CN104546851A - Particle composition as well as preparation method and preparation thereof - Google Patents
Particle composition as well as preparation method and preparation thereof Download PDFInfo
- Publication number
- CN104546851A CN104546851A CN201310521523.6A CN201310521523A CN104546851A CN 104546851 A CN104546851 A CN 104546851A CN 201310521523 A CN201310521523 A CN 201310521523A CN 104546851 A CN104546851 A CN 104546851A
- Authority
- CN
- China
- Prior art keywords
- granule
- menglusitena
- preparation
- levo
- filler
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a particle composition as well as a preparation method and a preparation thereof. The particle composition comprises montelukast particles and levocetirizine hydrochloride particles, wherein the montelukast particles are prepared from montelukast, a filler, a stabilizer and an adhesive; the levocetirizine hydrochloride particles are prepared from levocetirizine hydrochloride, the filler, the stabilizer and the adhesive; the stabilizer is meglumine; and the adhesive is hydroxypropyl-beta-cyclodextrin. The particle composition and the preparation thereof provided by the invention are stable in property; the content uniformity of active components of two medicines is improved; and the medicine quality completely accords with the national standard.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly a kind of particulate composition and preparation method thereof, preparation.
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.Classical symptom mainly paroxysmal sneeze, clear water sample nasal mucus, nasal obstruction and the rhinocnesmus of allergic rhinitis, part is with hyposmia, 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.
Menglusitena (montelukast) is a kind of high selectivity cysteinyl leukotriene (Cys-LT) receptor antagonist developed by Merck & Co., Inc. in recent years, the combination of its energy competitive antagonism leukotriene D and Cys-LT1 receptor.It is applied to clinical as a kind of novel nonsteroidal antasthmatic the earliest, and achieve the effect of affirmative clinically.Along with more deep to the understanding of leukotriene (LT) and receptor antagonist thereof, it is found that Menglusitena not only can improve the pulmonary function of asthmatic patient, and also having important using value in all many-sides such as antiinflammatory, immunity, such as Menglusitena can be used for the treatment of allergic rhinitis.
Levocetirizine is a kind of selectivity H1 receptor antagonist.In vitro Binding Characteristics research finds, levocetirizine (Xyzal) affinity to H1 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.In one that carries out in France random, double blinding, the research of placebo parallel control, 470 routine allergic rhinitis patients are divided into 4 groups at random, respectively oral hydrochloride levocetirizine 2.5mg, 5mg, 10mg and placebo, 2 weeks courses for the treatment of.Patient records the order of severity of previous 24h rhinitis every night, comprises sneeze, not autonomous watery nasal discharge, rhinocnesmus, ocular pruritis, nasal congestion symptom.Research display, levo-cetirizine hydrochloride group patient cardinal symptom is obviously improved, and except nasal congestion, all the other symptoms difference compared with placebo has significance (P=0.001).In addition, (except nasal congestion) than placebo more obviously (P=0.0001) on minimizing disease severity for levo-cetirizine hydrochloride tablets.Research also shows levo-cetirizine hydrochloride in dose-effect relationship, there is simple curve relation.Patient all can tolerate very well to all dosage of levo-cetirizine hydrochloride group, and adverse reaction rate is 10.2%, 5mg group in 10mg group is 1.7%, and each dosage group all occurs without serious adverse events.
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.
At present, in the research of Menglusitena hydrochloric acid levocetirizine compound preparation, factor both ways of mainly depositing blocks the development of compound preparation.On the one hand, Menglusitena is the moisture absorption very easily, and it is all unstable to meet light, wet, heat, oxygen and acid, and research finds, react after Menglusitena contacts with levo-cetirizine hydrochloride yellowing very soon, shows to there is incompatibility between Menglusitena and levo-cetirizine hydrochloride.On the other hand, Sugarless type pharmaceutical preparation is very important for diabetics, because mannitol does not have moisture absorption completely, and pleasantly sweet, glucose or sucrose can be replaced to use, and therefore mannitol shows stronger advantage as filler (or sweeting agent) in Sugarless type pharmaceutical preparation.But mannitol and levo-cetirizine hydrochloride are very unstable under the high temperature conditions, the related substance of the levo-cetirizine hydrochloride pharmaceutical preparation that research finds containing mannitol obviously increases, show also there is incompatibility between mannitol and levo-cetirizine hydrochloride, when preparing containing levo-cetirizine hydrochloride pharmaceutical preparation, the use of mannitol need be limited.Up to the present, for the incompatibility problem between Menglusitena and levo-cetirizine hydrochloride, and the restriction of preferred adjuvant mannitol in sugarless type formulations uses, and is showed no effective solution.
Summary of the invention
In view of this, the invention provides a kind of particulate composition and preparation method thereof, preparation.This particulate composition adding by meglumine, solve the incompatibility problem between Menglusitena and levo-cetirizine hydrochloride, improve the stability of Menglusitena, and improve the stability of levo-cetirizine hydrochloride, the adjuvant that mannitol be can be used as in compound preparation uses; Adding by HP-β-CD, the stability of Menglusitena can be improved, reduce oxidation product and generate, improve the uniformity of active constituents of medicine.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides a kind of particulate composition, it comprises Menglusitena granule and levocetirizine dihydrochloride granule;
Menglusitena granule comprises Menglusitena, filler, stabilizing agent, binding agent;
Levocetirizine dihydrochloride granule comprises levo-cetirizine hydrochloride, filler, stabilizing agent, binding agent;
Stabilizing agent is meglumine;
Binding agent is HP-β-CD.
