Solid preparation of hydrobromic acid constant mountain ketone and its use in the preparation of chicken eimeria drugs

Abstract

The application belongs to the technical field of medicine, and particularly relates to a solid preparation of hydrobromic acid halofuginone and its use in preparing a chicken Eimeria vaccine. The application effectively improves the dissolution of the preparation in water by preparing nanometer microspheres of the hydrobromic acid halofuginone. The specific technical scheme is as follows: 10 parts by weight of hydrobromic acid halofuginone, 5-8 parts by weight of wheat hydrolyzed protein, 80-100 parts by weight of dodecyl maltoside, and 20-30 parts by weight of PLGA are prepared into nanometer microspheres, and then pharmaceutically acceptable adjuvants are added to prepare a solid preparation, so that the dissolution speed of the product is significantly improved. The preparation process is simple and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a solid preparation of chrysanthemum hydrobromide and its use in the preparation of a treatment for Eimeria tenella in chickens. Background Technology

[0002] Changshanone was introduced from abroad in the 1980s. It is a halogenated derivative of Changshan alkaloid. It is a white or grayish-white crystalline powder, odorless and tasteless. Its chemical name is DL-trans-7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3H)-quinazolinone hydrobromide.

[0003] Coccidiosis is widespread in chickens, with a global incidence rate as high as 50% to 70%. It occurs in almost every chicken farming operation. In my country, due to the favorable environment, the survival and spread of oocysts are exacerbated, resulting in an even higher incidence rate and causing more severe economic losses to the chicken farming industry.

[0004] Studies have confirmed that chrysanthemum ketone has an inhibitory effect on various coccidia, and due to its low toxicity, wide safety margin, and almost no drug residues in meat and offal, it is widely used in the anticoccidial drug market, especially effective against chicken tenderloin, toxic coccidia, and Eimeria tenella. Currently, the most widely used form on the market is chrysanthemum ketone hydrobromide, but chrysanthemum ketone hydrobromide is poorly soluble in water, requiring mixing with feed before administration, which is inconvenient and affects efficacy, thus limiting the drug's widespread use.

[0005] CN201611053242.2 discloses a hydrobromic acid thiazoline solution and its preparation method, using hydrobromic acid thiazoline as the main ingredient, combined with dimethylacetamide, antioxidant, dimethyl sulfoxide and polyethylene glycol 400. Clinical results show that the hydrobromic acid thiazoline solution is more effective than thiazoline premix in treating coccidiosis in chickens, with a clearance rate of 93.0% after 4 days of administration.

[0006] CN201910976261.X discloses a soluble powder of thiazolinone hydrobromide and its preparation method, which is composed of thiazolinone hydrobromide, emulsifier, co-emulsifier and soluble solid adsorbent material. The soluble powder has a better anticoccidial effect than the thiazolinone hydrobromide premix.

[0007] CN202210252570.4 provides an oral solution of styraxone hydrobromide, comprising the components styraxone hydrobromide, a pH adjuster, a preservative, and distilled water.

[0008] The above methods attempt to solve the problem of poor hydrophilicity of the product by screening excipients, adjusting the composition ratio, and improving the preparation technology, but there are still some shortcomings, such as the use of a lot of organic solvents and the strict preparation methods that are not suitable for large-scale production, which cannot meet the needs of large-scale veterinary drug production. Summary of the Invention

[0009] In view of the shortcomings of the prior art, the present invention provides a water-soluble hydrobromic acid styraxone solid dosage form with a simple preparation process and suitable for industrial production.

[0010] Furthermore, the hydrobromide acetonide solid dosage form provided by the present invention is an oral dosage form, specifically granules, tablets or capsules.

[0011] To achieve the above objectives, the present invention prepares a hydrobromide acetonide nanosphere, which is then combined with pharmaceutically acceptable excipients to prepare an oral solid dosage form.

[0012] Preferably, the pharmaceutically acceptable excipient is an excipient; more preferably, the excipient is selected from one or more of diluents, stabilizers, binders, disintegrants, and lubricants.

