CN1864672A - A solid dispersion of ambroxol hydrochloride and composition thereof - Google Patents
A solid dispersion of ambroxol hydrochloride and composition thereof Download PDFInfo
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Abstract
The present invention relates to one kind of ambroxol hydrochloride dispersion and its preparation process and medicine composition. The ambroxol hydrochloride dispersion contains ambroxol hydrochloride and carrier material in the weight ratio of 1 to 0.3-10. The present invention aims at masking the bad smell of ambroxol hydrochloride.
Description
Technical field
The present invention relates to a kind of solid dispersion of ambroxol hydrochloride and preparation method thereof, and the pharmaceutical composition that contains this solid dispersion of ambroxol hydrochloride.
Background technology
Ambroxol hydrochloride (Ambroxol Hydrochloride) chemical name: methyl trans 4-[(2-amino-3,5 two bromo-phenyl)] amino] the Hexalin hydrochlorate.Structural formula is as follows:
Ambroxol hydrochloride is the respiratory mucus regulator of a new generation, has to promote that pulmonary surfactant generates, the effect that air flue is removed function, helped expectorant to discharge is secreted, improved to the adjusting sputum.Be applicable to acute and chronic respiratory tract disease, the thick sputum, the dys-expectoration that cause as acute and chronic bronchitis, bronchial asthma, bronchiectasis, pulmonary tuberculosis etc.
Ambroxol hydrochloride is slightly soluble in water, and this medicine mouthfeel is acute bitter, numb, and this bitterness and picotement are lasting, and it can not be sheltered by adding sweetener and correctives routinely, causes patient's drug compliance poor, especially is unfavorable for child's administration.Therefore need a kind of dissolubility that can increase medicine can cover its poor taste again.
Existing commercially available ambroxol hydrochloride oral liquid mouthfeel is pretty good, but that oral liquid exists dose is bigger, bad quantitatively, shortcomings such as less stable, to the patient take, carry, transportation etc. brings inconvenience and unsafe factor.
By the CN1628645A of Nanjing Golden Eagle Pharmaceutical Technology Development Co., Ltd's application, disclosed the preparation method of Orally disintegrating tablet of ambroxol hydrochloride.Oral cavity disintegration tablet is that the oral cavity does not need water or only have under the low amounts of water existence to place on the tongue, after rapid dissolving of chance saliva or the disintegrate, borrows swallowing act to go into the stomach onset.By the Orally disintegrating tablet of ambroxol hydrochloride disintegrate fast of adding conventional correctives and effervescent, also can instantaneously cover the bitterness and the picotement of oral administration, but fully after the disintegrate, still can leave over down bitterness, the picotement of ambroxol hydrochloride in the oral cavity, that is to say that this conventional preparation method can not cover the bad mouthfeel of ambroxol hydrochloride fully.
CN1628647A by Chengdu Al Ritter Pharmaceutical Co., Ltd's application, disclosed a kind of ambroxol hydrochloride granula, this invention is covered the extremely strong bitterness of medicine by adding correctives (as sucrose, stevioside, Fen Meiyi) and essence, but this medicine is slightly soluble in water, cause fraction to be dissolved in medicine in the water, still have stronger bitterness and picotement.
For this reason, a kind ofly can obviously hide bitterness, picotement and not influence the pharmaceutical preparation of medicine stripping and absorption and ambroxol-hydrochloride-containing that be suitable for suitability for industrialized production and the invention of preparation method has long-range social benefit.
Summary of the invention
The purpose of this invention is to provide a kind of solid dispersion of ambroxol hydrochloride, be specifically related to a kind of bitterness, the picotement that can cover ambroxol hydrochloride, and be suitable for solid dispersion of ambroxol hydrochloride of suitability for industrialized production and preparation method thereof.
Raw material and carrier material weight ratio are 1: 0.3～10 in the solid dispersion of ambroxol hydrochloride, preferred weight ratio 1: 3～5.
Carrier material is selected from ethyl cellulose, methylcellulose, Eudragit L type, Eudragit S type, Eudragit E type, Eudragit RL type, Eudragit RS type, acrylic resin II number or acrylic resin III number or above two or more material.Carrier material Eudragit L type is selected from Eudragit L100 or Eudragit L100-55, or above two kinds of materials.
Because the ambroxol hydrochloride bitter in the mouth, mouthfeel dissolubility numb and in water is relatively poor, adopts the tablet mouthfeel extreme difference of conventional wet granulation, no matter add the bad mouthfeel that any correctives also is difficult to cover medicine.Therefore, we consider from the dissolution time that delays drug release, need to select a kind of water-insoluble carrier that medicine is handled, and make medicine not stripping in the oral cavity, avoid ambroxol hydrochloride taste bud direct and in the oral cavity to contact, thereby improve bitter taste of drug and picotement.
Therefore, we prepare solid dispersion with different proportionings behind ambroxol hydrochloride raw material and the different model carrier material and carry out the taste masking test, and test method and result are as follows:
Ambroxol hydrochloride raw material and carrier material are dissolved in 95% ethanol, carry out spray drying after the stirring and dissolving, get the pastille powder.With the mouthfeel is that standard is investigated, compared, and result of the test shows that ethyl cellulose, Eudragit S type, Eudragit E type have the effect of better covering to the ambroxol hydrochloride picotement, but not obvious to the bitterness effect; Eudragit RL type, Eudragit RS type, EudragitL type (comprising L100, L100-55), acrylic resin (homemade) II number, III number all have ambroxol hydrochloride bitterness and picotement better covers effect.
The preferred Eudragit RL of carrier material type, Eudragit RS type, Eudragit L type (comprising L100, L100-55), acrylic resin II number or acrylic resin III number, or above two or more material.
All the offending taste of medicine can covered in varying degrees based on above these several carrier materials, in order to guarantee the taste masking effect of carrier material, do not influence simultaneously drug release again, we select acrylic resin II number, the III number carrier material as ambroxol hydrochloride for this reason, and have carried out the detection of related substance.Result of the test shows, when acrylic resin II number, III number were carrier material, the related substance of mensuration was a little more than Eudragit L100-55, Eudragit L100 type, Eudragit RS type, Eudragit RL type carrier.
Carrier material is Eudragit L100-55, Eudragit L100 type, Eudragit RS type or Eudragit RL type more preferably, or above two or more material.
Simultaneously, when being carrier with Eudragit L100-55, when guaranteeing that this product had taste masking effect preferably, dissolution rate and the degree of medicine in solid dispersion is the highest.The integrated survey result, Eudragit L100-55 is as the optimum carrier of this product.
Eudragit L100-55 is anionic methacrylic acid and ethyl acrylate copolymer, be the tasteless powder of white, because of containing a plurality of carboxyls in its structure, can produce the Electrostatic Absorption effect with the basic group of medicine, ambroxol hydrochloride is by embedding fully, is scattered in the Eudragit L100-55 space, be difficult for being dissolved in the saliva, avoid directly contacting with taste bud, minimizing or prevention are embedded in the stripping of medicine in the oral cavity wherein, thereby alleviate bad mouthfeel, play ideal taste masking effect, improved patient's the compliance of taking medicine.
The concrete preparation process of solid dispersion of ambroxol hydrochloride is as follows:
1. spray drying method: carrier material is added in the ethanol dissolves earlier, add the ambroxol hydrochloride raw material then and make its dissolving, after stirring, it is carried out spray drying, promptly get solid dispersion of ambroxol hydrochloride.
2. polishing: carrier material and ambroxol hydrochloride raw material are ground in mortar, sieve, promptly get solid dispersion of ambroxol hydrochloride.
3. coating method: earlier carrier material is dissolved in the ethanol, is injected to again in the ambroxol hydrochloride raw material, the ambroxol hydrochloride raw material is carried out coating, promptly get solid dispersion of ambroxol hydrochloride.
Analyze by differential scanning calorimetry, X-ray diffraction method the tasteless powder of solid of raw material and above-mentioned three kinds of technology gained ambroxol-hydrochloride-containings, raw material characteristic peak, the equal complete obiteration of diffraction maximum in three kinds of technology gained pressed powders as can be known, shown that the embedding effect is better, formed solid dispersion of ambroxol hydrochloride.
Another object of the present invention provides the pharmaceutical composition that contains solid dispersion of ambroxol hydrochloride.
The pharmaceutical composition of this solid dispersion of ambroxol hydrochloride can be various dosage forms such as oral cavity disintegration tablet, chewable tablet, mix suspension grain agent, dry suspension.
The pharmaceutical composition of solid dispersion of ambroxol hydrochloride of the present invention, for various dosage forms such as oral cavity disintegration tablet, chewable tablet, granule, need to add sweeting agent, correctives, disintegrating agent, the percentage by weight of each component is: solid dispersion of ambroxol hydrochloride 5～75%, sweeting agent 5～80%, correctives 0～2%, disintegrating agent 0～30%.
Sweeting agent comprises but is not limited to Icing Sugar, lactose, mannitol, sorbitol, aspartame, Sucralose, saccharin sodium, stevioside, erythrose.
Correctives includes but not limited to orange flavor, flavoring orange essence, strawberry essence, cherry essence, milk chocolate essence, cream flavour.
Disintegrating agent includes but not limited to polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium.
Water soluble adjuvant is selected mannitol, lactose, sucrose, maltodextrin, sorbitol.
Disintegrating agent selects that polyvinylpolypyrrolidone, carboxymethyl starch are received, interlinkage Sodium Tvlose, sodium alginate.
The present invention adopts spray drying process to obtain solid dispersion of ambroxol hydrochloride can fundamentally reach the purpose of covering bitterness and fiber crops flavor, and by adding suitable disintegrating agent dissolution is met the requirements; Add pharmaceutic adjuvants such as sweeting agent, correctives again, obtain good result aspect bitterness and the numb flavor covering.The external stripping height of this pharmaceutical composition by raw material is carried out embedding, makes the character of ambroxol hydrochloride more stable, meets drug standard.
In the chewable tablet development process, spray drying method, polishing, three kinds of technology gained of coating method solid dispersion through with suitable additive mixing after wet granulation, tabletting, gained tablet mouthfeel has notable difference, wherein best from the tablet mouthfeel of spray drying gained pressed powder, the two kinds of chewable tablet that the pressed powder that technology provided makes in back still have slight picotement in the process of chewing, the solid dispersion that three kinds of technology gained are described has bigger difference on microcosmic: the spray drying method medicine thoroughly is scattered in the carrier space with molecular forms, evenly, stable, be not subject to physical action as friction, the extruding and reassociate; Powder coating or granule coating technology are subjected to factor affecting controllabilitys such as coating process underpants film integrality, thickness to be slightly poorer than the former, and are prone to breakage and the effect that can not realize expecting in operations such as the follow-up granulation of preparation tablets, extruding; With lapping mode gained pressed powder mainly by increasing fully the contacting in increase medicine specific surface area of medicine and carrier surface, in the hope of reducing the gathering between drug molecule, so when follow-up further mixed or adding wetting agent with other additive was broken the Electrostatic Absorption balance, its taste masking effect also was subjected to influence to a certain degree naturally.Therefore, with spray drying method gained novel molecular embedding solid dispersion taste masking best results.
So, the solid dispersion of ambroxol hydrochloride that the present invention mentioned not is the solid dispersion of general meaning, but a kind of stable, novel molecule embedding techniques, and and if only if medicine is with in the molecularity embedded resin space or with resin generation crosslinked action the time, can form this even, stable novel solid dispersion of ambroxol hydrochloride, also have only this novel solid dispersion can really realize the effect of covering the bad smell of ambroxol hydrochloride.
The specific embodiment
Further specify the present invention with hereinafter embodiment, but used embodiment should not be construed as limiting the invention.
Embodiment one, preparation solid dispersion of ambroxol hydrochloride
Take by weighing after Eudragit L100-55 30g adds in 95% ethanol dissolving, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, the liquid that stirs is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature is controlled at 70-90 ℃, outlet temperature is controlled at 40-50 ℃, obtains Powdered solid dispersion of ambroxol hydrochloride.
Embodiment two, preparation solid dispersion of ambroxol hydrochloride
Take by weighing after Eudragit L100-55 60g adds in 95% ethanol dissolving, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, the liquid that stirs is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature is controlled at 70-90 ℃, outlet temperature is controlled at 40-50 ℃, obtains Powdered solid dispersion of ambroxol hydrochloride.
Embodiment three, preparation solid dispersion of ambroxol hydrochloride
Take by weighing Eudragit L100-55 90g, after adding in 95% ethanol dissolving, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, liquid after mixing is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature is controlled at 70-90 ℃, and outlet temperature is controlled at 40-50 ℃, obtains Powdered solid dispersion of ambroxol hydrochloride.
Embodiment four, preparation solid dispersion of ambroxol hydrochloride
Take by weighing Eudragit L100-55 120g, after hydroxypropyl cellulose 30g adds in 95% ethanol dissolving, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, liquid after stirring is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature 70-90 ℃, outlet temperature 40-50 ℃, obtain Powdered solid dispersion of ambroxol hydrochloride.
Embodiment five, preparation solid dispersion of ambroxol hydrochloride
Take by weighing Eudragit L100-55 150g, after adding in 95% ethanol dissolving, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, liquid after stirring is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature 70-90 ℃, outlet temperature 40-50 ℃, obtain the tasteless solid dispersion of ambroxol hydrochloride of Powdered pastille.
Embodiment six, preparation solid dispersion of ambroxol hydrochloride
Take by weighing Eudragit L100 type 90g, after adding in 95% ethanol dissolving, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, liquid after stirring is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature 70-90 ℃, outlet temperature 40-50 ℃, obtain Powdered solid dispersion of ambroxol hydrochloride.
Embodiment seven, preparation solid dispersion of ambroxol hydrochloride
Take by weighing Eudragit RS type 90g, after joining in 95% ethanol dissolving, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, liquid after stirring is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature 70-90 ℃, outlet temperature 40-50 ℃, obtain Powdered solid dispersion of ambroxol hydrochloride.
Embodiment eight, preparation solid dispersion of ambroxol hydrochloride
Take by weighing Eudragit RL type 90g, after joining in 95% ethanol dissolving, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, liquid after stirring is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature 70-90 ℃, outlet temperature 40-50 ℃, obtain Powdered solid dispersion of ambroxol hydrochloride.
Embodiment nine, preparation solid dispersion of ambroxol hydrochloride
Take by weighing acrylic resin II 20g, III 40g, after polyvidone 30g joins and dissolves in 95% ethanol, ambroxol hydrochloride 30g added in the above-mentioned solution dissolve, liquid after stirring is with spray dryer (QP3 type, Beijing Chemical Research Inst. Ministry of Chemical Industry) carries out spray drying, inlet temperature 70-90 ℃, outlet temperature 40-50 ℃, obtain Powdered solid dispersion of ambroxol hydrochloride.
Embodiment ten, preparation solid dispersion of ambroxol hydrochloride
Take by weighing Eudragit L100-55 type 90g, ambroxol hydrochloride 30g fully grinds in mortar, sieves, and again with after other adjuvant mixes, adds tabletting behind the binding agent system wet grain drying.
Embodiment 11, preparation solid dispersion of ambroxol hydrochloride
Take by weighing Eudragit L100-55 30g and be dissolved in 95% ethanol, add antiplastering aid Pulvis Talci, porogen crospolyvinylpyrrolidone, standby behind the mix homogeneously.
Take by weighing ambroxol hydrochloride 30g, after sucrose, mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone join the middle mix homogeneously of multipurpose fluid bed (WBF-11), it is dry to spray into the binding agent granulation, sprays into the above-mentioned polymer solution that has prepared again, the about 10%-25% of granule weightening finish.The granule of wrapping carries out the preparation of tablet samples.
Embodiment 12, the agent of solid dispersion of ambroxol hydrochloride mix suspension grain
According to embodiment one this solid dispersion of ambroxol hydrochloride of preparation, standby behind the mensuration content.
Prescription:
1000 bags of (g) percentage compositions of component (%)
Solid dispersion of ambroxol hydrochloride 60 15
Sucrose 180 45
Sucralose 0.5 0.1
Mannitol 131.5 32.9
Hydroxypropyl emthylcellulose 20 5
Essence 82
95% ethanol is an amount of
Operation:, prepare the agent of ambroxol hydrochloride mix suspension grain with the conventional preparation method of granule by the prescription consumption.
Embodiment 13, solid dispersion of ambroxol hydrochloride dry suspension
According to embodiment two these solid dispersion of ambroxol hydrochloride of preparation, standby behind the mensuration content.
Prescription:
1000 bags of (g) percentage compositions of component (%)
Solid dispersion of ambroxol hydrochloride 90 20
Sucrose 133.5 29.7
Sucralose 0.5 0.1
Mannitol 180 40
Tragakanta 20 4.4
Sodium carboxymethyl cellulose 20 4.4
Essence 6 1.3
Operation:, prepare the ambroxol hydrochloride dry suspension with the conventional preparation method of dry suspension by the prescription consumption
Embodiment 14, solid dispersion of ambroxol hydrochloride Orally disintegrating piece preparation method
According to embodiment three these solid dispersion of ambroxol hydrochloride of preparation, standby behind the mensuration content.
Prescription:
1000 (g) percentage compositions of component (%)
Solid dispersion of ambroxol hydrochloride 120 24
Erythritol 128.2 25.6
Sucralose 0.8 0.2
Crospolyvinylpyrrolidone 25 5
Low-substituted hydroxypropyl cellulose 40 8
Microcrystalline Cellulose 160 32
Mentholum 1 0.2
Citric acid 51
Sodium bicarbonate 51
Essence 10 2
Magnesium stearate 51
Operation:, prepare Orally disintegrating tablet of ambroxol hydrochloride with the conventional preparation method of oral cavity disintegration tablet by the prescription consumption.
Embodiment 15, solid dispersion of ambroxol hydrochloride chewable tablet preparation method
Solid dispersion of ambroxol hydrochloride according to the preparation of the foregoing description one to 11 method carries out assay respectively, calculates every inventory, adopts same prescription to carry out the preparation of sample, is that standard is investigated each sample with the dissolution.Solid dispersion with embodiment three preparations is an example:
Prescription: ambroxol hydrochloride chewable tablet 30mg/ sheet
1000 (g) percentage compositions of component (%)
Solid dispersion of ambroxol hydrochloride 120 15
Sucrose 200 24.9
Mannitol 360 44.9
Sucralose 0.8 0.1
Crospolyvinylpyrrolidone 56 7.0
Magnesium stearate 8 1.0
Sorbitol 50 6.2
Essence 8 1.0
The polyvinylpyrrolidone aqueous solution is an amount of
Operation:, prepare the ambroxol hydrochloride chewable tablet with the conventional preparation method of tablet by the prescription consumption.
By same prescription, adopt Eudragit as carrier material, the ambroxol hydrochloride chewable tablet sample that applying solid dispersion technology embodiment one to embodiment 11 prepares respectively compares mouthfeel, and the result is as follows:
| Embodiment | |||||||||||
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | |
| Mouthfeel | Generally | Generally | Good | Good | Good | Good | Good | Good | Good | Show slightly fiber crops | Good |
By above test relatively: the chewable tablet mouthfeel of embodiment one, two preparations shows slightly bitter, numb, but it is not too obvious, the sample mouthfeel of embodiment ten preparations shows slightly outside the picotement, and other have all reached the uncomfortable taste that has fundamentally improved ambroxol hydrochloride, and preparation method is fit to mechanization production.
Embodiment 16, dissolution experiment
Test according to the dissolution that the prepared sample of above embodiment carries out.Method is according to dissolution method (two appendix XC second methods of Chinese Pharmacopoeia version in 2005), is solvent with 0.1mol/L hydrochloric acid solution 900ml, and rotating speed is 75 rev/mins, operation in accordance with the law, sampling in the time of 30 minutes is measured trap at 244nm wavelength place, and test data sees the following form:
(wherein embodiment one, two is applied to embodiment 12, embodiment 13 respectively by the dissolution to above embodiment, therefore only to embodiment) investigate the result as can be seen, the dissolution that uses above carrier material to prepare sample all meets the requirements, and dissolution also improves under the prerequisite that guarantees the product mouthfeel.
Claims (10)
1, a kind of solid dispersion of ambroxol hydrochloride is characterized in that wherein ambroxol hydrochloride raw material and carrier material weight ratio are 1: 0.3～10.
2, solid dispersion of ambroxol according to claim 1 is characterized in that ambroxol hydrochloride raw material and carrier material weight ratio are 1: 3～5.
3, solid dispersion of ambroxol according to claim 1 and 2, it is characterized in that carrier material is selected from ethyl cellulose, methylcellulose, Eudragit L type, Eudragit S type, EudragitE type, Eudragit RL type, Eudragit RS type, acrylic resin II number or acrylic resin III number or above two or more material.
4, solid dispersion of ambroxol according to claim 3 is characterized in that carrier material Eudragit L type is selected from Eudragit L100 or Eudragit L100-55, or above two kinds of materials.
5, a kind of preparation method of solid dispersion of ambroxol hydrochloride is characterized in that it is a spray drying method, carrier material is added in the ethanol dissolve earlier, add the ambroxol hydrochloride raw material then and make its dissolving, after stirring, it is carried out spray drying, promptly get solid dispersion of ambroxol hydrochloride.
6, a kind of preparation method of solid dispersion of ambroxol hydrochloride is characterized in that it is a polishing, and carrier material and ambroxol hydrochloride raw material are ground in mortar, sieves, and promptly gets solid dispersion of ambroxol hydrochloride.
7, a kind of preparation method of solid dispersion of ambroxol hydrochloride is characterized in that it is a coating method, earlier carrier material is dissolved in the ethanol, is injected in the ambroxol hydrochloride raw material again, and ambroxol hydrochloride is carried out coating, promptly gets solid dispersion of ambroxol hydrochloride.
8, a kind of pharmaceutical composition of solid dispersion of ambroxol hydrochloride is characterized in that containing solid dispersion of ambroxol hydrochloride and pharmaceutically acceptable auxiliaries.
9, the pharmaceutical composition of solid dispersion of ambroxol hydrochloride according to claim 8 is characterized in that it is oral cavity disintegration tablet, chewable tablet, granule.
10, according to Claim 8 or the pharmaceutical composition of 9 described solid dispersion of ambroxol hydrochloride, the percentage by weight that it is characterized in that each component is: solid dispersion of ambroxol hydrochloride 5～75%, sweeting agent 5～80%, correctives 0～2%, disintegrating agent 0～30%.
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| CN101269055B (en) * | 2007-03-21 | 2011-12-14 | 北京德众万全药物技术开发有限公司 | Ambroxol hydrochloride oral cavity disintegrating tablet and method of producing the same |
| CN102327244A (en) * | 2011-09-30 | 2012-01-25 | 杭州康恩贝制药有限公司 | Ambroxol hydrochloride orally disintegrating tablet and preparation method thereof |
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| CN104382879A (en) * | 2014-12-09 | 2015-03-04 | 江西中医药大学 | Preparation method of colon targeting preparation |
| CN105412013A (en) * | 2015-12-08 | 2016-03-23 | 青岛正大海尔制药有限公司 | Preparing method for ambroxol salbutamol lipid solid dispersion |
| CN107737107A (en) * | 2017-12-02 | 2018-02-27 | 北京达因高科儿童药物研究院有限公司 | A kind of oral formulations of the composition containing L-084 and preparation method thereof |
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| CN100548286C (en) | 2009-10-14 |
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