Flurellana chewable tablet and preparation method and use thereof

Abstract

The invention discloses a flurellana chewable tablet and a preparation method and use thereof, and belongs to the field of pharmaceutical preparations. The flurellana chewable tablet of the present invention comprises, by weight, 30-60 parts of flurellana self-micelle solid dispersion; 20-60 parts of filler; 1-15 parts of disintegrant; 1-5 parts of lubricant; 1-5 parts of flavoring agent; wherein, the flurellana self-micelle solid dispersion comprises, by weight, 5-15 parts of flurellana; 25-35 parts of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; 1-6 parts of DSPE-PEG material modified by RRRRRRRR peptide; 1-6 parts of DSPE-PEG material modified by ATS peptide. The chewable tablet of the present invention has the advantages of high drug solubility, high oral bioavailability and long half-life of flurellana.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a flurellana chewable tablet and a preparation method and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to increase some understanding of the overall background of the invention, and should not be necessarily regarded as an admission or any form of suggestion that the information constitutes the prior art already known to ordinary technicians in this field.

[0003] Flurella, CAS No. 864731-61-3, chemical name is carbamoylbenzamide phenylisoxazoline, is an isoxazoline drug, which inhibits the activity of glutamate-β-aminobutyric acid and γ-aminobutyric acid gated chloride ion channels in the nervous system of arthropods, leading to depolarization and overexcitement, paralysis and death of parasites. Its insecticidal range includes mites, ticks, sphinctera, pedicel, diptera and hemiptera. The currently marketed flurella dosage forms for pet deworming include oral chewable tablets and topical dosage forms.

[0004] Fluorella has a high plasma protein binding rate and is mainly metabolized by the liver. Its half-life is about 12 to 15 days, and a single dose of 25 mg / kg can provide effective insecticidal activity for 12 weeks. However, fluorella is a highly lipid-soluble drug that is difficult to dissolve in water and physiological fluids. Its oral bioavailability is low, only about 20-30%, and the effective utilization rate of the drug is too low. Summary of the invention

[0005] Based on the problems existing in the prior art and due to the characteristics of pets themselves, the compliance of pets with medication is poor. The purpose of the present invention is to provide a chewable flurellanine tablet with high bioavailability, and it is expected that the tablet has a longer-term insecticidal activity to improve the medication compliance of animals.

[0006] The technical solution adopted by the present invention is as follows:

[0007] In a first aspect of the present invention, there is provided a flurellana chewable tablet, which comprises, by weight:

[0008] 30-60 parts of flurellane self-micellar solid dispersion;

[0009] Filler 20-60 parts;

[0010] 1-15 parts of disintegrant;

[0011] 1-5 parts of lubricant;

[0012] 1-5 parts of flavoring agent;

[0013] Wherein, the flurellane self-micelle solid dispersion comprises, by weight:

[0014] Flurella 5-15 parts;

[0015] 25-35 parts of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0016] RRRRRRRR peptide-modified DSPE-PEG material 1-6 parts;

[0017] 1-6 copies of ATS peptide-modified DSPE-PEG material.

[0018] In one or some embodiments of the present invention, the flurellana chewable tablet comprises, by weight:

[0019] 40-55 parts of flurellane self-micellar solid dispersion;

[0020] 30-40 parts of filler;

[0021] 5-10 parts of disintegrant;

[0022] 1-5 parts of lubricant;

[0023] 1-5 parts of flavoring agent.

[0024] In one or some embodiments of the present invention, the flurellan self-micelle solid dispersion comprises, by weight:

[0025] Flurellana 8-12 parts;

[0026] 30-35 parts of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0027] 3-6 parts of RRRRRRRR peptide-modified DSPE-PEG material;

[0028] 3-6 copies of ATS peptide-modified DSPE-PEG material.

[0029] In one or some embodiments of the present invention, the RRRRRRRR peptide-modified DSPE-PEG material is prepared by the following method:

[0030] Distearoylphosphatidylethanolamine-polyethylene glycol maleimide (DSPE-PEG-MAL) and cysR8 polypeptide (whose sequence is CRRRRRRRR) are mixed in a neutral phosphate buffer at a molar ratio of 1-2:1, preferably a molar ratio of 1.5:1, and reacted for 12-48 h, preferably 24 h, and then the reaction solution is dialyzed in a dialysis bag for 24-72 h, preferably 48 h, and the dialyzed solution is freeze-dried to obtain the product.

[0031] In one or some embodiments of the present invention, the ATS peptide-modified DSPE-PEG material is prepared by the following method:

[0032] Distearoylphosphatidylethanolamine-polyethylene glycol maleimide (DSPE-PEG-MAL) and polypeptide ATS-SH (whose sequence is GKGGEAKDGGC) are mixed in a neutral phosphate buffer at a molar ratio of 1-2:1, preferably a molar ratio of 1.5:1, and reacted for 12-48 hours, preferably 24 hours, and then the reaction solution is dialyzed in a dialysis bag for 24-72 hours, preferably 48 hours, and the dialyzed solution is freeze-dried to obtain the product.

[0033] In one or some embodiments of the present invention, the flurellan self-micelle solid dispersion is prepared by the following method:

[0034] Add the prescribed amount of flurellana, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, RRRRRRRR peptide-modified DSPE-PEG material and ATS peptide-modified DSPE-PEG material into an organic solvent and dissolve them, for example, at 40-50° C.; then concentrate them, for example, by vacuum rotary evaporation at 40-50° C., grind the obtained solid, sieve it, and dry it, for example, at 30-50° C., to obtain a flurellana self-micelle solid dispersion.

[0035] In one or some embodiments of the present invention, the polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer can be selected from, for example, a product of BASF Corporation of Germany with the trade name Soluplus®.

[0036] In one or some embodiments of the present invention, the filler is microcrystalline cellulose.

[0037] In one or some embodiments of the present invention, the disintegrant is selected from one or more combinations of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (PVPP), cross-linked sodium carboxymethyl cellulose (cCMC-Na), sodium hydroxymethyl cellulose, low-substituted hydroxypropyl cellulose (L-HPC) or dry starch; preferably, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0038] In one or some embodiments of the present invention, the lubricant is one or more combinations selected from silicon dioxide, magnesium stearate, talc, and glyceryl behenate; preferably, the lubricant is a combination of magnesium stearate and silicon dioxide, wherein the weight ratio of magnesium stearate to silicon dioxide is 2:1-1:2, preferably 1:1.

[0039] In one or some embodiments of the present invention, the flavoring agent is one selected from beef flavor, chicken flavor, and a sweetener; in the present invention, the sweetener includes but is not limited to one or more of sucrose, sorbitol, maltitol, isomalt, sucralose, etc.; preferably, the flavoring agent is beef flavor or chicken flavor.

[0040] In one or more embodiments of the present invention, the organic solvent includes but is not limited to ethanol, etc., for the purpose of dissolving raw materials and auxiliary materials.

[0041] In a second aspect of the present invention, a method for preparing the flurellana chewable tablets according to the first aspect is provided, the method comprising the following steps:

[0042] (a) Sieve the raw and auxiliary materials for use;

[0043] (b) After mixing the flurellan self-micelle solid dispersion and the lubricant, add 1 / 3 to 1 / 2 of the prescribed amount of disintegrant, and then add the filler, flavoring agent and the remaining prescribed amount of disintegrant, mix well, and press into tablets to obtain the product.

[0044] In the third aspect of the present invention, there is provided use of the flurellana chewable tablets described in the first aspect or the flurellana chewable tablets prepared by the preparation method described in the second aspect in the preparation of drugs for preventing and treating parasitic infections on the surface and / or in the body of animals, preventing canine heartworm disease and allergic dermatitis caused by fleas.

[0045] In one or some embodiments of the present invention, the animals include but are not limited to cats, dogs, and the like.

[0046] In one or some embodiments of the present invention, the external parasites are fleas, ticks, scabies, ear mites, demodex mites, fleas, lice, etc.; the internal parasites are roundworms, hookworms, whipworms, tapeworms, etc.

[0047] Compared with the related art known to the inventor, one of the technical solutions of the present invention has the following beneficial effects:

[0048] The invention uses an amphiphilic polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a main carrier material of a solid dispersion, uses a positively charged R8 peptide and a distearoyl phosphatidylethanolamine-polyethylene glycol material modified with an ATS peptide targeting adipose tissue as an auxiliary material, and prepares a flurellana solid dispersion that can form self-micelles in the gastrointestinal tract. The solid dispersion is used to prepare chewable tablets, thereby greatly increasing the drug solubility of a hydrophobic drug flurellana chewable tablet preparation.

[0049] On the above basis, the present invention utilizes the modification of ATS peptide and R8 transmembrane peptide targeting adipose tissue, so that on the one hand, the positively charged micelles can greatly improve the gastrointestinal absorption rate of the drug and improve the oral bioavailability of the drug; on the other hand, the ATS targeting peptide can deliver part of the flurellane-loaded micelles to the adipose tissue, and use the adipose tissue as a reservoir of the fat-soluble drug flurellane to slowly release the drug, thereby greatly extending the half-life of flurellane, thereby further improving the protection period of the drug against the target insect body. DETAILED DESCRIPTION

[0050] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0051] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations and / or combinations thereof.

[0052] Reagents and sources

[0053] DSPE-PEG-MAL, polypeptide ATS-SH (GKGGEAKDGGC), and cysR8 peptide (CRRRRRRRR) were purchased from Shanghai Chupeptide Biotechnology.

[0054] Simulated gastric and intestinal fluids: purchased from Biolabs.

[0055] Flurellana: purchased from Chongqing Pharmaceutical Preparation Engineering Technology Research Center.

[0056] F127: purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0057] PVPK30: purchased from Nanjing Elsa Biotechnology Co., Ltd.

[0058] Soluplus®: purchased from BASF, Germany.

[0059] Microcrystalline cellulose PH102: purchased from Huzhou Linghu Xinwang Chemical Co., Ltd.

[0060] The remaining reagents are commercially available.

[0061] Preparation of peptide-modified DSPE-PEG materials:

[0062] (1) Preparation of DSPE-PEG-ATS:

[0063] Distearoylphosphatidylethanolamine-polyethylene glycol maleimide (DSPE-PEG-MAL) and polypeptide ATS-SH (whose sequence is GKGGEAKDGGC) were mixed in a neutral phosphate buffer at a molar ratio of 1.5:1 and reacted for 24 hours. The reaction solution was then dialyzed in a dialysis bag for 48 hours, and the dialyzed solution was freeze-dried to obtain DSPE-PEG-ATS.

[0064] (2) Preparation of DSPE-PEG-R8:

[0065] Distearoylphosphatidylethanolamine-polyethylene glycol maleimide (DSPE-PEG-MAL) and cysR8 polypeptide (whose sequence is CRRRRRRRR) were mixed in a neutral phosphate buffer at a molar ratio of 1.5:1 and reacted for 24 hours. The reaction solution was then dialyzed in a dialysis bag for 48 hours, and the dialyzed solution was freeze-dried to obtain DSPE-PEG-R8.

[0066] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0067] Example 1 Preparation of Fluorana Solid Dispersion

[0068] According to the prescription in Table 1, the solid dispersion carrier material and flurellana were added to ethanol in a mass ratio of 4:1, stirred at 45°C until dissolved, and vacuum evaporated at 45°C to obtain a solid dispersion. The obtained solid was ground, passed through an 80-mesh sieve, and dried in a vacuum drying oven at 40°C for 8 h to obtain a flurellana solid dispersion.

[0069] Each of the solid dispersions of fluororana was subjected to an accelerated stability test at 40°C ± 2°C / 75%, RH ± 5% RH, and XRPD was used to detect whether crystallization occurred.

[0070] Table 1.

[0071]

[0072] The results in Table 1 show that Soluplus® has good compatibility with flurana. Within the specified period under the accelerated test conditions, no crystallization occurred, while F127 and PVPK30 showed crystallization, indicating that the two are not compatible when used as flurana carriers to prepare preparations.

