CN109620799B - Stable bromhexine hydrochloride liquid preparation composition and preparation method thereof - Google Patents
Stable bromhexine hydrochloride liquid preparation composition and preparation method thereof Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention discloses a stable bromhexine hydrochloride liquid preparation composition and a preparation method thereof. The liquid preparation composition comprises bromhexine hydrochloride with a pharmaceutically acceptable amount, an osmotic pressure regulator with a pharmaceutically acceptable amount, a stabilizer with a pharmaceutically acceptable amount, a pH value buffer with a pharmaceutically acceptable amount and water for injection, wherein the stabilizer is a chemically modified derivative of cyclodextrin or salt thereof. The invention selects the chemically modified derivative of cyclodextrin or the salt thereof as the stabilizer, utilizes the property of the chemically modified derivative of cyclodextrin or the salt thereof, utilizes the stabilizer to assist in dissolving bromhexine hydrochloride, can keep stable within the pH range of 1-14, does not precipitate bromhexine, and ensures the safety of clinical medication.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a liquid preparation bromhexine hydrochloride composition for parenteral administration and a preparation method thereof.
Background
Bromhexine hydrochloride has strong effect of dissolving phlegm, and can crack polysaccharide cellulose in the phlegm and thin the sputum. Inhibit goblet cells and mucous glands from synthesizing glycoprotein, reduce sialic acid in sputum, reduce sputum viscosity and facilitate discharge. Bromhexine hydrochloride has the effect of promoting cilia movement of respiratory mucosa. Bromhexine hydrochloride enters a human body and is widely distributed in all tissues of the whole body, after the bromhexine hydrochloride is statically dripped for 10-20 minutes, the blood concentration reaches the peak value, and the half-life period of the blood concentration is about 1.5-2 hours. Bromhexine has high binding rate with plasma protein, and the elimination half-life can reach 12 hours. About 85% to 90% of the metabolites are excreted in urine, and only a small amount of bromhexine is excreted in unchanged form, with a half-life of about 6.5 hours.
Bromhexine Hydrochloride (Bromhexine Hydrochloride) chemical Chinese name: N-methyl-N-cyclohexyl-2-amino-3, 5-dibromobenzylamine hydrochloride.
The structural formula is as follows:
the molecular formula is as follows: c14H20Br2N2·HCl
Molecular weight: 412.60
Bromhexine hydrochloride has a plurality of crystal forms, and the crystal form used for liquid preparations is the crystal form I. The bromhexine molecule does not contain a chiral center and does not contain a stereoisomer.
Bromhexine hydrochloride is white or off-white crystalline powder; slightly soluble in methanol or dimethyl sulfoxide, slightly soluble in ethanol or dichloromethane, very slightly soluble in water or acetonitrile, and hardly soluble in ethyl acetate; the pH value of the saturated aqueous solution is 3.0-5.0.
Bromhexine hydrochloride was first synthesized by Keck in 1963 and was originally developed by boringer invager, germany. In 2016, the Boringer's Invitrogen announced an asset exchange transaction agreement with Senoffine, which included bromhexine hydrochloride injection
Namely, the carrier of bromhexine hydrochloride injection has been changed to cenofine. On 1/9/1966, 4mg tablets were marketed in japan by the company briringer-haghan, followed by 2ml on 7/1976: 4mg of injection, inhalation solution and fine granules are sold on the market. Bromhexine hydrochloride injection from the company brigreger, invar, is also marketed in several countries, such as spain, italy, crohn's, france, etc.
The bromhexine hydrochloride injection is injected into adults 1-2 times a day, and 1-2 times a day (4-8 mg of bromhexine hydrochloride) are injected intramuscularly or intravenously.
According to the information of the auxiliary materials given in the latest specification of the Japanese bromhexine hydrochloride injection, the medicine is originally researched
The composition information of the raw and auxiliary materials is shown in Table 1.
TABLE 1 original medicine
The prescription composition
Bromhexine hydrochloride has very low solubility in water (about 1.1mg/ml), is highly dependent on the temperature of the dissolved water, and is very sensitive to changes in pH. Bromhexine hydrochloride injection published in Japan
IF documents address the problem that when the composition is combined with other solvents, pH changes may occur, leading to precipitation of the product (physicochemical changes).