In the present invention, research proves that meglumine can make Menglusitena surrounding molecules keep alkalescence, eliminate the impact of levo-cetirizine hydrochloride on Menglusitena, improve the stability of Menglusitena, overcome the incompatibility between Menglusitena and levo-cetirizine hydrochloride; Effectively can improve the incompatible difficult point of levo-cetirizine hydrochloride and mannitol, give full play to the advantage of mannitol as adjuvant preferred in sugar-free preparation.
In the present invention, research proves that HP-β-CD effectively can improve the stability of Menglusitena, solves the difficult problem that in general preparation, Menglusitena oxidation product is too high; Improve the degree of scatter of Menglusitena, the uniformity of Menglusitena and stripping are all had and improves significantly; Effectively can improve the bitterness of levo-cetirizine hydrochloride; Mannitol compressibility is bad, and HP-β-CD can improve the compressibility of granule, makes the smooth tabletting of the granule of high mannitol content.
As preferably, with parts by weight, in particulate composition, Menglusitena granule comprises Menglusitena 0.5 ~ 5 part, filler 85 ~ 98 parts, stabilizing agent 0.1 ~ 1 part, binding agent 1 ~ 7.2 part;
Levocetirizine dihydrochloride granule comprises levo-cetirizine hydrochloride 0.1 ~ 5 part, filler 89.96 ~ 98 parts, stabilizing agent 0.1 ~ 2.9 part, binding agent 1 ~ 5 part;
The mass ratio of Menglusitena granule and levocetirizine dihydrochloride granule is (0.5 ~ 2): 1.
Preferably, with parts by weight, Menglusitena granule comprises Menglusitena 0.8 ~ 3.6 part, filler 89.1 ~ 97 parts, stabilizing agent 0.14 ~ 0.2 part, binding agent 2 ~ 7.2 parts;
Levocetirizine dihydrochloride granule comprises levo-cetirizine hydrochloride 0.5 ~ 3.6 part, filler 89.96 ~ 97.1 parts, stabilizing agent 0.4 ~ 2.9 part, binding agent 2 ~ 3.6 parts;
The mass ratio of Menglusitena granule and levocetirizine dihydrochloride granule is (0.99 ~ 1.04): 1.
In embodiments more provided by the invention, with parts by weight, in particulate composition, Menglusitena granule comprises Menglusitena 0.8 part, filler 97 parts, stabilizing agent 0.2 part, binding agent 2 parts;
Levocetirizine dihydrochloride granule comprises levo-cetirizine hydrochloride 0.5 part, filler 97.1 parts, stabilizing agent 0.4 part, binding agent 2 parts;
The mass ratio of Menglusitena granule and levocetirizine dihydrochloride granule is 1:1.
In other embodiments provided by the invention, with parts by weight, in particulate composition, Menglusitena granule comprises Menglusitena 3.6 parts, filler 89.1 parts, stabilizing agent 0.14 part, binding agent 7.2 parts;
Levocetirizine dihydrochloride granule comprises levo-cetirizine hydrochloride 3.6 parts, filler 89.96 parts, stabilizing agent 2.9 parts, binding agent 3.6 parts;
The mass ratio of Menglusitena granule and levocetirizine dihydrochloride granule is 0.99:1.
Filler refers to the material accounting for preparation major part on volume, as mannitol, starch, microcrystalline cellulose, sorbitol etc.As preferably, the filler in the present invention is a kind of or both the above mixture in mannitol, lactose or microcrystalline Cellulose.
In embodiments more provided by the invention, filler is mannitol, and mannitol mouthfeel is good, can improve patient's medication compliance.
Present invention also offers the preparation method of this particulate composition, comprise the steps:
Getting Menglusitena, stabilizing agent, binding agent, filler mix with water, obtain montelukast sodium solution, through granulating, dry, granulate, obtaining Menglusitena granule;
Getting levo-cetirizine hydrochloride, stabilizing agent, binding agent, filler mix with water, obtain levo-cetirizine hydrochloride solution, through granulating, dry, granulate, obtaining levocetirizine dihydrochloride granule;
Get Menglusitena granule to mix with levocetirizine dihydrochloride granule, to obtain final product;
Stabilizing agent is meglumine;
Binding agent is HP-β-CD.
In the preparation method of particulate composition, as preferably, in montelukast sodium solution, the mass ratio of Menglusitena, filler, stabilizing agent, binding agent and water is (0.5 ~ 5): (85 ~ 98): (0.1 ~ 1): (1 ~ 7.2): (8 ~ 17.2);
In described levo-cetirizine hydrochloride solution, the mass ratio of levo-cetirizine hydrochloride, filler, stabilizing agent, binding agent and water is (0.1 ~ 5): (89.96 ~ 98): (0.1 ~ 2.9): (1 ~ 5): (5 ~ 15);
The mass ratio of Menglusitena granule and levocetirizine dihydrochloride granule is (0.5 ~ 2): 1.
In the preparation method of particulate composition, preferably, in montelukast sodium solution, the mass ratio of Menglusitena, filler, stabilizing agent, binding agent and water is (0.8 ~ 3.6): (89.1 ~ 97): (0.14 ~ 0.2): (2 ~ 7.2): (8 ~ 17.2);
In levo-cetirizine hydrochloride solution, the mass ratio of levo-cetirizine hydrochloride, filler, stabilizing agent, binding agent and water is (0.5 ~ 3.6): (89.96 ~ 97.1): (0.4 ~ 2.9): (2 ~ 3.6): (7.0 ~ 7.2);
The mass ratio of Menglusitena granule and levocetirizine dihydrochloride granule is (0.99 ~ 1.04): 1.
In embodiments more provided by the invention, in montelukast sodium solution, the mass ratio of Menglusitena, filler, stabilizing agent, binding agent and water is 0.8:97:0.2:2:8;
In levo-cetirizine hydrochloride solution, the mass ratio of levo-cetirizine hydrochloride, filler, stabilizing agent, binding agent and water is 0.5:97.1:0.4:2:7;
The mass ratio of Menglusitena granule and levocetirizine dihydrochloride granule is 1:1.
In other embodiments provided by the invention, with parts by weight, montelukast sodium solution comprises Menglusitena 3.6 parts, filler 89.1 parts, stabilizing agent 0.14 part, binding agent 7.2 parts, 17.2 parts, water;
Levo-cetirizine hydrochloride solution comprises levo-cetirizine hydrochloride 3.6 parts, filler 89.96 parts, stabilizing agent 2.9 parts, binding agent 3.6 parts, 7.2 parts, water;
The mass ratio of Menglusitena granule and levocetirizine dihydrochloride granule is 0.99:1.
In preparation method embodiments more provided by the invention, filler is a kind of or both the above mixture in mannitol, lactose or microcrystalline Cellulose.
Present invention also offers a kind of compound preparation, it comprises particulate composition provided by the invention and pharmaceutically acceptable adjuvant composition.
Preparation provided by the invention is oral formulations, and in embodiments more provided by the invention, the dosage form of compound preparation is granule or tablet.But those skilled in the art think that feasible oral formulations is all within protection scope of the present invention, and oral formulations kind is not limited thereto, and the present invention does not limit at this.
In embodiments more provided by the invention, when the dosage form of compound preparation is granule, on granule Chinese materia medica, acceptable adjuvant is lubricant.
Lubricant refers to and can reduce granule or the adjuvant of frictional force between tablet and die wall, makes tabletting difficulty to prevent frictional force large; When lubricant can make tabletting, pressure distribution is even, and makes the even density of tablet; Tablet is reduced by releasing required power in nib.In embodiments more provided by the invention, lubricant is magnesium stearate.But those skilled in the art think that feasible lubricant is all within protection scope of the present invention, and lubricant kind is not limited thereto, and the present invention does not limit at this.
As preferably, the mass ratio of the particulate composition in granule and pharmaceutically acceptable adjuvant is (99 ~ 99.9): (0.1 ~ 1).
In embodiments more provided by the invention, particulate composition and the obtained granule of pharmaceutically acceptable adjuvant (i.e. lubricant).In granule, the mass ratio of particulate composition and pharmaceutically acceptable adjuvant is 800:1.
In embodiments more provided by the invention, when the dosage form of compound preparation is tablet, on tablet Chinese materia medica, acceptable adjuvant is the mixture of sweeting agent, disintegrating agent, essence, pigment and lubricant.Sweeting agent, essence can improve the mouthfeel of medicine, improve the compliance of patient; Disintegrating agent can improve the dissolution rate of medicine; Pigment can improve the outward appearance of medicine; Lubricant can reduce frictional force, makes tabletting smooth.
As preferably, the mass ratio of particulate composition and pharmaceutically acceptable adjuvant is (90 ~ 99): (1 ~ 10).
In embodiments more provided by the invention, particulate composition and the obtained chewable tablet of pharmaceutically acceptable adjuvant (comprising sweeting agent, disintegrating agent, essence, pigment, lubricant).In chewable tablet, the mass ratio of particulate composition and pharmaceutically acceptable adjuvant is 18.7:1.
As preferably, in pharmaceutically acceptable adjuvant, the mass ratio of sweeting agent, disintegrating agent, essence, pigment and lubricant is (0.1 ~ 1): (0.5 ~ 6): (0.01 ~ 0.5): (0.1 ~ 1): (0.1 ~ 2).
In embodiments more provided by the invention, in pharmaceutically acceptable adjuvant, the mass ratio of sweeting agent, disintegrating agent, essence, pigment and lubricant is 1:4.5:0.25:0.25:1.6.
In embodiments more provided by the invention, sweeting agent is sucralose.But those skilled in the art think that feasible sweeting agent is all within protection scope of the present invention, and sweeting agent kind is not limited thereto, and the present invention does not limit at this.
In embodiments more provided by the invention, disintegrating agent is carboxymethylstach sodium, hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose are received, a kind of or both above mixture in crosslinked carboxymethyl fecula sodium.But those skilled in the art think that feasible disintegrating agent is all within protection scope of the present invention, and disintegrating agent kind is not limited thereto, and the present invention does not limit at this.
Add in the feed postition of disintegrating agent can be selected from, any one mode in additional, interior additional three kinds of modes, the present invention does not limit at this.
In embodiments more provided by the invention, essence is cherry essence.But those skilled in the art think that feasible essence is all within protection scope of the present invention, and essence kind is not limited thereto, and the present invention does not limit at this.
In embodiments more provided by the invention, pigment is red ferric oxide.But those skilled in the art think that feasible pigment is all within protection scope of the present invention, and kind of pigment is not limited thereto, and the present invention does not limit at this.
In embodiments more provided by the invention, lubricant is magnesium stearate.But those skilled in the art think that feasible lubricant is all within protection scope of the present invention, and lubricant kind is not limited thereto, and the present invention does not limit at this.
The invention provides a kind of particulate composition and preparation method thereof, preparation.This particulate composition comprises Menglusitena granule and levocetirizine dihydrochloride granule; Menglusitena granule comprises Menglusitena, filler, stabilizing agent, binding agent; Levocetirizine dihydrochloride granule comprises levo-cetirizine hydrochloride, filler, stabilizing agent, binding agent; Stabilizing agent is meglumine; Binding agent is HP-β-CD.By Stability Determination test under acceleration conditions, result shows particulate composition provided by the invention and preparation of Chinese medicine active component its related substances has increased slightly or do not increase, and its related substances increasing degree of reference preparation is comparatively large, show that preparation nature provided by the invention is stablized; By the Stability Determination test under long-term conditions, result shows the every inspection target of preparation provided by the invention does not all have significant change, in Menglusitena granule reference preparation determination of related substances, impurity increases to some extent, shows that preparation stability provided by the invention is good; Research shows that pharmaceutical formulation of the present invention solves the incompatibility problem between Menglusitena and levo-cetirizine hydrochloride further, improve the stability of Menglusitena, make Menglusitena no longer variable color, and improve the stability of levo-cetirizine hydrochloride, the adjuvant that mannitol be can be used as in compound preparation uses; By dissolution test measurement result, known preparation provided by the invention is placed after 10 days at 60 DEG C, and result of extraction is not also almost affected, and shows that the dissolution of particulate composition provided by the invention and preparation thereof is not subject to the impact of hot conditions; Menglusitena and levo-cetirizine hydrochloride are dissolved in binder solution respectively and carry out wet granulation, and active constituents of medicine uniformity of dosage units is greatly improved.As can be seen here, particulate composition provided by the invention and preparation nature thereof are stablized, and improve the uniformity of dosage units of two kinds of active constituents of medicine, and drug quality meets national standard completely.
Accompanying drawing explanation
The Dissolution profiles of Menglusitena when Fig. 1 shows that granule that embodiment 7 provides places 0 day;
The Dissolution profiles of Menglusitena when Fig. 2 shows that granule that embodiment 7 provides places 10 days at 60 DEG C;
Fig. 3 shows the Dissolution profiles of commercially available reference preparation Singulair;
The Dissolution profiles of levo-cetirizine hydrochloride when Fig. 4 shows that granule that embodiment 7 provides places 0 day;
The Dissolution profiles of levo-cetirizine hydrochloride when Fig. 5 shows that granule that embodiment 7 provides places 10 days at 60 DEG C.
Detailed description of the invention
The invention discloses a kind of particulate composition and preparation method thereof, preparation, 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 particulate composition provided by the invention and preparation method thereof, preparation, 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 particulate composition
The prescription of particulate composition is as shown in table 1.
The prescription of table 1 particulate composition
The preparation of Menglusitena granule: add purified water in stainless steel cask, adds meglumine and is stirred to dissolving; Continue to stir and add HP-β-CD to dissolving, finally adding Menglusitena and be stirred to dissolving, obtain the first binder solution, for subsequent use.Mannitol is crossed 26 mesh sieves and is placed in wet granulator; the first binder solution prepared is placed in wet granulator; soft material processed; soft material is crossed 26 mesh sieves and is granulated; 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes, continued to be dried to loss on drying≤2.0%(IR90 DEG C, dry 10 minutes); cross 26 mesh sieve granulate, obtain Menglusitena granule.
The preparation of levocetirizine dihydrochloride granule: add purified water in stainless steel cask, adds HP-β-CD and is stirred to dissolving; Continue to stir and add levo-cetirizine hydrochloride to dissolving; Finally add meglumine and be stirred to dissolving, obtain the second binder solution, for subsequent use.Mannitol is crossed 26 mesh sieves and is placed in wet granulator; the second binder solution prepared is placed in wet granulator; soft material processed; soft material is crossed 26 mesh sieves and is granulated; 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes, continued to be dried to loss on drying≤2.0%[infrared moisture meter (IR) 90 DEG C, dry 10 minutes]; cross 26 mesh sieve granulate, obtain levocetirizine dihydrochloride granule.
Menglusitena granule is mixed 60 minutes with levocetirizine dihydrochloride granule in mixer, to obtain final product.
The preparation of embodiment 2 particulate composition
The prescription of particulate composition is as shown in table 2.
