CN116327696A - Stable ambroxol oral solution - Google Patents
Stable ambroxol oral solution Download PDFInfo
- Publication number
- CN116327696A CN116327696A CN202310326717.4A CN202310326717A CN116327696A CN 116327696 A CN116327696 A CN 116327696A CN 202310326717 A CN202310326717 A CN 202310326717A CN 116327696 A CN116327696 A CN 116327696A
- Authority
- CN
- China
- Prior art keywords
- ambroxol
- solution
- oral
- essence
- hydrochloride
- 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
- 229940015596 ambroxol oral solution Drugs 0.000 title claims abstract description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 45
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 45
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960000985 ambroxol hydrochloride Drugs 0.000 claims abstract description 33
- 239000003381 stabilizer Substances 0.000 claims abstract description 22
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 19
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 19
- 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 claims abstract description 17
- 239000000600 sorbitol Substances 0.000 claims abstract description 17
- 229960001399 clenbuterol hydrochloride Drugs 0.000 claims abstract description 14
- OPXKTCUYRHXSBK-UHFFFAOYSA-N clenbuterol hydrochloride Chemical compound Cl.CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 OPXKTCUYRHXSBK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000008213 purified water Substances 0.000 claims abstract description 12
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical group [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000004299 sodium benzoate Substances 0.000 claims abstract description 12
- 235000010234 sodium benzoate Nutrition 0.000 claims abstract description 12
- 239000000022 bacteriostatic agent Substances 0.000 claims abstract description 10
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 10
- 239000003765 sweetening agent Substances 0.000 claims abstract description 10
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 34
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 23
- 229960005174 ambroxol Drugs 0.000 claims description 17
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 claims description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 17
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- 235000010356 sorbitol Nutrition 0.000 claims description 16
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 10
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229940048879 dl tartaric acid Drugs 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 8
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
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- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
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- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
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- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
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- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
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- 239000012362 glacial acetic acid Substances 0.000 claims description 2
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- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
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- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
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- 238000000034 method Methods 0.000 description 11
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- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 6
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 6
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- 238000007865 diluting Methods 0.000 description 5
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- 239000004289 sodium hydrogen sulphite Substances 0.000 description 5
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
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- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 2
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
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- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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Abstract
The invention discloses a stable ambroxol oral solution, wherein the active ingredients are ambroxol hydrochloride and clenbuterol hydrochloride, the stabilizer is ammonia water and sodium bicarbonate, the bacteriostatic agent is sodium benzoate, the sweetener is sorbitol, the solvent is propylene glycol, glycerol and purified water, and the pH value is 4.0-6.0. The invention improves the stability of the preparation and reduces the generation of impurities by optimizing the prescription. The ambroxol oral solution has the advantages of low content of related substances, high safety, good stability, simple preparation process and easy industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a stable ambroxol oral solution.
Background
Ambroxol hydrochloride is a mucolytic agent, can increase secretion of respiratory tract mucosa serous gland, reduce secretion of mucous gland, reduce viscosity of sputum, promote secretion of lung surface active substances, and increase exercise of bronchus cilia, so that the sputum is easy to be expectorated.
Clenbuterol hydrochloride is a selective beta receptor agonist and has the functions of relaxing bronchial smooth muscle, enhancing ciliated movement, dissolving mucus and promoting sputum discharge.
The ambroxol oral solution is a compound preparation consisting of ambroxol hydrochloride and clenbuterol hydrochloride, and the two active ingredients show pharmacodynamics cooperativity in treating obstructive respiratory diseases: ambroxol hydrochloride acts on secretions in the bronchial area, clenbuterol hydrochloride treats bronchospasm, and the two substances activate the bronchial mucus transport system in different ways, improving the opening of the bronchial system, thereby improving the respiration.
Ambroxol oral solutions developed by Sanofi-Aventis were marketed in 1984 in Germany for acute and chronic respiratory diseases, in particular spasmodic bronchitis, emphysema bronchitis and bronchial asthma.
Chinese patent document CN102258462A discloses a method for improving stability of ambroxol hydrochloride, and indicates that the stability of a main medicine is greatly influenced by glycerin contained in a prescription, and propylene glycol is used for replacing glycerin, so that the stability of the obtained product is good. Because the glycerin is deleted in the prescription, the taste of the oral solution is greatly affected, and the preparation process needs to be cooled after boiling water, so that unnecessary energy waste is caused, and the production is not beneficial to scale-up.
The Chinese patent document CN114601793A solves the problem of too fast impurity growth by adding the antioxidant sodium bisulphite into the prescription, but the sodium bisulphite can cause allergic reaction or asthma attack of sensitive people, and serious allergic reaction can endanger life.
Chinese patent document CN 102225049a discloses an ambroxol hydrochloride injection with stable pH. Researchers find that the pH value of ambroxol hydrochloride aqueous solution can change greatly before and after sterilization, the stability of injection is affected, and new impurities are generated. The pH value of the solution is ensured to be stable by utilizing a buffer salt system, the degradation of ambroxol hydrochloride to generate impurities B and E is reduced or avoided, the adopted buffer pair is any one pair of citric acid-disodium hydrogen phosphate and citric acid-sodium citrate, and the pH range of a buffer solution prepared by the buffer pair is selected to be between 4.5 and 5.5.
The Chinese patent document CN 106667902A discloses a stable ambroxol hydrochloride injection, which solves the technical problems that decomposition products are easily generated by illumination and increase along with the increase of pH by adding one or more of disodium ethylenediamine tetraacetate, acetic acid, sodium acetate, citric acid, disodium hydrogen phosphate or sodium dihydrogen phosphate as a stabilizer. The technical scheme in the patent document is only suitable for injection, and for oral solution, as auxiliary materials such as a bacteriostatic agent, a flavoring agent and the like are required to be added in the prescription to play a bacteriostatic role and improve the taste, the stability of ambroxol hydrochloride may be adversely affected by the auxiliary materials such as the bacteriostatic agent, the flavoring agent and the like.
Chinese patent document CN105287367a discloses an oral liquid preparation of ambroxol hydrochloride, which comprises the following raw materials: 4-8 parts of ambroxol hydrochloride, 200-300 parts of glycerin, 100-200 parts of sorbitol, 20-40 parts of propylene glycol, 1-3 parts of benzoic acid, 0.2-0.6 part of sucralose, 0.02-0.08 part of menthol, 0.2-0.4 part of essence, 0.05-1.20 parts of EDTA-2Na and 1000 parts of purified water; EDTA-2Na is added to replace saccharin sodium with sucralose, so that the color change is smaller, the total impurity content and the impurity B content are reduced, the potential safety hazard problem caused by saccharin sodium is solved, and the stability of the medicine is improved. However, EDTA-2Na added in the technical scheme belongs to a metal ion complexing agent, and can complex calcium ions in blood, so that the blood calcium level is reduced rapidly, and side effects such as muscle tremor, ache, convulsion, nausea and vomiting can be caused to patients after the use, and the patients need to be confirmed to have no hypocalcemia, hemophilia and the like before taking the medicine, so that the clinical application is limited.
The Chinese patent document CN 115137695A discloses an ambroxol Luo Yeti preparation and a preparation method thereof, wherein each milliliter of liquid preparation comprises 1-3 mg of ambroxol hydrochloride, 0.5-1.5 mug of clenbuterol hydrochloride, sorbitol, strawberry essence, glycerol, hydroxyethylcellulose, sodium benzoate, tartaric acid and propylene glycol. The product prepared by the method has good taste, good compliance, high safety, better than the commercial preparation, and good stability, and overcomes the problem of impurity growth of ambroxol hydrochloride in the placing process. According to the technical scheme, solid sorbitol is adopted to replace sorbitol solution, so that the stability of the preparation is improved, but hydroxyethyl cellulose is adopted in a prescription, the dissolution process of the hydroxyethyl cellulose in the amplifying production process is complex, and the energy consumption is high; the preparation temperature in the process of the technical proposal is higher, which also causes higher energy consumption; moreover, only the influence of liquid sorbitol on the stability of the preparation is focused, and the influence of solvents such as glycerol, propylene glycol and the like on the stability of the product is not focused.
Disclosure of Invention
Because ambroxol hydrochloride has a bitter taste, the oral preparation needs to be added with a flavoring agent to cover the bad taste, and needs to be added with a bacteriostatic agent. The applicant found in the research that, although the prior art provides a method for improving the stability of ambroxol hydrochloride injection, the method for adjusting the pH value of the solution can not meet the requirement of oral solution stability. Because the oral liquid contains propylene glycol and glycerol, contains the corrective and the bacteriostatic agent, has complex components, can cause the rise of impurities in the oral liquid, has adverse effect on the safety of clinical medication, has higher incidence of adverse reaction and greatly limits the clinical application of the preparation.
Aiming at the problems that an oral solution of ambroxol is unstable and impurities grow too fast in the prior art, the invention provides the stable oral solution of ambroxol.
The invention improves the stability of the preparation by optimizing the prescription, and can effectively improve the stability of the preparation by adding alkaline substances as stabilizing agents.
The specific technical scheme of the invention is as follows:
an oral solution of ambroxol comprises ambroxol hydrochloride, clenbuterol hydrochloride, a stabilizer, a bacteriostatic agent, a sweetener, a solvent and a pH value regulator, wherein the stabilizer is ammonia/ammonium compound and carbonate or bicarbonate, the bacteriostatic agent is sodium benzoate, the sweetener is sorbitol, the solvent is propylene glycol, glycerol and purified water, and the pH value of the oral solution is 4.0-6.0.
Preferably, the ammonia/ammonium compound is selected from one or more of ammonia water, ammonium chloride, ammonium bicarbonate and ammonium sulfate.
Preferably, the carbonate or bicarbonate is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate.
In a specific preferred embodiment, the stabilizer is ammonia water or sodium bicarbonate.
The concentration of the aqueous ammonia was 25% (w/v).
Preferably, the mass ratio of ambroxol hydrochloride to the stabilizer is 1:0.67-1:2.67, wherein the mass ratio of ammonia water to sodium bicarbonate is 1:0.5-1:2. More preferably, the mass ratio of ambroxol hydrochloride to the stabilizer is 1:1.33, and the mass ratio of ammonia water to sodium bicarbonate is 1:1.
Preferably, the pH regulator is one or more selected from DL-tartaric acid, glacial acetic acid, citric acid and hydrochloric acid.
The ambroxol oral solution provided by the invention also comprises other pharmaceutically acceptable auxiliary materials. Further, the other pharmaceutically acceptable auxiliary materials are aromatic agents, and are selected from one or more of juicy peach essence, yangshuo essence, grape essence, cherry essence, pomegranate essence, banana essence and strawberry essence.
The specific prescription of the oral solution comprises 1.5g/L ambroxol hydrochloride and 0.001g/L clenbuterol hydrochloride, 0.5 g/L-1.5 g/L ammonia water, 0.5 g/L-1.5 g/L sodium bicarbonate, 1.5 g/L-2.5 g/L sodium benzoate, 150 g/L-200 g/L sorbitol, 30 g/L-40 g/L propylene glycol, 120 g/L-150 g/L glycerin, 0.5 g/L-1.5 g/L DL-tartaric acid and 0.4 g/L-0.6 g/L aromatic.
The preparation method of the ambroxol oral solution comprises the following steps:
(1) Weighing 80% of purified water with a prescription amount, heating to 40-50 ℃, adding ammonia water and sodium bicarbonate with the prescription amount, stirring and dissolving;
(2) Adding sodium benzoate, glycerol, propylene glycol, and sorbitol (optionally adding other adjuvants such as fructus Persicae essence), stirring for dissolving;
(3) Adding pH regulator (such as DL-tartaric acid) to regulate pH to 4.0-6.0, stirring for dissolving;
(4) Adding ambroxol hydrochloride and clenbuterol hydrochloride with the prescribed amount, stirring and dissolving;
(5) Adding purified water to the full amount;
(6) Filling and screwing a cover;
(7) And (5) packaging.
Compared with the existing preparation and technology, the invention has the beneficial effects that:
1. according to the invention, by optimizing the prescription and adding alkaline substances such as ammonia water, sodium bicarbonate and the like into the prescription as the stabilizer, adverse effects of the bacteriostatic agent, the sweetener and the solvent on the stability of the medicine are inhibited, the increase of impurities is greatly reduced, and the stability of the preparation is greatly enhanced.
2. The oral solution of ambroxol has extremely low impurity content, the total impurity amount is only 0.03%, related substances slowly increase in the stability placing process, the total impurity amount slowly increases to 0.32% after accelerating for 6 months, the impurity increasing level is lower than that of samples prepared by other technical means, and the safety of clinical medication is ensured.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
Examples 1 to 6 examine the effect of bacteriostats, sweeteners and other adjuvants on the stability of the prescription
(1) Prescription of prescription
| Name of the name | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| Ambroxol hydrochloride | 0.15g | 0.15g | 0.15g | 0.15g | 0.15g | 0.15g |
| Clenbuterol hydrochloride | 0.0001g | 0.0001g | 0.0001g | 0.0001g | 0.0001g | 0.0001g |
| Sodium benzoate | Without adding | 0.2g | 0.2g | 0.2g | 0.2g | 0.2g |
| Sorbitol | 17.5g | Without adding | 17.5g | 17.5g | 17.5g | 17.5g |
| Stabilizing agent | Without adding | Without adding | Without adding | Without adding | Without adding | Without adding |
| Propylene glycol | 3.5g | 3.5g | Without adding | 3.5g | 3.5g | 3.5g |
| DL-tartaric acid | 0.1g | 0.1g | 0.1g | 0.1g | 0.1g | 0.1g |
| Glycerol | 13.5g | 13.5g | 13.5g | Without adding | 13.5g | 13.5g |
| Honey peach essence | 0.05g | 0.05g | 0.05g | 0.05g | Without adding | 0.05g |
| Purified water | To 100ml | To 100ml | To 100ml | To 100ml | To 100ml | To 100ml |
(2) Process for producing a solid-state image sensor
(1) Weighing 80% of purified water with a prescription amount, heating to 40-50 ℃, adding a stabilizer with a prescription amount (if any), stirring and dissolving;
(2) adding sodium benzoate, glycerol, propylene glycol, sorbitol and fructus Persicae essence (if any) in the amount of prescription, stirring and dissolving;
(3) adding a pH value regulator DL-tartaric acid, regulating the pH value of the solution to 4.0-6.0, and stirring for dissolution;
(4) adding ambroxol hydrochloride and clenbuterol hydrochloride with the prescribed amount, stirring and dissolving;
(5) adding purified water to the full amount;
(6) filling and screwing a cover;
(7) and (5) packaging.
Comparative example:
(1) Prescription of prescription
| Name of the name | Comparative example 1 | Comparative example 2 |
| Ambroxol hydrochloride | 0.15g | 0.15g |
| Clenbuterol hydrochloride | 0.0001g | 0.0001g |
| Sodium benzoate | 0.2g | 0.2g |
| Sorbitol | 17.5g | 17.5g |
| Sodium bisulfite | 0.1g | 0.1g |
| Propylene glycol | 3.5g | 3.5g |
| DL-tartaric acid | 0.1g (pH adjusted to 5.0) | 0.2g (pH 3.0) |
| Glycerol | 13.5g | 13.5g |
| Honey peach essence | 0.05g | 0.05g |
| Purified water | To 100ml | To 100ml |
(2) The preparation process comprises the following steps:
(1) weighing 80% of purified water with a prescription amount, heating to 40-50 ℃, adding sodium bisulphite with a prescription amount, stirring and dissolving;
(2) adding sodium benzoate, glycerol, propylene glycol, sorbitol and juicy peach essence in the prescription amount, stirring and dissolving;
(3) adding a pH value regulator DL-tartaric acid, and regulating the pH value of the solution;
(4) adding ambroxol hydrochloride and clenbuterol hydrochloride with the prescribed amount, stirring and dissolving;
(5) adding purified water to the full amount;
(6) filling and screwing a cover;
(7) and (5) packaging.
Stability test
Acceleration test conditions: the temperature is 40+/-2 ℃ and the relative humidity is 75+/-5 percent.
The impurity detection method comprises the following steps:
the checking method comprises the following steps: the measurement is carried out by high performance liquid chromatography (China pharmacopoeia 2020 edition, four-part rule 0512).
The specific operation is as follows:
solvent: 0.01mol/L diammonium phosphate solution (pH adjusted to 8.0 with phosphoric acid or ammonia) -acetonitrile (60:40)
Test solution: a low Wen Jinyang applicator was used. Precisely measuring 4ml of the product, placing in a 10ml measuring flask, diluting to scale with solvent, and shaking.
Control solution: precisely measuring a proper amount of the test solution, and quantitatively diluting the test solution by using a solvent to prepare a solution with the concentration of about 1.2 mug of ambroxol hydrochloride in each 1 ml.
Sensitivity solution: precisely measuring 5ml of control solution, placing in a 20ml measuring flask, diluting to scale with solvent, and shaking.
System applicability solution: taking a proper amount of impurity I reference substance, adding acetonitrile for dissolving and diluting to prepare a solution containing about 12 mug in each 1ml, precisely measuring 1ml, placing the solution into a 10ml measuring flask, taking about 6mg of ambroxol hydrochloride reference substance, placing the solution into the same 10ml measuring flask, adding a solvent for dissolving and diluting to a scale, and shaking uniformly.
Chromatographic conditions
Chromatographic column: agilent ZORBAX Eclipse XDB-C18, 4.6mm.times.150mm, 5 μm
Mobile phase a:0.01mol/L diammonium phosphate solution (pH adjusted to 8.0 with phosphoric acid or ammonia) -acetonitrile (85:15)
Mobile phase B: water-acetonitrile (15:85)
Flow rate: 1.0ml/min
Detection wavelength: 248nm
Column temperature: 35 DEG C
Sample injection amount: 20 μl of
Autoinjector temperature: 5 DEG C
Gradient procedure:
system applicability requirements: in the system applicability solution chromatogram, the separation degree between the impurity I peak and the ambroxol peak is more than 3.0, and the theoretical plate number is not less than 4000 according to the ambroxol peak. The signal to noise ratio of the peak height of the main component in the sensitivity solution chromatogram should be not less than 10.
Assay: precisely measuring the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatograms.
The calculation formula is as follows:
wherein: a is that Specific impurities The peak areas of single specific impurities (impurities I, II, III, IV and V) in a chromatogram of the sample solution;
A other single impurities The peak area of single impurities except specific impurities (impurity I, impurity II, impurity III, impurity IV and impurity V) in a chromatogram of the sample solution;
A control Is the main peak area in the chromatogram of the control solution;
f is the correction factor of specific impurities (impurity I, impurity II, impurity IV, impurity III and impurity V), and the correction factors of impurity I, impurity II, impurity IV, impurity III and impurity V are 1.2, 1.0 and 1.1 respectively.
Standard limits: the chromatogram of the sample solution contains impurity peaks, the peak areas of auxiliary material peaks before the relative retention time is 0.05 and the peak areas of clenbuter Luo Feng and auxiliary material peaks with the relative retention time between 0.36 and 0.44 are subtracted, the peak areas of impurity I and impurity V (the relative retention time is about 0.85) are calculated according to the corrected peak areas (multiplied by correction factors 1.2 and 1.1 respectively) and are not larger than the main peak area (1.0%) of the control solution, the peak areas of impurity II (the relative retention time is about 0.82), impurity III (the relative retention time is about 1.07) and impurity IV (the relative retention time is about 1.12) are not larger than 0.2 times (0.2%) of the main peak area of the control solution, the peak areas of other single impurities are not larger than 0.2 times (0.2%) of the main peak area of the control solution, and the sum of the peak areas of the corrected impurities is not larger than 1.5 times (1.5%) of the main peak area of the control solution. The chromatographic peak less than the main peak area of the sensitivity solution after correction was negligible (0.05%).
The results of the stability data of the colors of examples 1-6 and comparative examples 1-2 and the related substances and the raw ground products are shown in Table 1.
TABLE 1 influence of bacteriostats, sweeteners and solvents on prescription stability examination results
From examples 1-6 above, it is clear that the stability of the product is affected by the bacteriostat sodium benzoate, the sweetener sorbitol and the solvent, and especially the stability is affected more significantly by the addition of the sweetener sorbitol.
As is clear from example 6 and comparative examples 1-2, sodium bisulphite is added to the prescription, the stability is improved, but the impurity is still larger after 6 months of acceleration, and the sodium bisulphite is added to the prescription, so that allergic reaction or asthma attack of sensitive people can be caused, and serious allergic reaction can endanger life.
Examples 7 to 18 examined the stability effects of different types of alkaline stabilizers and combinations on oral liquids
Different kinds of stabilizers are examined:
a examine the different stabilizer combinations:
the color and stability data of the relevant substances and the raw products of examples 7-18 and comparative examples 1-2 are shown in the table 2 and table 3.
TABLE 2 examination of different kinds of stabilizers
Table 3 investigation results of different stability combinations
From examples 7 to 12, it is evident that the addition of ammonia water, ammonium bicarbonate, ammonium chloride, sodium carbonate, potassium carbonate and sodium bicarbonate can improve the stability of the oral liquid, and from examples 13 to 18, the combination of ammonia water and sodium bicarbonate can improve the stability more significantly.
Examples 19 to 24 examined the influence of the amounts and proportions of aqueous ammonia and sodium bicarbonate on the stability of oral liquids
The color and related material stability data for examples 19-24, comparative examples 1-2 and the results versus raw product stability data are shown in Table 4.
TABLE 4 examination of the amounts and proportions of Ammonia Water and sodium bicarbonate
Examples 19-21 above show that the addition of ammonia and sodium bicarbonate at the same time, 0.1 g-0.4 g per 100ml, i.e. the mass ratio of ambroxol hydrochloride to stabilizer (ammonia and sodium bicarbonate) is 1:0.67-1:2.67, and the mass ratio of ammonia to sodium bicarbonate is 1:0.5-1:2 (examples 22-24), has better stability.
From example 16, it is found that the stability is most significantly improved when the mass ratio of ambroxol hydrochloride to the stabilizer is 1:1.33 and the mass ratio of aqueous ammonia to sodium bicarbonate is 1:1.
In conclusion, the stability of the technical scheme of the invention is obviously better than that of the prior art, and the safety and effectiveness of the product are ensured.
Claims (10)
1. The ambroxol oral solution is characterized by comprising ambroxol hydrochloride and clenbuterol hydrochloride, a stabilizer, a bacteriostatic agent, a sweetener, a solvent and a pH value regulator, wherein the stabilizer is an ammonia/ammonium compound and carbonate or bicarbonate, the bacteriostatic agent is sodium benzoate, the sweetener is sorbitol, the solvent is propylene glycol, glycerol and purified water, and the pH value of the oral solution is 4.0-6.0.
2. The oral solution of ambroxol according to claim 1, wherein the ammonia/ammonium compound is selected from one or more of ammonia water, ammonium chloride, ammonium bicarbonate, ammonium sulfate.
3. The oral ambroxol solution according to claim 1, wherein the carbonate or bicarbonate is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate.
4. The oral ambroxol solution of claim 1, wherein the stabilizer is aqueous ammonia and sodium bicarbonate.
5. The oral solution of ambroxol according to claim 4, wherein the mass ratio of ambroxol hydrochloride to stabilizer is 1:0.67-1:2.67, and the mass ratio of ammonia water to sodium bicarbonate is 1:0.5-1:2.
6. The oral ambroxol solution of claim 5, wherein the mass ratio of ambroxol hydrochloride to stabilizer is 1:1.33 and the mass ratio of aqueous ammonia to sodium bicarbonate is 1:1.
7. The oral solution of ambroxol according to claim 1, wherein the pH adjustor is one or more selected from DL-tartaric acid, glacial acetic acid, citric acid, hydrochloric acid.
8. The oral ambroxol solution of claim 1, further comprising other pharmaceutically acceptable excipients.
9. The oral solution of ambroxol according to claim 8, wherein the other pharmaceutically acceptable auxiliary material is a flavoring agent selected from one or more of juicy peach essence, yandolo essence, grape essence, cherry essence, pomegranate essence, banana essence, and strawberry essence.
10. The oral solution of ambroxol according to claim 9, wherein the oral solution comprises ambroxol hydrochloride 1.5g/L and clenbuterol hydrochloride 0.001g/L, ammonia water 0.5g/L to 1.5g/L, sodium bicarbonate 0.5g/L to 1.5g/L, sodium benzoate 1.5g/L to 2.5g/L, sorbitol 150g to 200g/L, propylene glycol 30g to 40g/L, glycerin 120g to 150g/L, DL-tartaric acid 0.5g/L to 1.5g/L, and a fragrance 0.4g/L to 0.6g/L.
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| CN113975259A (en) * | 2021-09-14 | 2022-01-28 | 南京海纳医药科技股份有限公司 | Ambroxol hydrochloride compound effervescent tablet and preparation method thereof |
| CN115350150A (en) * | 2022-09-23 | 2022-11-18 | 海门普适医药有限公司 | Stable oral solution of ambroxol and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1820749A (en) * | 2006-04-03 | 2006-08-23 | 陈旭良 | Formula of amoxycillin sodium/ambroxo/ hydrochloride powder injection and its preparing method |
| CN101961307A (en) * | 2010-09-14 | 2011-02-02 | 武汉人福药业有限责任公司 | Oral liquid for treating respiratory disease and preparation method thereof |
| WO2013154347A1 (en) * | 2012-04-10 | 2013-10-17 | Hanmi Pharm. Co., Ltd. | Liquid formulation for oral administration comprising ambroxol, levodropropizine and buffering agent, and method for preparing the same |
| CN113975259A (en) * | 2021-09-14 | 2022-01-28 | 南京海纳医药科技股份有限公司 | Ambroxol hydrochloride compound effervescent tablet and preparation method thereof |
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