CN109620799A - 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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- CN109620799A CN109620799A CN201910070018.1A CN201910070018A CN109620799A CN 109620799 A CN109620799 A CN 109620799A CN 201910070018 A CN201910070018 A CN 201910070018A CN 109620799 A CN109620799 A CN 109620799A
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- bromhexine hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- 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
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
Abstract
The invention discloses a kind of stable bromhexine hydrochloride liquid preparation compositions and preparation method thereof.The liquid preparation composition include the bromhexine hydrochloride of pharmaceutically acceptable amount, the osmotic pressure regulator of pharmaceutically acceptable amount, the stability agent of pharmaceutically acceptable amount, pharmaceutically acceptable amount pH value buffer and water for injection, the stability agent be cyclodextrin chemically modified derivative or its salt.The present invention passes through the chemically modified derivative for selecting cyclodextrin or its salt as stabilizer, utilize the chemically modified derivative of cyclodextrin or the property of its salt, utilize the stabilizer hydrotropy bromhexine hydrochloride, it can keep stablizing within the scope of pH1-14, bromhexine will not be precipitated, it is ensured that the safety of clinical application.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to parenteral liquid preparation bromhexine hydrochloride composition and its
Preparation method, which is a kind of bronchitis treatment, for acute and mucolysis and treatment of chronic bronchial disease
Intractable pulmonary mucus.
Background technique
Bromhexine hydrochloride has stronger dissolve to stick phlegm effect, the polysaccharide fiber element in phlegm can be made to crack, desaturation sputum.Inhibit
Goblet cell and mucus body of gland synthesize glycoprotein, reduce the sialic acid in sputum, lower phlegm viscosity, are conducive to discharge.Hydrochloric acid bromine
Oneself newly still has the ciliary movement effect for promoting respiratory mucosa.Bromhexine hydrochloride, which enters in human body, is widely distributed in whole body each group
It knits, after intravenous infusion this product 10-20 points, haemoconcentration reaches peak value, and the half-life period of blood concentration is about 1.5-2 hours.Bromhexine
There is higher Percentage bound with plasma protein, elimination half-life period may be up to 12 hours.About 85% to 90% metabolite is by urinating
Discharge, only a small amount of bromhexine are discharged in constant form by urine, and half-life period about 6.5 hours.
Bromhexine hydrochloride (Bromhexine Hydrochloride) chemistry Chinese are as follows: N- methyl-N-cyclohexyl -2-
Amino -3,5- dibromobenzene methylamine hydrochloride.
Its structural formula are as follows:
Molecular formula: C14H20Br2N2·HCl
Molecular weight: 412.60
Bromhexine hydrochloride has multiple crystal forms, and the crystal form for liquid preparation is I crystal.Without in chirality in bromhexine molecule
The heart, no stereoisomer.
Bromhexine hydrochloride is the crystalline powder of white or off-white color；It is slightly molten in methanol or dimethyl sulfoxide, in ethyl alcohol or
Slightly soluble in methylene chloride, the soluble,very slightly in water or acetonitrile are almost insoluble in ethyl acetate；The pH value of its saturated aqueous solution is
3.0—5.0。
Bromhexine hydrochloride was synthesized in 1963 by Keck first, ground exploitation by German Boehringer Ingelheim company original.2016
In June in year, Boehringer Ingelheim is announced and Sino phenanthrene reaches assets swap trade agreement, this swapping agreement contains hydrochloric acid
Bromhexine injectionThat is the accredited quotient of bromhexine hydrochloride in injection has been changed to Sino phenanthrene.September 1 in 1966
Day, Boehringer Ingelheim company lists 4mg tablet in Japan, then lists 2ml:4mg injection in July, 1976, and list
The dosage forms such as inhalation solution and granula subtilis.The Bromhexine hydrochloride injection of Boehringer Ingelheim company also Spain, Italy, gram
Multiple country's listings such as Rhodia, France.
Bromhexine hydrochloride in injection is for adult, and daily 1-2 times, 1-2 (hydrochloric acid of intramuscular injection or intravenous injection
4-8mg of bromhexine).