The national drug administration has published a revised notice of the bromhexine hydrochloride injection specification (No. 89 in 2018), and requires the addition of a warning sign: the solution of the product is acidic, and the clinical application should be administered alone, so as to avoid the compatibility with alkaline drugs; when other medicines are needed to be used together, the medicines are required to be dripped separately, if the medicines and the product share the same infusion channel, 5% glucose injection is required to be fully flushed or an infusion tube is required to be replaced between the two groups of medicines.
Due to the inherent low solubility in water and the white turbidity phenomenon after the pH value of the bromhexine hydrochloride injection exceeds pH4.71, the bromhexine hydrochloride injection brings great safety influence on clinical safe medication.
According to the patent CN02139042.8, glucose is used for regulating osmotic pressure, anhydrous ethanol is used for assisting in dissolving bromhexine hydrochloride, for intravenous injection products, an organic solvent is added to generate unexpected clinical adverse reactions, particularly, allergy and the like occur to patients with specific constitution of ethanol, glucose and bromhexine inevitably generate bromhexine glucose adduct impurities, the impurities are also unexpected special auxiliary material impurities in medicines, and the clinical safety of the impurities is unknown.
Patent CN200710090358.8 also uses a large amount of ethanol, hydroxypropyl methylcellulose which cannot be used in injections, and glucose for adjusting osmotic pressure, which are undesirable inventions for high-risk injections.
Although the patent CN201110246847.4, CN201410129890.6 and CN201410242818.4 do not use organic solvent, glucose is used for adjusting osmotic pressure, the concentration of the glucose is 30-50g/L, and the invention will generate the undesired bromhexine glucose adduct impurity in the product.
Patent CN20141074138.X provides a 100ml large-capacity injection formula invention, but at present, due to the excessive tolerance of the main component of the product to the pH value in water, bromhexine is separated out due to the change of the pH value particularly in clinical medication, and the clinical safe medication is influenced.
Patent No. cn201410624129.x uses alcohols such as mannitol, xylitol and sorbitol as stability, but in this invention, sodium hydroxide is used to adjust the pH range to 2.0-5.0, while bromhexine in an aqueous solution, regardless of using ethanol, glucose, mannitol, xylitol, sorbitol, sodium chloride and the like as stability or osmotic pressure agent, if the pH value of the solution exceeds 4.7, bromhexine is inevitably precipitated, resulting in a white turbid solution, which is the dissolution characteristic of bromhexine hydrochloride due to its inherent pH value depending on tolerance.
From the above patent analysis, it is known that the use of glucose as an invention for regulating osmotic pressure or stability inevitably results in undesirable impurities (bromhexine glucose adduct) in the product, while other inventions restrict bromhexine hydrochloride and inevitably results in hydrochloric acid radical shedding and bromhexine free base precipitation when the pH of its inherent compound exceeds pH4.7 depending on tolerance, and inevitably has high administration risk in clinical use. These invention drawbacks are evident and pose a very high risk to both product quality and clinical administration. How to invent a better method to solve the technical problems that the bromhexine hydrochloride injection can not generate Maillard reaction with reducing saccharides, and the preparation and storage in bromhexine hydrochloride aqueous liquid with wider physiologically acceptable pH value and concentration are urgently needed to be solved in industrial pharmacy.
Disclosure of Invention
The invention aims to solve the technical problem of solving the problem of bromhexine precipitation caused by the change of the pH value of the liquid medicine in the clinical administration of the existing bromhexine hydrochloride injection and provides a more stable bromhexine hydrochloride injection and a preparation method thereof.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a stable bromhexine hydrochloride liquid preparation composition comprises bromhexine hydrochloride with a pharmaceutically acceptable amount, an osmotic pressure regulator with a pharmaceutically acceptable amount, a stabilizer with a pharmaceutically acceptable amount, a pH buffer with a pharmaceutically acceptable amount and water for injection, wherein the stabilizer is a chemically modified derivative of cyclodextrin or a salt thereof.
The present invention has been made experimentally and it has surprisingly been found that with chemically modified derivatives of the parent cyclodextrins (usually in the hydroxyl moiety) currently commercially available for injectable solutions, such as sulfobutylether betacyclodextrin and hydroxypropyl betacyclodextrins, it is possible to maintain a wide range of physiologically acceptable pH values (pH1.0-14) and concentrations of bromhexine (2-4mg/ml) in aqueous liquids for preparation and storage, and osmolytes may use sodium chloride, mannitol, etc. to avoid Maillard reactions (Maillard reactions) producing undesirable adjuvant adduct impurities. The concentration of the pharmaceutically acceptable stabilizer is 0.2-40% (W/V), so that the bromhexine can be stable in a wider physiological pH range of 1-14, and the bromhexine is compatible with alkaline medicaments so as not to separate out and influence the safety of clinical medication.
Specifically, the stabilizing agent is a sulfobutyl ether derivative or a salt thereof, or a 2-hydroxypropyl derivative or a salt thereof. The stability of the pharmaceutically acceptable amount is selected to be a chemically modified derivative of the parent cyclodextrin (usually at the hydroxyl moiety) which is of greater clinical safety while maintaining or improving the complexation ability of the cyclodextrin. The sulfobutyl ether derivative has higher water solubility and safety than the 2-hydroxypropyl derivative.
The stabilizing agent is sulfobutyl betacyclodextrin sodium. Sulfobutyl betacyclodextrin sodium, a sodium salt of a derivative of cyclodextrin, is widely used in liquid formulations to enhance the water solubility of hydrophobic compounds, and the degree of substitution is used for products of type 4-7. The clinical maximum safe dose of the inactive ingredients in the intravenous large infusion preparation published by the website of the U.S. food and drug administration can reach 96.23 percent (W/V), and the clinical maximum safe dose in the hydroxypropyl betacyclodextrin injection can reach 94.1 percent (W/V).
The content of the stabilizer in 1000ml of liquid preparation composition is 20-40 g/L.
One mixture ratio of the bromhexine hydrochloride liquid preparation is as follows: 1000ml of liquid preparation composition contains bromhexine hydrochloride 2-4 g, osmotic pressure regulator 21-23 g and pH value buffering liquid 1-1.1 g. The concentration of the pharmaceutically acceptable bromhexine hydrochloride in the water base is 2 mg/ml-4 mg/ml, and the requirement of clinical dosage is met; the pharmaceutically acceptable osmotic pressure regulator adopts sodium chloride and mannitol, the invention mainly considers D-mannitol, sorbitol, xylitol and maltitol are used in injection less, the safety is not high than that of D-mannitol, and the concentration of D-mannitol needs to keep the permeability of product quality to be 270-320 msOsmol/kg; the pharmaceutically acceptable acid-base pH regulator is tartaric acid, preferably L-tartaric acid, and its dosage should maintain pH within 2.2-3.2.
The pharmaceutically acceptable osmotic pressure regulator is sodium chloride or mannitol.
In the process of grinding the original product
When the quality analysis is carried out, a very large unknown impurity is found, the impurity amount exceeds 0.2%, the impurity is analyzed and found to be an adduct impurity formed by bromhexine hydrochloride and glucose, the theory of the adduct impurity is Maillard reaction (Maillard reaction), the new impurity is formed by structural rearrangement of amino and glucose in a bromhexine structural formula and is an undesired impurity in a medicine, and the impurity brings a very large safety hazard to intravenous administration, and the impurity amount exceeds an identification threshold (0.2%).
The fourth edition of the literature article, handbook of pharmaceutical excipients (eds. [ English ] R.C. Ro, etc.) proposes aldehydic glucose in the glucose chapter, which can react with organic amines, amides, amino acids, polypeptides and proteins; glucose will cause the amine group containing tablet to turn brown (Maillard reaction). In the adverse reaction part of the mannitol section, it is suggested that mannitol does not undergo Maillard reaction (Maillard reaction).
In the Maillard reaction (Maillard reaction), mainly reducing sugars and amino acids are involved in the reaction, and may be disaccharides, pentoses and hexoses. Among the disaccharides that may be used are lactose and sucrose; pentoses include xylose, ribose, and arabinose; the hexose may be glucose, fructose, mannose, galactose, etc. It is reported that the browning rate of five-carbon sugar is 10 times higher than that of six-carbon sugar, and in the reducing monosaccharide, the browning rate of five-carbon sugar is ordered as ribose > arabinose > xylose, and the browning rate of six-carbon sugar is ordered as galactose > mannose > glucose. The order of activity for the different sugars to react with lysine is xylose > galactose > glucose > fructose > sucrose. The type and concentration of amino acids also have a significant effect on the type of product of the Maillard reaction.
The Maillard reaction (Maillard reaction) is influenced by many factors, mainly the structure of sugars and amino acids, as well as temperature, reaction time, pH, moisture, high pressure, irradiation, etc., the former mainly affecting the type of Maillard reaction products and the latter usually being the kinetic influencing factor of the reaction. Generally, the Maillard reaction can occur under the condition of 20-25 ℃, and is greatly influenced by the temperature. The higher the temperature, the faster the browning speed. The reaction speed is increased by about 3-5 when the temperature is increased by 10 ℃.
The Maillard reaction (Maillard reaction) produces the final product, some of which are toxic substances. Acrylamide (acrylamide) and glycosylated end products (AGEs) are now well studied. Acrylamide is a neurotoxin and carcinogen that crosslinks with proteins to yield glycosylated end products (AGEs) that are associated with the formation of cataracts, arteriosclerosis, alzheimer's disease, kidney disease, diabetes.
The inventor collects the impurity after reacting bromhexine hydrochloride with glucose and uses liquid chromatography-mass spectrometry (LC-MS), detects the molecular weight of the impurity and deduces the structural formula as follows:
the molecular formula is as follows: c20H30Br2N2O5Molecular weight: 538.28
Research shows that if a process impurity C, D exists in a bromhexine hydrochloride bulk drug used for preparation production, the bromhexine hydrochloride bulk drug can generate Maillard reaction (Maillard reaction) with glucose, impurity peaks of the bromhexine hydrochloride bulk drug appear in a preparation product, particularly, new adduct impurities can appear after 24 hours in stability test under the condition that the bromhexine impurities C and D and the glucose form an acid solution after tartaric acid is added (about pH 3), and the structural formula is as follows:
the literature data at present do not carry out deep toxicological and pharmacological studies on the impurities generated after the Maillard reaction (Maillard reaction) of bromhexine and glucose, and do not report sufficient documents on clinical safety, so the impurities are the auxiliary material adduct impurities which are not expected to appear in medicines, particularly high-risk injection medicines. Research shows that if the bromhexine hydrochloride injection adopts glucose as an osmotic pressure regulator, new glucose adduct impurities are generated when process impurities C, D exist in bromhexine hydrochloride raw material medicines for preparation production. Therefore, the bromhexine hydrochloride liquid preparation does not select glucose as an osmotic pressure regulator, and selects sodium chloride or mannitol as the osmotic pressure regulator, so that even if the bromhexine hydrochloride bulk drug has the process impurity C, D, the production of a new glucose adduct impurity can not be caused, and the safety of the bromhexine hydrochloride liquid preparation is further ensured.
The bromhexine hydrochloride liquid preparation has a preferable formula, and in a 1000ml liquid preparation composition, the content of bromhexine hydrochloride is 2g-4g, the content of D-mannitol is 21g-23g, the content of sulfobutyl betacyclodextrin sodium is 20 g-40 g, and the content of L-tartaric acid is 1g-1.1 g.
A preparation method of a stable bromhexine hydrochloride liquid preparation composition comprises the following steps:
(1) weighing an osmotic pressure regulator and a pH buffer solution reagent according to the prescription amount, dissolving the osmotic pressure regulator and the pH buffer solution reagent into 60% injection water according to the prescription amount, stirring, dissolving, clarifying and filtering by using a 0.22 mu m filter membrane;
(2) additionally weighing 35% of injection water and bromhexine hydrochloride according to the prescription amount, adding the stabilizer according to the prescription amount under stirring, and stirring for clarification;
(3) adding the liquid medicine obtained in the step (2) into the solution obtained in the step (1) under stirring, stirring for 15-30 minutes, reducing the temperature to be below 30 ℃, measuring the content of an intermediate, adjusting the pH value of the liquid medicine to be 2.6 +/-0.02, adding water for injection to the prescription amount, and continuously stirring for 15-30 minutes;
(4) after the heat source is filtered out; filling; sterilizing at terminal to obtain
Further, in the step (2) of the preparation method, in the case of adding a chemically modified derivative of cyclodextrin or a salt thereof as a stabilizer, in the preparation of bromhexine hydrochloride injection, the temperature has no tolerance to the dissolution time of bromhexine hydrochloride at the same dosage ratio, the dissolution time is within 5min, in the commercial production of the preparation, a higher temperature aqueous solution is not necessary to dissolve bromhexine hydrochloride, and the dissolution temperature can be controlled within the range of 25-65 ℃ based on the actual requirement of the production.
In the step (2) of the preparation method, if the pH value of the liquid medicine is not in the range of 2.6 +/-0.02, the pH value can be adjusted to the range by using a hydrochloric acid solution (1mol/L) or a sodium hydroxide solution (1mol/L), water for injection is added to the prescribed amount, and the stirring is continued for 15 to 30 minutes.
In the step (3) of the preparation method, a four-stage filtration system is used for ultra-filtering a heat source; filling the mixture into a 2ml brown medium borosilicate ampoule bottle, and sealing the bottle after filling nitrogen; sterilizing at terminal (121 deg.C for 15-30 min). The color of the ampoule is brown, and the scanning transmittance in the range of 290 nm-450 nm ultraviolet light and 590 nm-610 nm visible light meets the requirement of the product for light-proof storage.
The invention has the beneficial effects that:
1. the invention selects the chemically modified derivative of cyclodextrin or the salt thereof as the stabilizer, utilizes the property of the chemically modified derivative of cyclodextrin or the salt thereof, utilizes the stabilizer to assist in dissolving bromhexine hydrochloride, can keep stable within the pH range of 1-14, does not precipitate bromhexine, and ensures the safety of clinical medication.
2. The invention selects the osmotic pressure regulator without glucose, so that even if the bromhexine hydrochloride raw material medicine produced by the preparation has the process impurity C, D, the bromhexine hydrochloride raw material medicine does not generate Maillard reaction (Maillard reaction) with glucose, and the glucose adduct impurity can be avoided from appearing in the preparation product.
3. The invention adopts sulfobutyl-beta-cyclodextrin sodium to assist in dissolving bromhexine hydrochloride to carry out liquid preparation operation, the dissolving time is only a few minutes, overhigh water temperature (70-90 ℃) is not needed to dissolve the bromhexine, and the bromhexine hydrochloride only needs to be prepared at 25-65 ℃, so that the stability of the medicine is maintained, the production time of the injection is further shortened, the industrial production cost of the preparation is saved, and the economic benefit is improved. The quality is stable and controllable.
Drawings
The accompanying drawings, which are included to provide a further understanding of the embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principles of the invention. In the drawings:
FIG. 1 is a MS spectrum of bromhexine glucose adduct impurity.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples and accompanying drawings, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not meant to limit the present invention.
Example 1:
the bromhexine hydrochloride injection containing the chemical stabilizer is prepared by the following method:
(1) d-mannitol and L-tartaric acid with the prescription amount are weighed and dissolved in 60% of water for injection with the prescription amount, stirred, dissolved and clarified, and filtered by a 0.22 mu m filter membrane.
(2) Additionally, 35 percent of injection water and bromhexine hydrochloride according to the prescription amount are weighed, and sulfobutyl-betacyclodextrin sodium according to the prescription amount is added into the mixture under stirring, stirred and clarified.
(3) Adding the liquid medicine obtained in the step (2) into the solution obtained in the step (1) under stirring, stirring for 15-30 minutes, reducing the temperature to below 30 ℃, measuring the content of the intermediate, monitoring the pH value of the liquid medicine to be 2.6 +/-0.02, adjusting the pH value of the liquid medicine to be in the range by using a hydrochloric acid solution (1mol/L) or a sodium hydroxide solution (1mol/L) if the pH value of the liquid medicine is not in the range, adding water for injection to the amount prescribed, and continuing stirring for 15-30 minutes.
(4) Performing ultra-filtration on a heat source by using a four-stage filtration system; filling the mixture into a 2ml brown medium borosilicate ampoule bottle, and sealing the bottle after filling nitrogen; sterilizing at terminal (121 deg.C for 15-30 min).
Example 2:
in this example, bromhexine hydrochloride injection containing a pharmaceutical stabilizer was prepared according to the same method as in example 1.
Example 3:
in this example, bromhexine hydrochloride injection containing a pharmaceutical stabilizer was prepared according to the same method as in example 1.
Example 4:
in this example, bromhexine hydrochloride injection containing a pharmaceutical stabilizer was prepared according to the same method as in example 1.
In the present invention, 1000ml of the solution temperature dependence study of bromhexine hydrochloride is performed by using sulfobutylbetacyclodextrin sodium and hydroxypropyl betacyclodextrin as pharmaceutically acceptable stabilizers, and the dissolution temperature and time statistics of bromhexine hydrochloride are as follows in Table 2-3, as in example 1:
TABLE 2 Sulfobutyl betacyclodextrin sodium temperature and dissolution time tolerance study
| Investigation of temperature | 25-35℃ | 45-65℃ | 75-85℃ |
| Measured temperature | 31.3℃ | 51.5℃ | 78.5℃ |
| Clarification time of bromhexine hydrochloride | 3 minutes | 45 seconds | 21 second |
| The dosage ratio of the sulfobutyl betacyclodextrin sodium | 1:10 | 1:10 | 1:10 |
TABLE 3 evaluation of temperature and dissolution time of hydroxypropyl betacyclodextrin according to tolerance
| Investigation of temperature | 25-35℃ | 45-65℃ | 75-85℃ |
| Measured temperature | 32.1℃ | 52.4℃ | 77.5℃ |
| Clarification time of bromhexine hydrochloride | 4 minutes | 52 seconds | 29 seconds |
| The dosage ratio of hydroxypropyl betacyclodextrin | 1:10 | 1:10 | 1:10 |
As shown in the above examination data, in the process of preparing 1000ml of bromhexine hydrochloride injection, the temperature has no dependence on the dissolution time of bromhexine hydrochloride under the same dosage ratio, the dissolution time is within 5min, in the commercial production of the preparation, a higher temperature aqueous solution is not necessary for dissolving bromhexine hydrochloride, and the dissolution temperature can be controlled within the range of 25-65 ℃ based on the actual production requirement.
The invention adopts sulfobutyl-beta-cyclodextrin sodium and hydroxypropyl-beta-cyclodextrin to help dissolve bromhexine hydrochloride, carries out solution preparation operation, has the dissolution time of only a few minutes, does not need to adopt overhigh water temperature (70-90 ℃) to dissolve bromhexine, only needs to carry out preparation at 25-65 ℃, keeps the stability of the medicament, further shortens the production time of the injection, saves the industrial production cost of the preparation and improves the economic benefit. The quality is stable and controllable.
The invention is researched according to the original
The formulation (see table 1) is prepared into 100ml of product, and the quality of the product is detected and shown in table 4 after the product is prepared according to the conventional injection production process (the temperature of dissolved water is 80 ℃). As can be seen from the data of the original recipe, the impurity content of the bromhexine glucose adduct impurity exceeds the identification threshold limit (0.2%), and the impurity content is added at the same timeThe addition of glucose requires the additional production of furfural impurities.
TABLE 4 original research
Comparison of formula quality
Remarking: the impurities marked "-" are all impurities produced by glucose;
is a product of silophile (japan);
is a product of silophile (spain).
In order to further prove that the water dissolution temperature is stable and reliable in product quality, 4 groups of medicines are prepared according to the example 1 at the water temperatures of 80 +/-2 ℃, 70 +/-2 ℃, 60 +/-2 ℃ and 50 +/-2 ℃ for examination, and the detection results are shown in tables 5-6.
TABLE 5 temperature screening test results of compounding solution (before sterilization)
TABLE 6 temperature screening test results of compounding solution (after 121 deg.C/15 min sterilization)
Remarking: N.D indicates no detection, and the structural formula of the impurity C, D is shown in the content of the invention; other impurities are disclosed in patent CN201410334638.9 for its structural formula; the L impurity is an impurity in the process of producing the bulk drug by a bromhexine synthetic route, and the structural formula is reported in other literature data.
In the invention, the bromhexine hydrochloride is dissolved by adopting pharmaceutically acceptable stabilizers of sulfobutylbetacyclodextrin sodium and hydroxypropyl betacyclodextrin, can be kept stable within the pH range of 1-14, and the bromhexine can not be separated out, thereby ensuring the safety of clinical medication. 100ml were prepared as in example 1, statistical tables 7-8 as follows:
TABLE 7 stability of hydroxypropyl betacyclodextrin bromhexine over a broad pH range
TABLE 8 stability of sodium sulfobutylbetacyclodextrin Brohexon over a broad pH Range
As shown by the above-mentioned data, no bromhexine is separated out in the process of preparing 100ml of bromhexine hydrochloride injection within a wide pH value range (1-14).
The bromhexine hydrochloride injection prepared by adding sulfobutylbetacyclodextrin sodium and hydroxypropyl betacyclodextrin which are pharmaceutically acceptable stabilizers is considered to have better stability, the clinical medication safety of the injection can be improved, the problem that the product cannot be compatible with alkaline liquid medicine in the clinical medication process is thoroughly solved, other modes are not needed to wash infusion pipelines, and the safety factor of clinical medication is improved.
