CN116637078A - Fluoro Lei Lana soft chewing composition, soft chewing tablet and preparation method and application thereof - Google Patents

Fluoro Lei Lana soft chewing composition, soft chewing tablet and preparation method and application thereof Download PDF

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CN116637078A
CN116637078A CN202210137143.1A CN202210137143A CN116637078A CN 116637078 A CN116637078 A CN 116637078A CN 202210137143 A CN202210137143 A CN 202210137143A CN 116637078 A CN116637078 A CN 116637078A
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lana
lei
polyethylene glycol
fluorine
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张许科
张文君
李焕娟
师梦超
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Luoyang Huizhong Animal Medicine Co ltd
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Luoyang Huizhong Animal Medicine Co ltd
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    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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    • A61K9/2004—Excipients; Inactive ingredients
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    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
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    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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Abstract

The application relates to a fluorine Lei Lana soft chewing composition with good palatability, a soft chewing tablet, a preparation method and application thereof. The fluorine Lei Lana soft chewing composition comprises fluorine Lei Lana, corn starch, soybean protein powder, chicken liver powder, hydroxypropyl cellulose, polyethylene glycol 3350, polyethylene glycol 15 hydroxystearate, glycerol and soybean oil. The fluorine Lei Lana soft chewing composition, particularly soft chewing tablets, prepared by the method has stable property and good palatability, and the preparation method is simple and is suitable for large-scale production and clinical application.

Description

Fluoro Lei Lana soft chewing composition, soft chewing tablet and preparation method and application thereof
Technical Field
The application relates to the field of pharmaceutical preparations, in particular to a fluorine Lei Lana soft chewing composition with good palatability, a soft chewing tablet, a preparation method and application thereof.
Background
Fluoro Lei Lana (Fluralaner), chemical name 4- [5- (3, 5-dichlorophenyl) -5-trifluoromethyl-4H-1, 2-oxazol-3-yl ] -2-methyl-N- [ 2-oxo-2- (2, 2-trifluoroethylamino) ] ethylbenzamide, belongs to isoxazolines, and acts mainly by interfering gamma-aminobutyric acid (GABA) gating chloride ion channel, similar to the targets of pesticides such as cyclopentadiene, phenylpyrazole and macrolides. Fluorine Lei Lana is a systemic antiparasitic agent and has good insecticidal activity against pests such as ticks, fleas, lice, hemiptera, diptera and parasitic arthropods, and the like, and has higher toxicity or equivalent to common pesticides. The fluorine Lei Lana has no obvious cross resistance with the existing pesticide, and has better insecticidal activity even on partial resistant pests.
Florarana was approved by the European Union and FDA in 2014 for tick and flea infections in pet dogs and cats; in month 4 of 2019, the fluororalston chewable tablet is approved to be marketed in China (trade name Bei Weiduo) for the treatment of flea and tick infections on canine body surfaces and the adjuvant treatment of allergic dermatitis caused by fleas.
The fluorine Lei Lana preparation chewable tablets can be rapidly absorbed after oral administration for dogs and cats, and can take effect in 2 hours, the insecticidal rate in 4 hours is more than 80%, the insecticidal rate in 8 hours is more than 95%, the maximum blood concentration is reached in 1 day, and the food can enhance the absorption; the distribution is wide; half-life is about 12-15 days, and administration is once in 12 weeks.
Patent CN104203214A discloses a soft chewing composition of Florana and a preparation method thereof, namelyCorresponding product Bei WeiduoThe patent mainly protects a fluorine Lei Lana composition containing pamoic acid or pharmaceutically acceptable salt and a preparation method thereof, and describes the important effect that the addition of pamoic acid or pharmaceutically acceptable salt thereof is more beneficial to forming in the process of forming a soft chewing agent; the two key auxiliary materials, namely pamoic acid and sodium pamoate, are not at medicinal level in China at present, and only have chemical level, so that manufacturers have few production facilities, the quality is uneven, and the quality control is not facilitated; the fluororalrana chewable tablet actually prepared by the patent has poor palatability in general response after being used by a pet owner (see https:// www.163.com/dy/arc/FNP 2CIVL0525T49G.html; https:// www.sohu.com/a/472762676_121094150; https:// www.zhihu.com/questin/426564216) and is unfavorable for oral administration of dogs.
Patent CN113476419a discloses a fluororalston chewable tablet for pets and a preparation method thereof, and the preparation method is simple, but the preparation formulation is hard, has hard texture and poor palatability, and does not see products to be marketed at present.
Patent CN104780908A discloses a preparation method of a fluororalston chewable tablet and a corresponding manufacturing equipment rotary molding machine. The procedure of adding the molding agent polyethylene glycol into the mixture after melting and uniformly mixing is required in the patent description, but the temperature is reduced after melting in the actual operation process, the polyethylene glycol is easy to separate out, and the operation is difficult in the actual mass production process; the technological parameters of the soft material temperature to be controlled at 35-45 ℃ are described in the patent, and in actual operation, the equipment temperature control is not easy to realize; the rotary molding machine of the chewable tablet molding equipment described in the patent is unusual in China, special customization is needed, the requirement on equipment performance is high, and the rotary molding machine is not easy to realize and popularize in the industrial production process.
Therefore, for the fluorine Lei Lana drug, a preparation with good palatability, simple preparation process, few steps, low common cost of equipment and convenient industrial production is needed.
Disclosure of Invention
In view of the above problems in the prior art, the application provides a fluororalston soft chewing composition, a soft chewing tablet and a preparation method thereof, and the prepared fluoro Lei Lana soft chewing composition, particularly the soft chewing tablet, has stable property and good palatability, and the preparation method is simple and is suitable for large-scale production and clinical application.
To achieve the above object, in one aspect, the present application provides a soft chewing composition of fluramine, which comprises fluorine Lei Lana, corn starch, soy protein powder, chicken liver powder, hydroxypropyl cellulose, polyethylene glycol 3350, polyethylene glycol 15 hydroxystearate, glycerin, and soybean oil.
As one embodiment of the application, the content of the fluorine Lei Lana is 5-20% w/w, the content of the corn starch is 10-30% w/w, the content of the chicken liver powder is 7.5-22.5% w/w, the total content of the polyethylene glycol 15 hydroxystearate, the glycerol and the soybean oil is 20-27.5% w/w, the total content of the hydroxypropyl cellulose and the polyethylene glycol 3350 is 10-20% w/w, and the balance is soybean protein powder; and the mass ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is 1:1-3:7.
As one embodiment of the present application, the corn starch is present in the soft chew composition in an amount of 15% to 20% w/w.
The corn starch may be present in an amount of 15% w/w, 16% w/w, 17% w/w, 18% w/w, 19% w/w, 20% w/w.
As an embodiment of the present application, the content of the chicken liver powder in the soft chewing composition is 17.5% to 22.5% w/w.
The chicken liver powder may be present in an amount of 17.5% w/w, 17.6% w/w, 17.7% w/w, 17.8% w/w, 17.9% w/w, 20% w/w, 20.1% w/w, 20.2% w/w, 20.3% w/w, 20.4% w/w, 20.5% w/w, 20.6% w/w, 20.7% w/w, 20.8% w/w, 20.9% w/w, 21% w/w, 21.1% w/w, 21.2% w/w, 21.3% w/w, 21.4% w/w, 21.5% w/w, 21.6% w/w, 21.7% w/w, 21.8% w/w, 21.9% w/w, 22% w/w, 22.1% w/w, 22.2% w, 22.3% w/w, 22.4% w/w.
As one embodiment of the present application, the sum of the contents of the polyethylene glycol 15 hydroxystearate, the glycerin and the soybean oil in the soft chewing composition is 22.5% to 25% w/w.
As one embodiment of the application, the sum of the content of the hydroxypropyl cellulose and the polyethylene glycol 3350 in the soft chewing composition is 12-15% w/w, and the mass ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is 5:7-1:2.
In the present application, the hydroxypropyl cellulose is used with polyethylene glycol 3350 as a binder in a soft chewing composition. The sum of the contents of the hydroxypropyl cellulose and the polyethylene glycol 3350 can be 12% w/w, 13% w/w, 14% w/w and 15% w/w, and the mass ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 can be 5:7, 5:8, 5:9 and 1:2.
