CN104666302A - Composition and preparation method thereof as well as oral liquid and preparation method of oral liquid - Google Patents
Composition and preparation method thereof as well as oral liquid and preparation method of oral liquid Download PDFInfo
- Publication number
- CN104666302A CN104666302A CN201310636537.2A CN201310636537A CN104666302A CN 104666302 A CN104666302 A CN 104666302A CN 201310636537 A CN201310636537 A CN 201310636537A CN 104666302 A CN104666302 A CN 104666302A
- Authority
- CN
- China
- Prior art keywords
- levo
- solution
- preparation
- water
- oral liquid
- 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.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicinal preparations, in particular to a composition and a preparation method thereof as well as an oral liquid and a preparation method of the oral liquid. The preparation method of the composition comprises the following steps: mixing montelukast sodium with first water to obtain a montelukast sodium solution; mixing levocetirizine hydrochloride with second water and adjusting the pH value to 6.5-9 to obtain a levocetirizine hydrochloride solution; mixing the montelukast sodium solution with the levocetirizine hydrochloride solution to obtain the composition. The montelukast sodium in the oral liquid provided by the invention is high in stability; the composition does not contain an organic solvent or a surfactant; medication of children is facilitated; and the preparation technology is simple.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly composition and method of making the same, oral liquid and preparation method thereof.
Background technology
Allergic rhinitis and allergic rhinitis (allergic rhinitis, AR), it is a kind of multi-factor disease being interacted by gene and environment and brought out, it is that the medium (mainly histamine) mediated primarily of IgE after contacting allergen by atopic individuals discharges, and has the nasal mucosa non-infectious inflammatory disease that panimmunity competent cell and cytokine etc. participate in.Its essential condition occurred has 3: 1. namely specific antigen causes the material of organism immune response; 2. atopic individuals and so-called individual variation, allergic constitution; 3. specific antigen and spy answer both type individualities to meet.Specific antigen derives from animal, plant, insecticide, fungus or occupational material, and as demodicid mite, pollen, animal scurf, fungus allergen, cockroach allergens, food allergens etc., its composition is protein or glycoprotein, and only a few is polysaccharide.The classical symptom of allergic rhinitis is mainly had a stuffy nose, nasal congestion, watery nasal discharge, sneeze, rhinocnesmus, and part is with hyposmia, and the allergic rhinitis of middle severe can have an impact to the quality of life of patient, can cause many Other diseases, make patient's disability.
In allergic rhinitis, the speed after anaphylactogen exposes is sent out mutually and in late phase reaction, nasal mucosa all can discharge the cysteinyl leukotriene (CysLTs) relevant to allergic rhinitis symptoms.Leukotriene is one group of inflammatory mediator that arachidonic acid produces through the metabolism of 5-lipoxygenase pathway, cysteinyl leukotriene (LTC
4, LTD
4, LTE
4) be wherein important inflammatory mediator, discharged by the various kinds of cell comprising mastocyte and eosinophilic granulocyte.These inflammatory mediators are combined with cysteinyl leukotriene receptor, excite the series of symptoms of allergic rhinitis, as increased nose airway resistance and nasal obstruction.
Menglusitena (montelukast) is a kind of high selectivity cysteinyl leukotriene (Cys-LT) receptor antagonist developed by Merck & Co., Inc. in recent years, effectively can alleviate the indication of allergic rhinitis, 1997 first in Finland and Mexico's listing, within 1998, obtain FDA approval to go on the market in the U.S., commodity are called SINGULAIR(Singulair), initial indication is treatment asthma.U.S. FDA adds in December, 2002 indication that Menglusitena alleviates seasonal allergic rhinitis, adds again the indication alleviating perennial allergic rhinitis in July, 2005.
Levocetirizine is a kind of antihistamine drug developed by Belgian UCB. S.A. (BE) Bruxelles Belgium, and it is selectivity H
1receptor antagonist, in treatment of allergic rhinitis, its curative effect and montelukast zero difference.In vitro Binding Characteristics research finds, levocetirizine (Xyzal) is to H
1the affinity of receptor is 2 times of cetirizine, and levocetirizine effectively can alleviate symptom that is adult and more than 6 years old child patient allergic rhinitis.The medicinal forms of levocetirizine is levo-cetirizine hydrochloride.
By the investigation to domestic and international clinical literature, more effective in alleviation nasal mucus, sneeze, rhinocnesmus etc. than corresponding folk prescription after known Menglusitena and levo-cetirizine hydrochloride drug combination, Menglusitena mainly also has the therapeutical effect alleviating nasal congestion, and levo-cetirizine hydrochloride only can alleviate the symptom such as rhinocnesmus, sneeze, centering severe cannot slow down nasal congestion symptom with the Allergic Rhinitis of nasal congestion, compound preparation can play complementary effect in curative effect.In addition, although Menglusitena hydrochloric acid levocetirizine compound preparation in curative effect be not as superior as 17-hydroxy-11-dehydrocorticosterone, can use or the long-term treatment medicine of severe rhinitis patient during 17-hydroxy-11-dehydrocorticosterone is not tolerated as being reluctant.
Menglusitena is the moisture absorption very easily, and it is all unstable, unstable in the solution to meet light, wet, heat, oxygen and acid, easily separate out precipitation, and related substance increases obviously after being heated.Research finds, react after Menglusitena contacts with levo-cetirizine hydrochloride yellowing very soon, shows to there is incompatibility between Menglusitena and levo-cetirizine hydrochloride, and this problem has blocked the development of compound preparation.At present, there is report to be dissolved in polyoxy hydrogenated castor oil by Menglusitena and make microemulsion, levo-cetirizine hydrochloride is dissolved in aqueous phase, two kinds of active component directly do not contact, the stability of oral liquid can be improved by the method, but employ polyoxy hydrogenated castor oil in this technique as solubilizing agent, polyoxy hydrogenated castor oil is a kind of surfactant, stimulation is had to skin and eyes, and oral liquid solution ph is between 7 ~ 11, in this pH value range, the dissolubility of Menglusitena in water increases, have part Menglusitena to transfer to from solubilizing agent in water, run into levo-cetirizine hydrochloride, still can react, reduce the stability of Menglusitena.Up to the present, for the incompatibility problem between Menglusitena and levo-cetirizine hydrochloride, effective solution is had not yet to see.
Summary of the invention
In view of this, the invention provides composition and method of making the same, oral liquid and preparation method thereof.The preparation method of this oral liquid can improve the stability of Menglusitena; Not containing organic solvent and surfactant in this oral liquid, convenient for children is taken medicine, and preparation technology is simple.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides a kind of preparation method of compositions, comprise the steps:
Get Menglusitena to mix with water with first, obtain montelukast sodium solution;
Get levo-cetirizine hydrochloride to mix with water with second, adjust ph to 6.5 ~ 9, obtain levo-cetirizine hydrochloride solution;
Get montelukast sodium solution and the mixing of levo-cetirizine hydrochloride solution, to obtain final product.
Under existing technical conditions, those skilled in the art think that levo-cetirizine hydrochloride and Menglusitena exist incompatibility, and levo-cetirizine hydrochloride can cause Menglusitena variable color, promote the increase of Menglusitena related substance.And in the present invention, when preparing the oral liquid containing Menglusitena and levo-cetirizine hydrochloride, by first regulating pH value to 6.5 ~ 9 of levo-cetirizine hydrochloride solution, again by montelukast sodium solution and the mixing of levo-cetirizine hydrochloride solution, thus improve the compatibility of levo-cetirizine hydrochloride and Menglusitena in oral liquid, inventor finds that levo-cetirizine hydrochloride has Stabilization to Menglusitena unexpectedly.
As preferably, the pH value regulated after levo-cetirizine hydrochloride and second mixes with water is 7 ~ 8.
Present invention also offers by the obtained compositions of the preparation method of said composition;
The preparation method of said composition is: get Menglusitena and mix with water with first, obtains montelukast sodium solution; Get levo-cetirizine hydrochloride to mix with water with second, adjust ph to 6.5 ~ 9, obtain levo-cetirizine hydrochloride solution; Get montelukast sodium solution and the mixing of levo-cetirizine hydrochloride solution, to obtain final product.
Present invention also offers a kind of preparation method of oral liquid, comprise the steps:
Get pharmaceutically acceptable adjuvant, Menglusitena and first with water, through the first mixing, obtain montelukast sodium solution;
Get levo-cetirizine hydrochloride and second with water, through the second mixing, adjust ph to 6.5 ~ 9, obtain levo-cetirizine hydrochloride solution;
Get montelukast sodium solution and levo-cetirizine hydrochloride solution, through the 3rd mixing, to obtain final product.
By research, prove that sucrose, sorbitol, maltose alcohol, propylene glycol, glycerol or sucralose can promote that Menglusitena related substance increases.As preferably, on Chinese materia medica of the present invention, acceptable adjuvant does not comprise sucrose, sorbitol, maltose alcohol, propylene glycol, glycerol or sucralose.
In embodiments more provided by the invention, in oral liquid provided by the invention, do not comprise sucrose, sorbitol or maltose alcohol.
As preferably, the pH value regulated after levo-cetirizine hydrochloride and second mixes with water is 7 ~ 8.
In embodiments more provided by the invention, pharmaceutically acceptable adjuvant is selected from a kind of or both the above mixture in antiseptic, sweeting agent, water soluble cyclodextrin derivant or essence.
As preferably, the first mixing is specially: get antiseptic and mix with water, obtain antiseptic solution, get sweeting agent and mix with antiseptic solution, then mix with water soluble cyclodextrin derivant, essence successively.In the present invention, the addition sequence of Menglusitena in the first mixing is not limited.In embodiments more provided by the invention, after pharmaceutically acceptable adjuvant mixes with water, then add Menglusitena, obtain montelukast sodium solution.
In embodiments more provided by the invention, first is 100:(0.05 ~ 1 with water and second with the mass ratio of the consumption summation of water, Menglusitena, levo-cetirizine hydrochloride, antiseptic, sweeting agent, water soluble cyclodextrin derivant and essence): (0.05 ~ 1): (0.02 ~ 0.2): (0.01 ~ 0.2): (5 ~ 30): (0.01 ~ 0.2).
In embodiments more provided by the invention, first is 100:0.104:0.1:0.1:0.05:15:0.06 with water and second with the mass ratio of the consumption summation of water, Menglusitena, levo-cetirizine hydrochloride, antiseptic, sweeting agent, water soluble cyclodextrin derivant and essence.
In embodiments more provided by the invention, antiseptic is cetylpyridinium chloride, can ensure that oral liquid provided by the invention not easily separates out precipitation, stablize under the high temperature conditions.But antiseptic is not limited thereto, those skilled in the art think that feasible antiseptic is all in the scope of protection of the invention, and the present invention does not limit at this.
In order to prevent the precipitation of principal agent in oral liquid, in oral liquid provided by the invention, with the addition of cosolvent.In embodiments more provided by the invention, cosolvent is water soluble cyclodextrin derivant.
In embodiments more provided by the invention, water soluble cyclodextrin derivant is HP-β-CD.But water soluble cyclodextrin derivant is not limited thereto, those skilled in the art think that feasible water soluble cyclodextrin derivant is all in the scope of protection of the invention, and the present invention does not limit at this.
In order to improve the mouthfeel of oral liquid, in embodiments more provided by the invention, sweeting agent is acesulfame potassium.
In order in and the acidity of water for industrial use, in embodiments more provided by the invention, while sweeting agent mixes with antiseptic solution, also add water soluble alkaline material.
In embodiments more provided by the invention, water soluble alkaline material is potassium sorbate and/or meglumine.
In embodiments more provided by the invention, the mass ratio of water soluble alkaline material and Menglusitena is (2 ~ 8): (10 ~ 200).
In embodiments more provided by the invention, the reagent of adjust ph is sodium hydroxide solution.But water soluble alkaline material is not limited thereto, those skilled in the art think that feasible water soluble alkaline material is all in the scope of protection of the invention, and the present invention does not limit at this.
Present invention also offers by the obtained oral liquid of the preparation method of this oral liquid;
The preparation method of this oral liquid is: get pharmaceutically acceptable adjuvant, Menglusitena and first with water, through the first mixing, obtain montelukast sodium solution; Get levo-cetirizine hydrochloride and second with water, through the second mixing, adjust ph to 6.5 ~ 9, obtain levo-cetirizine hydrochloride solution; Get montelukast sodium solution and levo-cetirizine hydrochloride solution, through the 3rd mixing, to obtain final product; As preferably, on Chinese materia medica of the present invention, acceptable adjuvant does not comprise sucrose, sorbitol, maltose alcohol, propylene glycol, glycerol or sucralose; In embodiments more provided by the invention, in oral liquid provided by the invention, do not comprise sucrose, sorbitol or maltose alcohol; As preferably, the pH value regulated after levo-cetirizine hydrochloride and second mixes with water is 7 ~ 8; In embodiments more provided by the invention, pharmaceutically acceptable adjuvant is selected from a kind of or both the above mixture in antiseptic, sweeting agent, water soluble cyclodextrin derivant or essence; As preferably, the first mixing is specially: get antiseptic and mix with water, obtain antiseptic solution, get sweeting agent and mix with antiseptic solution, then mix with water soluble cyclodextrin derivant, essence successively; In embodiments more provided by the invention, first is 100:(0.05 ~ 1 with water and second with the mass ratio of the consumption summation of water, Menglusitena, levo-cetirizine hydrochloride, antiseptic, sweeting agent, water soluble cyclodextrin derivant and essence): (0.05 ~ 1): (0.02 ~ 0.2): (0.01 ~ 0.2): (5 ~ 30): (0.01 ~ 0.2); In embodiments more provided by the invention, first is 100:0.104:0.1:0.1:0.05:15:0.06 with water and second with the mass ratio of the consumption summation of water, Menglusitena, levo-cetirizine hydrochloride, antiseptic, sweeting agent, water soluble cyclodextrin derivant and essence; In embodiments more provided by the invention, antiseptic is cetylpyridinium chloride; With the addition of cosolvent in oral liquid provided by the invention, in embodiments more provided by the invention, cosolvent is water soluble cyclodextrin derivant; Water soluble cyclodextrin derivant is HP-β-CD; Sweeting agent is acesulfame potassium; Also water soluble alkaline material is added while sweeting agent mixes with antiseptic solution; Water soluble alkaline material is potassium sorbate and/or meglumine; The mass ratio of water soluble alkaline material and Menglusitena is (2 ~ 8): (10 ~ 200); The reagent of adjust ph is sodium hydroxide solution.
The invention provides composition and method of making the same, oral liquid and preparation method thereof.The preparation method of said composition is: get Menglusitena and mix with water with first, obtains montelukast sodium solution; Get levo-cetirizine hydrochloride to mix with water with second, adjust ph to 6.5 ~ 9, obtain levo-cetirizine hydrochloride solution; Get montelukast sodium solution and the mixing of levo-cetirizine hydrochloride solution, to obtain final product.Known by stability test data, in oral liquid provided by the invention, Menglusitena stability is significantly increased relative to Menglusitena folk prescription oral liquid, shows that levo-cetirizine hydrochloride is improved the effect of stability to Menglusitena; Add sucrose, sorbitol or maltose alcohol in oral liquid prescription after, place 5 days at 60 DEG C, sulfoxide impurity, unknown impuritie and total impurities all increase considerably, wherein partial impurities exceeds limit standard, product quality is defective, and result shows that sucrose, sorbitol, maltose alcohol can promote that related substance increases; When preparing montelukast sodium solution, in water, add antiseptic, sweeting agent, water soluble cyclodextrin derivant, essence, Menglusitena successively, the stability of obtained oral liquid is better.As can be seen here, the preparation method of oral liquid provided by the invention can improve the stability of Menglusitena, and not containing organic solvent and surfactant in oral liquid, convenient for children is taken medicine, and preparation technology is simple.
Detailed description of the invention
The invention discloses composition and method of making the same, oral liquid and preparation method thereof, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination, realize and apply the technology of the present invention.
In composition and method of making the same provided by the invention, oral liquid and preparation method thereof, raw materials used medicine or adjuvant all can be buied by market.
Below in conjunction with embodiment, set forth the present invention further:
The preparation of embodiment 1 oral liquid
The prescription of oral liquid is as shown in table 1.All operations all carries out under lucifuge condition.
The prescription of table 1 oral liquid
| Prescription forms | Prescription consumption |
| Menglusitena (mg) | 104 |
| Levo-cetirizine hydrochloride (mg) | 100 |
| Meglumine (mg) | 10 |
| HP-β-CD (mg) | 15000 |
| Acesulfame potassium (mg) | 50 |
| Grape essence (mg) | 60 |
| Cetylpyridinium chloride (mg) | 100 |
| Water (mL) | 100 |
| pH | 7.38 |
Get cetylpyridinium chloride soluble in water, add meglumine and acesulfame potassium stirring and dissolving, add HP-β-CD stirring and dissolving, add grape essence stirring and dissolving, add Menglusitena stirring and dissolving, obtain montelukast sodium solution.
Get levo-cetirizine hydrochloride soluble in water, regulate pH to 7 with 1% sodium hydroxide, obtain levo-cetirizine hydrochloride solution.Getting levo-cetirizine hydrochloride solution is added in above-mentioned montelukast sodium solution, and limit edged stirs, and to obtain final product.
The preparation of embodiment 2 oral liquid
The prescription of oral liquid is as shown in table 2.All operations all carries out under lucifuge condition.
The prescription of table 2 oral liquid
Get cetylpyridinium chloride soluble in water, add potassium sorbate and acesulfame potassium stirring and dissolving, add HP-β-CD stirring and dissolving, add grape essence stirring and dissolving, add Menglusitena stirring and dissolving, obtain montelukast sodium solution.
Get levo-cetirizine hydrochloride soluble in water, regulate pH to 6.5 with 1% sodium hydroxide, obtain levo-cetirizine hydrochloride solution.Getting levo-cetirizine hydrochloride solution is added in above-mentioned montelukast sodium solution, and limit edged stirs, and to obtain final product.
The preparation of embodiment 3 oral liquid
The prescription of oral liquid is as shown in table 3.All operations all carries out under lucifuge condition.
The prescription of table 3 oral liquid
| Prescription forms | Prescription consumption |
| Menglusitena (mg) | 50 |
| Levo-cetirizine hydrochloride (mg) | 500 |
| Meglumine (mg) | 40 |
| HP-β-CD (mg) | 20000 |
| Acesulfame potassium (mg) | 10 |
| Grape essence (mg) | 200 |
| Cetylpyridinium chloride (mg) | 200 |
| Water (mL) | 100 |
| pH | 7.92 |
[0060]get cetylpyridinium chloride soluble in water, add meglumine and acesulfame potassium stirring and dissolving, add HP-β-CD stirring and dissolving, add grape essence stirring and dissolving, add Menglusitena stirring and dissolving, obtain montelukast sodium solution.
Get levo-cetirizine hydrochloride soluble in water, regulate pH to 8 with 1% sodium hydroxide, obtain levo-cetirizine hydrochloride solution.Getting levo-cetirizine hydrochloride solution is added in above-mentioned montelukast sodium solution, and limit edged stirs, and to obtain final product.
The preparation of embodiment 4 oral liquid
The prescription of oral liquid is as shown in table 4.All operations all carries out under lucifuge condition.
The prescription of table 4 oral liquid
| Prescription forms | Prescription consumption |
| Menglusitena (mg) | 1000 |
| Levo-cetirizine hydrochloride (mg) | 1000 |
| Potassium sorbate (mg) | 10 |
| HP-β-CD (mg) | 30000 |
| Acesulfame potassium (mg) | 100 |
| Grape essence (mg) | 100 |
| Cetylpyridinium chloride (mg) | 50 |
| Water (mL) | 100 |
| pH | 7.84 |
Get cetylpyridinium chloride soluble in water, add potassium sorbate and acesulfame potassium stirring and dissolving, add HP-β-CD stirring and dissolving, add grape essence stirring and dissolving, add Menglusitena stirring and dissolving, obtain montelukast sodium solution.
Get levo-cetirizine hydrochloride soluble in water, regulate pH to 9 with 1% sodium hydroxide, obtain levo-cetirizine hydrochloride solution.Getting levo-cetirizine hydrochloride solution is added in above-mentioned montelukast sodium solution, and limit edged stirs, and to obtain final product.
The preparation of embodiment 5 oral liquid
The prescription of oral liquid is as shown in table 5.All operations all carries out under lucifuge condition.
The prescription of table 5 oral liquid
| Prescription forms | Prescription consumption |
| Menglusitena (mg) | 500 |
| Levo-cetirizine hydrochloride (mg) | 50 |
| HP-β-CD (mg) | 5000 |
| Acesulfame potassium (mg) | 200 |
| Grape essence (mg) | 10 |
| Cetylpyridinium chloride (mg) | 20 |
| Water (mL) | 100 |
| pH | 7.52 |
Get cetylpyridinium chloride soluble in water, add acesulfame potassium stirring and dissolving, add HP-β-CD stirring and dissolving, add grape essence stirring and dissolving, add Menglusitena stirring and dissolving, obtain montelukast sodium solution.
Get levo-cetirizine hydrochloride soluble in water, regulate pH to 7.5 with 1% sodium hydroxide, obtain levo-cetirizine hydrochloride solution.Getting levo-cetirizine hydrochloride solution is added in above-mentioned montelukast sodium solution, and limit edged stirs, and to obtain final product.
Embodiment 6 Detection of Stability is tested
The oral liquid that Example 1 to 5 obtains carries out stability test.The condition of stability test is: place 2 weeks under 60 DEG C of conditions.Measure the data such as the related substance of the obtained oral liquid of embodiment 1 to 5 when 0 day and 2 weeks and content respectively, carry out study on the stability.
Menglusitena related substance detection method: lucifuge operates.Get oral liquid and cross 0.22 μm of filter membrane, as need testing solution.According to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D) test, be filler (Agilent SB-PHENYL4.6*50mm, 1.8 μm) with phenyl bonded silica; With 0.15% trifluoroacetic acid aqueous solution for mobile phase A, with 0.15% trifluoroacetic acid acetonitrile solution for Mobile phase B, carry out gradient elution by table 6 program; Flow velocity is 1.2mL per minute, and determined wavelength is 238nm, and column temperature is 30 DEG C.Another accurately weighed Menglusitena system suitability reference substance is appropriate, dissolve with solvent [methanol-water (9:1)] and dilute and make the solution of every 1mL containing montelukast system suitability reference substance 1mg, place 20 minutes under natural light, shake up, as system suitability solution, get system suitability solution 10 μ L injection liquid chromatography, record chromatogram, sulfoxide impurity, cis-isomer, montelukast and methyl ketone go out peak successively, the separating degree at cis-isomer peak and montelukast peak should be not less than 2.5, the separating degree at montelukast peak and methyl ketone peak should be not less than 1.5.Get contrast solution 10 μ L injection liquid chromatography, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10% ~ 20% of full scale; Precision measures need testing solution 10 μ L again, injection liquid chromatography respectively, if any impurity peaks in the chromatogram of need testing solution, its peak area is compared with contrast solution main peak area, and sulfoxide impurity must not cross 1.0%, and cis-isomer impurity must not cross 0.1%, methyl ketone impurity must not cross 0.1%, other single unknown impurities must not cross 0.1%, and total impurities must not cross 1.2%, and in need testing solution chromatogram, any impurity peaks being less than contrast solution main peak area 0.5 times can be ignored.Result is as shown in table 7.
Levo-cetirizine hydrochloride related substance detection method: lucifuge operates.Get oral liquid 5mg, put in 20mL measuring bottle, solubilizer [water-acetonitrile (58:42)] is appropriate, and be diluted to scale, shake up, 0.22 μm of membrane filtration, gets subsequent filtrate as need testing solution.Another precision takes two couples of chlorophenylmethyl piperazine 5mg, parachlorophenol 10mg and two rubigan methanol 5mg, put in 100mL measuring bottle, dissolve with solvent [water-acetonitrile (58:42)] and be diluted to scale, shake up, as impurity reference substance stock solution, precision measures each impurity reference substance stock solution 1mL and puts in 200mL measuring bottle, is diluted to scale with solvent [water-acetonitrile (58:42)], shake up, in contrast product solution.According to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D) test, be filler (CAPCELL PAK C18 5 μm, 4.6 × 250mm) with octadecylsilane chemically bonded silica; For mobile phase A with buffer (sodium heptanesulfonate 0.3g add water 580mL) (dilute sulfuric acid adjusts pH2.2), take acetonitrile as Mobile phase B, carry out gradient elution by table 8 program; Flow velocity is 1.0mL per minute, and determined wavelength is 230nm, and column temperature is 30 DEG C.Separately get levo-cetirizine hydrochloride reference substance and add the solution that acetonitrile-water (58:42) is mixed with 0.25mg/mL in right amount, get this solution 2mL, each impurity reference substance stock solution 1mL puts in same 200mL measuring bottle, scale is diluted to solvent [water-acetonitrile (58:42)], shake up, as system suitability solution.Get system suitability solution 20 μ L injection liquid chromatography, record chromatogram, two pairs of chlorophenylmethyl piperazines, levocetirizine, parachlorophenol and two rubigan methanol go out peak successively, the relative retention time of two pairs of chlorophenylmethyl piperazines, parachlorophenol and two rubigan methanol is respectively 0.9,1.1 and 3.8, and the separating degree at two pairs of chlorophenylmethyl piperazine peaks and levocetirizine peak all should conform with the regulations; Regulate detection sensitivity, make two pairs of chlorophenylmethyl piperazine peak heights be 20% of full scale.Precision measures each 20 μ L of reference substance solution, contrast solution and need testing solution again, respectively injection liquid chromatography, record chromatogram.If any the chromatographic peak consistent with two pairs of chlorophenylmethyl piperazine peaks, parachlorophenol peak and two rubigan methanol peak retention times in the chromatogram of need testing solution, by external standard method with calculated by peak area, two pairs of chlorophenylmethyl piperazines, parachlorophenol and two rubigan methanol all must not persalt levocetirizine labelled amount 0.5%, other single unknown impuritie peak areas must not be greater than levocetirizine peak area (0.5%) in contrast solution, and total impurities must not cross 1.0%.The impurity peaks being less than levocetirizine peak area 0.1 times in contrast solution in need testing solution chromatogram can be ignored.Result is as shown in table 9.
Menglusitena content assaying method: lucifuge operates, get oral liquid 1mL, add in 10mL volumetric flask, montelukast na concn is 0.1mg/mL, and solubilizer [methanol-water (9:1)] is appropriate, ultrasonic 10 minutes, solubilizer [methanol-water (9:1)] is diluted to scale, shake up, filter, get subsequent filtrate as need testing solution.According to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D) test, be filler (Agilent SB-PHENYL4.6*50mm, 1.8 μm) with phenyl bonded silica; With 0.15% trifluoroacetic acid aqueous solution for mobile phase A, with 0.15% trifluoroacetic acid acetonitrile solution for Mobile phase B, carry out gradient elution by table 6 program; Flow velocity is 1.2mL per minute, and determined wavelength is 238nm, and column temperature is 30 DEG C.Separately get Menglusitena reference substance 10mg, solubilizer [methanol-water (9:1)] dissolves and dilutes the solution made about containing 0.1mg in every 1mL, is measured in the same method, by external standard method with calculated by peak area, obtains final product.
Levo-cetirizine hydrochloride content assaying method: chromatographic condition and system suitability are for being filler with octadecyl silane, with 0.2% trifluoroacetic acid aqueous solution for mobile phase A, with 0.2% trifluoroacetic acid acetonitrile solution for Mobile phase B, determined wavelength is 230nm, flow velocity is 1.0mL per minute, carries out gradient elution by table 10 program; Concrete operation method: get oral liquid 1mL, is equivalent to levo-cetirizine hydrochloride 1.0mg, is placed in 10mL measuring bottle, solubilizer [water-acetonitrile (58:42)] ultrasonic 10 minutes in right amount, be diluted to scale, shake up, filter, precision measures subsequent filtrate 20 μ L, injection liquid chromatography, record chromatogram; Separately get levo-cetirizine hydrochloride reference substance 10mg, solubilizer [water-acetonitrile (58:42)] dissolves and dilutes the solution made about containing 0.1mg in every 1mL, is measured in the same method, by external standard method with calculated by peak area, obtains final product.
Content detection result is as shown in table 11.
Table 6 Menglusitena elution program
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 3 | 70 | 30 |
| 16 | 49 | 51 |
| 25 | 49 | 51 |
| 25.1 | 70 | 30 |
| 30 | 70 | 30 |
Menglusitena related substance testing result in table 7 oral liquid
Table 8 levo-cetirizine hydrochloride related substance detects elution program
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 58 | 42 |
| 30 | 58 | 42 |
| 50 | 20 | 80 |
[0087]
| 55 | 20 | 80 |
| 55.1 | 58 | 42 |
| 60 | 58 | 42 |
Levo-cetirizine hydrochloride related substance testing result in table 9 oral liquid
Table 10 levo-cetirizine hydrochloride content detection elution program
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 62 | 38 |
| 6 | 62 | 38 |
| 13 | 20 | 80 |
| 13.1 | 62 | 38 |
| 18 | 62 | 38 |
[0092]menglusitena and levo-cetirizine hydrochloride content detection result in table 11 oral liquid
From the result of the test of table 7, place 2 weeks at 60 DEG C, though the impurity of Menglusitena has increase, still meet quality standard.Result shows Menglusitena stable in properties in the oral liquid that embodiment 1 to 5 provides.
From table 9 result of the test, place 2 weeks at 60 DEG C, the impurity of levo-cetirizine hydrochloride does not significantly change.Result shows levo-cetirizine hydrochloride stable in properties in the oral liquid that embodiment 1 to 5 provides.
From table 11 result of the test, in the oral liquid that embodiment 1 to 5 provides, Menglusitena and levo-cetirizine hydrochloride content all meet quality standard, show Menglusitena and levo-cetirizine hydrochloride stable in properties in the oral liquid that embodiment 1 to 5 provides.
The preparation of comparative example 1 Menglusitena oral liquid
The prescription of oral liquid is as shown in table 12.All operations all carries out under lucifuge condition.
The prescription of table 12 Menglusitena oral liquid
| Prescription forms | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| Menglusitena (mg) | 104 | 104 | 104 | 104 |
| Meglumine (mg) | 10 | 10 | 10 | 10 |
| HP-β-CD (mg) | 15000 | 15000 | 15000 | 15000 |
| Acesulfame potassium (mg) | 50 | 50 | 50 | 50 |
| Sucrose (mg) | —— | 10000 | —— | —— |
| Sorbitol (mg) | —— | —— | 10000 | —— |
| Maltose alcohol (mg) | —— | —— | —— | 10000 |
| Grape essence (mg) | 60 | 60 | 60 | 60 |
| Cetylpyridinium chloride (mg) | 100 | 100 | 100 | 100 |
| Water (mL) | 100 | 100 | 100 | 100 |
| pH | 8.96 | 8.90 | 9.01 | 8.91 |
Get cetylpyridinium chloride soluble in water, add meglumine and acesulfame potassium stirring and dissolving, add HP-β-CD stirring and dissolving, add grape essence stirring and dissolving, add the one in sucrose, sorbitol or maltose alcohol, stirring and dissolving, adds Menglusitena stirring and dissolving, obtains Menglusitena oral liquid.
Get above-mentioned Menglusitena oral liquid to place 5 days at 60 DEG C, detect its related substances when 0 day and 5 days, detection method is with reference to the detection method of the Menglusitena related substance provided in embodiment 6.Result is as shown in table 13.
Table 13 Menglusitena related substance testing result
As shown in Table 13, when not adding levo-cetirizine hydrochloride in prescription, the oral liquid of prescription 1 is placed 5 days at 60 DEG C, and its unknown impuritie exceeds limit standard, and product quality is defective; And the data of related substance relative to 0 day after 2 weeks placed by the oral liquid that embodiment 1 provides at 60 DEG C, sulfoxide impurity and total impurities have increased slightly, but within limit standard, other related substance data have no significant change.Compared with the prescription 1 of comparative example 1, embodiment 1 adds levo-cetirizine hydrochloride, and the pH value of oral liquid reduces, and the stability of Menglusitena improves on the contrary.As can be seen here, levo-cetirizine hydrochloride is the key factor of the stability improving Menglusitena, not pH value.
Prescription 2,3,4 with the addition of sucrose, sorbitol, maltose alcohol respectively on the basis of prescription 1, place 5 days at 60 DEG C, sulfoxide impurity, unknown impuritie and total impurities all increase considerably, wherein partial impurities exceeds limit standard, product quality is defective, and result shows that sucrose, sorbitol, maltose alcohol can promote that related substance increases.As can be seen here, in montelukast sodium solution, do not add sucrose, sorbitol or maltose alcohol, be conducive to the stability maintaining Menglusitena.
The preparation of comparative example 2 oral liquid
The prescription of oral liquid is as shown in table 14.All operations all carries out under lucifuge condition.
The prescription of table 14 oral liquid
| Prescription forms | Prescription 5 | Prescription 6 | Prescription 7 |
| Menglusitena (mg) | 104 | 104 | 104 |
| Levo-cetirizine hydrochloride (mg) | 100 | 100 | 100 |
| Meglumine (mg) | 10 | 10 | 10 |
| HP-β-CD (mg) | 15000 | 15000 | 15000 |
| Acesulfame potassium (mg) | 50 | 50 | 50 |
| Sucrose (mg) | 10000 | —— | —— |
[0112]
| Sorbitol (mg) | —— | 10000 | —— |
| Maltose alcohol (mg) | —— | —— | 10000 |
| Grape essence (mg) | 60 | 60 | 60 |
| Cetylpyridinium chloride (mg) | 100 | 100 | 100 |
| Water (mL) | 100 | 100 | 100 |
| pH | 7.34 | 7.37 | 7.15 |
The preparation method of the oral liquid as shown in prescription 5,6,7 is:
Get cetylpyridinium chloride soluble in water, add meglumine and acesulfame potassium stirring and dissolving, add HP-β-CD stirring and dissolving, add grape essence stirring and dissolving, add the one in sucrose, sorbitol or maltose alcohol, stirring and dissolving, adds Menglusitena stirring and dissolving, obtains montelukast sodium solution.
Get levo-cetirizine hydrochloride soluble in water, regulate pH to 7 with 1% sodium hydroxide, obtain levo-cetirizine hydrochloride solution.Getting levo-cetirizine hydrochloride solution is added in above-mentioned montelukast sodium solution, and limit edged stirs, and to obtain final product.
Get above-mentioned oral liquid to place 5 days at 60 DEG C, detect its related substances when 0 day and 5 days, detection method is with reference to the detection method of the Menglusitena related substance provided in embodiment 6.Result is as shown in Table 15.
Table 15 Menglusitena related substance testing result
As shown in Table 15, prescription 5, 6, 7 with the addition of sucrose respectively on the prescription basis that embodiment 1 provides, sorbitol, maltose alcohol, place 5 days at 60 DEG C, sulfoxide impurity, unknown impuritie and total impurities all have increase, sulfoxide impurity, the content after 2 weeks placed by the oral liquid that unknown impuritie and total impurities content provide higher than embodiment 1 at 60 DEG C, but lower than prescription 2 in comparative example 1, 3, 4, result shows sucrose, sorbitol, maltose alcohol can promote that Menglusitena related substance increases, but relative to not adding the prescription of levo-cetirizine hydrochloride in comparative example 1, the stability of Menglusitena can be improved after adding levo-cetirizine hydrochloride.
The preparation of comparative example 3 oral liquid
The prescription (prescription 8) (prescription 8 is consistent with the prescription of the oral liquid that embodiment 1 provides) shown in table 16 of the oral liquid that this comparative example provides.All operations all carries out under lucifuge condition.
The prescription of table 16 oral liquid
| Prescription forms | Prescription 8 |
| Menglusitena (mg) | 104 |
| Levo-cetirizine hydrochloride (mg) | 100 |
| Meglumine (mg) | 10 |
| HP-β-CD (mg) | 15000 |
| Acesulfame potassium (mg) | 50 |
| Grape essence (mg) | 60 |
| Cetylpyridinium chloride (mg) | 100 |
| Water (mL) | 100 |
| pH | 7.35 |
Preparation method is:
Get cetylpyridinium chloride soluble in water, add HP-β-CD stirring and dissolving, add meglumine, acesulfame potassium and grape essence stirring and dissolving, add Menglusitena stirring and dissolving, obtain montelukast sodium solution.
Get levo-cetirizine hydrochloride soluble in water, regulate pH to 7 with 1% sodium hydroxide, obtain levo-cetirizine hydrochloride solution.Getting levo-cetirizine hydrochloride solution is added in above-mentioned montelukast sodium solution, and limit edged stirs, and to obtain final product.
The oral liquid that the preparation method that getting this comparative example provides obtains and the oral liquid that embodiment 1 provides are placed 5 days at 60 DEG C, detect its related substances when 0 day and 5 days, and detection method is with reference to the detection method of the Menglusitena related substance provided in embodiment 6.Result is shown in table 17.
Table 17 Menglusitena related substance testing result
As shown in Table 17, it is comparatively large that the oral liquid that this comparative example provides places the sulfoxide after 5 days and total impurities increasing degree at 60 DEG C, and the oral liquid that embodiment 1 provides places at 60 DEG C 2 weeks afterwards related substance do not increase or have increased slightly; Visible, the preparation method that embodiment 1 provides can improve the stability of Menglusitena.
When prescription is consistent with the prescription that embodiment 1 to 5 provides, except oral liquor provided by the invention (preparation technology), adopt the oral liquid that other oral liquor is obtained, as changed the addition sequence of component, the stability of Menglusitena is all lower than oral liquid provided by the invention.As can be seen here, the preparation method of oral liquid provided by the invention can improve the stability of Menglusitena.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a preparation method for compositions, is characterized in that, comprises the steps:
Get Menglusitena to mix with water with first, obtain montelukast sodium solution;
Get levo-cetirizine hydrochloride to mix with water with second, adjust ph to 6.5 ~ 9, obtain levo-cetirizine hydrochloride solution;
Get described montelukast sodium solution and the mixing of described levo-cetirizine hydrochloride solution, to obtain final product.
2. preparation method according to claim 1, is characterized in that, described pH value is 7 ~ 8.
3. a preparation method for oral liquid, is characterized in that, comprises the steps:
Get pharmaceutically acceptable adjuvant, Menglusitena and first with water, through the first mixing, obtain montelukast sodium solution;
Get levo-cetirizine hydrochloride and second with water, through the second mixing, adjust ph to 6.5 ~ 9, obtain levo-cetirizine hydrochloride solution;
Get described montelukast sodium solution and described levo-cetirizine hydrochloride solution, through the 3rd mixing, to obtain final product.
4. preparation method according to claim 3, is characterized in that, described pharmaceutically acceptable adjuvant does not comprise sucrose, sorbitol, maltose alcohol, propylene glycol, glycerol or sucralose.
5. preparation method according to claim 3, is characterized in that, described pH value is 7 ~ 8.
6. preparation method according to claim 3, is characterized in that, described pharmaceutically acceptable adjuvant is selected from a kind of or both the above mixture in antiseptic, sweeting agent, water soluble cyclodextrin derivant or essence.
7. preparation method according to claim 6, it is characterized in that, described first mixing is specially: get antiseptic and mix with water, obtain antiseptic solution, get sweeting agent to mix with described antiseptic solution, then mix with water soluble cyclodextrin derivant, essence successively.
8. preparation method according to claim 6, it is characterized in that, described first is 100:(0.05 ~ 1 with water and described second with the mass ratio of the consumption summation of water, described Menglusitena, described levo-cetirizine hydrochloride, described antiseptic, described sweeting agent, described water soluble cyclodextrin derivant and described essence): (0.05 ~ 1): (0.02 ~ 0.2): (0.01 ~ 0.2): (5 ~ 30): (0.01 ~ 0.2).
9. preparation method according to claim 7, is characterized in that, while described sweeting agent mixes with described antiseptic solution, also add water soluble alkaline material.
10. preparation method according to claim 9, is characterized in that, described water soluble alkaline material is potassium sorbate and/or meglumine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310636537.2A CN104666302B (en) | 2013-11-27 | 2013-11-27 | Composition and preparation method thereof, oral liquid and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310636537.2A CN104666302B (en) | 2013-11-27 | 2013-11-27 | Composition and preparation method thereof, oral liquid and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104666302A true CN104666302A (en) | 2015-06-03 |
| CN104666302B CN104666302B (en) | 2017-06-30 |
Family
ID=53302242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310636537.2A Active CN104666302B (en) | 2013-11-27 | 2013-11-27 | Composition and preparation method thereof, oral liquid and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104666302B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105828804A (en) * | 2013-12-19 | 2016-08-03 | 韩美药品株式会社 | Liquid formulation comprising montelukast or pharmaceutically acceptable salt thereof and method for preparing same |
| WO2019197939A1 (en) * | 2018-04-11 | 2019-10-17 | Hetero Healthcare Limited | Taste masked mouth dissolving formulation of montelukast sodium and levocetirizine hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011110939A2 (en) * | 2010-03-11 | 2011-09-15 | Rubicon Research Private Limited | Pharmaceutical compositions of substituted benzhydrylpiperazines |
| WO2012064304A2 (en) * | 2010-11-11 | 2012-05-18 | Mahmut Bilgic | Combinations comprising montelukast |
-
2013
- 2013-11-27 CN CN201310636537.2A patent/CN104666302B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011110939A2 (en) * | 2010-03-11 | 2011-09-15 | Rubicon Research Private Limited | Pharmaceutical compositions of substituted benzhydrylpiperazines |
| WO2012064304A2 (en) * | 2010-11-11 | 2012-05-18 | Mahmut Bilgic | Combinations comprising montelukast |
Non-Patent Citations (1)
| Title |
|---|
| 王晓颖: "孟鲁司特钠联合西替利嗪治疗咳嗽变异性哮喘", 《中国社区医师·医学专业》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105828804A (en) * | 2013-12-19 | 2016-08-03 | 韩美药品株式会社 | Liquid formulation comprising montelukast or pharmaceutically acceptable salt thereof and method for preparing same |
| WO2019197939A1 (en) * | 2018-04-11 | 2019-10-17 | Hetero Healthcare Limited | Taste masked mouth dissolving formulation of montelukast sodium and levocetirizine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104666302B (en) | 2017-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EA014234B1 (en) | Composition for the treatment of hepatitis c or dietary supplement for prevention or alleviation hepatitis c symptoms | |
| CN104546851B (en) | A kind of particulate composition and preparation method thereof, preparation | |
| CN101697969A (en) | Ornidazole medicinal composition and preparation method thereof | |
| CN102961469A (en) | Traditional Chinese medicine dispersible tablet for treating upper respiratory infection, and preparation method and quality detection method thereof | |
| CN104784157B (en) | A kind of montelukast oral membrane agent of stabilization | |
| CN104666302A (en) | Composition and preparation method thereof as well as oral liquid and preparation method of oral liquid | |
| CN109864975B (en) | Aripiprazole orally disintegrating tablet and preparation method thereof | |
| CN102940708A (en) | Traditional Chinese medicine chewable tablet for treating upper respiratory tract infection and preparation method of chewable tablet | |
| CN103191116A (en) | Dextromethorphan hydrobromide and guaiacol glycerin ether oral liquid and preparation method thereof | |
| CN104306331B (en) | A kind of Cetirizine Hydrochloride syrup | |
| CN103675135B (en) | A kind of content assaying method of Chinese medicine composition | |
| CN101461904A (en) | Method for testing Chinese medicinal composition for treating painful swelling of throat and constipation | |
| CN103381272A (en) | Method for improving levodropropizine taste by cyclodextrin clathration | |
| CN105230836A (en) | Health tea having adjuvant therapy effect on rhinitis, and preparation method and detection method thereof | |
| CN104546695A (en) | Oral Montelukast sodium liquid preparation and preparation method thereof | |
| Shoosanglertwijit et al. | Physical, chemical, and microbiological stability of extemporaneous furosemide suspensions | |
| CN102085194A (en) | Levetiracetam oral disintegrating tablet and preparation method thereof | |
| CN111096949A (en) | Cetirizine hydrochloride oral drop and preparation method thereof | |
| CN105878219B (en) | A kind of Li Gelieting pelliculae pro cavo oris and preparation method thereof | |
| Akinleye et al. | Effect of Ciklavit®-a Nigerian poly-herbal formulation on the dissolution profile of proguanil tablets: potential for herb-drug interaction | |
| CN103191309B (en) | Mailuoning granule and preparation method | |
| CN103330682B (en) | Potassium dehydroandrographolide succinate injection and preparation method | |
| CN103239432A (en) | Compound ambroxol hydrochloride composition granule and preparation method thereof | |
| CN105796578A (en) | Compound pharmaceutical composition for treating rhinitis in children | |
| Park et al. | Evaluation of food effects on the pharmacokinetics of Pelargonium sidoides and Coptis with each bioactive compound berberine and epicatechin after a single oral dose of an expectorant and antitussive agent UI026 in healthy subjects |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |