a reasonable formula composition, realizes easy demoulding, and ensures the product quality during long-term storage. The tablets are used in treating fleas and tick infections on the body surface of dogs, or allergic dermatitis caused by fleas.

[0026] The technical features and advantages of the present invention are as follows:

[0027] 1. Use low-cost auxiliary materials to better solve the high oiliness and viscosity of soft materials, and have good formability

[0028] Because the patent of the original preparation protects the application of pamoic acid or pharmaceutically acceptable salt in the preparation, and the two key auxiliary materials, pamoic acid and sodium pamoate, are not of pharmaceutical grade in China at present, but of chemical grade, and there are few manufacturers, and the price of sodium pamoate is high, which increases the product cost. The present invention adopts conventional pharmaceutical grade auxiliary materials, solves the high oiliness and viscosity of soft materials, achieves the same demoulding effect, has good formability, and has a low price, which greatly reduces the product cost.

[0029] 2. Good antiseptic and antibacterial effect

[0030] The pig liver powder is produced by fluidized bed spraying process, which reduces the microbial load level of the product, and adds auxiliary materials such as sodium benzoate with preservative and antibacterial effects, so that the microbial limits of the product still meet the regulations within the shelf life.

[0031] 3. The process is simple and feasible, which is conducive to industrial production

[0032] During production, conventional equipment such as conventional wet granulators, mixers, and molding machines are used without the need for special customization or modification. The preparation process is simple and feasible, which reduces the cost increase caused by equipment investment and has high feasibility of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The soft material state, wall adhesion and molding effect diagrams prepared in Example 1, Example 2 and Comparative Examples 1 to 4 are shown;

[0034] Figure 2 This is a diagram showing that when the amount of microcrystalline cellulose added in scheme 1 is 3.0% w / w, the prepared soft material is sticky and has wall adhesion;

[0035] Figure 3 This is the soft material molding effect diagram prepared when the addition amount of microcrystalline cellulose in scheme 1 is 3.0% w / w;

[0036] Figure 4 The renderings show the soft material state, wall adhesion and molding conditions of the flurellana soft chewable tablets prepared in Scheme 2-6. DETAILED DESCRIPTION

[0037] The present invention will be described in detail below in conjunction with the examples, and the materials mentioned in the examples are all conventional materials that can be obtained through commercial channels. In addition, the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. Some changes or adjustments made by those skilled in the art based on professional knowledge in the field also belong to the protection scope of the present invention.

[0038] Example 1

[0039] Flurellana soft chewable tablets for pets, calculated by weight percentage, include the following raw materials:

[0040] Flurellan 14.0%, sodium lauryl sulfate 1.0%, magnesium stearate 1.0%, polyethylene glycol 5.0%, sodium benzoate 0.5%, sucrose 5.0%, pork liver powder 10.0%, release agent microcrystalline cellulose 5.0%, glycerin 11.0%, soybean oil 13.8%, corn starch is supplemented to 100%.

[0041] The preparation method is as follows:

[0042] (1) Material preparation: flurellanine, corn starch, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, sucrose, preservatives, attractants, and release agent microcrystalline cellulose, grind and sieve, and set aside;

[0043] (2) adding flurellanil, corn starch, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, sucrose, a preservative, an attractant, and a release agent, microcrystalline cellulose, into a wet granulator according to the proportion, stirring and mixing until uniform, to obtain a premixed powder;

[0044] (3) transferring the obtained premixed powder to a mixer, starting stirring, and adding a mixed liquid of glycerin and soybean oil according to a ratio to prepare a soft chewable tablet soft material;

[0045] (4) Adding the soft chewable tablet material into a fully automatic forming machine to prepare a soft chewable tablet.

[0046] Example 2

[0047] The same as the fluororana soft chewable tablet for pets as described in Example 1, except that the release agent is carnauba wax, and the rest is the same as in Example 1.

[0048] The preparation method was carried out according to Example 1.

[0049] Example 3

[0050] Flurellana soft chewable tablets for pets, calculated by weight percentage, include the following raw materials:

[0051] Flurellan 14.0%, sodium lauryl sulfate 1.0%, magnesium stearate 2.0%, polyethylene glycol 8.0%, sodium benzoate 0.3%, sucrose 4.0%, pork liver powder 15.0%, release agent microcrystalline cellulose 6.0%, glycerin 11.0%, soybean oil 13.8%, corn starch is supplemented to 100%.

[0052] Comparative Example 1

[0053] The comparative example is the same as the pet flurellana soft chewable tablet described in Example 1, except that no release agent is added in the comparative example.

[0054] Comparative Example 2

[0055] The same as the flurellana soft chewable tablet for pets as described in Example 1, except that the release agent is stearic acid, and the rest is the same as Example 1.

[0056] The preparation method was carried out according to Example 1.

[0057] Comparative Example 3

[0058] The same as the flurellana soft chewable tablet for pets as described in Example 1, except that the release agent is polyethylene glycol 15-hydroxystearate, and the rest is the same as in Example 1.

[0059] The preparation method was carried out according to Example 1.

[0060] Comparative Example 4

[0061] The same as the flurellana soft chewable tablets for pets described in Example 1, except that the release agent is sodium dihydroxynaphthoate (the release agent used in the original research), and the rest is carried out as in Example 1.

[0062] The preparation method was carried out according to Example 1.

[0063] Experimental Example 1

[0064] The comparison of the soft material preparation and molding results of Example 1, Example 2 and Comparative Examples 1 to 4 is shown in Table 1. The soft material state, wall adhesion and molding effects are shown in Table 1. The effect diagram is shown in Figure 1 .

[0065] Table 1 Comparison of soft material preparation and molding results among Example 1, Example 2 and Comparative Examples 1 to 4

[0066]

[0067] The results show that when no release agent is added, or when stearic acid and polyethylene glycol 15-hydroxystearate are added as release agents respectively, the soft material is sticky, sticks to the wall, and the soft film cannot be formed; the soft material prepared by the present invention using microcrystalline cellulose, carnauba wax as a release agent and sodium bishydroxynaphthoate is brown and cookie dough-like, does not stick to the wall and can be formed well, with comparable effects.

[0068] Combining the test results of Example 1, Example 2 and Comparative Examples 1 to 4, it can be seen that the release agent has a great influence on the state and molding of the soft material. The release agent of the present invention effectively improves the high oiliness state and wall sticking of the soft material, and further improves the molding property. In the present invention, microcrystalline cellulose and carnauba wax are used as release agents. Microcrystalline cellulose can generally be used as an adsorbent, filler, anti-adhesive agent, disintegrant or adhesive. Carnauba wax is a natural food additive in the form of powder, flakes or irregularly shaped wax blocks. It has good oil retention, is non-toxic and highly safe, and can generally be used as a processing aid for candied fruit cake products. The present invention uses microcrystalline cellulose and carnauba wax as release agents. Microcrystalline cellulose absorbs the oily material in the prescription through the large pores in the structure and the oil retention of carnauba wax, thereby improving the oiliness and viscosity of the soft material and ultimately improving the molding effect of the product.

[0069] Scheme 1-6

[0070] The amount of microcrystalline cellulose and carnauba wax was further screened based on the soft material state, wall adhesion and molding conditions. The formula ratio is shown in Table 2, and the sample preparation method is the same as that in Example 1.

[0071] Table 2 Formula ratio (%, w / w)

[0072] name Solution 1 Solution 2 Solution 3 Solution 4 Solution 5 Solution 6 Flurellana 14.00 14.00 14.00 14.00 14.00 14.00 Sodium Lauryl Sulfate 0.30 0.30 0.30 0.30 0.30 0.30 Magnesium Stearate 3.00 3.00 3.00 3.00 3.00 3.00 Polyethylene glycol 8.00 8.00 8.00 8.00 8.00 8.00 sucrose 3.00 3.00 3.00 3.00 3.00 3.00 preservative 0.10 0.10 0.10 0.10 0.10 0.10 Appetite attractants 15.00 15.00 15.00 15.00 15.00 15.00 Microcrystalline Cellulose 3.00 4.00 / / / / Microcrystalline Cellulose / / 7.00 / / / Microcrystalline Cellulose / / / 10.00 / / Carnauba wax / / / / 4.00 / Carnauba wax / / / / / 4.00 Microcrystalline Cellulose / / / / / 4.00 glycerin 11.00 11.00 11.00 11.00 11.00 11.00 Soybean Oil 13.80 13.80 13.80 13.80 13.80 13.80 Corn starch 28.80 27.80 24.80 21.80 27.80 23.80 total 100.00 100.00 100.00 100.00 100.00 100.00

[0073] When the amount of microcrystalline cellulose added in scheme 1 was 3.0% w / w, the prepared soft material was sticky and had wall adhesion (see Figure 2 As shown), a small amount of the mold adheres during molding, and it cannot be completely demoulded, resulting in poor molding effect (see Figure 3 ), indicating that the soft material state, wall adhesion and molding conditions were improved when this dosage was used, but the effect was not good, so this dosage was abandoned.

[0074] The soft material and molding conditions of the flurellana soft chewable tablets prepared in Scheme 2-6 are shown in Table 3, and the soft material state, wall adhesion and molding effect diagram are shown in Figure 4 The test results show that the soft materials prepared with a release agent dosage of 4% to 10% (w / w) are all brown cookie dough-like, non-sticky, and have good tableting properties.

[0075] Table 3 Preparation of soft materials and molding results of Scheme 2-6

[0076]

[0077]

[0078] Scheme 7-11

[0079] The effects of different amounts of preservatives and antimicrobial agents (Schemes 7-10) and no preservatives (Scheme 11) on the microbial level of the product were investigated. The formulations of Schemes 7-11 are shown in Table 4, and the sample preparation method is the same as that of Example 1.

[0080] Table 4: Formula and dosage of Schemes 7-11 (%, w / w)

[0081] name Solution 7 Solution 8 Solution 9 Solution 10 Solution 11 Flurellana 14.00 14.00 14.00 14.00 14.00 Sodium Lauryl Sulfate 0.30 0.30 0.30 0.30 0.30 Magnesium Stearate 2.00 2.00 2.00 2.00 2.00 Polyethylene glycol 10.00 10.00 10.00 10.00 10.00 sucrose 5.00 5.00 5.00 5.00 5.00 Sodium Benzoate 0.05 / / / / Sodium Benzoate / 0.10 / / / Sodium Benzoate / / 0.20 / / Methylparaben / / / 0.18 / Propylparaben / / / 0.02 / Appetite attractants 22.00 22.00 22.00 22.00 22.00 Release agent 5.00 5.00 5.00 5.00 5.00 glycerin 11.00 11.00 11.00 11.00 11.00 Soybean Oil 13.80 13.80 13.80 13.80 13.80 Corn starch 16.85 16.80 16.70 16.70 16.90 total 100.00 100.00 100.00 100.00 100.00

[0082] The samples prepared in Schemes 7-11 were subjected to microbial limit tests to verify their antibacterial effects.

[0083] Experimental method: The flurellan soft chewable tablets prepared in Scheme 7-11 were packed in double aluminum blisters and placed under long-term conditions (25±2°C, 60%RH±5%RH) for 24 months. Samples were taken at 0, 12, and 24 months to detect microbial limits.

[0084] Microbial limit test method: Grind the product and make a 1:10 suspension dilution with sodium chloride peptone buffer, let it stand for 10 to 15 minutes, vortex mix it, and use it as the test solution. According to the microbial limit inspection of non-sterile products, the microbial count method (Appendix 1105 of the Chinese Pharmacopoeia 2020 Edition) and the control bacteria inspection method (Appendix 1106 of the Chinese Pharmacopoeia 2020 Edition) and the non-sterile microbial limit standard (Appendix 1107 of the Chinese Pharmacopoeia 2020 Edition), it should meet the requirements. The test results are shown in Table 5.

[0085] Table 5 Results of microbial limit investigation for schemes 7-11

[0086]

[0087] It can be seen from the above test results that the number of aerobic bacteria, molds and yeasts of the flurellana soft chewable tablets prepared by Schemes 7-10 was not significantly different from that of 0 days under long-term conditions for 24 months, and Escherichia coli and Salmonella were not detected, which met the standards; the number of aerobic bacteria, molds and yeasts of the flurellana soft chewable tablets prepared by Scheme 11 did not meet the standards under long-term conditions for 12 months, and Escherichia coli and Salmonella were not detected. The above results show that the addition of preservatives and antibacterial agents has a great influence on the microbial indicators of this product, and the addition amount range of the present invention can ensure that the microbial limits within the product validity period meet the regulations.

[0088] Experimental Example 2: Testing of the Mixing Uniformity of Flurellana Soft Chewable Tablets

[0089] The content uniformity of the soft materials of the flurellana soft chewable tablets prepared in Schemes 2-6 was tested respectively to verify the feasibility of the preparation method of the present invention. The test results are shown in Table 6.

[0090] Table 6 Content uniformity test results of Scheme 2-6

[0091]

[0092] From the above test results, it can be seen that the content uniformity of the soft material of the flurellana soft chewable tablets of Schemes 2-6 prepared according to the method of the present invention is relatively good, indicating that the preparation method of the present invention is feasible and reliable.

