VETERINARY BROMHEXINE HYDROCHLORIDE SOLUBLE POWDER, PREPARATION METHOD AND USE THEREOF

Abstract

A veterinary bromhexine hydrochloride soluble powder, a preparation method and use thereof are disclosed. The method includes: (1) weighing a prescription amount of bromhexine hydrochloride and a part of prescription amount of citric acid, performing a primary mixing, pulverizing, sieving and dividing the mixed material into three equal parts; (2) weighing a remaining prescription amount of citric acid, pulverizing, sieving and dividing it into three equal parts; (3) weighing a prescription amount of lactose, sieving, and weighing three parts of the lactose accounting for 10% of the total amount; (4) putting one part of the mixed material obtained in “1”, one part of citric acid obtained in “2” and one part of lactose obtained in “3” alternately into a multi-directional motion mixer; (5) notifying an QA to inspect semi-finished products; and (6) packaging qualified semi-finished products, and warehousing qualified finished products.

Claims

1. A veterinary bromhexine hydrochloride soluble powder, comprising 1-2% by mass of bromhexine hydrochloride, 8-15% by mass of co-solvent citric acid, with the mass being soluble auxiliary material lactose.

2. A method for preparing the veterinary bromhexine hydrochloride soluble powder, comprising: step 1: accurately weighing a prescription amount of bromhexine hydrochloride and a part of prescription amount of citric acid, performing a primary mixing for a certain time or a manual primary mixing, putting the resulting mixed material after the primary mixing into a pulverizer and pulverizing, and sieving the mixed material after the pulverizing and dividing the mixed material into three equal parts for later use; step 2: weighing a remaining prescription amount of citric acid, putting the citric acid into a pulverizer and pulverizing, and sieving the citric acid after the pulverizing and dividing the citric acid into three equal parts for later use; step 3: weighing a prescription amount of lactose, sieving the lactose, and weighing three parts of the lactose accounting for 10% of the total amount of the lactose for later use; step 4: putting one part of the mixed material obtained in step 1, one part of the citric acid obtained in step 2, and one part of the lactose obtained in step 3 alternately into a multi-directional motion mixer; step 5: after mixing, notifying an on-site quality assurer to take a semi-finished product for inspection, and inspecting morphology, solubility, moisture, content and content uniformity; and step 6: split charging, sealing and packaging the semi-finished product after being qualified through inspection, and warehousing a finished product after being qualified through inspection.

3. The method as claimed in claim 2, wherein in step 1, the citric acid is in an amount of 30% of the prescription amount, and the time for the primary mixing is 10 minutes.

4. The method as claimed in claim 2, wherein in step 1, the sieving is performed by a 100-mesh sieve.

5. The method as claimed in claim 2, wherein in step 2, the remaining prescription amount of citric acid is weighted, put into the pulverizer and pulverized, and the pulverized citric acid is sieved and divided into three equal parts for later use.

6. The method as claimed in claim 2, wherein in step 2, the sieving is performed by a 100-mesh sieve.

7. The method as claimed in claim 2, wherein in step 3, the sieving is performed by an 80-mesh sieve.

8. The method as claimed in claim 2, wherein in step 3, the prescription amount of lactose is weighted, and three parts of lactose accounting for 10% of the total amount of the lactose are weighted.

9. The method as claimed in claim 2, wherein in step 4, putting the materials into a multi-directional motion mixer is performed as follows: after each one part of the material is added, the materials are mixed for 10 minutes; then the remaining amount of lactose is added at one time and the materials are mixed for 20 minutes; wherein the content uniformity is monitored depending on conditions of a mixing equipment.

10. A drug for auxiliary treatment of respiratory diseases of livestock and poultry, wherein the drug is prepared by using a veterinary bromhexine hydrochloride soluble powder comprising 1-2% by mass of bromhexine hydrochloride, 8-15% by mass of co-solvent citric acid, with the mass being soluble auxiliary material lactose.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0032] The accompanying drawings, which are incorporated in and constitute part of this specification, illustrate embodiments of the invention and together with the description, serve to explain the principles of the invention. The embodiments illustrated herein are presently preferred, it being understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown, wherein:

[0033] FIG. 1 shows a flow chart of a method for preparing a veterinary bromhexine hydrochloride soluble powder according to an embodiment of the present disclosure.

[0034] FIG. 2 shows curves of average blood concentration versus time of bromhexine hydrochloride soluble powder (tested) taken orally by chicken for three different doses.

[0035] FIG. 3 shows curves of average blood concentration versus time of tested bromhexine hydrochloride soluble powder and a reference formulation which are taken orally by chicken.

DETAILED DESCRIPTION OF THE INVENTION

[0036] In order to make the objects, technical solutions, and advantages of the present disclosure clearer, the present disclosure will be further described in detail below in combination with examples. It should be understood that the specific examples described herein are only used to explain but not to limit the present disclosure.

[0037] Aiming at the problems in the prior art, the present disclosure provides a veterinary bromhexine hydrochloride soluble powder, a preparation method and use thereof. The present disclosure will be further described in detail below in combination with drawings.

[0038] As shown in FIG. 1, a method for preparing a veterinary bromhexine hydrochloride soluble powder according to an embodiment of the present disclosure includes the following steps:

[0039] S101: accurately weighing a prescription amount of bromhexine hydrochloride and a part of prescription amount of citric acid, performing a primary mixing for a certain time or a manual primary mixing, putting the resulting mixed material after the primary mixing into a pulverizer and pulverizing, and sieving the mixed material after the pulverizing and dividing the mixed material into three equal parts for later use;

[0040] S102: weighing a remaining prescription amount of citric acid, putting the citric acid into a pulverizer and pulverizing, and sieving the citric acid after the pulverizing and dividing the citric acid into three equal parts for later use;

[0041] S103: weighing a prescription amount of lactose, sieving the lactose, and weighing three parts of the lactose accounting for 10% of the total amount of the lactose for later use;

[0042] S104: putting one part of the mixed material obtained in S101, one part of the citric acid obtained in S102 and one part of the lactose obtained in S103 alternately into a multi-directional motion mixer;

[0043] S105: after mixing, notifying an on-site QA to take a semi-finished product for inspection, and inspecting morphology, solubility, moisture, content and content uniformity; and

[0044] S106: split charging, sealing and packaging the semi-finished product after being qualified through inspection, and warehousing a finished product after being qualified through inspection.

[0045] In S101 of an embodiment of the present disclosure, the citric acid is in an amount of 30% of the prescription amount, and the time for the primary mixing is 10 minutes.

[0046] In S101 of an embodiment of the present disclosure, the sieving is performed by a 100-mesh sieve.

[0047] In S102 of an embodiment of the present disclosure, the sieving is performed by a 100-mesh sieve.

[0048] In S103 of an embodiment of the present disclosure, the sieving is performed by an 80-mesh sieve.

[0049] In S104 of an embodiment of the present disclosure, putting the materials into a multi-directional motion mixer is performed as follows: after each one part of the material is added, the materials are mixed for 10 minutes; then the remaining amount of lactose is added at one time, and the materials are mixed for 20 minutes; wherein the content uniformity is monitored depending on the condition of the mixing equipment.

Example 1

[0050] The veterinary bromhexine hydrochloride soluble powder provided by this example consisted of 2 kg of bromhexine hydrochloride, 20 kg of citric acid, and lactose with an amount being supplement to 200 kg.

Example 2

[0051] The veterinary bromhexine hydrochloride soluble powder provided by this example consisted of 2 kg of bromhexine hydrochloride, 22 kg of citric acid, and lactose with an amount being supplement to 200 kg.

Example 3

[0052] The veterinary bromhexine hydrochloride soluble powder provided by this example consisted of 2 kg of bromhexine hydrochloride, 24 kg of citric acid, and lactose with an amount being supplement to 200 kg.

Example 4

[0053] The veterinary bromhexine hydrochloride soluble powder provided by this example consisted of 3 kg of bromhexine hydrochloride, 26 kg of citric acid, and lactose with an amount being supplement to 200 kg.

Example 5

[0054] The veterinary bromhexine hydrochloride soluble powder provided by this example consisted of 3 kg of bromhexine hydrochloride, 28 kg of citric acid, and lactose with an amount being supplement to 200 kg.

Example 6

[0055] The veterinary bromhexine hydrochloride soluble powder provided by this example consisted of 4 kg of bromhexine hydrochloride, 30 kg of citric acid, and lactose with an amount being supplement to 200 kg.

Example 7

[0056] The veterinary bromhexine hydrochloride soluble powder provided by this example consisted of 4 kg of bromhexine hydrochloride, 34 kg of citric acid, and lactose with an amount being supplement to 200 kg.

Example 8

[0057] The veterinary bromhexine hydrochloride soluble powder provided by this example consisted of 4 kg of bromhexine hydrochloride, 40 kg of citric acid, and lactose with an amount being supplement to 200 kg.

[0058] The products in the above 8 examples were investigated according to relevant methods of Chinese Veterinary Pharmacopoeia, 2015 Edition for their morphology, solubility, moisture content, related substances, and content. The results are shown in Table 1, which indicate that all the above examples result in formulations with high solubility and good stability.