As one embodiment of the present application, the content of the fluorine Lei Lana in the soft chewing composition is 15% w/w, the content of the corn starch is 15% w/w, the content of the soybean protein powder is 12.5% w/w, the content of the chicken liver powder is 22.5% w/w, the content of the polyethylene glycol 15 hydroxystearate is 2.5% w/w, the content of the glycerin is 7.5% w/w, the content of the soybean oil is 12.5% w/w, the content of the hydroxypropyl cellulose is 4.5% w/w, and the content of the polyethylene glycol 3350 is 8% w/w;
or the content of fluorine Lei Lana is 15% w/w, the content of corn starch is 20% w/w, the content of soybean protein powder is 12.5% w/w, the content of chicken liver powder is 17.5% w/w, the content of polyethylene glycol 15 hydroxystearate is 2.5% w/w, the content of glycerol is 7.5% w/w, the content of soybean oil is 12.5% w/w, the content of hydroxypropyl cellulose is 4.5% w/w, and the content of polyethylene glycol 3350 is 8% w/w;
or the content of fluorine Lei Lana is 15% w/w, the content of corn starch is 15% w/w, the content of soybean protein powder is 12.5% w/w, the content of chicken liver powder is 20% w/w, the content of polyethylene glycol 15 hydroxystearate is 2.5% w/w, the content of glycerol is 7.5% w/w, the content of soybean oil is 12.5% w/w, the content of hydroxypropyl cellulose is 5% w/w, and the content of polyethylene glycol 3350 is 10% w/w;
or the content of fluorine Lei Lana is 15% w/w, the content of corn starch is 18% w/w, the content of soybean protein powder is 12.5% w/w, the content of chicken liver powder is 20% w/w, the content of polyethylene glycol 15 hydroxystearate is 2.5% w/w, the content of glycerol is 7.5% w/w, the content of soybean oil is 12.5% w/w, the content of hydroxypropyl cellulose is 5% w/w, and the content of polyethylene glycol 3350 is 7% w/w.
In another aspect, the present application provides a method of preparing a soft chew composition of flurbiproflumilast comprising:
step (1): crushing fluorine Lei Lana to obtain fluorine Lei Lana powder with a particle diameter D90 less than or equal to 35 mu m;
step (2): uniformly mixing the fluorine Lei Lana powder obtained in the step (1) with soybean protein powder, chicken liver powder, hydroxypropyl cellulose and polyethylene glycol 3350 in a wet granulator for 10 minutes to obtain a mixed material;
step (3): and (3) uniformly mixing glycerol and polyethylene glycol 15 hydroxystearate, slowly adding the mixture obtained in the step (2) at a uniform speed, stirring, shearing for 2 minutes, uniformly mixing, adding soybean oil, stirring, shearing for 1 minute, and uniformly mixing to obtain the fluorine Lei Lana soft chewing composition. The fluorine Lei Lana soft chewing composition prepared by the method has moderate softness.
In still another aspect, the present application provides a method for preparing a soft chewable tablet of fluramine, the method comprising: and (3) putting the soft chewing composition obtained in the step (3) into a hydraulic forming machine to be pressed into fluorine Lei Lana soft chewing tablets.
Compared with the prior art, the preparation method of the soft chewable tablet has the advantages of simple preparation process: the liquid material and the solid material are uniformly mixed, and the mixing process can be carried out at room temperature without additional application of heat; the temperature of the soft material is not required to be additionally controlled in the forming process, so that the operation procedures in the preparation process of the fluorine Lei Lana soft chewing preparation are greatly simplified, and the industrialization is facilitated;
in addition, the production equipment used in the preparation method is a common wet granulator and a hydraulic forming machine in the preparation process, special customization is not needed, the preparation method is easier to realize and popularize in the industrialization process, and the production cost is indirectly reduced.
In yet another aspect, the application provides the use of a fluoro Lei Lana soft chew composition for the manufacture of a medicament for treating flea and tick infections on canine surfaces, and allergic dermatitis caused by fleas.