[0093] Experimental Example 2 Dissolution curve investigation test

[0094] The samples prepared in Schemes 2-6 and the original preparation (commercially available, trade name: Bravecto) were selected to investigate the in vitro dissolution curves, and f2 was used as an index to judge the similarity with the original preparation. Generally, if f2 is greater than 50, it means that the two dissolution curves are similar, and if f2 is less than 50, it is considered that the two dissolution curves are not similar. The similarity factors f2 of the dissolution curves of the flurellana soft chewable tablets prepared in Examples 3 to 7 of the present invention and the original preparation are 67, 57, 66, 64, and 60, respectively, all greater than 50, indicating that the samples prepared in Examples 3 to 7 of the present invention are similar in dissolution to the original preparation. The specific results are shown in Table 7.

[0095] Table 7 Dissolution curve results of Scheme 2-6 and original preparation

[0096]

[0097]

[0098] In summary, the use of the release agent of the present invention can effectively solve the problems of demoulding difficulty and poor formability caused by high oiliness and viscosity of the soft chewable tablets, and realize industrial production at the lowest cost without the need for special equipment. On the other hand, through the control of auxiliary materials and the use of antiseptic and antibacterial auxiliary materials, the microbial load level of the product is reduced, thereby ensuring the product quality.

[0099] The above description is only used to illustrate the technical solution of the present invention rather than to limit it. Other modifications or equivalent substitutions made to the technical solution of the present invention by ordinary technicians in this field, as long as they do not depart from the spirit and scope of the technical solution of the present invention, still fall within the scope of the technical solution of this application.

Claims

1. A soft chewable tablet of flurellana for pets, comprising the following raw materials by weight percentage: Flurellan 14.0%, sodium lauryl sulfate 0.3%-1.0%, magnesium stearate 1.0%-3.0%, polyethylene glycol 5.0%-10.0%, sucrose 3.0%-5.0%, preservatives 0.05%-0.5%, attractants 10.0%-22.0%, release agents 4.0%-10.0%, glycerin 11.0%, soybean oil 13.8%, corn starch supplemented 100%.

2. The fluororana soft chewable tablet for pets according to claim 1, characterized in that: The preservative is one or a combination of sodium benzoate, methylparaben, and propylparaben, and the preservative is sodium benzoate or a mixture of methylparaben and propylparaben.

3. The fluororana soft chewable tablet for pets according to claim 1, characterized in that: The attractant is pork liver powder or chicken liver powder.

4. The fluororana soft chewable tablet for pets according to claim 1, characterized in that: The attractant is pig liver powder.

5. The soft chewable tablet of fluororana for pets according to claim 1, characterized in that: The pork liver powder is produced by fluidized bed spray drying process.

6. The fluororana soft chewable tablet for pets according to claim 1, characterized in that: The release agent is microcrystalline cellulose and / or carnauba wax.

7. The fluororana soft chewable tablet for pets according to claim 1, characterized in that: The raw materials are as follows by weight percentage: Flurellan 14.0%, sodium lauryl sulfate 0.3%-1.0%, magnesium stearate 2.0%-3.0%, polyethylene glycol 8.0%-10.0%, sucrose 4.0%-5.0%, preservatives 0.05%-0.2%, attractants 15.0%-20.0%, release agents 5.0%-8.0%, glycerin 11.0%, soybean oil 13.8%, corn starch supplemented 100%.

8. A method for preparing the fluororana soft chewable tablet for pets according to any one of claims 1 to 7, comprising the following steps: (1) Flurellanine, corn starch, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, sucrose, preservatives, food attractants, and release agents are crushed and sieved for later use; (2) adding flurellanil, corn starch, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, sucrose, preservatives, attractants, and release agents into a wet granulator according to the proportion, stirring and mixing until uniform, to obtain a premixed powder; (3) transferring the obtained premixed powder to a mixer, starting stirring, and adding a mixed liquid of glycerin and soybean oil according to a ratio to prepare a soft chewable tablet soft material; (4) Adding the soft chewable tablet material into a fully automatic forming machine to prepare a soft chewable tablet.

9. The preparation method according to claim 7, characterized in that: In step (1), flurellana, corn starch, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, sucrose, preservatives, attractants, and release agents are crushed and sieved respectively, and the particle size range is: 60 mesh pass rate 100%, 80 mesh pass rate greater than or equal to 80%, 100 mesh pass rate greater than or equal to 60%, and the flurellana raw material is finely powdered by a jet mill, and the light scattering method is used for detection, and the D90 is less than 25μm.

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