[0073] Example 2 Analysis of the physicochemical properties of flurellane micellar solution

[0074] (1) Determination of the particle size and zeta potential of micellar particles

[0075] According to the method of Example 1, three parallel samples were prepared for each flurana solid dispersion. 5 mg of each flurana solid dispersion was taken, 10 mL of distilled water was added, and the mixture was stirred at 37°C for 30 min to obtain a micellar suspension, which was filtered through a 0.22 μm membrane to obtain a flurana micellar solution. After each micellar solution was appropriately diluted with deionized water, the particle size and zeta potential of the micellar particles were tested using a Malvern particle size analyzer. The results are shown in Table 2.

[0076] (2) Determination of drug loading of self-assembled micelles

[0077] According to the method of Example 1, three parallel samples were prepared for each flurana solid dispersion. 5 mg of each flurana solid dispersion was taken, 30 mL of distilled water was added, and the mixture was stirred at 37°C for 10 min to obtain a micellar suspension. 1 mL of each micellar suspension was taken and placed in an ultrafiltration centrifuge tube with a molecular weight cutoff of 10,000, and centrifuged at 12,000 r / min for 20 min. The filtrate in the outer tube was taken as a sample for determination of the flurana content.

[0078] The drug loading of the flurellane micellar solution was detected by HPLC, and the chromatographic conditions were as follows:

[0079] Chromatographic column: C18 column; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 1 mL / min; injection volume: 5 μL; detection wavelength: 265 nm; gradient elution program: 0-10 min: mobile phase A, 45%→5%; 10-20 min: mobile phase A, 5%→5%; 20-21 min: mobile phase A, 5%→45%.

[0080] Preparation of reference substance: Accurately weigh 10 mg of flurellanine reference substance, place it in a 10 mL volumetric flask, add appropriate amount of acetonitrile to dissolve to the mark, shake well, and use it as the reference substance stock solution, which is further diluted with acetonitrile as the reference substance solution.

[0081] Sample preparation: Mix the flurana sample solution with an equal amount of acetonitrile, treat with ultrasound for 1 min, and then inject the sample. Calculate the flurana drug loading according to the following formula.

[0082] Drug loading (%) = (m 总氟雷拉纳质量 -m 游离氟雷拉纳 ) / (m 载体 +m 总氟雷拉纳质量 )×100%

[0083] Table 2.

[0084] sample Particle size (nm) PDI Zeta potential (mV) Drug loading (wt%) SD-1 95.5±10.3 0.145±0.024 -18.2±2.3 17.5±1.3 SD-2 124.1±13.8 0.286±0.062 -12.6±3.5 8.6±1.5 SD-3 109.5±16.2 0.346±0.074 -1.2±0.2 5.2±1.1 SD-4 62.7±5.1 0.092±0.012 -5.3±0.5 16.2±0.8 SD-5 54.2±5.6 0.085±0.015 12.4±1.3 15.8±0.5

[0085] Table 2 shows that when PVPK30 and F127 are used as solid dispersion carriers for micelle self-assembly, the PDI values ​​are relatively large, indicating that the micelles have poor uniformity, which to a certain extent indicates that the self-assembled micelles have poor stability, and both have low drug loading capacity for flurellan.

[0086] Compared with SD-1, SD-4 and SD-5, Soluplus® alone has a higher drug loading capacity for flurellana, and the micelle particle size formed by self-assembly is relatively small, and the PDI value is low, indicating that its micelle stability is high. When Soluplus® is further compounded with DSPE-PEG material as a solid dispersion carrier, the drug loading capacity of the self-assembled micelles is further improved, the particle size of the micelles is greatly reduced, and the uniformity is increased. In particular, after the DSPE-PEG material is modified with two peptides, the ζ potential of SD-5 changes from negative to positive.

[0087] Based on the above results, Soluplus® was selected as the main carrier of self-micelle solid dispersion for further study.