The auxiliary material information gone out according to given in the newest specification of Japanese bromhexine hydrochloride in injection, original grind drugThe composition information of middle supplementary material is shown in Table 1.
1. original of table grinds drugComposition
The solubility of bromhexine hydrochloride in water is very low (about 1.1mg/ml), and height relies on dissolution coolant-temperature gage, and right
PH value variation is very sensitive.In the bromhexine hydrochloride in injection of Japanese publicationIn IF file, propose and its
His solvent compatibility is likely to occur the problem of pH value variation causes product to be precipitated (physicochemical change).
National Drug Administration discloses bromhexine hydrochloride in injection specification revision bulletin (2018 No. 89),
It is required that increasing " caveat ": the aobvious acidity of this product solution, clinical use should be administered alone, and be avoided and alkaline drug compatible use；It needs
When merging using other drugs, it should individually instil, same infusion channel is such as shared with this product, needs 5% grape between two groups of drugs
The abundant washing pipe of sugared injection or replacement perfusion tube.
Due to the intrinsic low solubility in its water, and after bromhexine hydrochloride in injection pH value pH4.71 if more than just
There is white opacity phenomenon, this brings very big security implication to data for clinical drug use.
In patent CN02139042.8 adjust osmotic pressure used glucose, and used dehydrated alcohol hydrotropy hydrochloric acid bromine oneself
Newly, for being injected intravenously liquid product, addition organic solvent can generate the clinical adverse of undesirable appearance, especially for second
There is alcohol specific system patient allergy etc. occur, and with bromhexine to necessarily lead to bromhexine glucose adducts miscellaneous for glucose
Undesirable special auxiliary material impurity, clinical safety are unknown in matter and drug.
Also ethyl alcohol has largely been used in patent CN200710090358.8, and has been used and can not be used for injection class
Hydroxypropyl methyl cellulose etc., while osmotic pressure being adjusted to also use glucose, these are all the undesirable hairs of high risk injection
It is bright.
Although patent CN201110246847.4, CN201410129890.6, CN201410242818.4 be not using having
Solvent, but osmotic pressure is adjusted to use glucose, concentration 30-50g/L, which will occur not expecting appearance in product
Bromhexine glucose adducts impurity.
Patent CN20141074138.X provide 100ml high-capacity injection formula invention, but at present such product because
Its principal component can cause the variation because of pH value to lead to bromhexine in water to the excessive accordance with tolerance of pH value especially in clinical application
It is precipitated, influences data for clinical drug use.
Patent CN201410624129.X uses the alcohols such as mannitol, xylitol, sorbierite as stability, but the invention
It is middle to use sodium hydroxide tune pH range for 2.0-5.0, and bromhexine is in aqueous solution, no matter using ethyl alcohol, glucose, sweet dew
Alcohol, xylitol, sorbierite, sodium chloride etc. are used as stability or osmotic pressure agent, if the pH value of solution is more than 4.7 bromine to be necessarily precipitated
Oneself is new, causes solution at white opacity phenomenon, this is dissolution characteristics caused by its intrinsic pH value accordance with tolerance of bromhexine hydrochloride.
It is analyzed from the above patent it is found that used glucose as the invention of tune osmotic pressure or stability, it must in product
So occur undesirable auxiliary material adduct impurity (bromhexine glucose adducts), and other inventions are restricted bromhexine hydrochloride it are solid
There is compound pH accordance with tolerance to cause necessarily to occur salt acid group more than pH4.7 to fall off bromhexine free alkali is precipitated, in clinical use
Certainly exist the high risk of administration.These invention defects obviously all bring product quality and clinical administration very high
Risk.How invention better method, with solve bromhexine hydrochloride in injection can not with recuding sugars generate Mei Lade it is anti-
It answers, while solving to prepare and store in the bromhexine hydrochloride waterborne liquid of acceptable pH value and concentration in wider physiological
Hiding, is industrial pharmacy technical problem anxious to be resolved.
Summary of the invention
The technical problem to be solved by the present invention is to overcome existing known bromhexine hydrochloride in injection in clinical administration because
Medical fluid pH value variation the problem of causing bromhexine to be precipitated, provides a kind of more stable bromhexine hydrochloride in injection and its preparation side
Method.
The technical proposal adopted by the invention to solve the above technical problems is that:
A kind of stable bromhexine hydrochloride liquid preparation composition, bromhexine hydrochloride, pharmacy including pharmaceutically acceptable amount
The osmotic pressure regulator of acceptable amount, the stability agent of pharmaceutically acceptable amount, the pH value buffer of pharmaceutically acceptable amount and injection
With water, the stability agent is the chemically modified derivative or its salt of cyclodextrin.
The present invention is had surprisingly found that by test, and the mother body cyclodextrin of injection is used for using commercially viable production at present
The chemically modified derivative of (usually in hydroxylic moiety), such as sulfobutyl ether betadex and HYDROXYPROPYL BETA-CYCLODEXTRIN
Class can maintain the water of the bromhexine (2-4mg/ml) of wider physiologically acceptable pH value (pH1.0-14) and concentration
Property liquid in prepare and storage, adjust osmotic pressure agent sodium chloride, mannitol etc. can be used to avoid Maillard reaction (Maillard
Reaction) generate the undesirable auxiliary material adduct impurity occurred.Pharmaceutically acceptable stabilizer concentration is 0.2%-40% (W/V),
Ensure that bromhexine can be stablized within the scope of wider physiological pH 1-14, bromhexine is not precipitated with alkaline drug compatibility and influences to face
Bed drug safety.
Specifically, the stability agent is sulfobutyl ether derivative or its salt or 2- hydroxypropyl derivatives or its salt.Pharmacy
The stability of acceptable amount is the chemically modified derivative for selecting mother body cyclodextrin (usually in hydroxylic moiety), derivative
Clinical safety it is higher, while keep or improve cyclodextrin complexing power.Its water-soluble and safety of sulfobutyl ether derivative
Property be higher than 2- hydroxypropyl derivatives.
The stability agent is sulphur butyl betadex sodium.Sulphur butyl betadex sodium is the derivative of cyclodextrin
Sodium salt, being widely used in liquid preparation enhances the water solubility of hydrophobic compound, and degree of substitution is used for the product of 4-7 type.In beauty
The clinical maximum safe dose of non-active ingredient is reachable in the intravenously administrable great transfusion preparation that Food and Drug Admistraton, state website is announced
96.23% (W/V), clinical maximum safe dose is up to 94.1% (W/V) in HYDROXYPROPYL BETA-CYCLODEXTRIN injection.
The content of stability agent is 20-40g/L in 1000ml liquid preparation composition.
A kind of proportion of bromhexine hydrochloride liquid preparation is constituted are as follows: bromhexine hydrochloride contains in 1000ml liquid preparation composition
Amount is 2-4g, and osmotic pressure regulator content is 21-23g, and pH value buffer content is 1-1.1g.Pharmaceutically acceptable hydrochloric acid
Bromhexine is 2mg/ml -4mg/ml in water base middle concentration, meets quantity requirement；Pharmaceutically acceptable osmotic pressure regulator
Using sodium chloride and mannitol, emphasis of the present invention considers PEARLITOL 25C, and sorbierite, xylitol, maltitol are in injection
Using considerably less, and safety, without PEARLITOL 25C height, it is 270-that concentration, which needs to keep permeability in product quality,
320msOsmol/kg；Pharmaceutically acceptable soda acid pH adjusting agent is tartaric acid, and most preferably L-TARTARIC ACID, dosage should be kept
PH value is in 2.2-3.2 ranges.
The pharmaceutically acceptable osmotic pressure regulator is sodium chloride or mannitol.
Product is being ground to originalDiscovery has a very big unknown impuritie, impurity when carrying out Quality analysis
Amount finds that this impurity is the adduct impurity that bromhexine hydrochloride and glucose are formed more than 0.2%, through analysis, is formed theoretical for beauty
Maillard reaction (Maillard reaction) is with glucose based on the amino in bromhexine structural formula by the new of structural rearrangement formation
Impurity, this impurity is undesirable impurity in drug, and this impurity brings very big safety hidden to intravenously administrable
Suffer from, impurity level has been more than identification threshold value (0.2%).
Documents and materials " pharmaceutic adjuvant handbook " fourth edition (work such as [English] sieve R.C) proposes aldehydic grape in glucose chapters and sections
Sugar can be reacted with organic amine, amide, amino acid, peptide and protein；The tablet that glucose will lead to amino-contained becomes brown
(Maillard reaction).Adverse reaction part in mannitol chapters and sections proposes that mannitol is not in Maillard reaction (Maillard
Reaction).
In Maillard reaction (Maillard reaction), mainly reduced sugar and the amino acid of reaction are participated in, can be double
Sugar, pentose and hexose.Available disaccharide has lactose and sucrose；Pentose has xylose, ribose and arabinose；Hexose have glucose,
Fructose, mannose, galactolipin etc..It is reported that pentose brown stain speed is 10 times of hexose, pentose is brown in reductive monosaccharide
Speed change degree is ordered as ribose > arabinose > xylose, and hexose is ordered as galactolipin > mannose > glucose.Different sugar
The activity order reacted with lysine is xylose > galactolipin > glucose > fructose > sucrose.The type and concentration pair of amino acid
The product types of Maillard reaction also have critically important influence.
There are many factor for influencing Maillard reaction (Maillard reaction), mainly have the structure of carbohydrate and amino acid, also
Temperature, reaction time, pH value, moisture, high pressure, irradiation etc., the former mainly influences the type of maillard reaction product, and the latter is usual
It is the dynamics influence factor of reaction.Maillard reaction generally can occur under the conditions of 20~25 DEG C, be influenced by temperature
It is very big.Temperature is higher, and brown stain speed is faster.Temperature is every to improve 10 DEG C, and reaction speed increases about 3~5.
Maillard reaction (Maillard reaction) generates final product, and some of ingredients are toxicant.It studies at present
More clearly there are acrylamide (acrylamide) and glycosylation end products (AGEs).Acrylamide is neurotoxin and cause
Cancer substance generates glycosylation end products (AGEs) with protein cross, formation, artery sclerosis with cataract, presenile
Dementia, nephrosis, diabetes are related.
Inventor will collect this impurity through LC-MS (LC-MS) after bromhexine hydrochloride and glucose response, detect this
Impurity molecule amount simultaneously derives that structural formula is as follows:
Molecular formula: C20H30Br2N2O5Molecular weight: 538.28
It has been investigated that if for, with the presence of process impurity C, D, can in the bromhexine hydrochloride bulk pharmaceutical chemicals of preparation production
Maillard reaction (Maillard reacts) occurs with glucose, occurs its impurity peaks in formulation products, especially bromhexine is miscellaneous
Matter C and D and glucose are formed under acid solution (pH3 or so), in study on the stability after 24 hours just after adding tartaric acid
It will appear new adduct impurity, structural formula is as follows:
Documents and materials generate such impurity with glucose Maillard reaction (Maillard reacts) for bromhexine afterwards at present
Deep toxicity and pharmacological research are not carried out, to clinical safety also without sufficient document report, therefore, this impurity
It is the auxiliary material adduct impurity for being not intended to occur in drug, especially occurs in high risk injection drug.Studies have shown that such as
If fruit bromhexine hydrochloride in injection using glucose as osmotic pressure regulator, it is former in the bromhexine hydrochloride produced for preparation
Expect that new glucose adducts impurity will be generated with the presence of process impurity C, D in medicine.Therefore, bromhexine hydrochloride of the invention
Liquid preparation does not select glucose as osmotic pressure regulator, selects sodium chloride or mannitol as osmotic pressure regulator, in this way
Even if the generation of new glucose adducts impurity will not be caused with the presence of process impurity C, D in bromhexine hydrochloride bulk pharmaceutical chemicals,
Further ensure the safety of bromhexine hydrochloride liquid preparation.
A kind of optimization formula of bromhexine hydrochloride liquid preparation of the invention, in the 1000ml liquid preparation composition,
Bromhexine hydrochloride content is 2g-4g, and PEARLITOL 25C content is 21g-23g, and sulphur butyl betadex sodium content is 20-40g, L-
Tartaric acid content is 1g-1.1g.
A kind of preparation method of stable bromhexine hydrochloride liquid preparation composition, includes the following steps:
(1) osmotic pressure regulator of recipe quantity is weighed, pH value buffering agents are dissolved in the water for injection of 60% recipe quantity
In, stirring and dissolving clarification, with 0.22 μm of membrane filtration；
(2) 35% injection water of recipe quantity and bromhexine hydrochloride are in addition weighed, the stability of recipe quantity is added under stiring
Agent, stirring clarification；
(3) (2) step medical fluid is added under stiring in (1) step solution, stirs 15-30 minutes, cools the temperature to
30 DEG C hereinafter, measurement intermediates content, regulating liquid medicine pH be 2.6 ± 0.02, add and inject water to recipe quantity, continue to stir
15-30 minutes；
(4) ultrafiltration is except after heat source；It is filling；Terminal sterilization to obtain the final product
Further, in the preparation method step (2), in the chemically modified derivative or its salt that cyclodextrin is added
In the case where as stabilizer, during preparing bromhexine hydrochloride in injection, under same amount ratio, temperature is to bromhexine hydrochloride
Dissolution time there is no accordance with tolerance, dissolution time is in 5min, in the commercially producing of preparation, higher temperature it is water-soluble
Liquid is not necessarily to dissolve bromhexine hydrochloride, and the actual needs based on production, solution temperature can control in 25-65 DEG C of model
It encloses.
In the preparation method step (2), if medical fluid pH value not 2.6 ± 0.02 range, hydrochloric acid solution can be used
(1mol/L) or sodium hydroxide solution (1mol/L), which are adjusted, arrives this range, adds and injects water to recipe quantity, continues stirring 15-
30 minutes.
In the preparation method step (3), carried out after ultrafiltration removes heat source with level Four filtration system；Boron in filling 2ml brown
In silicon ampoule bottle, sealed after inflated with nitrogen；Terminal sterilization (121 DEG C sterilize 15-30 minutes) to obtain the final product.Ampoule color is brown,
The range scans transmitance of 290nm -450nm ultraviolet light and 590nm -610nm visible light should meet product and be protected from light Storage Requirement.
The invention has the advantages that:
1, the present invention utilizes cyclodextrin by the chemically modified derivative for selecting cyclodextrin or its salt as stabilizer
Chemically modified derivative or the property of its salt can be in pH1-14 range using the stabilizer hydrotropy bromhexine hydrochloride
Interior holding is stablized, and bromhexine will not be precipitated, it is ensured that the safety of clinical application.
2, the present invention selects the osmotic pressure regulator of non-glucose, accordingly even when the bromhexine hydrochloride bulk pharmaceutical chemicals of preparation production
In with the presence of process impurity C, D, Maillard reaction (Maillard reacts) will not occur with glucose, can be avoided in preparation
Occurs glucose adducts impurity in product.
3, the present invention uses sulphur butyl betadex sodium hydrotropy bromhexine hydrochloride, operate with liquid, dissolution time
Only need a few minutes, and dissolve bromhexine without excessively high water temperature (70-90 DEG C), it is only necessary at 25-65 DEG C into
Row preparation, keeps the stability of drug, and then shorten the production time of injection, save the industrial production of preparation at
This, improves economic benefit.Its quality is stable, controllable.
Detailed description of the invention
Attached drawing described herein is used to provide to further understand the embodiment of the present invention, constitutes one of the application
Point, do not constitute the restriction to the embodiment of the present invention.In the accompanying drawings:
Fig. 1 is bromhexine glucose adducts impurity MS map.
Specific embodiment
To make the objectives, technical solutions, and advantages of the present invention clearer, below with reference to embodiment and attached drawing, to this
Invention is described in further detail, and exemplary embodiment of the invention and its explanation for explaining only the invention, are not made
For limitation of the invention.
Embodiment 1:
The bromhexine hydrochloride in injection of the stabilizer containing pharmacy is prepared using following methods in the present invention:
(1) PEARLITOL 25C of recipe quantity is weighed, L tartaric acid is dissolved in the water for injection of 60% recipe quantity, stirring and dissolving
Clarification, with 0.22 μm of membrane filtration.
(2) 35% injection water of recipe quantity and bromhexine hydrochloride are in addition weighed, the sulphur butyl of recipe quantity is added under stiring
Betadex sodium, stirring clarification.
(3) (2) step medical fluid is added under stiring in (1) step solution, stirs 15-30 minutes, cools the temperature to
30 DEG C hereinafter, measurement intermediates content, monitoring medical fluid pH is 2.6 ± 0.02, if medical fluid pH value can use salt not in this range
Acid solution (1mol/L) or sodium hydroxide solution (1mol/L), which are adjusted, arrives this range, adds and injects water to recipe quantity, continues to stir
It mixes 15-30 minutes.
(4) it is carried out after ultrafiltration removes heat source with level Four filtration system；In filling 2ml brown in borosilicate ampoule bottle, after inflated with nitrogen
Sealing；Terminal sterilization (121 DEG C sterilize 15-30 minutes) to obtain the final product.
Embodiment 2:
The bromhexine hydrochloride in injection of the stabilizer containing pharmacy is prepared with the preparation method of embodiment 1 in the present embodiment.
Embodiment 3:
The bromhexine hydrochloride in injection of the stabilizer containing pharmacy is prepared with the preparation method of embodiment 1 in the present embodiment.
Embodiment 4:
The bromhexine hydrochloride in injection of the stabilizer containing pharmacy is prepared with the preparation method of embodiment 1 in the present embodiment.
In the present invention, using pharmaceutically acceptable stability agent sulphur butyl betadex sodium and HYDROXYPROPYL BETA-CYCLODEXTRIN
Carry out hydrotropy bromhexine hydrochloride to investigate the accordance with tolerance of solution temperature, carries out preparation 1000ml, bromhexine hydrochloride dissolution by embodiment 1
Temperature and time statistical form 2-3 is as follows:
2. sulphur butyl betadex sodium temperature of table and dissolution time accordance with tolerance are investigated
| Investigate temperature | 25-35℃ | 45-65℃ | 75-85℃ |
| Observed temperature | 31.3℃ | 51.5℃ | 78.5℃ |
| Bromhexine hydrochloride settling time | 3 minutes | 45 seconds | 21 seconds |
| Sulphur butyl betadex sodium amount ratio | 1:10 | 1:10 | 1:10 |
3. HYDROXYPROPYL BETA-CYCLODEXTRIN temperature of table and dissolution time accordance with tolerance are investigated
| Investigate temperature | 25-35℃ | 45-65℃ | 75-85℃ |
| Observed temperature | 32.1℃ | 52.4℃ | 77.5℃ |
| Bromhexine hydrochloride settling time | 4 minutes | 52 seconds | 29 seconds |
| HYDROXYPROPYL BETA-CYCLODEXTRIN amount ratio | 1:10 | 1:10 | 1:10 |
Table as above is investigated shown in data, during preparing 1000ml bromhexine hydrochloride in injection, under same amount ratio, and temperature
There is no accordance with tolerance to the dissolution time of bromhexine hydrochloride, dissolution time is in 5min, in the commercially producing of preparation, compared with
The aqueous solution of high-temperature is not necessarily to dissolve bromhexine hydrochloride, and the actual needs based on production, solution temperature can be controlled
System is in 25-65 DEG C of range.
The present invention uses sulphur butyl betadex sodium and HYDROXYPROPYL BETA-CYCLODEXTRIN hydrotropy bromhexine hydrochloride, carries out with liquid
Operation, dissolution time only needs a few minutes, and dissolves bromhexine without excessively high water temperature (70-90 DEG C), it is only necessary to
It to be prepared at 25-65 DEG C, keep the stability of drug, and then shorten the production time of injection, be saved
The industrial production cost of preparation, improves economic benefit.Its quality is stable, controllable.
The present invention is ground by originalIt is formulated (being shown in Table 1) and prepares 100ml product, routinely process for preparing injection liquid
After preparation (80 DEG C of water temperature of dissolution), the quality of testing product is shown in Table 4.From former bedding-in side's detection data it is found that bromhexine glucose
Its impurity level of adduct impurity has been more than identification threshold limit (0.2%), while adding glucose and needing other generation furfural miscellaneous
Matter.
4. original of table is groundPrescription quality investigates comparison
Remarks: the impurity of mark " * " is the impurity that glucose generates；For luxuriant and rich with fragrance (Japan) Products of celo；For luxuriant and rich with fragrance (Spain) Products of celo.
The present invention is in order to further prove that dissolution water temperature is stable to the quality of product, reliable, in 80 DEG C ± 2 DEG C, 70 ± 2
DEG C, 60 DEG C ± 2 DEG C, prepare 4 groups of drugs by embodiment 1 under 50 DEG C of ± 2 DEG C of water temperatures and investigated, if detection is shown in Table 5-6.
5. dosing temperature screening experiment result of table (before sterilizing)
6. dosing temperature screening experiment result of table (after 121 DEG C/15min sterilizing)
Remarks: N.D expression is not detected, and impurity C, D structural formula is shown in the content of present invention；Other impurities are in patent
Its structural formula is disclosed in CN201410334638.9；L impurity is bromhexine synthetic route raw materials for production medicine process impurity, structural formula
It has been reported in other documents and materials.
In the present invention, using pharmaceutically acceptable stability agent sulphur butyl betadex sodium and HYDROXYPROPYL BETA-CYCLODEXTRIN
Carry out hydrotropy bromhexine hydrochloride, can keep stablizing within the scope of pH1-14, bromhexine will not be precipitated, it is ensured that the safety of clinical application
Property.Preparation 100ml is carried out by embodiment 1, statistical form 7-8 is as follows:
7. HYDROXYPROPYL BETA-CYCLODEXTRIN of table bromhexine steadiness within the scope of wider pH value
8. sulphur butyl betadex sodium of table bromhexine steadiness within the scope of wider pH value
Table as above is investigated shown in data, during preparing 100ml bromhexine hydrochloride in injection, at wider pH value (1-14)
In range, it is precipitated without bromhexine.
By being added to pharmaceutically acceptable stability agent sulphur butyl betadex sodium and HYDROXYPROPYL BETA-CYCLODEXTRIN preparation
Bromhexine hydrochloride in injection, it is believed that the present invention have better stability, can be improved the injection clinical application safety
Property, product can not rinse defeated with alkaline medical fluid compatibility problems during thoroughly solving clinical application without other modes
Liquid pipe line improves the safety coefficient of clinical application.
In order to further prove that the present invention can be precipitated without influencing bromhexine, use with the compatibility problems of alkaline drug
Sodium lactate ringer's injection, pH value 6.0-7.5 carry out compatibility with the bromhexine hydrochloride in injection prepared by embodiment 1 and examine
It examines, investigating the time is 48 hours, investigates data and is shown in Table 9.
9. bromhexine hydrochloride in injection of table and sodium lactate ringer's injection (250ml) Compatibility
The present invention further uses other to adjust containing pharmaceutically acceptable stability HYDROXYPROPYL BETA-CYCLODEXTRIN and osmotic pressure
Agent, pH adjusting agent prepared by embodiment 1 after with sodium lactate ringer's injection (250ml) Compatibility, the results are shown in Table 10-
11。
Other composite formulas of table 10.
11. bromhexine hydrochloride in injection of table and sodium lactate ringer's injection (250ml) 48 hours Compatibilities
It is above-mentioned the experimental results showed that, the present invention pass through select cyclodextrin chemically modified derivative or its salt as surely
Determine agent, it can using the stabilizer hydrotropy bromhexine hydrochloride using the chemically modified derivative of cyclodextrin or the property of its salt
To keep stablizing within the scope of pH1-14, bromhexine will not be precipitated, it is ensured that the safety of clinical application.
Above-described specific embodiment has carried out further the purpose of the present invention, technical scheme and beneficial effects
It is described in detail, it should be understood that being not intended to limit the present invention the foregoing is merely a specific embodiment of the invention
Protection scope, all within the spirits and principles of the present invention, any modification, equivalent substitution, improvement and etc. done should all include
Within protection scope of the present invention.
Claims (10)
1. a kind of stable bromhexine hydrochloride liquid preparation composition, bromhexine hydrochloride, pharmacy including pharmaceutically acceptable amount can
The osmotic pressure regulator of receiving amount, the stability agent of pharmaceutically acceptable amount, the pH value buffer of pharmaceutically acceptable amount and injection
Water, which is characterized in that the stability agent is the chemically modified derivative or its salt of cyclodextrin.
2. stable bromhexine hydrochloride liquid preparation composition according to claim 1, which is characterized in that the stability
Agent is sulfobutyl ether derivative or its salt or 2- hydroxypropyl derivatives or its salt.
3. stable bromhexine hydrochloride liquid preparation composition according to claim 1, which is characterized in that the stability
Agent is sulphur butyl betadex sodium.
4. stable bromhexine hydrochloride liquid preparation composition according to claim 1, which is characterized in that 1000ml liquid
The content of stability agent is 20-40g/L in preparation compositions.
5. stable bromhexine hydrochloride liquid preparation composition according to claim 4, which is characterized in that 1000ml liquid
Bromhexine hydrochloride content is 2-4g in preparation compositions, and osmotic pressure regulator content is 21-23g, and pH value buffer content is
1—1.1g。
6. stable bromhexine hydrochloride liquid preparation composition according to any one of claims 1 to 5, which is characterized in that
The pharmaceutically acceptable osmotic pressure regulator is sodium chloride or mannitol.
7. stable bromhexine hydrochloride liquid preparation composition according to any one of claims 1 to 5, which is characterized in that
The pharmaceutically acceptable pH value buffer is tartaric acid.
8. stable bromhexine hydrochloride liquid preparation composition according to any one of claims 1 to 5, which is characterized in that
In the 1000ml liquid preparation composition, bromhexine hydrochloride content is 2g-4g, and PEARLITOL 25C content is 21g-23g, sulphur butyl
Betadex sodium content is 20-40g, and L-TARTARIC ACID content is 1g-1.1g.
9. stable bromhexine hydrochloride liquid preparation composition according to any one of claims 1 to 5, which is characterized in that
The pH value of the liquid composition is 2.2-3.2.
10. a kind of preparation method of stable bromhexine hydrochloride liquid preparation composition, which is characterized in that include the following steps:
(1) weigh the osmotic pressure regulator of recipe quantity, pH value buffering agents are dissolved in the water for injection of 60% recipe quantity, stir
Dissolution clarification is mixed, with 0.22 μm of membrane filtration；
(2) 35% injection water of recipe quantity and bromhexine hydrochloride are in addition weighed, the stability agent of recipe quantity is added under stiring, stirs
Mix clarification；
(3) (2) step medical fluid is added under stiring in (1) step solution, stirs 15-30 minutes, cools the temperature to 30 DEG C
Hereinafter, measurement intermediates content, regulating liquid medicine pH is 2.6 ± 0.02, adds and injects water to recipe quantity, continues stirring 15-30
Minute；
(4) ultrafiltration is except after heat source；It is filling；Terminal sterilization to obtain the final product.
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| CN110251491A (en) * | 2019-06-21 | 2019-09-20 | 上海禾丰制药有限公司 | A kind of sucking bromhexine hydrochloride solution and preparation method thereof |
| 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 |
| CN113143855A (en) * | 2021-04-29 | 2021-07-23 | 北京阳光诺和药物研究股份有限公司 | Bromhexine hydrochloride oral liquid and preparation method thereof |
| CN114788809A (en) * | 2022-01-25 | 2022-07-26 | 江苏广承药业有限公司 | Loratadine liquid preparation |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110251491A (en) * | 2019-06-21 | 2019-09-20 | 上海禾丰制药有限公司 | A kind of sucking bromhexine hydrochloride solution and preparation method thereof |
| 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 |
| CN113143855A (en) * | 2021-04-29 | 2021-07-23 | 北京阳光诺和药物研究股份有限公司 | Bromhexine hydrochloride oral liquid 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 |
| CN114788809A (en) * | 2022-01-25 | 2022-07-26 | 江苏广承药业有限公司 | Loratadine liquid preparation |
| 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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