Drawings
Fig. 1 is a graph of dissolution of soft chewable tablets 5-8 and commercial product Bei Weiduo in a primary medium prepared in accordance with an embodiment of the present application.
Fig. 2 is a graph showing the particle size distribution of fluorine Lei Lana as an active ingredient in soft chewable tablets 1 to 5 prepared in accordance with the embodiment of the present application.
Fig. 3 is a graph of dissolution of chewable tablets 1-2, chewable tablets 6-7, the soft chew formulation of example 4, and commercially available product Bei Weiduo in a primary medium prepared in accordance with an embodiment of the present application.
Detailed Description
The advantages and features of the present application will become more apparent from the following description of the embodiments. These examples are illustrative only and are not intended to limit the scope of the application in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present application may be made without departing from the spirit and scope of the present application, but these changes and substitutions fall within the scope of the present application.
The chemical reagents used in the application are all analytically pure and purchased from the national drug group. The experimental methods provided by the application are conventional methods unless specified; the biological material, unless otherwise specified, is commercially available.
The effects of the present application will be described below with reference to examples
Example 1 exemplary formulations 1-4 of fluorine Lei Lana Soft chewing compositions
The compositions of the fluorine Lei Lana soft chewing compositions formulas 1 to 4 are shown in table 1:
TABLE 1 formulation composition (w/w) of the fluoro Lei Lana soft chew composition of the present application
Composition of the components Formulation 1 Formulation 2 Formulation 3 Formulation 4
Fluorine Lei Lana 15％ 15％ 15％ 15％
Corn starch 15％ 20％ 25％ 30％
Soybean protein powder 12.5％ 12.5％ 12.5％ 12.5％
Chicken liver powder 22.5％ 17.5％ 12.5％ 7.5％
Hydroxypropyl cellulose 4.5％ 4.5％ 4.5％ 4.5％
Polyethylene glycol 3350 8.0％ 8.0％ 8.0％ 8.0％
Polyethylene glycol 15 hydroxystearate 2.5％ 2.5％ 2.5％ 2.5％
Glycerol 7.5％ 7.5％ 7.5％ 7.5％
Soybean oil 12.5％ 12.5％ 12.5％ 12.5％
Totals to 100％ 100％ 100％ 100％
The inventors found that corn starch amounts in the formulation in the range of 15% to 30% w/w had negligible effect on palatability of the animal experiment. Under the condition of ensuring that the total weight of the formula is 100% w/w, the dosage of the chicken liver powder in the formulas 1-4 is examined, the dosage of the chicken liver powder mainly has an effect on the palatability of the product, and palatability tests are carried out on the formulas 1-4 of the fluorine Lei Lana soft chewing composition (the test method is the same as in example 5).
Soft chewable tablets 1 to 4 were prepared according to the above formulations 1 to 4 according to the preparation method of example 3 below, and the palatability test results are shown in table 2. The statistical result shows that when the dosage of the chicken liver powder in the formula is 17.5-22.5% w/w, the palatability is obviously better than that of the chicken liver powder in the formula, the dosage of the chicken liver powder in the formula is 7.5-12.5% w/w, and the total acceptance rate is more than 80%. The evaluation criteria for total eating, partial eating and total non-eating are shown in Table 4 below.
Table 2 results of palatability tests on soft chewable tablets prepared by formulas 1 to 4
Example 2 exemplary formulations 5-8 of fluorine Lei Lana Soft chewing compositions
TABLE 3 formulation composition (w/w) of the fluoro Lei Lana soft chew composition of the present application
Composition of the components Formulation 5 Formulation 6 Formulation 7 Formulation 8
Fluorine Lei Lana 15％ 15％ 15％ 15％
Corn starch 10％ 15％ 18％ 20％
Soybean protein powder 12.5％ 12.5％ 12.5％ 12.5％
Chicken liver powder 20％ 20％ 20％ 20％
Hydroxypropyl cellulose 10％ 5％ 5％ 3％
Polyethylene glycol 3350 10％ 10％ 7％ 7％
Polyethylene glycol 15 hydroxystearate 2.5％ 2.5％ 2.5％ 2.5％
Glycerol 7.5％ 7.5％ 7.5％ 7.5％
Soybean oil 12.5％ 12.5％ 12.5％ 12.5％
Totals to 100％ 100％ 100％ 100％
The compositions of the fluorine Lei Lana soft chew compositions formulas 5-8 are shown in table 3.