[0088] (3) Effects of simulated gastric and intestinal fluids on the self-assembly behavior of self-assembled micelles

[0089] According to the method of Example 1, three parallel samples were prepared for each flurellana solid dispersion. 5 mg of each prepared flurellana solid dispersion was added to 10 mL of simulated gastric fluid (pH 2.0, containing pepsin) or simulated intestinal fluid (pH 7.4, containing trypsin), stirred at 37°C for 10 min to obtain a micellar suspension, and filtered through a 0.22 μm membrane to obtain a flurellana micellar solution. After each micellar solution was appropriately diluted with deionized water, the particle size and ζ potential of the micellar particles were tested using a Malvern particle size analyzer. The results are shown in Tables 3 and 4.

[0090] According to the method of Example 1, three parallel samples were prepared for each flurana solid dispersion. 5 mg of each prepared flurana solid dispersion was added to 10 mL of simulated gastric fluid (pH 2.0, containing pepsin) or simulated intestinal fluid (pH 7.4, containing trypsin), and stirred at 37°C for 30 min to obtain a micellar suspension. 1 mL of each micellar suspension was taken and placed in an ultrafiltration centrifuge tube with a molecular weight cutoff of 10,000 Da, centrifuged at 12,000 r / min for 20 min, and the filtrate from the outer tube was taken as a sample for the determination of the flurana content. The determination method was as shown in (2), and the results are shown in Tables 3 and 4.

[0091] Table 3. Self-assembly behavior of micelles in simulated gastric fluid

[0092] sample Particle size (nm) PDI Zeta potential (mV) Drug loading (wt%) SD-1 112.6±12.7 0.158±0.054 -14.5±2.1 14.6±1.5 SD-4 70.5±6.4 0.123±0.075 -4.6±0.8 18.5±0.8 SD-5 46.3±5.2 0.074±0.017 16±2.1 18.7±0.9

[0093] Table 4. Self-assembly behavior of micelles in simulated intestinal fluid

[0094] sample Particle size (nm) PDI Zeta potential (mV) Drug loading (wt%) SD-1 128.6±15.4 0.216±0.084 -15.3±1.5 13.8±1.3 SD-4 80.9±8.6 0.103±0.035 -4.8±0.6 17.2±0.6 SD-5 48.5±6.7 0.098±0.021 10.5±1.2 18.1±0.4

[0095] Tables 3 and 4 show that the self-assembly behavior of micelles was not greatly affected in simulated gastric and intestinal fluids, and still maintained a high drug loading and uniform particle size distribution. The drug loading of SD-1 using Soluplus® alone as a carrier of self-micelle solid dispersions in simulated gastric and intestinal fluids was reduced, and the particle size and PDI increased. Using Soluplus® as the main carrier of self-micelle solid dispersions, SD-4 and SD-5 compounded with DSPE-PEG showed better stability in simulated gastric and intestinal fluids. In particular, SD-5 still maintained a positive potential.

[0096] Example 3 Preparation of Flurellana Chewable Tablets

[0097] (1) The preparation method of Tablet1-Tablet5, TabletD3-TabletD4 flurellana chewable tablets comprises the following steps:

[0098] (a) Pass all raw materials through an 80-mesh sieve and set aside;

[0099] (b) After mixing the flurellanine solid dispersion and lubricant (magnesium stearate / silicon dioxide), add 1 / 2 of the prescribed amount of disintegrant (cross-linked sodium carboxymethyl cellulose), then add the filler, flavoring agent (beef flavor) and the remaining prescribed amount of disintegrant, mix well, and compress into tablets.

[0100] (2) For Tablet D1-Tablet D2, the preparation method of the flurellana chewable tablet comprises the following steps:

[0101] (a) Pass all raw materials through an 80-mesh sieve and set aside;

[0102] (b) After mixing flurellanine with the lubricant (magnesium stearate / silicon dioxide), add 1 / 4 of the prescribed amount of disintegrant (cross-linked sodium carboxymethyl cellulose), then add the filler, flavoring agent (beef flavor) and the remaining prescribed amount of disintegrant, mix well, and compress into tablets.

[0103] Table 5

[0104]

[0105] Example 4 Preparation of Flurellana Chewable Tablets

[0106] A flurellana chewable tablet is prepared from the following components in parts by weight:

[0107] 45 parts of flurellan self-micelle solid dispersion; 40 parts of microcrystalline cellulose PH102; 9 parts of cross-linked sodium carboxymethyl cellulose; 4 parts of lubricant (magnesium stearate and silicon dioxide have a weight ratio of 1:1); 2 parts of beef flavor; wherein the flurellan self-micelle solid dispersion comprises, by weight: 10 parts of flurellan; 30 parts of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; 5 parts of DSPE-PEG material modified with RRRRRRRR peptide; and 5 parts of DSPE-PEG material modified with ATS peptide.

[0108] The preparation method is according to Examples 1 and 3.

[0109] Example 5 Preparation of Flurellana Chewable Tablets

[0110] A flurellana chewable tablet is prepared from the following components in parts by weight:

[0111] 50 parts of flurellan self-micelle solid dispersion; 39 parts of microcrystalline cellulose PH102; 6 parts of cross-linked polyvinylpyrrolidone (PVPP); 2 parts of lubricant (magnesium stearate and talc powder have a weight ratio of 1:1); 3 parts of chicken flavor; wherein the flurellan self-micelle solid dispersion comprises, by weight: 12 parts of flurellan; 35 parts of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; 3 parts of DSPE-PEG material modified by RRRRRRRR peptide; and 3 parts of DSPE-PEG material modified by ATS peptide.

[0112] The preparation method is according to Examples 1 and 3.

[0113] Example 6 Preparation of Flurellana Chewable Tablets

[0114] A flurellana chewable tablet is prepared from the following components in parts by weight:

[0115] 55 parts of flurellan self-micelle solid dispersion; 28 parts of microcrystalline cellulose PH102; 12 parts of low-substituted hydroxypropyl cellulose (L-HPC); 4 parts of glyceryl behenate; 1 part of beef flavor; wherein the flurellan self-micelle solid dispersion, in parts by weight, comprises: 8 parts of flurellan; 30 parts of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; 5 parts of DSPE-PEG material modified with RRRRRRRR peptide; and 5 parts of DSPE-PEG material modified with ATS peptide.

[0116] The preparation method is according to Examples 1 and 3.

[0117] Example 7 In vitro dissolution test of flurellana chewable tablets

[0118] Take 3 pieces of the flurellana chewable tablets prepared in Example 3 and the reference preparation Bravecto® (250 mg, Merck Animal Health Co., Ltd., USA) and use 900 mL of phosphate solution (pH 6.8, containing 1% sodium dodecyl sulfate) as the dissolution medium. Perform in vitro dissolution test at 37°C±0.5°C by slurry method. Take out 1 mL of dissolution solution at 5 min, 10 min, 30 min, 1 h, and 2 h, respectively, and add the same volume of dissolution medium at the same temperature. Filter with a filter membrane with a pore size of 0.22 μm, and test its dissolution using the HPLC method in Example 2. The 2 h cumulative release of each flurellana chewable tablet is shown in Table 6.

[0119] Table 6. Cumulative release of flurellana chewable tablets over 12 hours

[0120] Tablet1 Tablet2 Tablet3 Tablet4 Tablet5 Cumulative release in 2 h (%) 80.3±5.6 97.4±4.3 92.5±2.4 81.2±5.2 88.6±8.1 TabletD1 TabletD2 TabletD3 TabletD4 Bravecto® Cumulative release in 2 h (%) 31.2±5.1 42.1±4.6 50.8±6.5 44.6±3.8 81.5±5.4

[0121] As can be seen from Table 6, the flurellana chewable tablets Tablet1-Tablet5 have a high solubility, while the 12-hour cumulative release of the comparative preparations TabletD1 and TabletD2, which did not prepare flurellana into solid dispersions, did not exceed 45%, which was difficult to meet the preparation requirements. The comparative preparations TabletD1 and TabletD2 used mannitol and lactose as fillers, respectively, instead of microcrystalline cellulose as fillers, which led to poor drug release. The reason may be that mannitol and lactose affected the self-micelle process of the drug, affecting the dissolution of flurellana.

[0122] Example 8 In vivo pharmacokinetic study of flurellana chewable tablets

[0123] Eighteen male beagles (weight between 10-12kg) were divided into three groups, 6 in each group. They were fasted for 12h before taking the medicine, and the test preparations (Tablet2, Tablet3) and the control preparations (Bravecto®) were taken at a dosage of 25 mg / kg. 5 ml of blood was collected before administration (0h) and 6h, 12h, 1d, 2d, 3d, 5d, 7d, 10d, 14d, 17d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, and 70d after administration, respectively, and placed in a heparin-coated test tube, centrifuged, and the upper plasma was taken and then stored in a -20℃ refrigerator for analysis. The blood concentration of flurellana in beagles was determined by high performance liquid chromatography, and the pharmacokinetic parameters are shown in Table 7.

[0124] Table 7. Pharmacokinetic parameters of flurellana chewable tablets

[0125] Tablet2 Tablet3 Bravecto® <![CDATA[C max (μg / mL)]]> 3.86±0.84 4.12±0.71 3.35±0.78 <![CDATA[T max ]]> 18.42±5.31 16.53±4.21 21.67±5.73 AUC (μg*h / L) 1332.51±428.35 1853.45±612.47 1232.53±536.58 <![CDATA[T 1 / 2 (h)]]> 302.3±46.5 357.2±39.7 296.4±35.8

[0126] As can be seen from Table 7, Tablet 2 and Tablet 3 have greater C max , smaller T max and larger AUC (the AUC of Tablet3 is 1.39 times and 1.5 times that of Tablet2 and Bravecto®, respectively), which indicates that Tablet2 and Tablet3 form self-assembled micelles in the gastrointestinal tract to accelerate the absorption of flurellana, and Tablet3 has a larger C max , smaller T max and a larger AUC, which may be due to the introduction of modified peptides in the DSPE-PEG-ATS and DSPE-PEG-R8 used in the preparation of Tablet3 self-micelle solid dispersions, which is beneficial to the absorption of the drug, which may be attributed to the effect of the R8 peptide cation in accelerating gastrointestinal absorption. In particular, for T 1 / 2 Tablet3 has a half-life that is about 1 / 5 longer than Bravecto®, which may be due to the introduction of ATS peptide in DSPE-PEG-ATS, which can mediate the micelles to target adipose tissue in the body circulation, and after being absorbed by adipose tissue, it acts as a drug reservoir to slowly release the drug, thereby extending the drug half-life. This will further increase the drug's protection period against the target insect body.

[0127] Example 9 Anti-insect Effect of Flurellana Chewable Tablets

[0128] Eighteen male beagles (weighing between 10-12 kg) were divided into three groups (untreated control group, test preparation (Tablet3) group and control preparation (Bravecto®) group), with 6 animals in each group. The test preparation (Tablet3) group and the control preparation (Bravecto®) group were administered once, with a dosage of 25 mg / kg, and the administration diary was day 0. Each of the three groups of test animals was infested with 50 ticks on the 2nd, 12th, 28th, 56th and 84th days, and the total number of ticks on the body of the test animals was counted 2 days after the infestation to evaluate the anti-tick effect of Flurellana chewable tablets. The results are shown in Table 8.

[0129] Table 8. Anti-tick efficacy of Flurellana chewable tablets

[0130] Day 4 Day 14 Day 30 Day 58 Day 86 Unprocessed 28 36 31 36 42 Tablet3 0 0 0 0 2 Bravecto® 0 0 0 5 24

[0131] As can be seen from the table, Tablet3 has a longer-lasting antiparasitic effect than Bravecto®.

[0132] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A flurellana chewable tablet, characterized in that: The flurellana chewable tablet is composed of the following raw materials in parts by weight: 30-60 parts of flurellane self-micellar solid dispersion; Filler 20-60 parts; 1-15 parts of disintegrant; 1-5 parts of lubricant; 1-5 parts of flavoring agent; The filler is microcrystalline cellulose; The flurellane self-micelle solid dispersion is composed of the following raw materials in parts by weight: Flurella 5-15 parts; 25-35 parts of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; RRRRRRRR peptide-modified DSPE-PEG material 1-6 parts; 1-6 parts of ATS peptide-modified DSPE-PEG material; The amino acid sequence of the ATS peptide is: GKGGEAKDGGC.

2. The chewable tablet of flurellana according to claim 1, characterized in that: The flurellana chewable tablet is composed of the following raw materials in parts by weight: 40-55 parts of flurellane self-micellar solid dispersion; 30-40 parts of filler; 5-10 parts of disintegrant; 1-5 parts of lubricant; 1-5 parts of flavoring agent.

3. The fluororana chewable tablet according to claim 1 or 2, characterized in that: The flurellane self-micelle solid dispersion is composed of the following raw materials in parts by weight: Flurellana 8-12 parts; 30-35 parts of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; 3-6 parts of RRRRRRRR peptide-modified DSPE-PEG material; 3-6 copies of ATS peptide-modified DSPE-PEG material.

4. The chewable tablet of flurellana according to claim 1 or 2, characterized in that: The RRRRRRRR peptide-modified DSPE-PEG material is prepared by the following method: Distearoylphosphatidylethanolamine-polyethylene glycol maleimide and CRRRRRRRR peptide are mixed in a neutral phosphate buffer at a molar ratio of 1-2:1 for reaction for 12-48 hours, and then the reaction solution is dialyzed in a dialysis bag for 24-72 hours, and the dialyzed solution is freeze-dried to obtain the product.

5. The chewable tablet of flurellana according to claim 1 or 2, characterized in that: The ATS peptide-modified DSPE-PEG material is prepared by the following method: Distearoylphosphatidylethanolamine-polyethylene glycol maleimide and polypeptide ATS-SH are mixed in a neutral phosphate buffer at a molar ratio of 1-2:1 for reaction for 12-48 hours, and then the reaction solution is dialyzed in a dialysis bag for 24-72 hours, and the dialyzed solution is freeze-dried to obtain; Wherein, the amino acid sequence of the ATS peptide is: GKGGEAKDGGC.

6. The flurellana chewable tablet according to claim 1 or 2, characterized in that: The flurellan self-micelle solid dispersion is prepared by the following method: adding a prescribed amount of flurellan, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, RRRRRRRR peptide-modified DSPE-PEG material and ATS peptide-modified DSPE-PEG material into an organic solvent for dissolution; then concentrating, grinding, sieving and drying the obtained solid to obtain the flurellan self-micelle solid dispersion.

7. The flurellana chewable tablet according to claim 1 or 2, characterized in that: The disintegrant is selected from one or more combinations of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or dry starch.

8. The flurellana chewable tablet according to claim 1 or 2, characterized in that: The lubricant is one or more combinations selected from silicon dioxide, magnesium stearate, talc, and glyceryl behenate; and / or The flavoring agent is one selected from beef flavor, chicken flavor, and a sweetener; wherein the sweetener is one or more of sucrose, sorbitol, maltitol, isomalt, and sucralose.

9. The method for preparing the flurana chewable tablets according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: (a) Sieve the raw and auxiliary materials for use; (b) After mixing the flurellan self-micelle solid dispersion and the lubricant, add 1 / 3 to 1 / 2 of the prescribed amount of disintegrant, and then add the filler, flavoring agent and the remaining prescribed amount of disintegrant, mix well, and press into tablets to obtain the product.

10. Use of the flurellana chewable tablets according to any one of claims 1 to 8 or the flurellana chewable tablets prepared by the method according to claim 9 in the preparation of a drug for preventing and treating parasitic infections on the body surface and / or in the body and preventing canine heartworm disease; the surface parasites are fleas, ticks, scabies, ear mites, demodex mites, and lice; the internal parasites are ascaris, hookworms, whipworms, and tapeworms.

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