CN111568861A - Bromhexine hydrochloride oral liquid for livestock and poultry as well as preparation method and application thereof - Google Patents
Bromhexine hydrochloride oral liquid for livestock and poultry as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN111568861A CN111568861A CN202010447161.0A CN202010447161A CN111568861A CN 111568861 A CN111568861 A CN 111568861A CN 202010447161 A CN202010447161 A CN 202010447161A CN 111568861 A CN111568861 A CN 111568861A
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- CN
- China
- Prior art keywords
- livestock
- poultry
- oral liquid
- bromhexine hydrochloride
- hydrochloride oral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960002335 bromhexine hydrochloride Drugs 0.000 title claims abstract description 97
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 239000007788 liquid Substances 0.000 title claims abstract description 95
- 244000144972 livestock Species 0.000 title claims abstract description 89
- 244000144977 poultry Species 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 11
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims abstract description 7
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 7
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- 206010057190 Respiratory tract infections Diseases 0.000 claims abstract description 6
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- 239000002904 solvent Substances 0.000 claims abstract description 5
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- 238000004659 sterilization and disinfection Methods 0.000 claims description 7
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
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- 239000006184 cosolvent Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
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- 238000007789 sealing Methods 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- -1 polyoxyethylene octylphenol Polymers 0.000 claims description 2
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- 230000000694 effects Effects 0.000 abstract description 15
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- 229960001484 edetic acid Drugs 0.000 abstract 1
- 229940001607 sodium bisulfite Drugs 0.000 abstract 1
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- PGNYNCTUBKSHHL-UHFFFAOYSA-N 2,3-diaminobutanedioic acid Chemical compound OC(=O)C(N)C(N)C(O)=O PGNYNCTUBKSHHL-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
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- 229930182555 Penicillin Natural products 0.000 description 9
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- 206010013975 Dyspnoeas Diseases 0.000 description 8
- 229960002727 cefotaxime sodium Drugs 0.000 description 8
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 8
- 235000013330 chicken meat Nutrition 0.000 description 8
- 241000282465 Canis Species 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 239000007927 intramuscular injection Substances 0.000 description 5
- 238000010255 intramuscular injection Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
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- 238000009395 breeding Methods 0.000 description 4
- 230000001488 breeding effect Effects 0.000 description 4
- 229960003870 bromhexine Drugs 0.000 description 4
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 4
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- 230000028327 secretion Effects 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- MNQUGTOXDUBSJZ-UHFFFAOYSA-N 2-bromo-4-chloro-6-[[cyclohexyl(methyl)amino]methyl]aniline Chemical compound C1CCCCC1N(C)CC1=CC(Cl)=CC(Br)=C1N MNQUGTOXDUBSJZ-UHFFFAOYSA-N 0.000 description 2
- QIYWHKWTMAEJLS-UHFFFAOYSA-N 4-bromo-2-chloro-6-[[cyclohexyl(methyl)amino]methyl]aniline Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Cl)=C1N QIYWHKWTMAEJLS-UHFFFAOYSA-N 0.000 description 2
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- 239000002253 acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
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- YIICVSCAKJMMDJ-SNVBAGLBSA-N Peganine Chemical class C1=CC=C2N=C3[C@H](O)CCN3CC2=C1 YIICVSCAKJMMDJ-SNVBAGLBSA-N 0.000 description 1
- 206010037368 Pulmonary congestion Diseases 0.000 description 1
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- 238000002555 auscultation Methods 0.000 description 1
- 229960002233 benzalkonium bromide Drugs 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
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Classifications
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
-
- 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
-
- 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
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Emergency Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of livestock and poultry medicines, and discloses bromhexine hydrochloride oral liquid for livestock and poultry, a preparation method and application thereof, wherein bromhexine hydrochloride is dissolved in a latent solvent, polyethylene glycol 6000 is added and mixed uniformly, an aqueous solution prepared from sodium bisulfite, ammonium acetate, ethylene diamine tetraacetic acid, organic acid and water is added and mixed uniformly, and then the bromhexine hydrochloride oral liquid is prepared by adjusting the pH value by the organic acid, fixing the volume by purified water and filtering; the bromhexine hydrochloride oral liquid for livestock and poultry can be used as a medicine for treating respiratory tract infection of livestock and poultry. The bromhexine hydrochloride oral liquid for livestock and poultry has the advantages that the content of related substances is obviously reduced, the long-term storage stability is higher, and the treatment effect is good; the preparation method is simple, wide in raw material source, low in price and suitable for industrial production. The bromhexine hydrochloride oral liquid for livestock and poultry is suitable for being taken by livestock and poultry with respiratory tract infection.
Description
Technical Field
The invention belongs to the field of livestock and poultry medicines, and relates to an oral liquid for livestock and poultry, in particular to bromhexine hydrochloride oral liquid for livestock and poultry, and a preparation method and application thereof.
Background
With the continuous expansion of modern breeding scale, intensive breeding occupies an important position in the breeding industry. The breeding density is increased, the feed management and epidemic disease prevention and control measures are lagged behind, so that the probability of respiratory diseases infected by livestock is increased, the weight gain, the feed conversion rate, the laying rate and the like of the livestock are seriously influenced, and the economic benefit of a farm is seriously lost. At present, the pathogenic microorganisms causing respiratory diseases of livestock and poultry mainly comprise infectious laryngotracheitis virus, infectious bronchitis virus, mycoplasma, newcastle disease virus and the like. At present, the common medicine for preventing and treating the symptoms is 5 percent erythromycin thiocyanate soluble powder or Shuanghuanglian injection, but the treatment effect still needs to be improved.
Disclosure of Invention
The invention aims to provide bromhexine hydrochloride oral liquid for livestock and poultry, so as to provide an oral medicine which has good stability, low related substances and good treatment effect;
the invention also aims to provide a preparation method of the bromhexine hydrochloride oral liquid for livestock and poultry;
the invention also aims to provide the application of the bromhexine hydrochloride oral liquid for livestock and poultry.
In order to achieve the purpose, the invention adopts the technical scheme that:
the bromhexine hydrochloride oral liquid for livestock and poultry comprises the following raw materials of active ingredients in parts by weight per 100 parts by volume:
0.3-6.0 parts of bromhexine hydrochloride, 2.4-60 parts of polyethylene glycol 6000, 0.03-0.2 part of sodium bisulfite, 0.015-0.05 part of disodium ethylene diamine tetraacetate, 0.09-2.7 parts of ammonium acetate and 0.6-18.0 parts of glacial acetic acid;
the raw materials for preparing the effective components also comprise: 20-60 parts by volume of latent solvent, and supplementing to 100 parts by volume with water;
wherein the proportion of the parts by weight to the parts by volume is kg: and L.
As a limitation, the pH value of the bromhexine hydrochloride oral liquid for livestock and poultry is 3.5-5.5.
As another limitation, the cosolvent is at least one of ethanol, propylene glycol, N-dimethylacetamide, dimethyl sulfoxide, and polyoxyethylene octylphenol ether-10.
The invention also provides a preparation method of the bromhexine hydrochloride oral liquid for livestock and poultry, which comprises the following steps of:
1) dissolving sodium bisulfite, ammonium acetate, disodium ethylene diamine tetraacetate and organic acid in water, and mixing to obtain an aqueous solution A;
2) adding bromhexine hydrochloride into the cosolvent for dissolving, adding polyethylene glycol 6000 into the obtained solution B, and uniformly mixing to obtain a mixed solution C;
3) and adding the aqueous solution A into the mixed solution C, uniformly mixing, adjusting the pH value by using organic acid, fixing the volume by using purified water, and filtering to obtain filtrate, namely the bromhexine hydrochloride oral liquid for livestock and poultry.
As a limitation, after filtration, the filtrate is sterilized.
As a further limitation, the filtrate is subjected to subpackaging and sealing after filtration and before sterilization; and (5) sterilizing the filtrate, and packaging.
As a further limitation, the sterilization is radiation sterilization.
As another limitation, in the step 1), when bromhexine hydrochloride is added, the temperature of the latent solvent is 60-70 ℃;
before adding the polyethylene glycol 6000, cooling the solution B to 30-40 ℃;
in the step 3), adjusting the pH value to 3.5-5.5;
the filtration is microporous filter element filtration.
By way of further limitation, the pore size of the microporous filter element is 0.45 μm, 0.22 μm, or 0.20 μm.
The invention also provides an application of the bromhexine hydrochloride oral liquid for livestock and poultry, and the bromhexine hydrochloride oral liquid for livestock and poultry is used as a medicine for treating respiratory tract infection of livestock and poultry.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the technical progress that:
bromhexine hydrochloride, also known as bromhexine and benzalkonium bromide, is a semi-synthetic hydrochloride of vasicine derivatives, is first synthesized by Keck in 1963, and is marketed in China in 1973. The product can directly act on bronchial gland to promote lysosome release of mucus secretory cell, and differentiate and crack viscous carbohydrate fiber in phlegm; 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; it also stimulates gastric mucosa to reflexively cause respiratory tract glandular secretion increase, and makes sputum dilute, and is widely used for auxiliary treatment of human respiratory tract diseases.
The invention does not use benzoic acid, sorbitol and salt thereof as preservative, thus improving the safety of medication, and the stability of appearance and performance is enhanced by adding sodium bisulfite as antioxidant and EDTA-2Na as chelating agent; after propylene glycol and polyethylene glycol 6000 are added, the content of related substances (impurities such as N-methyl-N-cyclohexyl-2-amino-3-chloro-5-bromobenzylamine or N-methyl-N-cyclohexyl-2-amino-5-chloro-3-bromobenzylamine) in the prepared bromhexine hydrochloride oral liquid for livestock and poultry is obviously reduced, the bromhexine hydrochloride oral liquid is easy to store and has higher stability in the long-term storage process. The preparation method is simple, wide in raw material source, low in price and suitable for industrial production.
The bromhexine hydrochloride oral liquid for livestock and poultry is used for livestock and poultry with respiratory tract infection; the preparation method is used for preparing bromhexine hydrochloride oral liquid for livestock and poultry.
Detailed Description
The present invention is further illustrated by the following specific examples, which are to be construed as merely illustrative, and not limitative of the remainder of the disclosure.
Example 1 preparation method of bromhexine hydrochloride oral liquid for livestock and poultry
The preparation of 10L bromhexine hydrochloride oral liquid for livestock and poultry in the embodiment comprises the following steps in sequence:
1) dissolving 0.01kg of sodium bisulfite, 0.03kg of ammonium acetate and 0.0015kg of disodium ethylenediaminetetraacetate (EDTA-2 Na) in 6L of purified water (referred to as first purified water), and stirring at room temperature to obtain an aqueous solution A1；
2) Heating 2L propylene glycol to 65 deg.C, adding 0.1kg bromhexine hydrochloride, stirring and dissolving to obtain solution B1(ii) a Mixing the solution B1Cooling to 35 deg.C, adding 0.8kg polyethylene glycol 6000, and stirring to obtain mixed solution C1；
3) Mixed liquor C1Adding the aqueous solution A while stirring, uniformly stirring, adjusting the pH value to 4.4 by using 0.315kg of glacial acetic acid, fixing the volume to 10L by using purified water, and filtering by using a 0.45 mu m micropore filter element to obtain the bromhexine hydrochloride oral liquid for livestock and poultry, wherein the pH value is 4.4; wherein, glacial acetic acid and ammonium acetate form buffer salt which can stabilize the pH value of the solution.
Separately packaging and sealing the bromhexine hydrochloride oral liquid for livestock and poultry, performing 6 kilogray radiation sterilization, and finally packaging to obtain the independently packaged bromhexine hydrochloride oral liquid for the sterilized livestock and the market for the livestock, wherein the pH value is still 4.4.
The bromhexine hydrochloride oral liquid for livestock and poultry is used for livestock and poultry with respiratory tract infection.
Example 2-6 bromhexine hydrochloride oral liquid for livestock and poultry and preparation method thereof
Examples 2 to 6 are respectively a bromhexine hydrochloride oral liquid for livestock and poultry and a preparation method thereof, the steps of the bromhexine hydrochloride oral liquid are basically the same as those of example 1, the differences are only in the dosage of raw materials and the process parameters, and the specific details are shown in table 1:
TABLE 1 summary of the process parameters of examples 2 to 6
The contents of the other portions of examples 2 to 6 are the same as those of example 1.
Example 7 quality and stability of bromhexine hydrochloride oral liquid for livestock and poultry
Taking commercially available bromhexine hydrochloride oral liquid for livestock and poultry prepared in examples 1-6, determining the stability of the bromhexine hydrochloride oral liquid according to the requirements of the guidance principle of the stability test of raw material medicaments and preparations in the appendix 9001 of the 2015 edition of Chinese veterinary pharmacopoeia, and detecting the content of related substances by using a high performance liquid chromatography, wherein the test conditions are as follows: the commercial package is placed for 24 months at 25 +/-2 ℃ and RH60% +/-10%, and the detection results of the contents of the related substances are shown in Table 2:
TABLE 2 summary of the results of the content testing of the related substances of bromhexine hydrochloride oral liquid for livestock and poultry available on the market prepared in examples 1 to 6
In table 2, the impurities are N-methyl-N-cyclohexyl-2-amino-3-chloro-5-bromobenzylamine or/and N-methyl-N-cyclohexyl-2-amino-5-chloro-3-bromobenzylamine, etc., and both of these impurities are represented by impurity I, because they cannot be clearly distinguished in the hplc detection.
As shown in Table 2, the related substances in the commercially available bromhexine hydrochloride oral liquid for livestock and poultry prepared in examples 1 to 6 can be kept stable for 24 months.
Example 8 test of therapeutic effect of bromhexine hydrochloride oral liquid for livestock and poultry on AA broiler Infectious Bronchitis (IB)
Averagely dividing 3200 AA broiler chickens suffering from Infectious Bronchitis (IB) at the age of 26 days into eight groups, namely a blank group, a control group and an A group8Group B8Group C8Group D8Group E8Group F8Group, wherein the blank group did not take any drug, and the control group drunk 5% erythromycin thiocyanate soluble powder and A8Bromhexine hydrochloride oral liquid for livestock and poultry prepared in group-mixed feeding example 1 and5% erythromycin thiocyanate soluble powder B for drinking8Bromhexine hydrochloride oral liquid for livestock and poultry prepared in group-mixed feeding example 2 and 5% erythromycin thiocyanate soluble powder for drinking, C8Bromhexine hydrochloride oral liquid for livestock and poultry prepared in group-mixed feeding example 3 and 5% erythromycin thiocyanate soluble powder for drinking, D8Group-mixed bromhexine hydrochloride oral liquid prepared in example 4 and 5% erythromycin thiocyanate soluble powder for drinking, and E8Bromhexine hydrochloride oral liquid for livestock and poultry prepared in example 5 and 5% erythromycin thiocyanate soluble powder and F for drinking are mixed8The bromhexine hydrochloride oral liquid prepared in example 6 and 5% erythromycin thiocyanate soluble powder are drunk for livestock and poultry. Wherein, control group A8~F8The group is that 5% erythromycin thiocyanate soluble powder is added into drinking water, the addition amount is 2.5g per liter of water, and the control group and A8~F8The dose of the 5% erythromycin thiocyanate soluble powder for group drinking is 0.6 g/(d only) of the 5% erythromycin thiocyanate soluble powder, A8~F8The dose of the bromhexine hydrochloride oral liquid for livestock and poultry prepared in the examples 1 to 6 which are respectively eaten in the group is reduced to 0.45 mg/(kg. d) of bromhexine hydrochloride.
Control group, A8~F8After the group is respectively mixed with the medicines, the illness state is quickly controlled, and the fatality rate is obviously lower than that of the blank group. After administration A8~F8The treatment effect is obvious, and after the composition is taken for 1 day, the mental state of sick chickens is obviously improved; after 2 days, the clinical symptoms of nasal discharge, lacrimation, nasal swelling, cough, sneeze, stretching neck, opening mouth, gasping and the like of the sick chicken are obviously reduced; after 4 days, the clinical symptoms of the sick chickens basically disappear, the hoarseness cry basically disappears at night, and the chicken flocks are recovered to be normal. After 5 days, the control group still has clinical symptoms of individual chickens, and after 10 days, the clinical symptoms basically disappear in the blank group. The statistical result shows that the self-healing rate of the blank group is 83.25%, although the mortality rate is not high, the clinical symptoms are slowly eliminated, and the clinical symptoms of the control group are eliminated compared with A8~F8The group is slow. A. the8~F8The cure rate of the group is more than or equal to 98.50, the fatality rate is obviously lower than that of the blank group, and the clinical symptoms are eliminated quickly. Specific therapeutic effect comparison data are shown in table 3.
TABLE 3 summary of the therapeutic effects of AA Infectious Bronchitis (IB) in broilers
From the test and table 3, it can be seen that after the sick chickens suffering from the infectious bronchitis take the bromhexine oral liquid for livestock and poultry and the 5% erythromycin thiocyanate soluble powder, the illness state is controlled quickly, the fatality rate is obviously lower than that of the blank group, the clinical symptoms of the sick chickens basically disappear after 4 days, the hoarseness cry basically disappears at night, and the chickens recover to be normal. Therefore, the bromhexine hydrochloride oral liquid for livestock and poultry has obvious effect on treating the Infectious Bronchitis (IB).
Example 9 test of therapeutic Effect of bromhexine hydrochloride oral liquid for livestock and poultry on swine influenza
Epidemiological clinical symptoms of sick pigs suffering from influenza are as follows: the sick pigs suddenly generate heat, are lassitude, have reduced appetite, are usually laid down together, are reluctant to move, and mucus flows out of eyes and nose at the initial stage of disease. When the body temperature of the sick pig is increased to 40-41.5 ℃, anorexia or no eating, muscular pain, unwilling to stand, viscous liquid flowing out of eyes and nose, and conjunctival congestion appear. The sick pigs have dyspnea, dyspnea and cough, are breathed in an abdominal mode, are in a dog sitting posture, and can hear asthma of the sick pigs at night. The joint pain of individual sick pigs, especially the clinical symptoms of the pigs with good fat condition are serious.
The examination shows that the larynx, trachea and bronchus are full of mucus containing air bubbles, mucous membrane is congested and swollen, blood is sometimes mixed, the lung interstitium is widened, lymph node is swollen, congestion and splenomegaly are caused, gastrointestinal mucous membrane has catarrhal hemorrhagic inflammation, and liquid containing cellulose substances is accumulated in the pleuroperitoneal cavity and the pericardial cavity.
Combining the epidemiological clinical symptom identification, selecting 56 sick pigs proved to have influenza by the epidemiological clinical identification, randomly and averagely dividing the sick pigs into 7 groups, wherein each group comprises 8 pigs which are respectively a control group and a group A9Group B9Group C9Group D9Group E9Group F9Group, in which control group was injected with Shuanghuanglian injection and A9Group irrigation drinking of bromhexine hydrochloride oral liquid prepared in example 1 for livestock and poultry and injection of Shuanghuanglian injection and B9Group irrigation drinking of bromhexine hydrochloride oral liquid prepared in example 2 for livestock and poultry and injection of Shuanghuanglian injection C9Group irrigation drinking of bromhexine hydrochloride oral liquid prepared in example 3 for livestock and poultry, and injection of Shuanghuanglian injection and D9Group irrigation drinking of bromhexine hydrochloride oral liquid prepared in example 4 for livestock and poultry, and injection of Shuanghuanglian injection and E9Group irrigation oral liquid of bromhexine hydrochloride for livestock and poultry prepared in example 5 and injection of Shuanghuanglian injection F9The bromhexine hydrochloride oral liquid prepared in the example 6 is drunk in a group filling manner, and the Shuanghuanglian injection is injected. Wherein A is9~F9The dose of the bromhexine hydrochloride oral liquid for livestock and poultry prepared in the examples 1-6 which are respectively infused in the group is 0.45 mg/(kg. d) of bromhexine hydrochloride, and the dose of the Shuanghuanglian injection is 15 mL/(kg. head).
A9~F9After the pigs with diseases drink the bromhexine hydrochloride oral liquid for livestock and poultry prepared in examples 1-6 respectively, the disease condition is controlled quickly, and A starts from day 29~F9The pigs in the group are gradually active, the activity is increased, the appetite is improved, and particularly the dyspnea symptom is obviously improved. The control group of pigs had reduced appetite and respiratory symptoms compared with A9~F9Group Severe, 4 days after administration, A9~F9The symptoms of the pigs in the group basically disappear, the activity is increased, the appetite is recovered to be normal, and the effective rate is 100.0%. Specific therapeutic effect comparison data are shown in table 4.
TABLE 4 summary of the therapeutic effects of swine influenza
The swine influenza is mostly caused in autumn and winter, the influenza is relatively quick, the fatality rate is generally 4-10%, and the experiment and the table 4 show that after the sick swine drink the bromhexine oral liquid for livestock and poultry and simultaneously inject the Shuanghuanglian injection, the clinical symptoms are quickly recovered. Therefore, the bromhexine hydrochloride oral liquid for livestock and poultry has good auxiliary treatment effect on the swine influenza.
Example 10 test of therapeutic Effect of bromhexine hydrochloride oral liquid for livestock and poultry on infectious bronchitis of canine
The canine infectious tracheobronchitis is also called canine cough or canine pit cough, is a common clinical disease of small animals, mainly presents symptoms of laryngitis, tracheitis, bronchitis, tonsillitis and pneumonia, has different clinical manifestations, and makes the clinical manifestations of puppies more severe. Paroxysmal dry cough, retching or retching, nasal leakage, more nasal fluid flowing out along with breathing, tonsil swelling and anorexia often appear in sick dogs. Some dogs may develop paroxysmal dyspnea, vomiting, diarrhea, and the like. The course of the disease is prolonged, and the sick dog is in mental retardation, anorexia and muscle tremor, and finally pneumonia, respiratory urge, visual mucosa cyanosis and even death can occur.
The cesarean-examination dead dogs mainly have pneumonia, bronchitis pathological changes, pulmonary congestion, excess change and incomplete swelling; congestion and bleeding of bronchial lymph nodes, congestion and brittleness or thickening of bronchial mucous membranes, and large amount of secretion in the lumen. Proliferative adenoma lesions are sometimes seen.
Combining the epidemiological clinical symptom identification, 21 cases of dogs with canine infectious tracheobronchitis proved by epidemiological clinical identification are selected in one year, the dogs are sequentially divided into 7 groups, and each group comprises 3 dogs which are respectively a control group and a10Group B10Group C10Group D10Group E10Group F10Group, wherein control group was intravenously injected with 10mL of SHUANGHUANGLIAN injection +1g of cefotaxime sodium, A10The bromhexine hydrochloride oral liquid prepared in example 1 is drunk in a group manner, and 10mL of Shuanghuanglian injection and 1g of cefotaxime sodium and B are injected10The bromhexine hydrochloride oral liquid prepared in example 2 is drunk in a group manner, and 10mL of Shuanghuanglian injection and 1g of cefotaxime sodium and C are injected10Sudoku oral liquid of bromhexine hydrochloride prepared in example 3 and injected with 10mL Shuanghuanglian injection +1g cefotaxime sodium and D10The bromhexine hydrochloride oral liquid prepared in example 4 is drunk in a group manner, and 10mL of Shuanghuanglian injection and 1g of cefotaxime sodium and E are injected10Groupwise irrigation of bromhexine hydrochloride for livestock and poultry prepared in example 5New oral liquid and injection of 10mL Shuanghuanglian injection and 1g cefotaxime sodium and F10The bromhexine hydrochloride oral liquid prepared in example 6 is drunk in a group-feeding manner, and 10mL of Shuanghuanglian injection and 1g of cefotaxime sodium are injected. Wherein A is10~F10The dose of the bromhexine hydrochloride oral liquid for livestock and poultry prepared in the examples 1-6 which is respectively infused in the group is 0.45 mg/(kg. d) of bromhexine hydrochloride.
3 control groups of sick dogs which are singly injected with 10mL of Shuanghuanglian injection and 1g of cefotaxime sodium intravenously have the symptoms basically disappeared after 7 days of treatment and return to normal after 10 days; a. the10~F10After the bromhexine hydrochloride oral liquid for livestock and poultry prepared in the examples 1-6 is drunk in a group filling manner, the condition of the livestock and poultry is controlled quickly, the dogs become active gradually from day 2, the activity is increased, the appetite is improved, particularly the dyspnea symptom is obviously improved, and after the oral liquid is taken for 4 days, the symptom basically disappears, the activity is increased, and the appetite is recovered to be normal. The treatment effect on the canine infectious tracheobronchitis is relatively known, and the bromhexine hydrochloride oral liquid for livestock and poultry has a good auxiliary treatment effect on the canine infectious tracheobronchitis.
Example 11 efficacy test of treatment of infectious bronchitis in calves with bromhexine hydrochloride oral liquid for livestock and poultry
Epidemiological clinical symptoms of sick cattle with infectious bronchitis are as follows: the sick cattle have listlessness, inappetence, rumination stoppage, conjunctival flushing, accelerated pulse, dyspnea, accelerated frequency and increased nasal secretion, the body temperature rises to 39.5-41 ℃, and the auscultation lung shows that the respiratory sound is weakened and has twittering pronunciation. In the later stage of onset, the respiratory sound gradually becomes weaker and the number of leukocytes increases.
Combining the epidemiological clinical symptom identification, selecting 56 calves proved to have infectious bronchitis through epidemiological clinical identification, randomly and averagely dividing the calves into 7 groups, wherein each group comprises 8 calves which are respectively a control group and a A11Group B11Group C11Group D11Group E11Group F11Group, control group, penicillin and A11Group infusion of bromhexine hydrochloride oral liquid and intramuscular injection of penicillin and B prepared in example 1 for livestock and poultry11Group infusion of bromhexine hydrochloride oral liquid and intramuscular injection of penicillin and C prepared in example 211Group infusion of bromhexine hydrochloride oral liquid and intramuscular injection of penicillin and D prepared in example 311Group infusion of bromhexine hydrochloride oral liquid and intramuscular injection of penicillin and E for livestock and poultry prepared in example 411Group infusion of bromhexine hydrochloride oral liquid and intramuscular injection of penicillin and F prepared in example 511The livestock and poultry prepared in the example 6 are infused with bromhexine hydrochloride oral liquid and injected with penicillin in groups. Wherein A is11~F11The dose of the bromhexine hydrochloride oral liquid for livestock and poultry prepared in the examples 1-6 which are respectively drunk in groups is reduced to 0.45 mg/(kg. d) of bromhexine hydrochloride, and the injection dose of penicillin is reduced to 100-200 ten thousand international units and is 2-3 times per day.
A11~F11After the group calves respectively drink the bromhexine hydrochloride oral liquid prepared in the examples 1-6, the condition of the livestock and the poultry is quickly controlled, and from day 2, A11~F11The combined calf is gradually lively, the activity is increased, the appetite is obviously improved, the rumination is gradually recovered, and particularly, the dyspnea symptom is obviously improved. The control group calf has reduced appetite and dyspnea, etc. compared with A11~F11Group Severe, 4 days after administration, A11~F11The disease of the calves is basically disappeared, the activity is increased, the appetite and the rumination are recovered to be normal, and the effective rate is 100.0 percent. Specific therapeutic effect comparison data are shown in table 5.
TABLE 5 therapeutic Effect List of infectious bronchitis of calves
Infectious bronchitis is more frequent in calves, generally, the incidence rate is higher at 2-3 months of age, the popularity is faster, and as can be known from the experiment and the table 5, clinical symptoms of sick calves are rapidly recovered after the calves are drunk with bromhexine oral liquid and are injected with penicillin intramuscularly. Therefore, the bromhexine hydrochloride oral liquid for livestock and poultry has a good auxiliary treatment effect on infectious bronchitis of calves.
It should be noted that the embodiments 1 to 6 are only preferred embodiments of the present invention, and are not intended to limit the present invention in other forms, and any person skilled in the art may use the above technical contents as a teaching to make changes or modifications to the equivalent embodiments with equivalent changes, but all those simple changes, equivalent changes and modifications made to the above embodiments without departing from the technical spirit of the present invention, and still all those embodiments fall within the scope of the present invention.
Claims (10)
1. The bromhexine hydrochloride oral liquid for livestock and poultry is characterized in that raw materials for preparing active ingredients of the bromhexine hydrochloride oral liquid comprise the following raw materials in parts by weight per 100 parts by volume:
0.3-6.0 parts of bromhexine hydrochloride, 2.4-60 parts of polyethylene glycol 6000, 0.03-0.2 part of sodium bisulfite, 0.015-0.05 part of disodium ethylene diamine tetraacetate, 0.09-2.7 parts of ammonium acetate and 0.6-18.0 parts of glacial acetic acid;
the raw materials for preparing the effective components also comprise: 20-60 parts by volume of latent solvent, and supplementing to 100 parts by volume with water;
wherein the proportion of the parts by weight to the parts by volume is kg: and L.
2. The bromhexine hydrochloride oral liquid for livestock and poultry according to claim 1, which is characterized in that the pH value of the bromhexine hydrochloride oral liquid for livestock and poultry is 3.5-5.5.
3. The bromhexine hydrochloride oral liquid for livestock and poultry according to claim 1 or 2, characterized in that the cosolvent is at least one of ethanol, propylene glycol, N-dimethylacetamide, dimethyl sulfoxide and polyoxyethylene octylphenol ether-10.
4. A preparation method of bromhexine hydrochloride oral liquid for livestock and poultry in any one of claims 1 to 3, which is characterized by comprising the following steps in sequence:
1) dissolving sodium bisulfite, ammonium acetate and disodium ethylene diamine tetraacetate in water, and mixing to obtain an aqueous solution A;
2) adding bromhexine hydrochloride into the cosolvent for dissolving, adding polyethylene glycol 6000 into the obtained solution B, and uniformly mixing to obtain a mixed solution C;
3) and adding the aqueous solution A into the mixed solution C, uniformly mixing, adjusting the pH value by glacial acetic acid, fixing the volume by water, and filtering to obtain filtrate, namely the bromhexine hydrochloride oral liquid for livestock and poultry.
5. The method for preparing bromhexine hydrochloride oral liquid for livestock and poultry according to claim 4, characterized in that after filtration, the filtrate is sterilized.
6. The method for preparing bromhexine hydrochloride oral liquid for livestock and poultry according to claim 5, is characterized in that the filtrate is subjected to subpackaging and sealing after filtration and before sterilization.
7. The preparation method of bromhexine hydrochloride oral liquid for livestock and poultry according to claim 5 or 6, characterized in that the sterilization is radiation sterilization.
8. The preparation method of bromhexine hydrochloride oral liquid for livestock and poultry according to any one of claims 4 to 6, characterized in that,
in the step 1), when bromhexine hydrochloride is added, the temperature of the latent solvent is 60-70 ℃;
before adding the polyethylene glycol 6000, cooling the solution B to 30-40 ℃;
in the step 3), adjusting the pH value to 3.5-5.5;
the filtration is microporous filter element filtration.
9. The method for preparing bromhexine hydrochloride oral liquid for livestock and poultry according to claim 8, wherein the pore diameter of the microporous filter element is 0.45 μm, 0.22 μm or 0.20 μm.
10. The use of bromhexine hydrochloride oral liquid for livestock and poultry in any one of claims 1 to 3, characterized in that the bromhexine hydrochloride oral liquid for livestock and poultry is used as a medicament for treating respiratory tract infection of livestock and poultry.
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| CN105596318A (en) * | 2016-01-07 | 2016-05-25 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride new solution composition used for inhalation and preparing method thereof |
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| CN101784257A (en) * | 2007-07-31 | 2010-07-21 | 方济各安吉利克化学联合股份有限公司 | Stable liquid pharmaceutical composition based on trazodone |
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| CN115715763A (en) * | 2022-12-15 | 2023-02-28 | 郑州新泽生物科技有限公司 | Bromhexine hydrochloride solid microspheres and preparation method thereof |
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