CN110898041B - Bromhexine hydrochloride solution preparation for inhalation and preparation method thereof - Google Patents
Bromhexine hydrochloride solution preparation for inhalation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutics, and particularly relates to a bromhexine hydrochloride solution preparation for inhalation and a preparation method thereof. A bromhexine hydrochloride solution formulation for inhalation, said bromhexine solution comprising: bromhexine hydrochloride, a pH regulator and a solvent. The bromhexine hydrochloride solution preparation for inhalation provided by the invention has low impurity content, and the degradation rate of bromhexine in the long-term storage process of a solvent is low, wherein the content of the impurity E can be controlled within the range of less than 0.05%; namely, the inhalation solution preparation has high stability, reliable quality, high safety and long storage time; in addition, no preservative is added into the solution preparation, so that the safety coefficient of the solution preparation is higher, and the solution preparation has a proper taste and fully covers the bitter taste of bromhexine.
Description
Technical Field
The invention belongs to the field of pharmaceutics, and particularly relates to a bromhexine hydrochloride solution preparation for inhalation and a preparation method thereof.
Background
Bromhexine, chemical name is N-methyl-N-cyclohexyl-2-amino-3, 5-dibromo benzyl amine, molecular formula C 14 H 2 0Br 2 N 2 CAS:3572-43-8, which is a semi-synthetic product obtained by structurally modifying vasicine (vasicine), white or off-white crystalline powder; no odor and no taste; slightly soluble in ethanol or chloroform, and very slightly soluble in water.
Bromhexine hydrochloride directly acts on bronchial glands, which can promote lysosome release of mucus secretory cells to differentiate and crack mucopolysaccharide fibers in sputum; can also inhibit the synthesis of acid glycoprotein in mucous gland and goblet cell, so that the acid glycoprotein can be secreted with low viscosity, thereby reducing the viscosity of sputum and facilitating expectoration; in addition, bromhexine hydrochloride can stimulate gastric mucosa to reflexively cause respiratory tract glandular secretion increase, and makes sputum dilute, so that the phlegm of bronchitis, asthma, emphysema and the like can be easily coughed out, and the bromhexine hydrochloride is an expectorant with the function of dissolving respiratory tract mucus.
At present, bromhexine hydrochloride tablets, granules, syrups and injections are widely used in clinic, and with the popularization of inhalation therapy in the medical field, the demand for the inhalant is also increasing. The oral or intravenous administration needs to act on airway secretory cells through blood circulation, so that airway secretion is increased, and the viscosity of sputum is reduced; the inhalation preparation can rapidly act on airway secretory cells, can directly act on respiratory tract parts, enhances the effect of eliminating phlegm, and can reduce the occurrence of side effects of a digestive system.
At present, bromhexine hydrochloride solution is not inhaled in China and is sold on the market, belonging to a domestic clinical lack variety. Although the bromhexine hydrochloride atomized solution is marketed abroad, the marketed product contains a preservative which influences the safety of the bromhexine hydrochloride atomized solution.
Disclosure of Invention
In order to solve the technical problems, the invention provides a bromhexine hydrochloride solution preparation for inhalation and a preparation method thereof. The bromhexine hydrochloride solution preparation for inhalation has low impurity content and low degradation rate of bromhexine in the long-term storage process of a solvent, namely, the bromhexine hydrochloride solution preparation has high stability, reliable quality, high safety and long storage time; in addition, the solution preparation of the invention is not added with any preservative, so that the safety coefficient is higher, and the solution preparation of the invention has proper taste, fully covers the bitter taste of bromhexine, and improves the compliance of patients.
The first purpose of the invention is to provide a bromhexine hydrochloride solution preparation for inhalation, which is realized by the following technical scheme:
a formulation of a bromhexine hydrochloride solution for inhalation, said bromhexine solution comprising: bromhexine hydrochloride, a pH regulator and a solvent.
In the above bromhexine hydrochloride solution formulation for inhalation, as a preferred embodiment, a single dose of the bromhexine solution formulation contains 4mg of bromhexine hydrochloride.
In the above bromhexine hydrochloride solution formulation for inhalation, as a preferred embodiment, the mass ratio of the pH adjusting agent to the bromhexine hydrochloride is from 0.25 to 0.75 (such as 0.27.
In the above-mentioned bromhexine hydrochloride solution preparation for inhalation, as a preferred embodiment, the bromhexine solution comprises 0.1 to 4mg/mL of bromhexine hydrochloride, preferably 0.1 to 3mg/mL of bromhexine hydrochloride.
In the above bromhexine hydrochloride solution formulation for inhalation, as a preferred embodiment, the pH adjusting agent is tartaric acid.
In the above-mentioned bromhexine hydrochloride solution preparation for inhalation, as a preferred embodiment, the content of the impurity E in the bromhexine solution is less than 0.05% (e.g., the content of the impurity E is 0.045%, 0.04%, 0.03%, 0.025%, 0.02%, 0.015%, 0.01%, 0.005%, 0.002%, 0.0%). The impurity E is 6, 8-dibromo-3-cyclohexyl-3-methyl-1, 2,3, 4-tetrahydrochysene quinazoline-3-quaternary ammonium salt with the structural formula
The quality and the safety of the bromhexine solution preparation are seriously influenced by the high content of the impurity E in the bromhexine solution preparation, and the inventor of the invention surprisingly finds that the content of the impurity E in the solution preparation can be controlled by adjusting the dosage of the tartaric acid, thereby ensuring the quality and the safety of the solution preparation.
In the above bromhexine hydrochloride solution formulation for inhalation, as a preferred embodiment, the solvent is water or a mixed solvent composed of water and an appropriate amount of a co-solvent. Illustratively, the water is deionized water, distilled water, or water for injection, or the like.
In the above-mentioned bromhexine hydrochloride solution formulation for inhalation, as a preferred embodiment, the pH of the bromhexine solution is 2.5 to 3.5 (e.g., 2.6, 2.8, 3.0, 3.2, 3.4), preferably 2.6 to 2.8.
In the invention, an ultrasonic atomizer or an air compression atomizer is adopted, and the bromhexine hydrochloride solution preparation for inhalation is inhaled into a respiratory system in an atomization mode, can directly act on a focus part, and has the advantages of quick response, safety and effectiveness. Bromhexine can be directly delivered to the lung of a patient by an inhalation administration mode, thereby obviously relieving symptoms and shortening the course of disease. The medicine directly enters the respiratory tract, so that the toxic and side effects of the medicine are obviously reduced, which is particularly important for cancer patients.
The second purpose of the invention is to provide a preparation method of a bromhexine hydrochloride solution preparation for inhalation, which comprises the following steps:
(1) Sequentially adding tartaric acid and bromhexine hydrochloride in a prescription amount into a solvent, and stirring until the tartaric acid and the bromhexine hydrochloride are completely dissolved to obtain a pre-inhalation solution;
(2) Finely filtering the pre-suction solution obtained in the step (1) to obtain a bromhexine solution; and filling the bromhexine solution into an ampoule under the aseptic condition, sealing and packaging to obtain the bromhexine hydrochloride solution preparation for inhalation.
In the above-mentioned preparation method, as a preferred embodiment, in the step (1), the solvent is heated to 40 to 60 ℃ (for example, 42 ℃, 45 ℃, 50 ℃, 55 ℃, 57 ℃) and then the prescribed amounts of tartaric acid and bromhexine hydrochloride are sequentially added. The content of the impurity E is increased due to the overhigh temperature of the solvent, so that the quality and the safety of the bromhexine solution preparation are influenced; the excessively low temperature of the solvent can cause the excessively long dissolution time of bromhexine hydrochloride, further cause the increase of the residual oxygen amount in the bromhexine solution preparation, and also cause the increase of the total impurity content in the bromhexine solution preparation, further influencing the quality and the safety of the bromhexine solution preparation. In addition, the inventors have surprisingly found that the addition of bromhexine hydrochloride first results in a long dissolution time and thus in an increase in the total impurity content of the bromhexine solution formulation; the bromhexine hydrochloride can be quickly dissolved by adding the tartaric acid and then adding the bromhexine hydrochloride, probably because the bromhexine hydrochloride can be quickly combined with the tartaric acid to form hydrogen bonds, so that the dissolution of the bromhexine hydrochloride is accelerated.
In the above production method, as a preferable embodiment, in the step (2), the fine filtration is performed using a 0.22 μm filter.
In the above preparation method, as a preferred embodiment, in the step (2), the bromhexine solution is filled in an ampoule and sealed under nitrogen. On one hand, the residual oxygen amount in the bromhexine solution can be reduced, and on the other hand, the introduction of other unnecessary pollution sources can be avoided.
Compared with the prior art, the invention has the following technical effects:
1. the bromhexine hydrochloride solution preparation for inhalation provided by the invention has low impurity content and low degradation rate of bromhexine in the long-term storage process of a solvent, wherein the content of the impurity E can be controlled within the range of less than 0.05%; namely, the inhalation solution preparation has high stability, reliable quality, high safety and long storage time; in addition, no preservative is added in the solution preparation, so that the safety coefficient of the solution preparation is higher, and the solution preparation has a proper taste and fully covers the bitter taste of bromhexine.
2. By adopting the charging sequence of the preparation method and controlling the temperature of the solvent in the preparation process, the content of impurities in the solution preparation can be well reduced; in addition, the preparation method is simple and easy to operate, low in production cost and easy for industrial production.
Detailed Description
The preparation process and the dosage of the materials used in the preparation or the materials used in the preparation in the following examples of the pharmaceutical preparation are not limited to the words, and all methods containing the pharmaceutical preparation provided by the present invention are within the scope of the present invention.
Bromhexine hydrochloride used in the examples is purchased from the market, and is purified by a conventional method before use to ensure that the content of the impurity E is lower than 0.01 percent; in the embodiment of the invention, the content of the impurity E in the bromhexine hydrochloride is 0.001 percent; in addition, those who do not specify specific conditions in the examples of the present invention proceed according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Examples 1 to 7
Examples 1-7 bromhexine hydrochloride solution formulations for inhalation were prepared in the same manner and in different formulations, and the specific amounts of bromhexine hydrochloride and tartaric acid used in the formulations are shown in table 1.
(1) Sequentially adding tartaric acid and bromhexine hydrochloride in a prescription amount into water for injection at 50 ℃, and stirring until the tartaric acid and the bromhexine hydrochloride are completely dissolved to obtain a pre-inhalation solution;
(2) Finely filtering the pre-suction solution obtained in the step (1) by adopting a 0.22 mu m filter membrane to obtain a bromhexine solution; before and after filling the bromhexine solution, filling nitrogen into the ampule for protection, filling the bromhexine solution into the ampule under the aseptic condition, sealing the opening of the ampule and packaging the ampule to obtain the bromhexine hydrochloride solution preparation for inhalation of the invention.
TABLE 1 concrete amounts of bromhexine hydrochloride and tartaric acid in the formulations of examples 1-7
Example 8
Prescription
Bromhexine hydrochloride 1.5mg/ml
Tartaric acid 0.75mg/ml
(1) Sequentially adding tartaric acid and bromhexine hydrochloride in a prescription amount into deionized water at 45 ℃, and stirring until the tartaric acid and the bromhexine hydrochloride are completely dissolved to obtain a pre-imbibed solution;
(2) Finely filtering the pre-suction solution obtained in the step (1) by adopting a 0.22 mu m filter membrane to obtain a bromhexine solution; and (3) filling nitrogen into the ampoule before and after filling the bromhexine solution, filling the bromhexine solution into the ampoule under the aseptic condition, sealing the ampoule, and packaging to obtain the bromhexine hydrochloride solution preparation for inhalation, wherein the pH value of the bromhexine hydrochloride solution preparation is 2.65.
Example 9
Prescription
Bromhexine hydrochloride 3mg/ml
Tartaric acid 0.9mg/ml
(1) Sequentially adding tartaric acid and bromhexine hydrochloride in a prescription amount into distilled water at the temperature of 58 ℃, and stirring until the tartaric acid and the bromhexine hydrochloride are completely dissolved to obtain a pre-inhalation solution;
(2) Finely filtering the pre-absorbed solution obtained in the step (1) by adopting a 0.22 mu m filter membrane to obtain a bromhexine solution; and (3) filling nitrogen into the ampoule before and after filling the bromhexine solution for protection, filling the bromhexine solution into the ampoule under the aseptic condition, sealing the ampoule, and packaging to obtain the bromhexine hydrochloride solution preparation for inhalation, wherein the pH value of the bromhexine hydrochloride solution preparation is 2.6.
Example 10
Prescription
Bromhexine hydrochloride 1mg/ml
Tartaric acid 0.75mg/ml
(1) Sequentially adding tartaric acid and bromhexine hydrochloride in a prescription amount into deionized water at 40 ℃, and stirring until the tartaric acid and the bromhexine hydrochloride are completely dissolved to obtain a pre-imbibed solution;
(2) Finely filtering the pre-suction solution obtained in the step (1) by adopting a 0.22 mu m filter membrane to obtain a bromhexine solution; before and after filling the bromhexine solution, filling nitrogen into the ampule for protection, filling the bromhexine solution into the ampule under the aseptic condition, sealing the opening of the ampule and packaging the ampule to obtain the bromhexine hydrochloride solution preparation for inhalation, wherein the pH value of the bromhexine hydrochloride solution preparation is 2.9.
Example 11
Prescription
Bromhexine hydrochloride 2mg/ml
Tartaric acid 0.9mg/ml
(1) Taking bromhexine hydrochloride and tartaric acid with the prescription amount, sequentially adding the bromhexine hydrochloride and the tartaric acid into water for injection at 50 ℃, and stirring until the bromhexine hydrochloride and the tartaric acid are completely dissolved to obtain a pre-inhalation solution;
(2) Finely filtering the pre-suction solution obtained in the step (1) by adopting a 0.22 mu m filter membrane to obtain a bromhexine solution; and (3) filling nitrogen into the ampoule before and after filling the bromhexine solution, filling the bromhexine solution into the ampoule under the aseptic condition, sealing the ampoule, and packaging to obtain the bromhexine hydrochloride solution preparation for inhalation, wherein the pH value of the bromhexine hydrochloride solution preparation is 2.71.
Example 12
Prescription
Bromhexine hydrochloride 2mg/ml
Tartaric acid 0.9mg/ml
(1) Sequentially adding tartaric acid and bromhexine hydrochloride in the prescription amount into water for injection at 65 ℃, and stirring until the tartaric acid and the bromhexine hydrochloride are completely dissolved to obtain a pre-inhalation solution;
(2) Finely filtering the pre-suction solution obtained in the step (1) by adopting a 0.22 mu m filter membrane to obtain a bromhexine solution; and (3) filling nitrogen into the ampoule before and after filling the bromhexine solution, filling the bromhexine solution into the ampoule under the aseptic condition, sealing the ampoule, and packaging to obtain the bromhexine hydrochloride solution preparation for inhalation, wherein the pH value of the bromhexine hydrochloride solution preparation is 2.69.
Test examples stability test
The bromhexine hydrochloride solution preparation for inhalation prepared in the examples 1 to 12 is taken and placed at the temperature of 60 ℃ for 10 days;
the content of bromhexine and impurities in the inhalation solution preparations prepared in examples 1 to 12 on day 0 and the content of bromhexine and impurities in the inhalation solution preparations of examples 1 to 12 after accelerated test were measured by HPLC; detection conditions are as follows: a chromatographic column: phenomenex Gemini 5 μm C18 250 x 4.6mm; mobile phase: phosphate buffer solution (1.0 g of monopotassium phosphate is taken, 900ml of water is added for dissolving, the pH value is adjusted to 7.0 by using 0.5mol/L sodium hydroxide solution, the solution is diluted to 1000ml by using water and is shaken up) is taken as a mobile phase A, acetonitrile is taken as a mobile phase B, and gradient elution is carried out; flow rate: 1.0ml/min; column temperature: at 40 ℃; detection wavelength: 245nm; the detection results are shown in Table 2; the change in the pH was measured and observed.
TABLE 2 Change in bromhexine content of inhaled bromhexine hydrochloride solution formulations before and after accelerated testing
As can be seen from Table 2, the content of E as an impurity in the bromhexine hydrochloride solution for inhalation in the scope of the present invention was not only much less than 0.05% but also low in total impurities after accelerated testing.
Claims (7)
1. A method for preparing bromhexine solution preparation for inhalation is characterized in that the bromhexine solution consists of bromhexine hydrochloride, a pH regulator and a solvent; wherein the content of the first and second substances,
the pH regulator is tartaric acid;
the solvent is water;
the mass ratio of the pH regulator to the bromhexine hydrochloride is 0.25-0.5;
the pH value of the bromhexine solution is 2.6-2.8;
the preparation method of the bromhexine solution preparation comprises the following steps:
(1) Sequentially adding tartaric acid and bromhexine hydrochloride in a prescription amount into a solvent, and stirring until the tartaric acid and the bromhexine hydrochloride are completely dissolved to obtain a pre-inhalation solution;
(2) Finely filtering the pre-suction solution obtained in the step (1) to obtain a bromhexine solution; filling the bromhexine solution into an ampoule under the aseptic condition, sealing and packaging to obtain the bromhexine solution preparation for inhalation;
wherein, in the step (1), the solvent is heated to 40-58 ℃, and then tartaric acid and bromhexine hydrochloride with the prescribed dosage are sequentially added.
2. The method of claim 1, wherein the bromhexine solution formulation comprises 4mg of bromhexine hydrochloride in a single dose.
3. The method of claim 1, wherein the bromhexine solution comprises 0.1 to 4mg/mL bromhexine hydrochloride.
4. The method of claim 3, wherein the bromhexine solution comprises 0.1 to 3mg/mL bromhexine hydrochloride.
5. The process according to claim 1, characterized in that the bromhexine solution has an impurity E content of less than 0.05%.
6. The production method as set forth in claim 1, wherein in the step (2), the fine filtration is performed using a 0.22 μm filter.
7. The preparation method according to claim 6, wherein in the step (2), the bromhexine solution is filled in an ampoule and sealed under nitrogen.
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| Title |
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| Effects of inhaled bromhexine on the bronchomotor tone in rats and guinea pigs;Miwa MISAWA等;《Folia pharmacol. japon》;19891231;第94卷;123-128 * |
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