CN102309442A - Ambroxol hydrochloride oral aqueous composition and preparation method thereof - Google Patents
Ambroxol hydrochloride oral aqueous composition and preparation method thereof Download PDFInfo
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Abstract
The invention provides an oral aqueous composition, which comprises 0.1 to 1 percent (w/v) of ambroxol hydrochloride, 0.05 to 0.2 percent (w/v) of solution thickener, 0.005 to 0.05 percent (w/v) of freshener, a stabilizer and water, wherein the stabilizer is a substance for forming a medicinal solvent system by combining the water. The invention also provides a preparation method for the composition. The oral aqueous composition has the advantages of cool and refreshing mouthfeel, wide application range and the like, is clear and stable, does not contain any natural or semi-synthetic sweetener, and is suitable for patients who suffer from diabetes and people who are allergic to the semi-synthetic sweetener.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, relate to contain the oral waterborne compositions of ambroxol hydrochloride more specifically, the present invention also relates to the method for preparing of this fluid composition.
Background technology
Ambroxol hydrochloride is the sputum lytic agent, and its chemical name is: trans 4-[(amino-3, the 5 two bromo-phenyl of 2-) methyl-amino] Hexalin hydrochlorate.Ambroxol hydrochloride can stimulate the bronchorrhea glandular secretion to be easier to mobile mucus to make sputum dilution, and toughness reduces, and can increase the generation and the secretion of pulmonary surfactant; Thereby reduction airway resistance; Reduce mucous adhesive force, activate the mucociliary function, promote the mucociliary transhipment.Compare with the first generation and second filial generation expelling phlegm drugs; Ambroxol hydrochloride is except that having powerful mucolysis effect, and its maximum characteristics are that it can stimulate alveolar type II cells, promotes the synthetic and secretion of alveolar surfactant; Thereby effectively strengthen mucus transport, promote expectoration.This composition belongs to the lubricated type expectorant of mucosa, is applicable to that mainly thick sputum is difficult for the patient of expectoration.
The ambroxol hydrochloride bitter in the mouth, and have the paralysis sense after taking.In addition, ambroxol hydrochloride is slightly soluble in water, and all unstable to high temperature and oxidation.
The dosage form of the Chinese ambroxol hydrochloride that has gone on the market has granule, pill (slow release), tablet (ordinary tablet, dispersible tablet, effervescent tablet, chewable tablet and oral cavity disintegration tablet), capsule (slow release), injection, sterile injection powder, syrup and oral solution at present.Wherein, oral solution because of easy to use, dosage accurately, need not disintegrate and stripping, absorption and advantage such as rapid-action, obtained numerous doctors and patient's favor, the huge market demand.
Publication number CN1546008A has described a kind of " ambroxol hydrochloride liquid slow releasing preparation and preparation method thereof "; Publication number CN101103968A discloses a kind of " ambroxol oral liquid that mouthfeel is good "; Claim according to CN101103968A; According to the preparation of CN1546008A embodiment preparation, when 24 human aspiration testers carry out blind method research, find that this liquid slow-release preparation has bad sensory qualities; Especially most of volunteers have the sensation (referring to, CN101103968A page 3 the 2nd paragragh reciprocal) of paralysis on tongue.CN101103968A aims to provide the oral aqueous solution with good sense organ aspect character, and the compositions of embodiment 1 contains the sucrose of 45% (w/v), and said composition is not suitable for diabetics; The preparation of embodiment 2 and embodiment 3 all contains the sorbitol of 25% (w/v), but therefore heavy dose of sorbitol oral administration is as osmotic laxative treatments; These preparations are not suitable for the responsive patient of sorbitol; Especially child's gastrointestinal function zoon not as yet is relatively responsive, more Ying Shenyong.
Publication number CN101352417A discloses a kind of " ambroxol hydrochloride oral solution and preparation method thereof ", and its disclosed prescription contains the sucrose of 30% (w/v), is not suitable for diabetics equally.
Under technical field press for that mouthfeel is good, steady quality, medication compliance are strong, be suitable for the wide clarifying ambroxol hydrochloride oral solution of crowd.
Summary of the invention
An object of the present invention is to provide that refrigerant, the sweet taste of inlet is lasting, steady quality, medication compliance are strong, be suitable for the wide ambroxol hydrochloride oral fluid composition of crowd.
A further object of the present invention provides the method for preparing of said fluid composition.
The inventor finds after deliberation, after an amount of cellulose derivative is met the water complete swelling, can cover the bitterness and paralysis sense of ambroxol hydrochloride through the viscosity that improves solution.Thereby avoid the use of the taste that a large amount of natural sweeteners or semi-synthetic sweeting agent improve ambroxol hydrochloride oral solution.In addition, introduce multiple stabilizing agent, be combined to form suitable medicinal solvent system, can improve the dissolubility of ambroxol hydrochloride, make solution keep clarification with water.
The objective of the invention is to realize through following design:
A kind of oral waterborne compositions, it comprises: 0.1-1% (w/v) ambroxol hydrochloride, 0.05-0.2% (w/v) solution thickening agent, 0.005-0.05% (w/v) freshener, stabilizing agent and water.
Described solution thickening agent preferably is selected from hydroxyethyl-cellulose, hypromellose, hydroxypropyl cellulose, and best solution thickening agent is a hydroxyethyl-cellulose.
Described freshener be for can improve any component of using of the refrigerant sense of solution, preferably Mentholum, menthol, Oleum menthae, Herba Menthae glycerol ketals, amide of mint or menthanol lactic acid ester.
Described stabilizing agent is the material that can form suitable medicinal solvent system with the water combination.Described stabilizing agent can be selected from glycerol, propylene glycol or its combination.In a preferred embodiment, the consumption of glycerol is at 2-20% (w/v).In another preferred embodiment, the consumption of propylene glycol is at 5-25% (w/v).
In a preferred embodiment, described compositions also comprises one or more pH regulator agent, with the pH regulator of described compositions to 2.5-4.5.Described pH regulator agent is selected from citric acid, malic acid, hydrochloric acid and phosphoric acid, and best pH regulator agent is a citric acid.
In other embodiment preferred, described compositions also can randomly comprise following component:
The antiseptic that one or more have bacteriostasis is selected from benzoic acid, sodium benzoate, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, butoben, sorbic acid and potassium sorbate, and consumption is at 0.05-0.25% (w/v);
Chelating agen is selected from edetic acid, EDTAP dipotassium ethylene diamine tetraacetate, disodium edetate, CaEDTA, edetate sodium, edetate trisodium, and consumption is at 0.005-0.1% (w/v);
One or more synthetic sweeteners are selected from saccharin sodium, aspartame, sucralose and acesulfame-K, and consumption is at 0.01-0.3% (w/v), and preferred synthetic sweetener is a sucralose;
One or more correctivess improve the taste of oral administration solution, to improve child's medication compliance.Correctives is selected from essence such as dark plum, Cortex cocois radicis, milk, pears, Mel, Citrua paradiai, blue berry, Fructus Litchi, dark plum essence preferably, and consumption is at 0.05-0.4% (v/v).
Another aspect of the present invention provides the method for preparing of the present composition, comprising:
(a) the solution thickening agent with 0.05-0.2% (w/v) is scattered in the stabilizing agent of the 10-30% that accounts for total stabilizing agent weight, adds water then and stirs, and obtains disperse object a;
(b) in 0.1-1% (w/v) ambroxol hydrochloride, add water and stir, obtain disperse object b;
(c) merge disperse object a and b, and inwardly add the stabilizing agent of surplus, the water of 0.005-0.05% (w/v) freshener and surplus stirs and obtains oral Aquo-composition of the present invention.
In other technical scheme, described method for preparing comprises:
(a) the solution thickening agent with 0.05-0.2% (w/v) is scattered in the stabilizing agent of the 20-40% that accounts for total stabilizing agent weight, adds water then and stirs, and obtains disperse object a;
(b) in 0.1-1% (w/v) ambroxol hydrochloride, add water and stir, obtain disperse object b;
(b-1): with above-mentioned other optional components in the present composition, like pH regulator agent, antiseptic, chelating agen, the synthetic sweetener disperse object b-1 that obtains soluble in water; And/or
(b-2): under the situation that has essence to exist, the 0.005-0.05% in the present composition (w/v) freshener is dissolved in the essence;
(c) merge disperse object a, b, b-1 with or b-2, and inwardly add the stabilizing agent of surplus and the water of surplus, stirring obtains oral Aquo-composition of the present invention.
Preferably, this method also comprises step (d): the compositions of step (c) gained is filtered, preferably cross 200 order stainless steel sifts to storage cylinder.
In preferred embodiments, the step of said method (a) is carried out under heating and stirring condition; Particularly, this step is carried out being heated under 60-70 ℃ the stirring condition.
The percent that uses among this paper (% (w/v)) specific shown clearly and is explained only if has, and refers generally to contain the parts by weight that are defined material in the 100 parts by volume compositionss, as containing the gram number that is defined material in 100 milliliters of compositionss.
Compositions of the present invention has following advantage:
1. taste: enter the mouth refrigerant, sugariness is moderate, sweet taste is lasting, tongue does not have the paralysis sense, has fruit aroma, men and women, old and young all to like.
2. quality: these article are clear and bright oral administration solution.Sample was placed 6 months at low temperature (4-8 ℃), and solution still keeps clarification, and not seeing has deposition to separate out.Sample was placed 10 days at 60 ℃, and character and pH value remain unchanged, and content does not have obvious decline, and related substance remains on 0.5% with interior (limit of regulation related substance is 1.0% in the quality standard).Explain that this quality is stable, sunstroke prevention is freeze proof, is suitable for selling in each department, national north and south throughout the year.
3. applied widely: these article do not contain natural or semi-synthetic sweeting agent, and diabetics is suitable for, and double synthetic sweetener (like sorbitol, lactose etc.) allergy sufferers also is suitable for.
The specific embodiment
Based on embodiment the present invention is done further detailed description below.Should be understood that these embodiment only supply to set forth usefulness of the present invention, is not to be used for limiting protection scope of the present invention.
Embodiment 1
Prescription:
The composition consumption
Ambroxol hydrochloride 3kg
Hyetellose 1kg
Citric acid 0.48kg
Propylene glycol 100kg
Glycerol 100kg
Acesulfame-K 1.0kg
Mentholum 0.15kg
Benzoic acid 2.0kg
Dark plum essence 2.0kg
Disodium edetate 1.0kg
Pure water adds to 1000L
(1) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, adds the pure water of about 150L, stirs, and makes dissolving fully.
(2) get the pill tank that has cleaned, the hydroxyethyl-cellulose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(3) get the pill tank that has cleaned, the benzoic acid of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 20kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, the acesulfame-K of recipe quantity is dissolved in the pure water of 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 1.
Embodiment 2
Prescription:
The composition consumption
Ambroxol hydrochloride 3kg
Hypromellose 1.5kg
Citric acid 0.48kg
Propylene glycol 200kg
Glycerol 20kg
Acesulfame-K 0.5kg
Sucralose 0.05kg
Mentholum 0.2kg
Benzoic acid 1.5kg
Dark plum essence 1.5kg
Disodium edetate 1.0kg
Pure water adds to 1000L
(1) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, adds the pure water of about 150L, stirs, and makes dissolving fully.
(2) get the pill tank that has cleaned, the hypromellose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(3) get the pill tank that has cleaned, the benzoic acid of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 120kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, in the pure water that the acesulfame-K and the sucralose of recipe quantity is dissolved in about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 2.
Embodiment 3
Prescription:
The composition consumption
Ambroxol hydrochloride 3kg
Hypromellose 1.0kg
Citric acid 0.48kg
Propylene glycol 200kg
Glycerol 100kg
Acesulfame-K 0.5kg
Sucralose 0.1kg
Mentholum 0.2kg
Sodium benzoate 1.0kg
Dark plum essence 1.0kg
Cocoanut flavour 1.0kg
Disodium edetate 0.5kg
Pure water adds to 1000L
(1) the recipe quantity sodium benzoate is added in the allotment a mixing bowl, add the pure water of about 150L, stir, make dissolving fully.
(2) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, stirs, and makes dissolving fully.
(3) get the pill tank that has cleaned, the hypromellose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 160kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, in the pure water that the acesulfame-K and the sucralose of recipe quantity is dissolved in about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 3.
Embodiment 4
Prescription:
The composition consumption
Ambroxol hydrochloride 3kg
Hypromellose 2.0kg
Citric acid 0.48kg
Propylene glycol 250kg
Glycerol 20kg
Sucralose 0.1kg
Mentholum 0.1kg
Sodium benzoate 1.0kg
Dark plum essence 2.0kg
Disodium edetate 0.2kg
Pure water adds to 1000L
(1) the recipe quantity sodium benzoate is added in the allotment a mixing bowl, add the pure water of about 150L, stir, make dissolving fully.
(2) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, stirs, and makes dissolving fully.
(3) get the pill tank that has cleaned, the hypromellose of recipe quantity is added in the propylene glycol of about 75kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 175kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, the recipe quantity sucralose is dissolved in the pure water of about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 4.
Embodiment 5
Prescription:
The composition consumption
Ambroxol hydrochloride 6kg
Hypromellose 2.0kg
Citric acid 0.4kg
Propylene glycol 250kg
Glycerol 50kg
Sucralose 0.05kg
Saccharin sodium 0.4kg
Mentholum 0.2kg
Sodium benzoate 1.0kg
Dark plum essence 4.0kg
Disodium edetate 0.5kg
Pure water adds to 1000L
(1) the recipe quantity sodium benzoate is added in the allotment a mixing bowl, add the pure water of 150L, stir, make dissolving fully.
(2) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, stirs, and makes dissolving fully.
(3) get the pill tank that has cleaned, the hypromellose of recipe quantity is added in the propylene glycol of about 75kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 175kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, recipe quantity saccharin sodium and sucralose are dissolved in the pure water of about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 5.
Embodiment 6
Prescription:
The composition consumption
Ambroxol hydrochloride 6kg
Hypromellose 1.3kg
Citric acid 0.4kg
Propylene glycol 100kg
Glycerol 150kg
Sucralose 0.1kg
Acesulfame-K 0.8kg
Mentholum 0.3kg
Benzoic acid 1.5kg
Dark plum essence 4.0kg
Disodium edetate 0.5kg
Pure water adds to 1000L
(1) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, adds the pure water of about 150L, stirs, and makes dissolving fully.
(2) get the pill tank that has cleaned, the hypromellose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(3) get the pill tank that has cleaned, the benzoic acid of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 20kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, recipe quantity acesulfame-K and sucralose are dissolved in the pure water of 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 6.
Embodiment 7
Prescription:
The composition consumption
Ambroxol hydrochloride 6kg
Hydroxyethyl-cellulose 1.0kg
Citric acid 0.4kg
Propylene glycol 100kg
Glycerol 150kg
Acesulfame-K 3.0kg
Mentholum 0.05kg
Benzoic acid 2.0kg
Dark plum essence 1.0kg
Disodium edetate 0.1kg
Pure water adds to 1000L
(1) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, adds the pure water of about 150L, stirs, and makes dissolving fully.
(2) get the pill tank that has cleaned, the hydroxyethyl-cellulose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(3) get the pill tank that has cleaned, the benzoic acid of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(4) get the pill tank that has cleaned, in the about 50L pure water of ambroxol hydrochloride adding with recipe quantity, stir, make fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 20kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, the recipe quantity acesulfame-K is dissolved in the pure water of about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 7.
Embodiment 8
Prescription
The composition consumption
Ambroxol hydrochloride 6kg
Hydroxyethyl-cellulose 1.0kg
Citric acid 0.4kg
Propylene glycol 100kg
Glycerol 150kg
Acesulfame-K 3.0kg
Mentholum 0.05kg
Methyl hydroxybenzoate 1.8kg
Propylparaben 0.2kg
Dark plum essence 1.0kg
Disodium edetate 0.1kg
Pure water adds to 1000L
(1) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, adds the pure water of about 150L, stirs, and makes dissolving fully.
(2) get the pill tank that has cleaned, the hydroxyethyl-cellulose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(3) get the pill tank that has cleaned, the methyl hydroxybenzoate of recipe quantity and propylparaben are added in the propylene glycol of about 40kg, stir to make fully and dissolves.With in this lysate input allotment a mixing bowl, stir and make complete mix homogeneously then.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 20kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, the recipe quantity acesulfame-K is dissolved in the pure water of about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 8.
Embodiment 9
Prescription:
The composition consumption
Ambroxol hydrochloride 6kg
Hydroxyethyl-cellulose 1.0kg
Citric acid 0.4kg
Propylene glycol 100kg
Glycerol 150kg
Acesulfame-K 3.0kg
Mentholum 0.05kg
Benzoic acid 0.5kg
Methyl hydroxybenzoate 0.9kg
Propylparaben 0.1kg
Dark plum essence 1.0kg
Disodium edetate 0.1kg
Pure water adds to 1000L
(1) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, adds the pure water of about 150L, stirs, and makes dissolving fully.
(2) get the pill tank that has cleaned, the hydroxyethyl-cellulose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(3) get the pill tank that has cleaned, the methyl hydroxybenzoate of recipe quantity and propylparaben are added in the propylene glycol of about 40kg, stir and make dissolving fully, the benzoic acid with recipe quantity adds in the pill tank then, and stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 20kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, the recipe quantity acesulfame-K is dissolved in the pure water of about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 9.
Embodiment 10
Prescription:
The composition consumption
Ambroxol hydrochloride 3kg
Hydroxyethyl-cellulose 1.0kg
Citric acid 0.48kg
Propylene glycol 100kg
Glycerol 100kg
Sucralose 0.1kg
Mentholum 0.15kg
Methyl hydroxybenzoate 1.8kg
Propylparaben 0.2kg
Dark plum essence 1.0kg
Disodium edetate 0.1kg
Pure water adds to 1000L
(1) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, adds the pure water of about 150L, stirs, and makes dissolving fully.
(2) get the pill tank that has cleaned, the hydroxyethyl-cellulose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(3) get the pill tank that has cleaned, the methyl hydroxybenzoate of recipe quantity and propylparaben are added in the propylene glycol of about 40kg, stir to make fully and dissolves.With in this lysate input allotment a mixing bowl, stir and make complete mix homogeneously then.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 20kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, the recipe quantity sucralose is dissolved in the pure water of about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 10.
Embodiment 11
Prescription:
The composition consumption
Ambroxol hydrochloride 3kg
Hypromellose 1.5kg
Citric acid 0.48kg
Propylene glycol 100kg
Glycerol 100kg
Acesulfame-K 2.0kg
Mentholum 0.15kg
Benzoic acid 0.5kg
Methyl hydroxybenzoate 0.9kg
Propylparaben 0.1kg
Dark plum essence 1.0kg
Disodium edetate 0.1kg
Pure water adds to 1000L
(1) citric acid and the disodium edetate with recipe quantity adds in the allotment a mixing bowl, adds the pure water of about 150L, stirs, and makes dissolving fully.
(2) get the pill tank that has cleaned, the hypromellose of recipe quantity is added in the propylene glycol of about 40kg, stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl,, continue to be stirred to material and be dissolved into settled solution fully then, stop heating then keeping being heated to 60-70 ℃ under the stirring condition.
(3) get the pill tank that has cleaned, the methyl hydroxybenzoate of recipe quantity and propylparaben are added in the propylene glycol of about 40kg, stir and make dissolving fully, the benzoic acid with recipe quantity adds in the pill tank then, and stirring makes fully and is uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(4) get the pill tank that has cleaned, the ambroxol hydrochloride of recipe quantity is added in the pure water of about 50L, stirring makes fully to be uniformly dispersed.With in this dispersion liquid input allotment a mixing bowl, stir and make dissolving fully then.
(5) glycerol of recipe quantity is allocated in a mixing bowl with the propylene glycol input of the about 20kg of residue, stirred and make complete mix homogeneously.
(6) get the pill tank that has cleaned, the recipe quantity acesulfame-K is dissolved in the pure water of about 20L, then lysate is added in the allotment a mixing bowl, stir and make complete mix homogeneously.
(7) keeping under the stirring condition, with the composition cools in the allotment a mixing bowl to room temperature.The recipe quantity Mentholum is dissolved in the essence of recipe quantity, adds then in the allotment a mixing bowl, stir and make complete mix homogeneously.
(8) in the allotment a mixing bowl, add pure water, stir and make complete mix homogeneously to target volume.
(9) liquid that will allocate in a mixing bowl is filtered in the storage cylinder through 200 order stainless steel sifts while stirring, obtains the product of embodiment 11.
Test Example 1: estimate taste
Evaluation object: embodiment 1-embodiment 11 prepared samples
Evaluation index: refrigerant sense, sugariness, paralysis sense
Evaluation criterion:
(1) refrigerant sense: be divided into from weak to strong+, ++, +++, ++ ++, ++ +++Pyatyi; The degree and the score (5 are divided into full marks) of each rank representative be respectively+faint refrigerant sense (1 minute), ++ medium refrigerant sense (3 minutes), +++refrigerant sense suit (5 minutes), ++ ++ refrigerant sense is stronger; But still can accept (4 minutes), ++ +++superpower refrigerant sense, slightly sense stimulates (2 minutes).
(2) sugariness: be divided into from weak to strong+, ++, +++, ++ ++, ++ +++, ++ ++ ++ six grades; The degree and the score (5 are divided into full marks) of each rank representative be respectively+too bitter (0 minute), ++ inlet has faint sweet taste; Aftertaste bitter (1 minute), +++inlet sugariness is suitable; Aftertaste have slight bitterness (3 minutes), ++ ++ the inlet sugariness is suitable, aftertaste do not have bitterness (4 minutes), ++ +++inlet sugariness is suitable, aftertaste still pleasantly sweet (5 minutes), ++ ++ ++ too sweet greasy (3 minutes).
(3) paralysis sense: be divided into from weak to strong+, ++, +++, ++ ++ level Four; The degree of each rank representative and score (5 are divided into full marks) be respectively+do not have paralysis feel (5 minutes), ++ slight paralysis sense is arranged behind the clothes; But disappear soon (4 minutes), ++ behind+the clothes tangible paralysis sense is arranged; Lasting several minutes can disappear (2 minutes), ++ ++ intensive paralysis sense is arranged, and longer duration causes oral cavity discomfort (0 minute).
(4) overall score: PTS 1-7 is divided into defective, and 8-10 is divided into qualified, and 11-13 is divided into satisfaction, and 13-15 is divided into very satisfied.
The person of assessing: 20 volunteers
Assess method: single blind method, gargle with clear water earlier before tasting, fill in after the trial test and assess table.At last with the meansigma methods of all volunteers' scorings score as each item evaluation index.
The overall merit result
| Evaluation index | Refrigerant sense | Sugariness | The paralysis sense | PTS |
| Embodiment 1 | 5 minutes +++() | 3 minutes +++() | ++ (4 minutes) | 12 |
| Embodiment 2 | ++ ++ (4 minutes) | ++ ++ (4 minutes) | + (5 minutes) | 13 |
| Embodiment 3 | ++ ++ (4 minutes) | ++ +++(5 minutes) | + (5 minutes) | 14 |
| Embodiment 4 | ++ (3 minutes) | 3 minutes +++() | + (5 minutes) | 11 |
| Embodiment 5 | ++ ++ (4 minutes) | ++ +++(5 minutes) | + (5 minutes) | 14 |
| Embodiment 6 | ++ +++(2 minutes) | ++ +++(5 minutes) | + (5 minutes) | 12 |
| Embodiment 7 | + (1 minute) | ++ ++ (4 minutes) | + (5 minutes) | 10 |
| Embodiment 8 | + (1 minute) | ++ ++ (4 minutes) | + (5 minutes) | 10 |
| Embodiment 9 | + (1 minute) | ++ ++ (4 minutes) | + (5 minutes) | 10 |
| Embodiment 10 | 5 minutes +++() | ++ ++ (4 minutes) | ++ (4 minutes) | 13 |
| Embodiment 11 | 5 minutes +++() | ++ ++ (4 minutes) | + (5 minutes) | 14 |
Test Example 2: estimate stability
1. evaluation object: embodiment 1-embodiment 11 prepared samples
2. experimental condition: 1. low temperature (4-8 ℃) was placed 6 months; 2. high temperature (60 ℃) was placed 10 days
3. evaluation index:
Low temperature sample: clarity
High temperature sample: character, pH value, content, related substance
4. evaluation result
4.1 low temperature sample: all samples is after low temperature is placed 6 months, and solution still keeps clarification, and all not seeing has deposition to separate out.
4.2 high temperature sample:
| Evaluation index | Character | PH value | Content (%) | Related substance (%) |
| Evaluation criterion | Colourless or almost colourless clear liquid | 2.5-4.5 | 95.0-105.0 | ≤1.0 |
| Embodiment 1 | Achromatism and clarity solution | 3.12 | 99.6 | 0.32 |
| Embodiment 2 | Achromatism and clarity solution | 3.20 | 101.3 | 0.31 |
| Embodiment 3 | Achromatism and clarity solution | 3.26 | 99.4 | 0.32 |
| Embodiment 4 | Achromatism and clarity solution | 3.25 | 98.9 | 0.33 |
| Embodiment 5 | Achromatism and clarity solution | 3.31 | 100.8 | 0.34 |
| Embodiment 6 | Achromatism and clarity solution | 3.28 | 99.2 | 0.36 |
| Embodiment 7 | Achromatism and clarity solution | 3.25 | 100.5 | 0.37 |
| Embodiment 8 | Achromatism and clarity solution | 3.33 | 100.4 | 0.35 |
| Embodiment 9 | Achromatism and clarity solution | 3.30 | 101.2 | 0.38 |
| Embodiment 10 | Achromatism and clarity solution | 3.27 | 99.4 | 0.29 |
| Embodiment 11 | Achromatism and clarity solution | 3.24 | 99.6 | 0.30 |
All samples each item index is compared with initial value and is not all seen remarkable change, and interpret sample is all more stable to low temperature and high temperature.
Claims (10)
1. an oral waterborne compositions is characterized in that said composition comprises: 0.1-1% (w/v) ambroxol hydrochloride, 0.05-0.2% (w/v) solution thickening agent, 0.005-0.05% (w/v) freshener, stabilizing agent and water; Described stabilizing agent is to make up the material that can form the medicinal solvent system with water.
2. compositions as claimed in claim 1 is characterized in that, described solution thickening agent is selected from hydroxyethyl-cellulose, hypromellose, hydroxypropyl cellulose;
Described freshener is selected from Mentholum, menthol, Oleum menthae, Herba Menthae glycerol ketals, amide of mint or menthanol lactic acid ester;
Described stabilizing agent is selected from glycerol, propylene glycol or its combination.
3. compositions as claimed in claim 2 is characterized in that, described solution thickening agent is a hydroxyethyl-cellulose.
4. compositions as claimed in claim 2 is characterized in that, the consumption of described glycerol is at 2-20% (w/v); The consumption of described propylene glycol is at 5-25% (w/v).
5. compositions as claimed in claim 1 is characterized in that, described compositions also comprises the pH regulator agent that is selected from citric acid, malic acid, hydrochloric acid and phosphoric acid.
6. compositions as claimed in claim 5 is characterized in that, described pH regulator agent is a citric acid.
7. like claim 5 or 6 described compositionss, it is characterized in that the pH of described compositions is 2.5-4.5.
8. like claim 1 or 5 described compositionss, it is characterized in that described compositions also comprises one or more in the following component:
The antiseptic that one or more have bacteriostasis is selected from benzoic acid, sodium benzoate, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, butoben, sorbic acid and potassium sorbate, and consumption is at 0.05-0.25% (w/v);
Chelating agen is selected from edetic acid, EDTAP dipotassium ethylene diamine tetraacetate, disodium edetate, CaEDTA, edetate sodium, edetate trisodium, and consumption is at 0.005-0.1% (w/v);
One or more synthetic sweeteners are selected from saccharin sodium, aspartame, sucralose and acesulfame-K, and consumption is at 0.01-0.3% (w/v), and preferred synthetic sweetener is a sucralose;
One or more correctivess are selected from essence such as dark plum, Cortex cocois radicis, milk, pears, Mel, Citrua paradiai, blue berry, Fructus Litchi, dark plum essence preferably, and consumption is at 0.05-0.4% (v/v).
9. preparation of compositions method as claimed in claim 1 is characterized in that, this method comprises:
(a) the solution thickening agent with 0.05-0.2% (w/v) is scattered in the stabilizing agent of the 10-30% that accounts for total stabilizing agent weight, adds water then and stirs, and obtains disperse object a, and preferably, this step is carried out being heated under 60-70 ℃ the stirring condition;
(b) in 0.1-1% (w/v) ambroxol hydrochloride, add water and stir, obtain disperse object b; With
(c) merge disperse object a and b, and inwardly add the stabilizing agent of surplus, the water of 0.005-0.05% (w/v) freshener and surplus stirs and obtains required compositions.
10. method for preparing as claimed in claim 9 is characterized in that, described method also comprises:
(d) compositions of step (c) gained is filtered.
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| CN107496349A (en) * | 2017-07-28 | 2017-12-22 | 海南先通药业有限公司 | Filling ambroxol hydrochloride injection composition of a kind of plastic ampoule and preparation method thereof |
| CN107519129A (en) * | 2017-09-19 | 2017-12-29 | 哈药集团三精制药有限公司 | A kind of ambroxol hydrochloride oral solution and preparation method thereof |
| CN111494314A (en) * | 2020-06-01 | 2020-08-07 | 上海信谊金朱药业有限公司 | Ambroxol hydrochloride oral solution and preparation method thereof |
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