[0013] The hydrobromide acetonide nanospheres of the present invention are composed of the following components: 10 parts by weight of hydrobromide acetonide, 5-8 parts by weight of hydrolyzed wheat protein, 80-100 parts by weight of dodecyl maltodextrin, and 20-30 parts by weight of PLGA.

[0014] In one embodiment, the hydrobromic acid thiazoline nanospheres of the present invention are composed of the following components: 10 parts by weight of thiazoline, 7.5 parts by weight of hydrolyzed wheat protein, 70 parts by weight of dodecyl maltodextrin, and 25 parts by weight of PLGA.

[0015] Furthermore, the present invention also provides a method for preparing the above-mentioned hydrobromic acid zeolite nanospheres, comprising the following steps:

[0016] (1) Dissolve styraxone hydrobromide, wheat hydrolysate, and dodecyl maltodextrin in water at 15-30°C to obtain solution A, which is then set aside.

[0017] (2) Dissolve PLGA in an organic solvent to obtain solution B, and set aside for later use;

[0018] (3) Place solutions A and B in a high-speed homogenizer, first perform high-pressure emulsification and circulation, then stir at medium speed to obtain an emulsion;

[0019] (4) Collect the nanospheres by high-speed centrifugation and wash them with water to obtain hydrobromic acid styraxone nanospheres.

[0020] The inventors discovered that when phosphate buffer is added in step (1) to adjust the pH to 5.5-6.5, the prepared hydrobromic acid styraxone nanospheres have a more uniform particle size.

[0021] In the embodiments, the buffer solution is a citrate buffer solution, a phosphate buffer solution, or an acetate buffer solution. In one preferred embodiment, the buffer solution is a phosphate buffer solution. In one preferred embodiment, the pH of the buffer solution is 5.8.

[0022] The organic solvent mentioned in step (2) is chloroform.

[0023] In step (3), the material temperature in the high-speed homogenizer is controlled at 20-25℃.

[0024] In step (3), the rotation speed of the high-speed homogenizer is 17,000 rpm.

[0025] The present invention also provides the use of the aforementioned hydrobromide styraxone solid dosage form in the preparation of a drug for treating Eimeria tenella in chickens.

[0026] Compared with the prior art, the technical effects of the present invention are significant:

[0027] By preparing hydrobromide styraxone, wheat hydrolyzed protein, dodecyl maltodextrin, and PLGA into nanospheres, the resulting products exhibit uniform size and high stability. The addition of excipients significantly improves the disintegration and dissolution rates of the final product, as well as enhances its permeability. This solves the problems of existing hydrobromide styraxone formulations being poorly soluble in water and having low dissolution rates, thus meeting the clinical needs for styraxone formulations. Attached Figure Description

[0028] Figure 1 Encapsulation efficiency values ​​of hydrobromic acid styracil microspheres in each example group:

[0029] Figure 2 Example: Stability observation of hydrobromide styraxone preparation. Detailed Implementation

[0030] The beneficial effects of the present invention will be further described below through embodiments. It should be understood that the following embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. At the same time, obvious changes and modifications made by those skilled in the art according to the present invention are also included within the scope of protection of the present invention.

[0031] Example 1: Preparation of hydrobromide acetonide granules is as follows:

[0032]

[0033] Preparation process:

[0034] (1) Dissolve styraxone hydrobromide, wheat hydrolysate, and dodecyl maltodextrin in an appropriate amount of water at 30°C, and adjust the pH to 5.5 with phosphate buffer to obtain solution A for later use.

[0035] (2) Dissolve PLGA in chloroform to obtain solution B, and set aside;

[0036] (3) Place solutions A and B in a high-speed homogenizer, first perform high-pressure emulsification and circulation, then stir at medium speed to obtain an emulsion; control the material temperature in the high-speed homogenizer at 25℃; the speed of the high-speed homogenizer is 17000 rpm;

[0037] (4) Collect the nanospheres by high-speed centrifugation, wash with water, and then obtain hydrobromic acid styraxone nanospheres;

[0038] (5) After mixing the hydrobromic acid styraxone nanospheres and excipients evenly, hydrobromic acid styraxone granules are prepared.

[0039] Example 2: Preparation of hydrobromide acetonide granules is as follows:

[0040]

[0041] Preparation process:

[0042] (1) Dissolve styraxone hydrobromide, wheat hydrolysate, and dodecyl maltodextrin in an appropriate amount of water at 30°C, and adjust the pH to 5.5 with phosphate buffer to obtain solution A for later use.

[0043] (2) Dissolve PLGA in an organic solvent to obtain solution B, and set aside for later use;

[0044] (3) Place solutions A and B in a high-speed homogenizer, first perform high-pressure emulsification and circulation, then stir at medium speed to obtain an emulsion; control the material temperature in the high-speed homogenizer at 20℃; the speed of the high-speed homogenizer is 17000 rpm;

[0045] (4) Collect the nanospheres by high-speed centrifugation, wash with water, and then obtain hydrobromic acid styraxone nanospheres;

[0046] (5) After mixing the hydrobromic acid styraxone nanospheres and excipients evenly, hydrobromic acid styraxone granules are prepared.

[0047] Example 3: Preparation of hydrobromide acetonide granules is as follows:

[0048]

[0049] Preparation process:

[0050] (1) Dissolve styraxone hydrobromide, wheat hydrolysate, and dodecyl maltodextrin in an appropriate amount of water at 25°C, and adjust the pH to 6.0 with phosphate buffer to obtain solution A for later use.

[0051] (2) Dissolve PLGA in an organic solvent to obtain solution B, and set aside for later use;

[0052] (3) Place solutions A and B in a high-speed homogenizer, first perform high-pressure emulsification and circulation, then stir at medium speed to obtain an emulsion; control the material temperature in the high-speed homogenizer at 22℃; the speed of the high-speed homogenizer is 17000 rpm;

[0053] (4) Collect the nanospheres by high-speed centrifugation, wash with water, and then obtain hydrobromic acid styraxone nanospheres;

[0054] (5) After mixing the hydrobromic acid styraxone nanospheres and excipients evenly, hydrobromic acid styraxone granules are prepared.

[0055] Example 4: Preparation of hydrobromide acetonide granules is as follows:

[0056]

[0057] Preparation process:

[0058] (1) Dissolve styraxone hydrobromide, wheat hydrolysate, and dodecyl maltodextrin in an appropriate amount of 30°C water, add phosphate buffer to adjust the pH to 6.5, and obtain solution A for later use;

[0059] (2) Dissolve PLGA in an organic solvent to obtain solution B, and set aside for later use;

[0060] (3) Place solutions A and B in a high-speed homogenizer, first perform high-pressure emulsification and circulation, then stir at medium speed to obtain an emulsion; control the material temperature in the high-speed homogenizer at 25℃; the speed of the high-speed homogenizer is 17000 rpm;

[0061] (4) Collect the nanospheres by high-speed centrifugation, wash with water, and then obtain hydrobromic acid styraxone nanospheres;

[0062] (5) After mixing the hydrobromic acid styraxone nanospheres and excipients evenly, hydrobromic acid styraxone granules are prepared.

[0063] Example 5: Preparation of hydrobromide acetonide granules is as follows:

[0064]

[0065] Preparation process:

[0066] (1) Dissolve styraxone hydrobromide, wheat hydrolysate, and dodecyl maltodextrin in an appropriate amount of 30°C water, add phosphate buffer to adjust the pH to 6.5, and obtain solution A for later use;

[0067] (2) Dissolve PLGA in an organic solvent to obtain solution B, and set aside for later use;

[0068] (3) Place solutions A and B in a high-speed homogenizer, first perform high-pressure emulsification and circulation, then stir at medium speed to obtain an emulsion; control the material temperature in the high-speed homogenizer at 25℃; the speed of the high-speed homogenizer is 17000 rpm;

[0069] (4) Collect the nanospheres by high-speed centrifugation, wash with water, and then obtain hydrobromic acid styraxone nanospheres;

[0070] (5) After mixing the hydrobromic acid styraxone nanospheres and excipients evenly, hydrobromic acid styraxone granules are prepared.

[0071] Comparative Example 1: The preparation of hydrobromide acetonide granules is as follows:

[0072]

[0073] Preparation process:

[0074] (1) Dissolve styraxone hydrobromide, wheat hydrolysate, and dodecyl maltodextrin in an appropriate amount of water at 30°C to obtain solution A, which is then set aside.

[0075] (2) Dissolve PLGA in an organic solvent to obtain solution B, and set aside for later use;

[0076] (3) Place solutions A and B in a high-speed homogenizer, first perform high-pressure emulsification and circulation, then stir at medium speed to obtain an emulsion; control the material temperature in the high-speed homogenizer at 25℃; the speed of the high-speed homogenizer is 17000 rpm;

[0077] (4) Collect the nanospheres by high-speed centrifugation, wash with water, and then obtain hydrobromic acid styraxone nanospheres;

[0078] (5) After mixing the hydrobromic acid styraxone nanospheres and excipients evenly, hydrobromic acid styraxone granules are prepared.

[0079] Comparative Example 2: The preparation of hydrobromide acetonide granules is as follows:

[0080]

[0081] Preparation process:

[0082] (1) Hydrobromic acid acetonide and PLGA are dissolved in acetonitrile to prepare an organic phase for later use.

[0083] (2) Poloxamer 407 was prepared into an aqueous solution.

[0084] (3) The prepared organic phase (2 mL) was added to the poloxamer 407 aqueous solution at a rate of 1 mL / min using a syringe, stirred for 15 h, and then rotary evaporated at 40 °C for 30 min to obtain a nanoparticle suspension.

[0085] (4) The suspension was centrifuged at 10°C and 25,000 rpm for 30 min to separate the supernatant and obtain the drug-coated nanoparticle precipitate.

[0086] (5) The nanoparticles were precipitated and dispersed in water, sucrose was added, ultrasonicated for 5 min, and then freeze-dried to obtain hydrobromic acid styraxone nanoparticles.

[0087] (6) After mixing the hydrobromic acid styraxone nanoparticles and excipients evenly, hydrobromic acid styraxone granules are prepared.

[0088] Comparative Example 3: The preparation of hydrobromide granules is as follows:

[0089]

[0090] Preparation process:

[0091] (1) Dissolve PLGA in an organic solvent to form an organic phase;

[0092] (2) An internal aqueous phase is formed in the presence of hydrobromide, wheat hydrolysate, and dodecyl maltodextrin, with the concentration of hydrobromide being 0.5% to 5% (g / ml).

[0093] (3) The aqueous phase is added slowly dropwise to the oil phase under stirring to form a primary emulsion;

[0094] (4) The colostrum is added to the external aqueous phase under stirring to form a secondary emulsion. The external aqueous phase is an aqueous solution of CaCl2 containing an emulsifier, the concentration of which is 0.5% to 3% (g / ml) and the concentration of which is 0.5% to 4% (g / ml).

[0095] (5) Transfer the double emulsion solution to the external aqueous phase, stir to remove the organic solvent, centrifuge, wash and collect the microspheres. The external aqueous phase is an aqueous solution of CaCl2 containing emulsifier, the concentration of emulsifier is 0.5% to 3% (g / ml) and the concentration of CaCl2 is 0.5% to 4% (g / ml).

[0096] (6) The collected microspheres were suspended in a solution containing a freeze-drying protectant and a filler, and then freeze-dried to obtain PLGA composite microspheres loaded with hydrobromic acid acetonide.

[0097] (7) After mixing the hydrobromic acid styraxone nanospheres and excipients evenly, hydrobromic acid styraxone granules are prepared.

[0098] Verification of Examples

[0099] 1. Particle size determination:

[0100] Take an appropriate amount of the hydrobromic acid styraxone nanospheres prepared in Examples 1 and 3, add 100 μl of 3% PVA, mix well, coat on a glass slide, and measure the particle size under a microscope.

[0101] Calculations showed that the average particle size of the hydrobromic acid styraxone nanospheres prepared in Examples 1 and 3 was controlled between 120 μm and 160 μm.

[0102] 2. Dissolution test

[0103] Dissolution was determined according to Method II, General Chapter 0931, Part IV, Chinese Pharmacopoeia 2020 Edition. The dissolution medium was 0.1 mol / L hydrochloric acid. The dissolution results are shown in Table 1.

[0104] Table 1 Results of Dissolution Test

[0105]

[0106] 3. Encapsulation efficiency of the hydrobromide formulation in the example:

[0107] The microsphere formulations prepared in each example were dissolved in DMSO solution, and an acetate-ammonium acetate buffer (pH 4.3) was added. The mixture was centrifuged at 13000 rpm for 3 min. The supernatant was collected, filtered through a 0.22 μm organic filter, and injected for analysis. The encapsulation efficiency was calculated. Results are as follows: Figure 1 As shown.

[0108] 4. Stability observation of hydrobromide styraxone preparation in the example

[0109] Accelerated stability testing was performed on the formulations of the examples to determine their stability under high temperature (40°C) and high humidity (relative humidity 75±5%). Samples were taken at months 0, 1, 2, 3, 5, and 6 to determine the content of related substances (impurity A and impurity B). The results are as follows. Figure 2 As shown.

[0110] 5. Example: Efficacy test of hydrobromide styraxone preparation against chicken coccidiosis.

[0111] Experimental animals and grouping: Healthy 20-day-old dwarf yellow broiler chickens, half male and half female, were selected and fed normally for 4 days. 20 chickens were then used as the normal control group. On day 5, 1 mL of sporulated oocyst fluid (containing 1×10⁻⁶ oz.) from another 120 chickens was inoculated into them. 5 The samples were divided into four groups: Example 1, Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3. After grouping, each group was administered the drug according to the administration method. On the 6th day after administration, each group was weighed (and the dead chickens during the experiment were also counted and weighed), and feces were collected.

[0112] Administration method: The normal control group was administered the same as in Example 1. For the other groups, the products prepared according to Examples 1, 2, Comparative Examples 1, 2, and 3 of this invention were added to the drinking water of chicks, while commercially available formulations were added to their feed. The dosage was 0.2 mg / kg (calculated as thiazolinone hydrobromide). Administration was continued for 6 consecutive days.

[0113] The results of the experiment were observed and recorded and are shown in Table 2.

[0114] Table 2 Results of pharmacodynamic tests

[0115] Example 1 27.9 0 100 Example 2 26.2 0 100 Comparative Example 1 10.2 35 85 Comparative Example 2 19.7 21 95 Comparative Example 3 13.0 28 90 Commercially available formulations 21.3 2 100

Claims

1. A solid dosage form of styraxone hydrobromide, characterized in that, The solid dosage form is prepared from styraxone nanospheres and excipients; wherein the styraxone hydrobromide nanospheres are composed of the following components: 10 parts by weight of styraxone hydrobromide, 5-8 parts by weight of hydrolyzed wheat protein, 80-100 parts by weight of dodecyl maltodextrin, and 20-30 parts by weight of PLGA. The preparation method of the hydrobromic acid styraxone nanospheres includes the following steps: (1) Dissolve styraxone hydrobromide, wheat hydrolysate, and dodecyl maltodextrin in water at 15-30°C, and adjust the pH to 5.5-6.5 with phosphate buffer to obtain solution A for later use; (2) Dissolve PLGA in an organic solvent to obtain solution B, and set aside; (3) Place solution A and solution B in a high-speed homogenizer and perform high-pressure emulsification circulation at 17,000 rpm at 20-25℃, followed by medium-speed stirring to obtain an emulsion. (4) Collect the nanospheres by high-speed centrifugation, wash with water, and then obtain hydrobromic acid styraxone nanospheres.

2. The solid dosage form as described in claim 1, characterized in that, The hydrobromic acid styracin nanospheres are composed of the following components: 10 parts by weight of styracin, 7.5 parts by weight of hydrolyzed wheat protein, 70 parts by weight of dodecyl maltodextrin, and 25 parts by weight of PLGA.

3. The solid dosage form as described in claim 1, characterized in that, The excipients are selected from one or more of diluents, stabilizers, binders, disintegrants, and lubricants.

4. The solid dosage form as described in claim 1, characterized in that, The solid dosage form is one of tablets, granules, or capsules.

5. The use of the hydrobromide acetophenone solid dosage form as described in claim 1 in the preparation of a drug for treating Eimeria coccidia in chickens.

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