In order to further prove that the invention can be compatible with alkaline drugs without influencing bromhexine precipitation, sodium lactate ringer injection with the pH value of 6.0-7.5 is adopted to be compatible with bromhexine hydrochloride injection prepared according to example 1 for 48 hours, and the investigation data are shown in Table 9.
TABLE 9 compatibility study of bromhexine hydrochloride injection and sodium lactate ringer's injection (250ml)
The invention further adopts other hydroxypropyl betacyclodextrin with pharmaceutically acceptable stability, an osmotic pressure regulator and a pH regulator to prepare the compound according to example 1, and then the compound is matched with sodium lactate ringer's injection (250ml) for investigation, and the results are shown in tables 10-11.
TABLE 10 other composition formulations
TABLE 11 compatibility of bromhexine hydrochloride injection and sodium lactate ringer's injection (250ml) for 48 hours
The experimental results show that the invention can keep the stability in the pH range of 1-14 by selecting the chemically modified derivative of cyclodextrin or the salt thereof as the stabilizer and utilizing the property of the chemically modified derivative of cyclodextrin or the salt thereof to help dissolve bromhexine hydrochloride by the stabilizer, so that the bromhexine cannot be separated out, and the safety of clinical medication is ensured.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (2)
1. A stable bromhexine hydrochloride liquid preparation composition consists of bromhexine hydrochloride, D-mannitol, L-tartaric acid, sulfobutyl betacyclodextrin sodium and water for injection with pharmaceutically acceptable amount, and is characterized in that in 1000ml of the liquid preparation composition, the content of the bromhexine hydrochloride is 2g-4g, the content of the D-mannitol is 21g-23g, the content of the sulfobutyl betacyclodextrin sodium is 20 g-40 g, and the content of the L-tartaric acid is 1g-1.1 g; the liquid composition has a pH of 2.2 to 3.2.
2. A preparation method of a stable bromhexine hydrochloride liquid preparation composition is characterized by comprising the following steps:
(1) weighing D-mannitol and L-tartaric acid according to the prescription amount, dissolving the D-mannitol and the L-tartaric acid into 60% of water for injection according to the prescription amount, stirring, dissolving, clarifying, and filtering with a 0.22 mu m filter membrane;
(2) additionally weighing 35% injection water and bromhexine hydrochloride according to the prescription amount, adding the sulfobutyl-betacyclodextrin sodium according to the prescription amount under stirring, stirring and clarifying;
(3) adding the liquid medicine obtained in the step (2) into the solution obtained in the step (1) under stirring, stirring for 15-30 minutes, reducing the temperature to be below 30 ℃, measuring the content of an intermediate, adjusting the pH value of the liquid medicine to 2.2-3.2, adding water for injection to the prescription amount, and continuously stirring for 15-30 minutes;
(4) after the heat source is filtered out; filling; sterilizing at the terminal;
the prescription amount is 1000ml of liquid preparation composition, the content of bromhexine hydrochloride is 2g-4g, the content of D-mannitol is 21g-23g, the content of sulfobutyl betacyclodextrin sodium is 20 g-40 g, and the content of L-tartaric acid is 1g-1.1 g.
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| CN112546001A (en) * | 2021-01-05 | 2021-03-26 | 河北智同生物制药股份有限公司 | Bromhexine hydrochloride freeze-dried powder injection for injection and preparation method thereof |
| CN113143855B (en) * | 2021-04-29 | 2022-09-09 | 北京阳光诺和药物研究股份有限公司 | Bromhexine hydrochloride oral liquid and preparation method thereof |
| CN114788809B (en) * | 2022-01-25 | 2023-04-14 | 江苏广承药业有限公司 | Loratadine liquid preparation |
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| CN104306329A (en) * | 2014-11-07 | 2015-01-28 | 石家庄科仁医药科技有限公司 | Bromhexine hydrochloride injection and preparation method and application thereof |
| CN104434786A (en) * | 2014-12-09 | 2015-03-25 | 石家庄科仁医药科技有限公司 | Stable bromhexine hydrochloride sodium chloride injection composition |
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| CN104306329A (en) * | 2014-11-07 | 2015-01-28 | 石家庄科仁医药科技有限公司 | Bromhexine hydrochloride injection and preparation method and application thereof |
| CN104434786A (en) * | 2014-12-09 | 2015-03-25 | 石家庄科仁医药科技有限公司 | Stable bromhexine hydrochloride sodium chloride injection composition |
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