Bromhexine hydrochloride composition and preparation method thereof

Abstract

The invention provides a bromhexine hydrochloride composition which comprises bromhexine hydrochloride, a cosolvent and a solvent, the content of bromhexine hydrochloride is 1-10w / v%, the content of the cosolvent is 10-50v / v%, and the bromhexine hydrochloride composition further comprises phenol. The bromhexine hydrochloride composition is stable in property and high in solubility, can be mutually soluble with water in any ratio, is simple in production process, is suitable for a bromhexine hydrochloride preparation produced industrially, and achieves the effect through optimization of components and proportions.

Description

Technical Field

[0001] The invention belongs to the field of veterinary drug preparation, and particularly relates to a bromhexine hydrochloride composition and a preparation method thereof. Background Art

[0002] Respiratory diseases have always been a type of disease that restricts the development of the breeding industry. If individual animals become ill, the entire herd will be infected, seriously affecting production efficiency.

[0003] Bromhexine Hydrochloride was developed by Boehringer Ingelheim in Germany and marketed in the 1960s under the trade name "Bisouping". It was marketed in my country in the 1970s. Boehringer Ingelheim conducted systematic preclinical pharmacology, toxicology and clinical studies on bromhexine hydrochloride and marketed it in Germany for the first time. It is now marketed in most countries in the world, including China, and has become a best-selling expectorant.

[0004] Bromhexine hydrochloride is slightly soluble in ethanol or chloroform and very slightly soluble in water, so there are many technical difficulties in preparing liquid preparations, especially high-content liquid preparations. Summary of the invention

[0005] The purpose of the present invention is to provide a bromhexine hydrochloride composition and a preparation method thereof in view of the problems existing in the prior art.

[0006] The invention provides a bromhexine hydrochloride preparation which has stable properties, significant effects, can be miscible with water in any ratio, has a simple production process and is suitable for industrial production. The effects are achieved by optimizing components and proportions.

[0007] In order to achieve the above object, the present invention provides a bromhexine hydrochloride preparation, comprising bromhexine hydrochloride, a cosolvent, an antibacterial agent, a stabilizer and a solvent. The present invention uses phenol as both an antibacterial agent and a stabilizer, thereby improving the stability and solubility of the bromhexine hydrochloride preparation, and in combination with antibiotics, improving the clinical effect of the antibiotics.

[0008] The invention provides a bromhexine hydrochloride composition, comprising bromhexine hydrochloride, a cosolvent and a solvent, wherein the content of the bromhexine hydrochloride is 1-10 w / v %, the content of the cosolvent is 10-50 v / v %, and the bromhexine hydrochloride composition further comprises phenol.

[0009] Preferably, the content of phenol is 0.5-2.5 w / v%.

[0010] Any of the above is preferably that the content of bromhexine hydrochloride is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 w / v % and ranges therebetween.

[0011] Preferably, any of the above items has a co-solvent content of 10, 20, 30, 40, 50 v / v % and ranges therebetween.

[0012] Preferably, any of the above items has a phenol content of 0.5, 1.0, 1.5, 2.0, 2.5 w / v % and ranges therebetween.

[0013] Preferably, in any of the above items, the co-solvent is at least one of N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, and diethylene glycol monoethyl ether.

[0014] Preferably, in any of the above items, the solvent is one or more of water or alcohols.

[0015] Preferably, the alcohol is propylene glycol.

[0016] Any one of the above is preferably that the bromhexine hydrochloride composition also includes an antibiotic.

[0017] Preferably, any of the above items is that the antibiotic is one of macrocyclic drugs, tetracycline drugs, quinolone drugs, and chloramphenicol drugs.

[0018] Preferably, any of the above items is that the antibiotic is preferably at least one of tylosin tartrate, doxycycline hydrochloride, tilmicosin phosphate, tulathromycin, and enrofloxacin.

[0019] The present invention also provides a method for preparing the bromhexine hydrochloride composition described in any one of the above items, comprising the following steps:

[0020] Step 1, stirring the cosolvent, phenol and solvent evenly;

[0021] Step 2, adding bromhexine hydrochloride and antibiotics into step 1, heating, stirring until dissolved, fixing the volume of the solvent to 100% of the total volume of the bromhexine hydrochloride composition, and filtering.

[0022] Preferably, the volume of the solvent in step 1 is 50% of the total volume of the bromhexine hydrochloride composition.

[0023] Any of the above is preferably that in step 2, the heating temperature does not exceed 60° C. Preferably, during the preparation process, the heating is slowly performed according to the dissolution rate, and the temperature does not exceed 60° C.

[0024] Any of the above is preferably that in step 2, the heating temperature of the dissolution process is 30, 40, 50, 60°C, or not more than 40°C, or not more than 50°C, or not more than 60°C.

[0025] The present invention has the following beneficial technical effects:

[0026] 1. The product has high content, low unit production cost, simple preparation process, and is suitable for industrial production;

[0027] 2. The bromhexine hydrochloride composition is used in combination with antibiotics to increase the drug concentration of antibiotics in the respiratory system. The combination of the two can improve the clinical effect of antibiotics;

[0028] 3. The bromhexine hydrochloride composition of the present invention is a liquid preparation, which dissolves faster in water than solid preparations and is easy to use;

[0029] 4. Phenol not only serves as an antibacterial agent of the preparation, but also improves the stability of the bromhexine hydrochloride preparation and unexpectedly increases its solubility in water. It can be diluted with water in any ratio and there is no precipitation within 24 hours, thus meeting the needs of different clinical customer groups. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The concentration-time curve of doxycycline in lung tissue after single gavage administration in preferred embodiment 2 of the present invention is shown. DETAILED DESCRIPTION

[0031] The specific implementation of the present invention will be described in detail below. In order to avoid too many unnecessary details, the well-known structures or functions will not be described in detail in the following embodiments.

[0032] Unless otherwise defined, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0033] All numerical designations, such as temperature, time, concentration, including ranges, are approximate. It is to be understood, although not always expressly stated, that all numerical designations are preceded by the term "about". It is also to be understood, although not always expressly stated, that the reagents described herein are merely examples and that equivalents thereof are known in the art.

[0034] Example 1

[0035] A bromhexine hydrochloride composition comprises 1g of bromhexine hydrochloride, 10ml of diethylene glycol monoethyl ether, 10g of tylosin tartrate, 0.5g of phenol, and propylene glycol to make up to 100ml.

[0036] The solution was prepared by:

[0037] (1) adding a prescribed amount of phenol to a mixed solution of a prescribed amount of diethylene glycol monoethyl ether and 50% propylene glycol, and stirring until dissolved;

[0038] (2) Add the prescribed amount of bromhexine hydrochloride and tylosin tartrate to (1) in sequence and stir until dissolved; dilute to 100 ml with propylene glycol;

[0039] (3) Filter and package.

[0040] Example 2

[0041] A bromhexine hydrochloride composition comprises 5 g of bromhexine hydrochloride, 40 ml of N,N-dimethylacetamide, 30 g of doxycycline hydrochloride, 1.5 g of phenol, and propylene glycol to make up to 100 ml.

[0042] The solution was prepared by:

[0043] (1) adding a prescribed amount of phenol to a mixed solution of a prescribed amount of N,N-dimethylacetamide and 50% propylene glycol, and stirring until dissolved;

[0044] (2) Add the prescribed amount of bromhexine hydrochloride and doxycycline hydrochloride to (1) in sequence and stir until dissolved; dilute to 100 ml with propylene glycol;

[0045] (3) Filter and package.

[0046] Example 3

[0047] A bromhexine hydrochloride composition comprises 7 g of bromhexine hydrochloride, 20 ml of dimethyl sulfoxide, 30 g of tilmicosin phosphate, 2.5 g of phenol, and the mixture is made up to 100 ml with purified water.

[0048] The solution was prepared by:

[0049] (1) adding a prescribed amount of phenol to a mixed solution of a prescribed amount of dimethyl sulfoxide and 50% purified water, and stirring until dissolved;

[0050] (2) Add the prescribed amount of bromhexine hydrochloride and tilmicosin phosphate to (1) in sequence, stir until dissolved; and dilute to 100 ml with purified water;

[0051] (3) Filter and package.

[0052] Example 4

[0053] A bromhexine hydrochloride composition comprises 2 g of bromhexine hydrochloride, 25 ml of N-methylpyrrolidone, 10 g of tulathromycin, 0.5 g of phenol, and the mixture is made up to 100 ml with purified water.

[0054] The solution was prepared by:

[0055] (1) adding the prescribed amount of phenol to a mixed solution of the prescribed amount of N-methylpyrrolidone and 50% purified water, and stirring until dissolved;

[0056] (2) Add the prescribed amount of bromhexine hydrochloride and tulathromycin to (1) in sequence, stir until dissolved; and dilute to 100 ml with purified water;

[0057] (3) Filter and package.

[0058] Example 5

[0059] A bromhexine hydrochloride composition comprises 5g of bromhexine hydrochloride, 50ml of N,N-dimethylformamide, enrofloxacin, 1g of phenol, and propylene glycol to make up to 100ml.

[0060] The solution was prepared by:

[0061] (1) adding a prescribed amount of phenol to a mixed solution of a prescribed amount of N,N-dimethylformamide and 50% propylene glycol, and stirring until dissolved;

[0062] (2) Add the prescribed amount of bromhexine hydrochloride and enrofloxacin to (1) in sequence and stir until dissolved; dilute to 100 ml with propylene glycol;

[0063] (3) Filter and package.

[0064] Comparative Example 1

[0065] The components and preparation method are basically the same as those of Example 2, except that Comparative Example 1 does not contain phenol.

[0066] Comparative Example 2

[0067] The components and preparation method are basically the same as those of Example 2, except that Comparative Example 2 does not contain bromhexine hydrochloride.

[0068] Test Example 1 Stability Test

[0069] The prepared samples of the embodiments of the present invention and the comparative examples were placed at 60° C. for 30 days. On the 10th day and the 30th day, relevant indicators were tested as shown in Table 1.

[0070] Table 1:

[0071]

[0072]

[0073] Each embodiment has good stability. Compared with the embodiment 2 with the addition of phenol, the impurities in the comparative embodiment 1 without the addition of phenol increased by about 2.4% in 30 days, and the content of bromhexine hydrochloride decreased by about 3.0%, indicating that phenol has the effect of increasing the stability of bromhexine hydrochloride.

[0074] Test Example 2: Stability test of aqueous solution of bromhexine hydrochloride preparation

[0075] 1. Materials and methods

[0076] (1) Test drugs: preparations of Example 2 and Comparative Example 1.

[0077] (2) Test method: Each preparation was diluted with tap water at a ratio of 1:10 / 1:50 / 1:100 / 1:500 / 1:1000, and the drug precipitation was observed.

[0078] (II) The test results are shown in Table 2.

[0079] Table 2: Precipitation at different dilution ratios

[0080]

[0081] The results show that phenol can improve the solubility of bromhexine hydrochloride at a high content, and the bromhexine hydrochloride composition provided by the present invention can be diluted with water in any ratio.

[0082] Test Example 3: Drug concentration test of bromhexine hydrochloride preparation in respiratory system of animals

[0083] 1. Materials and methods

[0084] (1) Test drugs: preparations of Example 2 and Comparative Example 2.

[0085] (2) Test method: 250 healthy yellow-feathered broilers were randomly divided into two groups. The preparations of Example 2 and Comparative Example 2 were diluted 100 times for standby use. The two preparations were administered orally to the yellow-feathered broilers at a dose of 20 mg / kg body weight of doxycycline hydrochloride. Ten chickens were killed at 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 h, respectively, and their lungs were taken to detect the content of doxycycline hydrochloride in the lungs.

[0086] (II) Test results

[0087] The drug-time curves of doxycycline in Example 2 and Comparative Example 2 in the lung tissue of yellow-feathered broiler chickens are shown in FIG. Figure 1 The specific pharmacokinetic parameters of doxycycline in lung tissue of yellow-feathered broiler chickens at different time points were analyzed by WinNonlin. Table 3 shows the specific pharmacokinetic parameters. max The elimination half-life was 2.88±2.39μg / g and 10.56±3.17μg / g, respectively. 1 / 2β The peak time was 6.36±2.17h and 6.67±2.89h respectively. max They were 0.78±0.35h and 0.89±0.26h respectively, and the areas under the drug-time curve were 19.05±12.77h*ug / g and 50.61±10.11h*ug / g respectively. It can be seen that bromhexine hydrochloride has a synergistic effect.

[0088] Table 3: Pharmacokinetic parameters of doxycycline (n=10)

[0089]

[0090]

[0091] The above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A bromhexine hydrochloride composition, comprising bromhexine hydrochloride, a cosolvent and a solvent, characterized in that: The content of bromhexine hydrochloride is 1-10w / v%, the content of the co-solvent is 10-50v / v%, and the bromhexine hydrochloride composition further comprises phenol.

2. bromhexine hydrochloride composition as claimed in claim 1, is characterized in that, The content of the phenol is 0.5-2.5 w / v%.

3. bromhexine hydrochloride composition as claimed in claim 2, is characterized in that, The co-solvent is at least one of N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, and diethylene glycol monoethyl ether.

4. bromhexine hydrochloride composition as claimed in claim 3, is characterized in that, The solvent is one or more of water or alcohols.

5. bromhexine hydrochloride composition as claimed in claim 4, is characterized in that, The alcohol is propylene glycol.

6. bromhexine hydrochloride composition as claimed in claim 5, is characterized in that, The bromhexine hydrochloride composition also includes antibiotics.

7. bromhexine hydrochloride composition as claimed in claim 6, is characterized in that, The antibiotic is one of macrocyclic drugs, tetracycline drugs, quinolone drugs, and chloramphenicol drugs.

8. according to the preparation method of each described bromhexine hydrochloride composition of claim 1 to 7, comprise the following steps: Step 1, stirring the cosolvent, phenol and solvent evenly; Step 2, adding bromhexine hydrochloride and antibiotics into step 1, stirring until dissolved, fixing the volume of the solvent to 100% of the total volume of the bromhexine hydrochloride composition, and filtering.

9. The preparation method according to claim 8, characterized in that: The volume of the solvent in step 1 is 50% of the total volume of the bromhexine hydrochloride composition.

10. The preparation method according to claim 8, characterized in that: In step 2, during the stirring and dissolving process, the solution is heated to a temperature not exceeding 60°C.

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