The inventors found that corn starch levels in the formulation in the range of 10% to 20% w/w had negligible effect on drug dissolution release. Under the condition of ensuring that the total formulation amount is 100% w/w, the dosage of the adhesive (hydroxypropyl cellulose and polyethylene glycol 3350) and the proportion of the two components in the formulations 5-8 are examined, the dosage of the adhesive and the proportion of the two components mainly have influence on the in vitro dissolution of products, and main medium in vitro dissolution tests (the test method is the same as that of the example 6) are carried out on the formulations 5-8 of the fluorine Lei Lana soft chewing composition.
According to the above formulations 5 to 8, soft chewable tablets 5 to 8 were prepared according to the preparation method of example 3 below, and the evaluation results are shown in fig. 1. Wherein the adhesive dosage is 12-15% w/w, the ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is only in the range of 5:7-1:2 (formula 6 and formula 7), the dissolution curve can be well matched with the commercial product Bei Weiduo (f2=70 and f2=64), the adhesive dosage is 20% w/w, the ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is 1:1 (formula 5), the dissolution overall is slow (f2=39), the adhesive dosage is 10% w/w, the ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is 3:7 (formula 8), and the dissolution overall is faster (f2=46).
The result shows that the dosage of the adhesive and the proportion of the two components can have influence on the dissolution and release of the medicine, and the synergistic effect of the two components is the best when the mass ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is 5:7-1:2, the final formula preferably has the dosage of 12-15% w/w, wherein the mass ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is 5:7-1:2.
Example 3 Soft chewable composition of Fluoro Lei Lana and method for preparing Soft chewable tablets
A method of preparing the fluoro Lei Lana soft chew composition of the present application, said method comprising:
step (1): crushing fluorine Lei Lana to obtain fluorine Lei Lana powder with a particle diameter D90 less than or equal to 35 mu m;
step (2): uniformly mixing the fluorine Lei Lana powder obtained in the step (1) with soybean protein powder, chicken liver powder, hydroxypropyl cellulose and polyethylene glycol 3350 in a wet granulator for 10 minutes to obtain a mixed material;
step (3): and (3) uniformly mixing glycerol and polyethylene glycol 15 hydroxystearate, slowly adding the mixture obtained in the step (2) at a uniform speed, stirring and shearing for 2 minutes, uniformly mixing, adding soybean oil, stirring and shearing for 1 minute, and uniformly mixing to obtain the soft fluorine Lei Lana chewing composition with moderate softness.
The preparation method of the fluorine Lei Lana soft chewable tablet comprises the following steps: and (3) putting the soft chewing composition obtained in the step (3) of the preparation method of the soft chewing composition into a hydraulic forming machine to be pressed into the fluorine Lei Lana soft chewing tablet.
Fig. 2 is a graph showing the particle size distribution of fluorine Lei Lana as an active ingredient in soft chewable tablets 1 to 5 prepared in accordance with the embodiment of the present application.
Compared with the method disclosed by the patent CN104203214A, CN113476419A, the preparation method disclosed by the application has the advantages that the preparation process is simpler: the liquid material and the solid material are uniformly mixed, and the mixing process can be carried out at room temperature without additional application of heat; the temperature of the soft material is not required to be additionally controlled in the forming process, so that the operation procedures in the preparation process of the fluorine Lei Lana soft chewing preparation are greatly simplified, and the industrialization is facilitated. In addition, the production equipment used in the preparation method is a common wet granulator and a hydraulic forming machine in the preparation process, special customization is not needed, the preparation method is easier to realize and popularize in the industrialization process, and the production cost is indirectly reduced.
Example 4 comparative soft chew formulation
The active ingredient proportion of the fluorine Lei Lana soft chewing composition disclosed by the application is 15%, and the similar formula E composition and the preparation method disclosed by the patent CN104203214A are selected for carrying out.
Example 5 palatability test
30 pet dogs are selected according to the veterinary drug palatability evaluation guiding principle Guideline on the demonstration of palatability of veterinary medicinal products to develop palatability tests of different drugs.
The test method comprises the following steps: the palatability test was performed by taking chewable tablets 1,2, 6, 7, the soft-chew fluoro Lei Lana preparation prepared in example 4 and comparing more than one canine house with the commercially available product Bei Wei, and the palatability test was performed by selecting 30 pet dogs that had normal mental appetite and had not been treated with the relevant product for the last month. In the whole test, 6 medicines are subjected to palatability investigation for 6 times, only one medicine is inspected each time, and in the range of ensuring safe dosage, the test dogs have a certain memory function on the smell and taste of the same medicine in a short time, so that after each medicine inspection is finished, the next test is performed at intervals of more than 48 hours. In each trial, a fixed time period was selected as the administration time.
The weight of each test dog is estimated before the test, the test person feeds the medicine into the dog feeding basin according to the weight, the dog feeds the medicine into the palm or the dog feeds the medicine, the stopwatch counts the time for 2 minutes, the feeding condition of each dog to the test sample is observed, the feeding condition is expressed as 'full feeding, partial feeding or no feeding', the feeding condition is used as a main palatability judgment standard, if the medicine feeds the medicine in 2 minutes, the time from the start of feeding to the completion of swallowing of the dog is accurately recorded, the feeding condition is used as a minor palatability judgment standard, the specific judgment is shown in table 4, and the test result is shown in table 5.
Table 4 canine feeding condition decision criteria
TABLE 5 results of palatability test of dogs on the 4 drugs described above
As can be seen from table 5, the fluoro Lei Lana soft chewable tablets 1,2, 6 and 7 prepared by the present application all had good palatability, with overall acceptance greater than 80%, while the commercial product Bei Weiduo and comparative example 4 had poor palatability results, with overall acceptance less than 50%, with no significant advantage in palatability over the fluoro Lei Lana soft chewable tablets prepared by the present application.
Example 5 dissolution comparison test
For oral solid preparations, in-vitro dissolution is an important evaluation means for evaluating the performance of the preparation, and the disintegration dissolution condition and in-vivo bioavailability of the medicine in vivo can be primarily judged; for imitation drug products, the in-vitro dissolution is generally consistent with that of the original reference preparation, and the in-vivo bioequivalence probability with that of the reference preparation can be improved. The fluorine Lei Lana soft chewable tablet prepared by the application belongs to a imitated product, and the reference preparation is a commercial product Bei Weiduo, so that the in vitro dissolution comparison test of the self-developing agent and the reference preparation is carried out, and the fluorine Lei Lana soft chewable tablet has great significance for in vivo bioequivalence. The similarity factor f2 is a parameter for measuring the similarity of the two dissolution curves, the larger the f2 value is, the more similar the two dissolution curves are proved, generally, f2 is more than or equal to 50, and is taken as an index that the two dissolution curves are similar, and f2 is less than 50, the two dissolution curves are considered to be dissimilar.
The dissolution profile of the main medium was compared with that of the comparative commercial product Bei Weiduo for the chewable tablets 1,2, 6, 7 and Lei Lana soft chewable formulations prepared in example 4, and the results are shown in fig. 3. Fig. 3 shows that the dissolution profile of soft chewable tablets 1,2, 6, 7 of fluorine Lei Lana prepared according to the present application fits well with the commercially available product Bei Weiduo, with a similarity factor greater than 60 (f2=74, f2=66, f2=70, f2=64); the soft chewable formulation of example 4 produced a dissolution profile dissimilar to that of commercial product Bei Weiduo, with a similarity factor of less than 50 (f2=36).
Example 6 stability test
The stability of the samples was observed for chewable tablet 1, chewable tablet 2, chewable tablet 6, and chewable tablet 7 using a double aluminum blister pack and placed under accelerated conditions for 6 months (40 ℃ ± 2 ℃,75% rh±5% rh) and for 12 months under long term conditions (25 ℃ ± 2 ℃,60% rh±5% rh), and the results are shown in table 6 below.
Table 6 results of stability test of samples
As can be seen from table 6, the soft chewable tablets 1,2, 6 and 7 of fluorine Lei Lana prepared by the present application have good stability under accelerated conditions for 6 months and long-term conditions for 12 months, and have no significant change in quality compared with 0 day. The fluorine Lei Lana soft chewable tablet prepared by the application has good stability.
EXAMPLE 7 fuzzing of key components of a fluorine Lei Lana Soft chewing composition
The inventor repeatedly searches the range of active ingredient fluorine Lei Lana and key components of polyethylene glycol 15 hydroxystearate, glycerol and soybean oil in the fluorine Lei Lana soft chewing composition, and a brief list of partial prescriptions is presented below for convenience of explanation:
TABLE 7 fuzzing (w/w) of the soft chew composition components of fluoro Lei Lana
The inventor discovers that the dosage of the fluorine Lei Lana as an active ingredient and the dosage of liquid components (polyethylene glycol 15 hydroxystearate, glycerol and soybean oil) in the formula can obviously influence the demoulding condition of the soft chewable tablet in the preparation process. The amounts of fluorine Lei Lana as an active ingredient and polyethylene glycol 15 hydroxystearate, glycerol and soybean oil as key components (sample preparation according to the preparation method of example 3) were examined while ensuring 100% w/w of the total formulation, and the soft chewing composition of the above formulation was pressed using a hydroforming machine. Wherein the dosage of fluorine Lei Lana is 5-20% w/w, the total dosage of polyethylene glycol 15 hydroxystearate, glycerol and soybean oil is 22.5-25% w/w (formulas 9-14), the situation that the demolding can not be smoothly carried out is avoided, and the prepared soft chewable tablet is complete, smooth and free from defects; when the total dosage of polyethylene glycol 15 hydroxystearate, glycerol and soybean oil is 27.5% w/w (formula 15), the prepared soft chewable tablet is too soft and is easy to deform after demolding; when the total amount of polyethylene glycol 15 hydroxystearate, glycerol and soybean oil is 20% w/w (formula 16), the preparation process is under the condition that the demolding can not be smoothly performed, and the prepared soft chewable tablet has defects and burrs.
The result shows that the dosage of the active ingredient fluorine Lei Lana is 5-20% w/w, the dosage of polyethylene glycol 15 hydroxystearate is 1.5-3.0% w/w, the dosage of glycerol is 6.5-10% w/w, the dosage of soybean oil is 11-17% w/w, and the total dosage of polyethylene glycol 15 hydroxystearate, glycerol and soybean oil is 22.5-25% w/w, the soft chewing tablet can be smoothly demoulded in the pressing process by adopting a hydraulic forming machine, the soft chewing tablet does not adhere to a die, and the tablet has complete and smooth appearance and is not defective.
The above examples do not discuss the amount of soy protein powder, and in other formulations that do not deviate from the above definitions of the amount of other components, proper adjustment of the amount of soy protein powder does not significantly affect the above-described related properties of the chewable tablet. In some preferred embodiments, the soy protein powder is present in an amount of 10% to 15% w/w.
The present application is not limited to the above-mentioned embodiments, but is capable of modification and variation in all embodiments without departing from the spirit and scope of the present application.

Claims (10)

1. A soft chewing composition of fluramine comprising: fluorine Lei Lana, corn starch, soybean protein powder, chicken liver powder, hydroxypropyl cellulose, polyethylene glycol 3350, polyethylene glycol 15 hydroxystearate, glycerol and soybean oil.
2. The fluorine Lei Lana soft chew composition of claim 1, wherein the fluorine Lei Lana is present in an amount of 5-20% w/w, the corn starch is present in an amount of 10-30% w/w, the chicken liver powder is present in an amount of 7.5-22.5% w/w, the polyethylene glycol 15 hydroxystearate, the glycerol and the soybean oil are present in a total amount of 20-27.5% w/w, and the hydroxypropyl cellulose and the polyethylene glycol 3350 are present in a total amount of 10-20% w/w, the balance being soy protein powder;
and the mass ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is 1:1-3:7.
3. The fluoro Lei Lana soft chew composition of claim 2, wherein the corn starch is present in an amount of 15-20% w/w.
4. The fluoro Lei Lana soft chew composition of claim 2, wherein the chicken liver powder is present in the soft chew composition in an amount of 17.5-22.5% w/w.
5. The fluoro Lei Lana soft chew composition of claim 2, wherein the combined amount of polyethylene glycol 15 hydroxystearate, glycerin and soybean oil is 22.5% to 25% w/w.
6. The fluorine Lei Lana soft chew composition of claim 2, wherein the sum of the contents of hydroxypropyl cellulose and polyethylene glycol 3350 is 12-15% w/w and the mass ratio of hydroxypropyl cellulose to polyethylene glycol 3350 is 5:7-1:2.
7. The fluorine Lei Lana soft chew composition of any of claims 3-5, wherein the fluorine Lei Lana is 15% w/w, the corn starch is 15% w/w, the soy protein powder is 12.5% w/w, the chicken liver powder is 22.5% w/w, the polyethylene glycol 15 hydroxystearate is 2.5% w/w, the glycerin is 7.5% w/w, the soybean oil is 12.5% w/w, the hydroxypropyl cellulose is 4.5% w/w, and the polyethylene glycol 3350 is 8% w/w; or (b)
The content of fluorine Lei Lana is 15% w/w, the content of corn starch is 20% w/w, the content of soybean protein powder is 12.5% w/w, the content of chicken liver powder is 17.5% w/w, the content of polyethylene glycol 15 hydroxystearate is 2.5% w/w, the content of glycerol is 7.5% w/w, the content of soybean oil is 12.5% w/w, the content of hydroxypropyl cellulose is 4.5% w/w, and the content of polyethylene glycol 3350 is 8% w/w; or (b)
The content of fluorine Lei Lana is 15% w/w, the content of corn starch is 15% w/w, the content of soybean protein powder is 12.5% w/w, the content of chicken liver powder is 20% w/w, the content of polyethylene glycol 15 hydroxystearate is 2.5% w/w, the content of glycerol is 7.5% w/w, the content of soybean oil is 12.5% w/w, the content of hydroxypropyl cellulose is 5% w/w, and the content of polyethylene glycol 3350 is 10% w/w; or (b)
The content of fluorine Lei Lana is 15% w/w, the content of corn starch is 18% w/w, the content of soybean protein powder is 12.5% w/w, the content of chicken liver powder is 20% w/w, the content of polyethylene glycol 15 hydroxystearate is 2.5% w/w, the content of glycerol is 7.5% w/w, the content of soybean oil is 12.5% w/w, the content of hydroxypropyl cellulose is 5% w/w, and the content of polyethylene glycol 3350 is 7% w/w.
8. A method of preparing a soft chew composition of flurazon, the method comprising:
step (1): crushing fluorine Lei Lana to obtain fluorine Lei Lana powder with a particle diameter D90 less than or equal to 35 mu m;
step (2): uniformly mixing the fluorine Lei Lana powder obtained in the step (1) with soybean protein powder, chicken liver powder, hydroxypropyl cellulose and polyethylene glycol 3350 in a wet granulator for 10 minutes to obtain a mixed material;
step (3): and (3) uniformly mixing glycerol and polyethylene glycol 15 hydroxystearate, slowly adding the mixture obtained in the step (2) at a uniform speed, stirring, shearing for 2 minutes, uniformly mixing, adding soybean oil, stirring, shearing for 1 minute, and uniformly mixing to obtain the fluorine Lei Lana soft chewing composition.
9. A method for preparing a soft chewable tablet of fluramine, the method comprising:
the fluorine Lei Lana soft chewing composition prepared by the preparation method of claim 8 is put into a hydraulic forming machine to be pressed into fluorine Lei Lana soft chewing tablets.
10. Use of a fluoro Lei Lana soft chew composition according to any one of claims 1-7 in the manufacture of a medicament for treating flea and tick infections on canine surfaces, and allergic dermatitis caused by fleas.
CN202210137143.1A 2022-02-15 2022-02-15 Fluoro Lei Lana soft chewing composition, soft chewing tablet and preparation method and application thereof Pending CN116637078A (en)

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