TABLE-US-00001 TABLE 1 Results of quality analysis of different examples Investigated Items Examples Total No. Morphology Solubility Moisture Impurity I Impurities Content 1 White Completely 4.7 Not 0.53 98.61 powder dissolved detected 2 White Completely 4.8 Not 0.52 98.75 powder dissolved detected 3 White Completely 4.8 Not 0.53 99.12 powder dissolved detected 4 White Completely 4.9 Not 0.54 98.54 powder dissolved detected 5 White Completely 4.7 Not 0.55 98.48 powder dissolved detected 6 White Completely 4.8 Not 0.53 99.05 powder dissolved detected 7 White Completely 4.9 Not 0.55 98.58 powder dissolved detected 8 White Completely 5.1 Not 0.56 99.21 powder dissolved detected

[0059] In the present disclosure, tests for technical effects and technical solutions were performed. For the product prepared in Example 1, the content uniformity of the prepared bromhexine hydrochloride soluble powder was measured according to the measuring method for content uniformity in Appendix 0941 of Chinese Veterinary Pharmacopoeia, 2015 Edition. The results are shown in Table 2. The results show that the average of content uniformity of the prepared bromhexine hydrochloride soluble powders is 98.65 and relative standard deviation (RSD) is 0.17%, which meets the requirements of Chinese Veterinary Pharmacopoeia, 2015 Edition on content uniformity of soluble powder, indicating that the preparation method could be used in industrialization.

TABLE-US-00002 Table 2 Content uniformity of the bromhexine hydrochloride soluble powder Serial Number 1 2 3 4 5 6 7 8 9 10 Average RSD % Content/% 98.87 98.85 98.56 98.67 98.72 98.35 98.62 98.58 98.81 98.49 98.65 0.17%

[0060] The product prepared in Example 1 was subjected to strong light irradiation test (illuminance 4500×±5001×), high temperature (40° C.) test, and high humidity (25° C., relative humidity 90%) test respectively, according to “Guiding Principles of Veterinary Drug Stability Test Technology” in Chinese Veterinary Pharmacopoeia, 2015 Edition. The results are shown in Table 3. The results show that the prepared bromhexine hydrochloride soluble powder has no significant changes in content of bromhexine hydrochloride, related substances and moisture after 15 days.

TABLE-US-00003 TABLE 3 Results of influence factor test on bromhexine hydrochloride soluble powder Bromhexine Hydrochloride Total Tested Items Solubility Moisture Content Impurity I Impurities Light 0 days Meet the 4.7 98.68 Not detected 0.53 irradiation requirement test 5 days Meet the 4.8 98.72 Not detected 0.53 requirement 10 days  Meet the 4.7 98.65 Not detected 0.54 requirement High 0 days Meet the 4.7 98.68 Not detected 0.53 temperature requirement test 5 days Meet the 4.7 98.58 Not detected 0.54 requirement 10 days  Meet the 4.8 98.51 Not detected 0.54 requirement High 0 days Meet the 4.7 98.68 Not detected 0.53 humidity requirement test 5 days Meet the 4.8 98.65 Not detected 0.54 requirement 10 days  Meet the 4.8 98.74 Not detected 0.53 requirement

[0061] The product prepared in Example 1 was placed at a temperature of 40±2° C. and a relative humidity of 75±5% for 6 months, and samples were taken at 0 day and the end of 1, 2, 3, and 6 months, and subjected to an accelerated test respectively, according to “Guiding Principles of Veterinary Drug Stability Test Technology” in Chinese Veterinary Pharmacopoeia, 2015 Edition. The results are shown in Table 4.

TABLE-US-00004 TABLE 4 Results of accelerated test of the bromhexine hydrochloride soluble powder Investigated Time at which the sample was taken and tested Items 0 day 1 month 2 months 3 months 6 months Solubility Meet the Meet the Meet the Meet the Meet the requirement requirement requirement requirement requirement Moisture/% 4.7 4.8 4.7 4.7 4.8 Impurity I/% Not detected Not detected Not detected Not detected 0.11 Total  0.53  0.56  0.61  0.63 0.74 Impurities/% Content/% 98.68 98.65 98.61 98.54 98.28

[0062] Pharmacokinetic tests of bromhexine hydrochloride soluble powder in chickens were carried out based on three administration dosages of 50 mg/kg.Math.bw, 150 mg/kg.Math.bw and 250 mg/kg.Math.bw. The results show that bromhexine has a linear pharmacokinetic characteristic in chickens. Curves of average blood concentration versus time are shown in FIG. 2.

[0063] A bioequivalence study was conducted on the products described herein, according to the announcement of Ministry of Agriculture of the People's Republic of China No. 2337 “Quality Management Regulations for Veterinary Drug Clinical Trials” and “Guiding Principles for Bioequivalence Testing of Veterinary Chemicals”, by using 70 healthy chickens which were randomly divided into 2 groups and using QUENTAN POUDRE® produced by Boehringer-Ingelheim as a reference group. Bioequivalence were analyzed using the bioequivalence analysis module of WinNonlin software. The results are shown in FIG. 3 and Table 5.

TABLE-US-00005 TABLE 5 Parameters of bioequivalence analysis of the tested bromhexine hydrochloride soluble powder and reference formulations 90% Confidence interval Parameters P value CI_90_lower CI_90_Upper Ln(AUClast) 0.52 95.02 102.14 Ln(AUCobs) 0.63 95.57 102.39 Ln(C.sub.max) 0.48 93.18 103.51

[0064] Of note, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “includes”, and/or “including,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

[0065] As well, the corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. The embodiment was chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.

[0066] Having thus described the invention of the present application in detail and by reference to embodiments thereof, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims as follows: