CN111714477B

CN111714477B - Phlegm eliminating composition and preparation method of oral liquid thereof

Info

Publication number: CN111714477B
Application number: CN202010716282.0A
Authority: CN
Inventors: 汪安国; 李梁梁; 李凤华; 田玉虎
Original assignee: Shandong Soocom Animal Remedy Co ltd
Current assignee: Shandong Soocom Animal Remedy Co ltd
Priority date: 2020-07-23
Filing date: 2020-07-23
Publication date: 2021-06-15
Anticipated expiration: 2040-07-23
Also published as: CN111714477A

Abstract

The invention provides a phlegm eliminating composition and a preparation method of an oral liquid thereof, belonging to the technical field of medicinal preparations. The composition contains bromhexine hydrochloride and menthol, can be dissolved in a certain solvent, and is prepared into oral liquid under the action of an emulsifier and a cosurfactant. The oral liquid has good stability, no discoloration after long-term storage, stable content of bromhexine hydrochloride and menthol, and good effect of clearing heat and eliminating phlegm.

Description

Phlegm eliminating composition and preparation method of oral liquid thereof

Technical Field

The invention belongs to the technical field of medicinal preparations, and particularly relates to an expectorant composition containing bromhexine hydrochloride and menthol and a preparation method of an oral liquid thereof.

Background

Bromhexine hydrochloride is a novel mucus-soluble expectorant synthesized according to the structure of an effective component (caricaine) extracted from medicinal plant Adhatoda vasica, and has strong effect of dissolving mucus. Can differentiate and crack mucopolysaccharide fiber in the sputum, and inhibit synthesis of mucopolysaccharide, so as to reduce sialic acid (one of acidic mucopolysaccharide components) content in the sputum, thereby reducing viscosity of the sputum, and has nausea and phlegm eliminating effects after oral administration, so that the sputum is easy to expectorate, and the respiratory tract is unblocked. The traditional Chinese medicine composition is clinically used for treating acute and chronic bronchitis, asthma, bronchiectasis and emphysema, and is particularly suitable for people with difficulty in white sticky sputum expectoration and symptoms such as acute qi and the like caused by wide blockage of small bronchus by sputum.

Mentholum is a saturated cyclic alcohol obtained from oleum Menthae Dementholatum, and has effects of dispelling pathogenic wind, clearing away heat and toxic materials. It can be used as wind-expelling medicine for treating headache, and inflammation of nose, pharynx, and larynx.

Bromhexine hydrochloride is dissolved in water to a very small extent, so that the content of oral bromhexine hydrochloride preparations on the market is low at present, the phlegm eliminating effect of the medicine is influenced, and a blank exists in the high-concentration oral bromhexine hydrochloride preparations on the market. Bromhexine hydrochloride and menthol have the functions of supplementing each other in medicine property, and can jointly act on infection of a respiratory system to achieve the effects of clearing heat and eliminating phlegm. However, the market of the complex product of bromhexine hydrochloride and menthol, particularly the oral preparation, is blank at present.

Disclosure of Invention

In order to solve the above problems, the present invention provides a composition containing bromhexine hydrochloride and menthol, which can be prepared into an oral liquid for eliminating phlegm.

The specific technical scheme is as follows:

a composition for eliminating phlegm comprises bromhexine hydrochloride and menthol;

in the above composition, bromhexine hydrochloride: the weight ratio of the menthol to the menthol is 1: 4-1: 1.

The composition can be used for preparing medicine for eliminating phlegm.

Bromhexine hydrochloride and menthol are both dissolved in water very slightly, and when the composition is prepared into water-soluble oral liquid, the bromhexine hydrochloride and the menthol need to be dissolved in advance by adopting a proper solvent;

the solvent can be any solvent which is nontoxic to human body or medically proved to be applicable to human body, and dimethyl sulfoxide or dimethyl acetamide is preferable.

In order to assist the solvent to better dissolve bromhexine hydrochloride and menthol, a corresponding cosolvent can be added in the preparation of the oral liquid;

the cosolvent can be any cosolvent which is nontoxic to human bodies or can be taken by human bodies according to medical certification;

the cosolvent can adopt one or two of emulsifier and cosurfactant according to the dissolution condition;

the emulsifier is one of tween 80 and RH40 (polyoxyethylene hydrogenated castor oil), and the cosurfactant is one of propylene glycol and glycerol.

An oral liquid for eliminating phlegm comprises bromhexine hydrochloride, Mentholum, solvent, emulsifier, cosurfactant and water; the oral liquid comprises, by 100mL, 1-2 g of bromhexine hydrochloride, 2-4 g of menthol, 30-35 mL of a solvent, 0-15 mL of a cosurfactant, 5-15 g of an emulsifier and the balance of water;

preferably, the solvent in the oral liquid is one of dimethyl sulfoxide or dimethyl acetamide, the emulsifier is one of tween 80 and RH40, and the cosurfactant is one of propylene glycol and glycerol.

The preparation method of the oral liquid comprises the following steps:

adding bromhexine hydrochloride and menthol into a solvent, and stirring until the bromhexine hydrochloride and the menthol are completely dissolved; then adding an emulsifier and a cosurfactant, and uniformly stirring; the resulting solution was added to water with stirring until completely clear.

The invention has the following technical effects:

(1) the bromhexine hydrochloride and the menthol can be used in combination to achieve a synergistic effect on the removal of sputum, and the bromhexine hydrochloride in the oral liquid can reach a high content of 2% (W/V), so that the defect of low content of bromhexine hydrochloride in the oral liquid in the market is overcome;

(2) the oral liquid has good stability, does not change color after long-term storage, and has stable content of bromhexine hydrochloride and menthol;

(3) the oral liquid can be mutually dissolved with water in any proportion, and can be added into water for drinking;

(4) the oral liquid composition has proper taste, no bitter taste of bromhexine hydrochloride and little adverse reaction of nausea and vomiting.

Detailed Description

Terms used in the present invention have generally meanings as commonly understood by one of ordinary skill in the art, unless otherwise specified.

The present invention will be described in further detail with reference to the following data in conjunction with specific examples. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.

Example 1

The oral liquid comprises the following components:

bromhexine hydrochloride	1g
		Menthol crystal	2g
Dimethylacetamide	30mL
		Tween 80	6g
Water (W)	Balance of
		In total	100mL

The preparation method of the oral liquid comprises the following steps:

(1) adding bromhexine hydrochloride and menthol into dimethylacetamide, and stirring until the bromhexine hydrochloride and the menthol are completely dissolved;

(2) adding tween 80, and stirring;

(3) and (3) adding the solution system obtained in the step (2) into water, and stirring while adding until the solution system is completely clear.

Example 2

The oral liquid comprises the following components:

bromhexine hydrochloride	1.5g
		Menthol crystal	2g
Dimethylacetamide	30mL
		RH40	15g
Water (W)	Balance of
		In total	100mL

The preparation method of the oral liquid comprises the following steps:

(2) adding RH40, and stirring;

Example 3

The oral liquid comprises the following components:

bromhexine hydrochloride	1g
		Menthol crystal	2.5g
Dimethyl sulfoxide	35mL
		Tween 80	10g
Propylene glycol	15mL
		Water (W)	Balance of
In total	100mL

The preparation method of the oral liquid comprises the following steps:

(1) adding bromhexine hydrochloride and menthol into dimethyl sulfoxide, and stirring until the bromhexine hydrochloride and the menthol are completely dissolved;

(2) adding propylene glycol, stirring, adding Tween 80, and stirring;

Example 4

The oral liquid comprises the following components:

bromhexine hydrochloride	2g
		Menthol crystal	2g
Dimethyl sulfoxide	35mL
		RH40	15g
Propylene glycol	15mL
		Water (W)	Balance of
In total	100mL

The preparation method of the oral liquid comprises the following steps:

(2) adding propylene glycol, stirring, adding RH40, and stirring;

Example 5

The oral liquid comprises the following components:

the preparation method of the oral liquid comprises the following steps:

(2) adding RH40, and stirring;

Example 6

The oral liquid comprises the following components:

bromhexine hydrochloride	2g
		Menthol crystal	4g
Dimethylacetamide	33mL
		Tween 80	10g
Water (W)	Balance of
		In total	100mL

The preparation method of the oral liquid comprises the following steps:

(2) adding tween 80, and stirring;

Example 7

The oral liquid comprises the following components:

bromhexine hydrochloride	1g
		Menthol crystal	3.5g
Dimethyl sulfoxide	35mL
		Tween 80	10g
Glycerol	12mL
		Water (W)	Balance of
In total	100mL

The preparation method of the oral liquid comprises the following steps:

(2) adding glycerol, stirring, adding Tween 80, and stirring;

Example 8

The oral liquid comprises the following components:

the preparation method of the oral liquid comprises the following steps:

(2) adding glycerol, stirring, adding RH40, and stirring;

Synergistic test

Experimental animals: healthy Kunming mice, each half male and female, weigh 250 g-280 g;

grouping: mice were randomly divided into four ABCD groups of 10 mice each, each with a male and female half.

Group A is blank control group, and the stomach is irrigated with normal saline according to 2 mL/kg;

group B is bromhexine hydrochloride group, 1% (W/V) bromhexine hydrochloride solution (prepared according to example 1 without adding menthol) is diluted by 10 times, and the mixture is perfused by 2 mL/kg;

group C is menthol group, 2% (W/V) menthol solution (prepared according to example 1 without bromhexine hydrochloride) is diluted by 10 times, and the mixture is perfused by 2 mL/kg;

group D was combined and the solution containing bromhexine hydrochloride and menthol (prepared as in example 1) was diluted 10-fold and gavaged at 2 mL/kg.

And (3) treatment: 0.5h after the gavage, 0.5mL of 0.25% phenol red solution was intraperitoneally injected, and 0.5h after the injection, the mice were sacrificed, and the trachea was isolated. Inserting the needle into the trachea, fixing, and sucking 5% NaHCO₃And (5) irrigating with the solution. Injecting lavage liquid into a colorimetric tube, repeating for 3 times, performing colorimetric on the colorimetric tube at 546nm of wavelength of a spectrophotometer, measuring absorbance, calculating phenol red concentration of sputum according to a linear regression equation, and calculating relative percentage of phenol red excretion (phenol red excretion/blank excretion in experimental group)Control phenol red excretion). The test results are shown in Table 1.

TABLE 1 comparison of phenol Red excretion amounts in each group

Group of	Phenol Red discharge (μ g/mL)	Relative percentage (%)
			A	2.543182±0.163548	100
B	4.543218±0.512346	179
			C	2.568491±0.368431	101
D	5.324646±0.245813	209

As can be seen from the table, the phenol red excretion amounts of the group B and the group D are higher than those of the group A, and the group D is obviously higher than that of the group B, which indicates that B, D both groups have the effect of eliminating phlegm, and the group D is obviously better than that of the group B. The combination of bromhexine hydrochloride and menthol shows that the phlegm eliminating effect is obviously better than that of single bromhexine hydrochloride. The group C of Mentholum has no obvious effect of eliminating phlegm.

Effect of different solvents, emulsifiers and co-surfactants on the solubility of the compositions

Solvent impact test: adding 1g of bromhexine hydrochloride and 2g of menthol into a test tube with a plug, respectively adding 10mL of alternative solvents (ethanol, acetic acid, dimethylacetamide, dimethyl sulfoxide, ethyl acetate, propylene glycol, glycerol, isopropanol and n-butanol), observing the dissolution condition, and then gradually increasing the solvent to 20mL to observe the dissolution condition. The test results are shown in Table 2.

Emulsifier impact test: dissolving 1g of bromhexine hydrochloride and 2g of menthol in 20mL of screened solvent, adding 20mL of water, gradually adding alternative emulsifiers (Tween 80, polyoxyethylene hydrogenated castor oil RH40, span 80, polyethylene glycol PEG400, fatty alcohol polyoxyethylene ether OE20 and octyl phenol polyoxyethylene ether OP10) from 1g to 10g, and observing the change of the solution. The test results are shown in Table 3.

Cosurfactant effect test: taking 1g bromhexine hydrochloride and 2g menthol, preparing 100mL transparent solution by using the screened solvent and emulsifier, gradually adding alternative cosurfactant (propylene glycol, glycerol, isopropanol and n-butanol) from 1mL to 10mL, and observing the change of the solution. The test results are shown in Table 4.

TABLE 2 Effect of solvent System results

As can be seen from the table, only dimethylacetamide and dimethylsulfoxide were able to completely dissolve 1g of bromhexine hydrochloride and 2g of menthol when the solvent was increased to 20mL, so that dimethylacetamide or dimethylsulfoxide was selected as the solvent.

TABLE 3 Effect of emulsifiers test results

Kind of solvent

Tween 80

RH40

Span 80

PEG400

OE20

OP10

Dimethylacetamide

Semi-transparent

Layering

Turbidity

Dimethyl sulfoxide

Semi-transparent

Layering

Turbidity

As can be seen from the table, Tween 80 and RH40 have the best emulsification effect on the solution, so the emulsifier is Tween 80 or RH 40.

TABLE 4 Effect of cosurfactants on results

As can be seen from the table, when the solvent is dimethylacetamide, none of the four cosurfactants has a positive effect on the solution system; when the solvent is dimethyl sulfoxide, the propylene glycol and the glycerol can make the solution more transparent, and when the solvent is dimethyl sulfoxide, the propylene glycol or the glycerol can be added as a cosurfactant.

Water solubility test

The test samples of example 1, example 3, example 5 and example 8 were dissolved in 1-fold water, 2-fold water, 5-fold water, 10-fold water, 50-fold water and 100-fold water, respectively, and the test results were shown in Table 5 after standing and observation for 4 hours.

TABLE 5 Water solubility test results of various examples

Bitterness test

1% (W/V) bromhexine hydrochloride solution (prepared according to example 1 without adding menthol) and bromhexine hydrochloride menthol solution (prepared according to example 1) were prepared, and 10 volunteers were blinded. The test results are shown in Table 6.

TABLE 6 bitter taste test results

	Bitter taste (number of people)	Not bitter taste (number of people)
			1% bromhexine hydrochloride solution	10	0
Bromhexine hydrochloride menthol solution	1	9

As can be seen from the table, 10 simple bromhexine hydrochloride solutions were bitter, while 9 bromhexine hydrochloride solutions were not bitter, indicating that menthol was effective in eliminating the bitter taste of bromhexine hydrochloride.

Nausea and retching test

Experimental animals: healthy minks weigh 1.3-1.8 kg;

grouping: minks were randomly divided into four ABCD groups of 10 animals each.

Group A is blank control group, and the stomach is irrigated with normal saline according to 20 mL/kg;

group B is bromhexine hydrochloride group, 2% (W/V) bromhexine hydrochloride solution (prepared according to example 4 without adding menthol) is perfused into stomach according to 20 mL/kg;

group C was menthol group, 2% (W/V) menthol solution (prepared as in example 4 without bromhexine hydrochloride) was gavaged at 20 mL/kg;

group D was combined and a solution of bromhexine hydrochloride in menthol (prepared as in example 4) was gavaged at 20 mL/kg.

Mink reactions were observed and retching and vomiting times were recorded over 6 h. The test results are shown in Table 7.

TABLE 7 emetic effect of groups on minks

Group of	Causing vomiting rate	Average number of retching	Mean number of vomiting
				A	0/10	0	0
B	8/10	78	4
				C	0/10	0	0
D	1/10	1	0

As can be seen from the table, high doses of bromhexine hydrochloride can cause most (8/10) mink nausea and vomiting, and the effect of the combination of the bromhexine hydrochloride and menthol on mink nausea and vomiting is greatly reduced. The adverse reaction of nausea and vomiting caused by the coordination of the menthol and the bromhexine hydrochloride can be effectively reduced.

Stability test

With example 1, example 3, example 5 and example 8 as test samples, respectively, an accelerated test (simulating a commercially available package, temperature 40 ℃. + -. 2 ℃ C., relative humidity 75%. + -. 5%, standing for 6 months) and a long-term stability test (simulating a commercially available package, temperature 25 ℃. + -. 2 ℃ C., relative humidity 60%. + -. 10%, standing for 12 months) were carried out, and the test results are shown in tables 8, 9 and 10.

TABLE 8 detection results of bromhexine hydrochloride menthol solution on day 0

Detecting items	Example 1	Example 3	Example 5	Example 8
					Traits	Colorless clear solution	Colorless clear solution	Colorless clear solution	Colorless clear solution
Authentication	Positive for	Positive for	Positive for	Positive for
					PH	3.22	3.34	3.25	3.41
Bromhexine hydrochloride impurity E	0.003％	0.005％	0.004％	0.006％
					Bromhexine hydrochloride total impurities	0.016％	0.018％	0.015％	0.019％
Bromhexine hydrochloride content	98.4％	99.6％	97.2％	101.1％
					Menthol content	100.7％	98.5％	101.4％	99.2％

TABLE 9 accelerated test results of bromhexine hydrochloride menthol solution

Detecting items	Example 1	Example 3	Example 5	Example 8
					Traits	Colorless clear solution	Colorless clear solution	Colorless clear solution	Colorless clear solution
Authentication	Positive for	Positive for	Positive for	Positive for
					PH	3.19	3.35	3.23	3.46
Bromhexine hydrochloride impurity E	0.010％	0.013％	0.011％	0.012％
					Bromhexine hydrochloride total impurities	0.023％	0.025％	0.021％	0.024％
Bromhexine hydrochloride content	98.5％	99.4％	97.6％	100.9％
					Menthol content	100.3％	98.7％	101.3％	99.5％

TABLE 10 Long-term stability test results for bromhexine hydrochloride menthol solution

Detecting items	Example 1	Example 3	Example 5	Example 8
					Traits	Colorless clear solution	Colorless clear solution	Colorless clear solution	Colorless clear solution
Authentication	Positive for	Positive for	Positive for	Positive for
					PH	3.21	3.35	3.25	3.43
Bromhexine hydrochloride impurity E	0.007％	0.009％	0.008％	0.011％
					Bromhexine hydrochloride total impurities	0.019％	0.022％	0.018％	0.023％
Bromhexine hydrochloride content	98.3％	99.6％	97.0％	101.4％
					Menthol content	100.6％	98.4％	101.1％	99.0％

In conclusion, the bromhexine hydrochloride menthol solution has good stability, does not change color after long-term storage, has stable content of bromhexine hydrochloride and menthol and has low impurity content of bromhexine hydrochloride.

The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.

Claims

1. An oral liquid is characterized in that 100mL of the oral liquid comprises 1-2 g of bromhexine hydrochloride, 2-4 g of menthol, 30-35 mL of a solvent, 0-15 mL of a cosurfactant, 5-15 g of an emulsifier and the balance of water; the oral liquid is prepared by dissolving bromhexine hydrochloride and menthol in a solvent according to a mass ratio of 1: 4-1: 1, wherein the solvent is one of dimethyl sulfoxide and dimethylacetamide; in the process of preparing the oral liquid, an emulsifier is used for promoting the emulsification of a solution system, wherein the emulsifier is one of Tween 80 and RH 40; in the process of preparing the oral liquid, a cosurfactant is used for promoting the dissolution of a solvent and the transparency of a solution system, and the cosurfactant is one of propylene glycol and glycerol.

2. The process for preparing the oral liquid according to claim 1, which comprises the steps of: