Compound soft chewable tablet as well as preparation method and application thereof

Abstract

The invention relates to the technical field of animal medicines, and particularly discloses a compound soft chewable tablet as well as a preparation method and application thereof. The compound soft chewable tablet comprises the following raw materials in percentage by weight: 0.4% of tofacitinib, 1% of an echinacea extract, 10-20% of pork liver powder, 10-20% of polyethylene glycol, 3-15% of a release agent, 0.3-1% of lauryl sodium sulfate, 1-3% of magnesium stearate, 2-5% of sucrose, 0.05-0.5% of a preservative, 11% of glycerol, 13-15% of soybean oil and the balance of corn starch. The tofacitinib citrate and the echinacea extract are adopted to prepare the soft chewable tablet, the process has no special requirements on equipment, the process is simple and feasible, and industrial production is utilized; by adopting conventional equipment such as a wet granulator, a mixer and a forming machine, the prepared oral product has the characteristics of stability, palatability, safety and effectiveness.

Description

Technical Field

[0001] The present invention relates to the technical field of animal medicine, and in particular to a compound soft chewable tablet and a preparation method and application thereof. Background Art

[0002] Tofacitinib is an oral Janus kinase inhibitor (JAK inhibitor) with immunomodulatory and anti-inflammatory activity. Following administration, tofacitinib binds to the JAK enzyme, preventing activation of the JAK signal transducer and activator of transcription (STAT) pathway. Tofacitinib primarily inhibits JAK1 and JAK3, and slightly inhibits JAK2, thereby inhibiting factors associated with the JAK / STAT pathway. It is currently approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to or intolerance to methotrexate.

[0003] Echinacea, also known as Echinacea, is a perennial herb belonging to the genus Echinacea in the Asteraceae family. According to domestic and international research reports, Echinacea contains a variety of bioactive ingredients, including polysaccharides, glycoproteins, caffeic acid derivatives, alkylamides, and volatile oils.

[0004] There are currently no reports on the combined use of tofacitinib and echinacea in pet allergic dermatitis and atopic dermatitis.

[0005] The existing technology lacks a targeted compound drug for canine allergic dermatitis. Due to the unpleasant and bitter taste of traditional Chinese medicine, pets are very sensitive to smell and taste, which can easily lead to food refusal, directly affecting the efficacy of the drug. Conventional veterinary tablets have poor palatability and low dog compliance. A compound soft chewable tablet designed specifically for dogs is provided. Through the synergistic effect of tofacitinib and echinacea, it reduces itching and inflammation. The soft chewable tablet formulation improves palatability and increases canine voluntary drug intake. Summary of the Invention

[0006] In order to overcome the deficiencies of the prior art, the present invention provides a compound soft chewable tablet that improves palatability, reduces itching and inflammation, and can be eaten independently by dogs, as well as a preparation method and application thereof.

[0007] The present invention is achieved through the following technical solutions: A compound soft chewable tablet comprises the following raw materials, calculated by weight percentage: 0.4% tofacitinib, 1% echinacea extract, 10-20% pig liver powder, 10-20% polyethylene glycol, 3-15% release agent, 0.3-1% sodium lauryl sulfate, 1-3% magnesium stearate, 2-5% sucrose, 0.05-0.5% preservative, 11% glycerol, 13-15% soybean oil, and the remainder is corn starch.

[0008] Its further preferred weight ratio is: Tofacitinib 0.4%, Echinacea extract 1%, pig liver powder 20%, polyethylene glycol 20%, release agent 5%, sodium lauryl sulfate 1%, magnesium stearate 1%, sucrose 5%, preservative 0.22%, glycerin 11%, soybean oil 15%, and the rest is corn starch.

[0009] In the present invention, tofacitinib downregulates the immune response by inhibiting the JAK-STAT pathway (mainly targeting JAK1 / JAK3) and is commonly used to treat autoimmune diseases such as rheumatoid arthritis and psoriasis; Echinacea is traditionally used to enhance immunity, and its active ingredients (such as alkylamides, polysaccharides, etc.) may enhance innate immunity by activating macrophages and promoting the secretion of cytokines (such as IL-6, TNF-α); the synergistic use of the two can effectively regulate the problem of decreased body defense function due to immunosuppression.

[0010] Among the constituent raw materials of the present invention, the coordination effect of various other auxiliary materials can effectively bring into play the synergistic effect of tofacitinib and Echinacea, allowing the two to be deeply integrated and enhance the immune function of animals.

[0011] A better technical solution of the present invention is: The pig liver powder is used as a flavoring agent in the formula to adjust the taste of the chewable tablets and increase the feed intake of animals.

[0012] The preservative is one or both of sodium benzoate and propylparaben; more preferably, the preservative is a mixture of sodium benzoate and propylparaben.

[0013] The release agent is one or both of microcrystalline cellulose and carnauba wax; more preferably, the release agent is a mixture of microcrystalline cellulose and carnauba wax.

[0014] The preparation method of the above-mentioned compound soft chewable tablet comprises the following steps: (1) Add tofacitinib, echinacea extract, pig liver powder, corn starch, a release agent, sodium lauryl sulfate, magnesium stearate, sucrose, and a preservative into a wet granulator, and stir and mix until uniform to obtain a premixed powder; (2) The obtained premixed powder is transferred to a mixer, stirring is started, glycerin and soybean oil are added in sequence, and after mixing evenly, molten polyethylene glycol is added and mixed evenly to prepare a soft chewable tablet material; (3) Add the soft chewable tablet material into a fully automatic forming machine to prepare a soft chewable tablet.

[0015] The present invention further discloses the use of the compound soft chewable tablet for treating pruritus associated with allergic dermatitis and atopic dermatitis in canines.

[0016] The present invention uses tofacitinib and echinacea extract to prepare soft chewable tablets. The process has no special requirements for equipment, is simple and feasible, and can be produced on an industrial scale. Conventional equipment such as a wet granulator, a mixer, and a molding machine are used to prepare the oral product, which is stable, palatable, safe, and effective, is suitable for canines to eat independently, and has a significant effect on treating pet allergic dermatitis and characteristic dermatitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The present invention will be further described below with reference to the accompanying drawings.

[0018] Figure 1 This is a curve diagram of the dynamic changes in mouse ear thickness in Example 2 of the present invention. DETAILED DESCRIPTION

[0019] The present invention will be described in detail below with reference to the examples. 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 construed as limiting the scope of the present invention. Any changes or adjustments made by those skilled in the art based on their professional knowledge in the field also fall within the scope of protection of the present invention.

[0020] Example 1: A composite soft chewable tablet This embodiment is prepared from the following raw and auxiliary materials: tofacitinib 0.4% (equivalent to tofacitinib citrate 0.65%), echinacea extract 1%, pig liver powder 10-20%, polyethylene glycol 10-20%, release agent 3-15%, sodium lauryl sulfate 0.3-1%, magnesium stearate 1-3%, sucrose 2-5%, preservative 0.05-0.5%, glycerin 11%, soybean oil 13-15%, and corn starch makes up 100%.

[0021] The preparation method is as follows: (1) According to the above ratio, tofacitinib citrate, echinacea extract, corn starch, pig liver powder, sodium lauryl sulfate, magnesium stearate, release agent, sucrose, and preservative are added to a wet granulator and stirred until uniform to obtain a premixed powder; (2) The obtained premixed powder is transferred to a mixer, stirring is started, and a mixed liquid of glycerol and soybean oil is added according to the ratio. After mixing evenly, molten polyethylene glycol is added and mixed thoroughly to prepare a soft chewable tablet soft material; (3) Add the soft chewable tablet material into the fully automatic forming machine to prepare the soft chewable tablet.

[0022] Table 1 Different formulations and dosages of Example 1 (%, w / w) Five groups of compound soft chewable tablets were prepared using the above five formulations. The preparation steps were as described above and the process parameters during the preparation process remained unchanged. The performance of the five groups of compound soft chewable tablets was tested. The soft materials prepared by formulations II and III were sticky and adhered to the wall. They adhered to the mold during molding, and the demolding and molding effects were poor. In contrast, the soft material prepared by formulation I did not stick to the wall, was easy to demold, and had good tableting properties.

[0023] From the above comparison, it can be seen that in the formulation of the present invention, the release agent is preferably in the form of a composite of two components, and the application effect of a release agent of a single component is poor.

[0024] Samples of Formulations I, IV, and V were packaged in double aluminum blister packs and tested for microbial limits to verify their antibacterial efficacy. Testing using the microbial count method (Appendix 1105 of the Chinese Pharmacopoeia 2020, Edition), the control bacteria test method (Appendix 1106 of the Chinese Pharmacopoeia 2020, Edition 2020), and the non-sterile microbial limit standards (Appendix 1107 of the Chinese Pharmacopoeia 2020, Edition 2020) confirmed that the counts of aerobic bacteria, molds, and yeasts in Formulations IV and V no longer met the standards after 12 months of long-term storage. The dosage of preservatives and antibacterial agents used in Formulation I ensured compliance with the prescribed microbial limits within the product's shelf life.

[0025] The processing results of tablets of different specifications prepared according to Formula I are as follows: Among them, the TZ-1 code means each tablet contains 3.6mg of tofacitinib + 9mg of echinacea extract, and the TZ-2 code means each tablet contains 5.4mg of tofacitinib + 13.5mg of echinacea extract.

[0026] Example 2: Calcipotriol-induced atopic dermatitis in BALB / c mice On Day 1, 20 mice were randomly divided into five groups (Y1-Y5) based on right ear thickness and body weight, with three mice in each group, for a total of 15 mice. From Day 1 to Day 10, mice in the calcipotriol-induced group (Y2-Y5) received a 10 μL calcipotriol working solution applied daily to the dorsal and ventral sides of the right ear, for a total of 20 μL per mouse. The calcipotriol induction dose was 1 nmol / 20 μL / mouse. No treatment was performed in the Y1 group. Right ear thickness was measured on Days 1, 3, 5, 7, and 9, and the dynamic changes in ear thickness were plotted.

[0027] This example establishes a calcipotriol-induced atopic dermatitis model in BALB / c mice to demonstrate the pharmacodynamic activity of the combined formula of tofacitinib and Echinacea against dermatitis in mice. Figure 1 shown.

[0028] Example 3: Product Performance Example (1) Palatability The sample prepared using the embodiment of the present invention 1 is evaluated for palatability, and the test method is: 40 healthy mature beagles are selected and divided into two groups, 20 beagles per group, and placebo soft chewable tablets are provided to the first group of animals, and the second group of animals provides a soft chewable tablet (TZ-1) containing 3.6mg tofacitinib and is investigated for palatability. The weight of each experimental dog is assessed before the test and administered by weight. Medicine is put into a food bowl, and dogs are induced to eat autonomously or medicine is placed in the palm of the hand for feeding, and a stopwatch is used for timing, and 2 minutes is a time limit. The feeding situation of each dog to the test sample is observed, and a tablet is taken orally separately every day for 3 consecutive days.

[0029] Acceptability of the soft chewable tablets was 79.5% for the placebo group and 78.5% for the drug group.

[0030] Overall, the combination containing tofacitinib and echinacea was palatable.

[0031] (2) Stability The 3.6 mg (TZ-1) and 5.4 mg (TZ-2) soft chewable tablets were shown to be stable in double aluminum blister packaging at 40°C / 75% relative humidity over 1 month and 2 months, with assay results ranging from 98.5% to 100.5%.

[0032] Example 4: Product therapeutic effect Case 1: Corgi, 1 year old, weight 10.1 kg, Subcutaneous papular dermatitis, severe itching and scratching before medication, once a day, one TZ-2 tablet each time; medication for 10 days; After taking one TZ-2 tablet, the scratching was relieved. After 10 days of medication, the scratching phenomenon did not occur again, and the symptoms of subcutaneous papular dermatitis were significantly improved.

[0033] Case 2: French bulldog, 2 years old, weight 9.5kg, For dermatitis accompanied by itching, take one TZ-1 tablet twice a day. After 3 days of medication, the itching was significantly relieved. After 15 days of medication, the dermatitis symptoms basically disappeared.

[0034] Case 3: Golden Retriever, 4 years old, weight 30kg, The pet had multiple skin diseases, moderate itching, and regular attacks. The skin disease under the armpits of the fore toes was severe. The pet was treated with TZ-2 tablets three times a day and the antibiotic cefadroxil for one week. After that, the antibiotic was stopped and TZ-2 tablets three times a day were continued for three days. The skin disease recovered and the pet stopped scratching after the drug was stopped.

[0035] Case 4: Shiba Inu, 3 years old, weight 15kg, Allergic dermatitis, wet and itchy feet, pets licking the affected area, once a day, one TZ-1 tablet plus one TZ-2 tablet each time; on the third day of medication, licking was significantly reduced, and improved significantly after one week of medication.

[0036] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or make equivalent replacements for some or all of the technical features therein. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and description of the present invention.

Claims

1. A compound soft chewable tablet, characterized by: Calculated by weight percentage, the raw materials include: tofacitinib 0.4%, echinacea extract 1%, pig liver powder 10-20%, polyethylene glycol 10-20%, release agent 3-15%, sodium lauryl sulfate 0.3-1%, magnesium stearate 1-3%, sucrose 2-5%, preservative 0.05-0.5%, glycerin 11%, soybean oil 13-15%, and the rest is corn starch.

2. The compound soft chewable tablet according to claim 1, wherein: Calculated by weight percentage, it includes the following raw materials: tofacitinib 0.4%, echinacea extract 1%, pig liver powder 20%, polyethylene glycol 20%, release agent 5%, sodium lauryl sulfate 1%, magnesium stearate 1%, sucrose 5%, preservative 0.22%, glycerin 11%, soybean oil 15%, and corn starch 20.38%.

3. The compound soft chewable tablet according to claim 1, wherein: The preservative is one or both of sodium benzoate and propylparaben.

4. The compound soft chewable tablet according to claim 3, wherein: The preservative is a mixture of sodium benzoate and propylparaben.

5. The compound soft chewable tablet according to claim 1, wherein: The release agent is one or both of microcrystalline cellulose and carnauba wax.

6. The compound soft chewable tablet according to claim 5, wherein: The release agent is a mixture of microcrystalline cellulose and carnauba wax.

7. The method for preparing the compound soft chewable tablet according to claim 1, characterized in that it comprises: The steps are as follows: (1) adding tofacitinib, echinacea extract, pig liver powder, corn starch, a release agent, sodium lauryl sulfate, magnesium stearate, sucrose, and a preservative into a wet granulator, stirring and mixing until uniform, to obtain a premixed powder; (2) transferring the obtained premixed powder into a mixer, turning on the stirring, adding glycerin and soybean oil in sequence, mixing evenly, adding molten polyethylene glycol, and mixing evenly to prepare a soft chewable tablet material; (3) adding the soft chewable tablet material into a fully automatic molding machine to prepare a soft chewable tablet.

8. Use of the compound soft chewable tablet according to claim 1 for treating pruritus associated with allergic dermatitis and atopic dermatitis in canines.

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