The prescription of table 2 particulate composition
The preparation of Menglusitena granule: add purified water in stainless steel cask, adds meglumine and is stirred to dissolving; Continue to stir and add HP-β-CD to dissolving, finally adding Menglusitena and be stirred to dissolving, obtain the first binder solution, for subsequent use.Mannitol, MCC cross 26 mesh sieves respectively; mix homogeneously is placed in wet granulator; the first binder solution prepared is placed in wet granulator; soft material processed, soft material is crossed 26 mesh sieves and is granulated, and 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes; continue to be dried to loss on drying≤2.0%(IR90 DEG C; dry 10 minutes), cross 26 mesh sieve granulate, obtain Menglusitena granule.
The preparation of levocetirizine dihydrochloride granule: add purified water in stainless steel cask, adds HP-β-CD and is stirred to dissolving; Continue to stir and add levo-cetirizine hydrochloride to dissolving; Finally add meglumine and be stirred to dissolving, obtain the second binder solution, for subsequent use.Mannitol, MCC cross 26 mesh sieves respectively; mix homogeneously is placed in wet granulator; the second binder solution prepared is placed in wet granulator; soft material processed, soft material is crossed 26 mesh sieves and is granulated, and 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes; continue to be dried to loss on drying≤2.0%(IR90 DEG C; dry 10 minutes), cross 26 mesh sieve granulate, obtain levocetirizine dihydrochloride granule.
Menglusitena granule is mixed 60 minutes with levocetirizine dihydrochloride granule in mixer, to obtain final product.
The preparation of embodiment 3 particulate composition
The prescription of particulate composition is as shown in table 3.
The prescription of table 3 particulate composition
The preparation of Menglusitena granule: add purified water in stainless steel cask, adds meglumine and is stirred to dissolving; Continue to stir and add HP-β-CD to dissolving, finally adding Menglusitena and be stirred to dissolving, obtain the first binder solution, for subsequent use.Mannitol is crossed 26 mesh sieves and is placed in wet granulator; the first binder solution prepared is placed in wet granulator; soft material processed; soft material is crossed 26 mesh sieves and is granulated; 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes, continued to be dried to loss on drying≤2.0%(IR90 DEG C, dry 10 minutes); cross 26 mesh sieve granulate, obtain Menglusitena granule.
The preparation of levocetirizine dihydrochloride granule: add purified water in stainless steel cask, adds HP-β-CD and is stirred to dissolving; Continue to stir and add levo-cetirizine hydrochloride to dissolving; Finally add meglumine and be stirred to dissolving, obtain the second binder solution, for subsequent use.Mannitol is crossed 26 mesh sieves and is placed in wet granulator; the second binder solution prepared is placed in wet granulator; soft material processed; soft material is crossed 26 mesh sieves and is granulated; 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes, continued to be dried to loss on drying≤2.0%(IR90 DEG C, dry 10 minutes); cross 26 mesh sieve granulate, obtain levocetirizine dihydrochloride granule.
Menglusitena granule is mixed 60 minutes with levocetirizine dihydrochloride granule in mixer, to obtain final product.
The preparation of embodiment 4 particulate composition
The prescription of particulate composition is as shown in table 4.
The prescription of table 4 particulate composition
The preparation of Menglusitena granule: add purified water in stainless steel cask, adds meglumine and is stirred to dissolving; Continue to stir and add HP-β-CD to dissolving, finally adding Menglusitena and be stirred to dissolving, obtain the first binder solution, for subsequent use.Mannitol, lactose cross 26 mesh sieves respectively; mix homogeneously is placed in wet granulator; the first binder solution prepared is placed in wet granulator; soft material processed, soft material is crossed 26 mesh sieves and is granulated, and 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes; continue to be dried to loss on drying≤2.0%(IR90 DEG C; dry 10 minutes), cross 26 mesh sieve granulate, obtain Menglusitena granule.
The preparation of levocetirizine dihydrochloride granule: add purified water in stainless steel cask, adds HP-β-CD and is stirred to dissolving; Continue to stir and add levo-cetirizine hydrochloride to dissolving; Finally add meglumine and be stirred to dissolving, obtain the second binder solution, for subsequent use.Mannitol, lactose cross 26 mesh sieves respectively; mix homogeneously is placed in wet granulator; the second binder solution prepared is placed in wet granulator; soft material processed, soft material is crossed 26 mesh sieves and is granulated, and 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes; continue to be dried to loss on drying≤2.0%(IR90 DEG C; dry 10 minutes), cross 26 mesh sieve granulate, obtain levocetirizine dihydrochloride granule.
Menglusitena granule is mixed 60 minutes with levocetirizine dihydrochloride granule in mixer, to obtain final product.
The preparation of embodiment 5 particulate composition
The prescription of particulate composition is as shown in table 5.
The prescription of table 5 particulate composition
The preparation of Menglusitena granule: add purified water in stainless steel cask, adds meglumine and is stirred to dissolving; Continue to stir and add HP-β-CD to dissolving, finally adding Menglusitena and be stirred to dissolving, obtain the first binder solution, for subsequent use.Mannitol is crossed 26 mesh sieves and is placed in wet granulator; the first binder solution prepared is placed in wet granulator; soft material processed; soft material is crossed 26 mesh sieves and is granulated; 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes, continued to be dried to loss on drying≤2.0%(IR90 DEG C, dry 10 minutes); cross 26 mesh sieve granulate, obtain Menglusitena granule.
The preparation of levocetirizine dihydrochloride granule: add purified water in stainless steel cask, adds HP-β-CD and is stirred to dissolving; Continue to stir and add levo-cetirizine hydrochloride to dissolving; Finally add meglumine and be stirred to dissolving, obtain the second binder solution, for subsequent use.Mannitol is crossed 26 mesh sieves and is placed in wet granulator; the second binder solution prepared is placed in wet granulator; soft material processed; soft material is crossed 26 mesh sieves and is granulated; 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes, continued to be dried to loss on drying≤2.0%[infrared moisture meter (IR) 90 DEG C, dry 10 minutes]; cross 26 mesh sieve granulate, obtain levocetirizine dihydrochloride granule.
Menglusitena granule is mixed 60 minutes with levocetirizine dihydrochloride granule in mixer, to obtain final product.
The preparation of embodiment 6 particulate composition
The prescription of particulate composition is as shown in table 6.
The prescription of table 6 particulate composition
The preparation of Menglusitena granule: add purified water in stainless steel cask, adds meglumine and is stirred to dissolving; Continue to stir and add HP-β-CD to dissolving, finally adding Menglusitena and be stirred to dissolving, obtain the first binder solution, for subsequent use.Mannitol, MCC cross 26 mesh sieves respectively; mix homogeneously is placed in wet granulator; the first binder solution prepared is placed in wet granulator; soft material processed, soft material is crossed 26 mesh sieves and is granulated, and 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes; continue to be dried to loss on drying≤2.0%(IR90 DEG C; dry 10 minutes), cross 26 mesh sieve granulate, obtain Menglusitena granule.
The preparation of levocetirizine dihydrochloride granule: add purified water in stainless steel cask, adds HP-β-CD and is stirred to dissolving; Continue to stir and add levo-cetirizine hydrochloride to dissolving; Finally add meglumine and be stirred to dissolving, obtain the second binder solution, for subsequent use.Mannitol, MCC cross 26 mesh sieves respectively; mix homogeneously is placed in wet granulator; the second binder solution prepared is placed in wet granulator; soft material processed, soft material is crossed 26 mesh sieves and is granulated, and 45 DEG C of dryings crossed 26 mesh sieve granulate after 15 minutes; continue to be dried to loss on drying≤2.0%(IR90 DEG C; dry 10 minutes), cross 26 mesh sieve granulate, obtain levocetirizine dihydrochloride granule.
Menglusitena granule is mixed 60 minutes with levocetirizine dihydrochloride granule in mixer, to obtain final product.
The preparation of embodiment 7 granule
The prescription of granule is as shown in table 7.
The prescription of table 7 granule
| Kind | Supplementary material title | Recipe quantity (g/3 ten thousand bags) |
| Particulate composition | The particulate composition that embodiment 1 is obtained | 30000 |
| Lubricant | Magnesium stearate | 37.5 |
The particulate composition that Example 1 obtains mixes 5 minutes with magnesium stearate in mixer, and after qualified to empty bag air-tightness confirmation, start fill, loading amount 1g/ bag, obtains granule.
The preparation of embodiment 8 chewable tablet
The prescription of chewable tablet is as shown in table 8.
The prescription of table 8 chewable tablet
| Kind | Supplementary material title | Recipe quantity (g/10 ten thousand) |
| Particulate composition | The particulate composition that embodiment 2 is obtained | 28480 |
| Sweeting agent | Sucralose | 200 |
| Disintegrating agent | Carboxymethylstach sodium | 900 |
| Essence | Cherry essence | 50 |
| Pigment | Red ferric oxide | 50 |
| Lubricant | Magnesium stearate | 320 |
The particulate composition that Example 2 obtains mixes 5 minutes with sucralose, carboxymethylstach sodium, cherry essence, red ferric oxide, magnesium stearate, tabletting in mixer, obtains chewable tablet.
The preparation of embodiment 9 granule
The prescription of granule is as shown in table 9.
The prescription of table 9 granule
| Kind | Supplementary material title | Recipe quantity (g) |
| Particulate composition | The particulate composition that embodiment 3 is obtained | 17960 |
| Lubricant | Magnesium stearate | 18 |
The particulate composition that Example 3 obtains mixes 5 minutes with magnesium stearate in mixer, and after qualified to empty bag air-tightness confirmation, start fill, loading amount 1g/ bag, obtains granule.
The preparation of embodiment 10 chewable tablet
The prescription of chewable tablet is as shown in table 10.
The prescription of table 10 chewable tablet
| Kind | Supplementary material title | Recipe quantity (g) |
| Particulate composition | The particulate composition that embodiment 4 is obtained | 20820 |
| Sweeting agent | Sucralose | 34 |
| Disintegrating agent | Hydroxypropyl cellulose | 2041 |
| Essence | Cherry essence | 170 |
| Pigment | Red ferric oxide | 34 |
| Lubricant | Magnesium stearate | 34 |
The particulate composition that Example 4 obtains mixes 5 minutes with sucralose, hydroxypropyl cellulose, cherry essence, red ferric oxide, magnesium stearate, tabletting in mixer, obtains chewable tablet.
The preparation of embodiment 11 granule
The prescription of granule is as shown in table 11.
The prescription of table 11 granule
| Kind | Supplementary material title | Recipe quantity (g) |
| Particulate composition | The particulate composition that embodiment 5 is obtained | 30000 |
| Lubricant | Magnesium stearate | 303 |
The particulate composition that Example 5 obtains mixes 5 minutes with magnesium stearate in mixer, and after qualified to empty bag air-tightness confirmation, start fill, loading amount 1g/ bag, obtains granule.
The preparation of embodiment 12 chewable tablet
The prescription of chewable tablet is as shown in table 12.
The prescription of table 12 chewable tablet
| Kind | Supplementary material title | Recipe quantity (g) |
| Particulate composition | The particulate composition that embodiment 6 is obtained | 28480 |
| Sweeting agent | Sucralose | 36 |
| Disintegrating agent | Polyvinylpolypyrrolidone | 36 |
| Essence | Cherry essence | 0.7 |
| Pigment | Red ferric oxide | 72 |
| Lubricant | Magnesium stearate | 143.3 |
The particulate composition that Example 6 obtains mixes 5 minutes with sucralose, polyvinylpolypyrrolidone, cherry essence, red ferric oxide, magnesium stearate, tabletting in mixer, obtains chewable tablet.
Embodiment 13 accelerated test condition stability inferior is investigated
(derive from Mo Shadong drugmaker, commodity are called for granule (batch number: 20121101,20121102,20121103) and the commercially available Singulair of 3 lot numbers that Example 7 is obtained
lot number is 0000148425A, the reference preparation as Menglusitena related substance), carry out stability test.Stability test comprises accelerated test and long term test.Wherein, accelerated test is: temperature be 40 ± 2 DEG C, relative humidity be 75 ± 5%RH accelerated test condition under 6 months, measure the data such as the obtained granule of embodiment 7 and the right cetirizine content of the hydrochloric acid of reference preparation 0,1,2,3,6 month time, moisture, dissolution, sign content and related substance respectively, carry out study on the stability; Long term test is: (derive from Mo Shadong drugmaker, commodity are called for granule (batch number: 20121101,20121102,20121103) and the commercially available Singulair of 3 lot numbers that Example 7 is obtained
lot number is 0000148425A, the reference preparation as Menglusitena related substance) be housed in climatic chamber, control temperature and relative humidities are 25 ± 2 DEG C and 60 ± 10%RH, after 3,6 months sampling investigate and with 0 month data and trace analysis.Menglusitena part and reference preparation Singulair contrast, and levo-cetirizine hydrochloride part, because not having reference preparation, contrasts with self 0 day data.
Moisture measures with reference to aquametry (Chinese Pharmacopoeia version in 2010 two annex VIII M first method A).The right cetirizine of assay, related substance, hydrochloric acid and dissolution all adopt HPLC method to measure.Microbial limit detection method is improved according to " Chinese Pharmacopoeia " version in 2010 two annex microbial limit test.
Menglusitena related substance detection method: lucifuge operates, the granule 2500mg that Example 7 is obtained, add in 10mL volumetric flask, montelukast na concn is 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 13 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 10mg, 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.
Levo-cetirizine hydrochloride related substance detection method: lucifuge operates, the granule 1000mg that Example 7 is obtained, put in 10mL measuring bottle, solubilizer [water-acetonitrile (58:42)] is appropriate, ultrasonic 10 minutes, 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 related substance 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 C185 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 14 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 12.5mg and add acetonitrile-water (58:42) to 50ml, be mixed with the solution of 0.25mg/mL, get this solution 2mL, each related substance 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 about 0.9,1.1 and 3.8 respectively, 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 about 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.
Menglusitena content assaying method: lucifuge operates, the granule 250mg that Example 7 is obtained, 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 15 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 16 program; Concrete operation method: the granule 1000mg that Example 7 is obtained, be equivalent to levo-cetirizine hydrochloride 2.5mg, be placed in 25mL measuring bottle, solubilizer [water-acetonitrile (58:42)] ultrasonic 10 minutes in right amount, is diluted to scale, shakes up, filter, precision measures subsequent filtrate 20 μ L, injection liquid chromatography, record chromatogram; Separately get levo-cetirizine hydrochloride reference substance 12.5mg to 50ml volumetric flask, 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.
Microbial limit detection method: asepticly take the obtained granule 10g of embodiment 7, add pH7.0 sterile NaCl-peptone buffer agent containing 0.3% Ovum Gallus domesticus Flavus lecithin and 3% polyoxyethylene sorbitan monoleate to 100mL, jolting is uniformly dispersed to test sample, makes 1:10 test liquid.Bacteria fungi and yeasts count, gets the average dispensing of 1:10 test liquid 1.0mL in 2 plates, every ware 0.5mL, checks (Chinese Pharmacopoeia 2010 editions second annex XI J) in accordance with the law.Escherichia coli checks, gets 1:10 test liquid 10mL, adds in cholate lactose medium 100mL, checks (Chinese Pharmacopoeia 2010 editions second annex XI J) in accordance with the law.Examination criteria is: in 1g test sample, and bacterial population must not more than 1000CFU, and mycete, yeast count must not more than 100CFU, and escherichia coli must not detect.
Accelerated test result is as shown in table 17, table 18, and long-term test results is as shown in table 19, table 20.
Table 13 Menglusitena related substance detects 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 |
Table 14 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 |
| 55 | 20 | 80 |
| 55.1 | 58 | 42 |
| 60 | 58 | 42 |
Table 15 Menglusitena content detection elution program
| Time (minute) | 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 |
Table 16 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 |
Table 17 accelerated test measurement result (40 ± 2 DEG C, 75 ± 5%RH)
Table 18 accelerated test determination of related substances result (40 ± 2 DEG C, 75 ± 5%RH)
Note: ND represents and does not detect.
Table 19 long term test measurement result (25 ± 2 DEG C, 60 ± 5%RH)
Table 20 long term test determination of related substances result (25 ± 2 DEG C, 60 ± 5%RH)
Note: ND represents and does not detect.
From the result of the test of table 17, table 18, through the acceleration environment study on the stability of 6 months, result shows, and in Menglusitena related substance, sulfoxide impurity and total impurities have increased slightly; In levo-cetirizine hydrochloride related substance, maximum single unknown impuritie and total impurities increase to some extent; Other inspection items have no significant change.And reference preparation Singulair (
) sulfoxide impurity and total impurities increasing degree are comparatively large in determination of related substances, content and dissolution have no significant change.Result shows, the granule stable in properties that the embodiment of the present invention 7 provides.
From the result of the test of table 19, table 20, through the long-term conditions study on the stability of 6 months, result shows, and in all investigation projects, the every inspection target of the granule that embodiment 7 provides all does not have significant change, Menglusitena granule reference preparation Singulair (
) impurity increases to some extent in determination of related substances, content and dissolution have no significant change.Result shows, having good stability of the granule that the embodiment of the present invention 7 provides.
The preparation that Example 8 to 12 is obtained, carries out accelerating and long-term study on the stability, and the determination data of the granule that result and embodiment 7 obtain is close, shows that the preparation nature that embodiment 8 to 12 obtains is stablized.
As can be seen here, compound preparation stable in properties provided by the invention, can overcome the incompatibility between Menglusitena and levo-cetirizine hydrochloride, also can overcome the incompatibility between mannitol and levo-cetirizine hydrochloride.
Embodiment 14 accelerated test condition stability inferior is investigated
The chewable tablet that the granule that Example 7 obtains, embodiment 8 obtain is placed 10 days respectively at 60 DEG C, measures its related substances, carries out study on the stability.Result is as shown in table 21, table 22, table 23, table 24.
Menglusitena determination of related substances result in the granule that table 21 embodiment 7 is obtained
Levo-cetirizine hydrochloride determination of related substances result in the granule that table 22 embodiment 7 is obtained
| Impurity | Parachlorophenol | Chlorodiphenyl methanol | Histantin | Unknown impuritie | Total impurities |
| Standard (%) | 0.5 | 0.5 | 0.5 | 0.5 | 1.0 |
| 0 day | Do not detect | Do not detect | Do not detect | 0.193 | 0.357 |
| Place 10 days for 60 DEG C | Do not detect | Do not detect | Do not detect | 0.335 | 0.695 |
Menglusitena determination of related substances result in the chewable tablet that table 23 embodiment 8 is obtained
Levo-cetirizine hydrochloride determination of related substances result in the chewable tablet that table 24 embodiment 8 is obtained
| Impurity | Parachlorophenol | Chlorodiphenyl methanol | Histantin | Unknown impuritie | Total impurities |
| Standard (%) | 0.5 | 0.5 | 0.5 | 0.5 | 1.0 |
| 0 day | Do not detect | Do not detect | Do not detect | 0.087 | 0.087 |
| Place 10 days for 60 DEG C | Do not detect | Do not detect | Do not detect | 0.127 | 0.671 |
As shown in Table 21, in the granule that result display embodiment 7 provides, Menglusitena composition is highly stable under the high temperature conditions, and related substance does not increase substantially, and drug quality meets national standard completely; As shown in Table 22, in the granule that result display embodiment 7 provides, levo-cetirizine hydrochloride composition is highly stable under the high temperature conditions, and related substance trace increases, and drug quality meets national standard completely.As can be seen here, the granule stable in properties that embodiment 7 provides, drug quality meets national standard completely.
As shown in Table 23, in the chewable tablet that result display embodiment 8 provides, Menglusitena related substance trace increases, and drug quality meets national standard completely; As shown in Table 24, in the chewable tablet that result display embodiment 8 provides, levo-cetirizine hydrochloride related substance trace increases, and drug quality meets national standard completely.As can be seen here, the chewable tablet stable in properties that embodiment 8 provides, drug quality meets national standard completely.
The preparation that Example 9 to 12 is obtained, carries out study on the stability, and the determination data of the preparation that result and embodiment 7,8 obtain is close, shows that the preparation nature that embodiment 9 to 12 obtains is stablized.
As can be seen here, compound preparation stable in properties provided by the invention, can overcome the incompatibility between Menglusitena and levo-cetirizine hydrochloride, also can overcome the incompatibility between mannitol and levo-cetirizine hydrochloride.
Embodiment 15 dissolution test
The granule that Example 7 obtains is placed 10 days at 60 DEG C, and then [derive from Mo Shadong drugmaker, commodity are called with commercially available Singulair
lot number is 0000148425A, reference preparation as Menglusitena dissolution (stripping quantity)] carry out dissolution test, obtain the dissolution of Menglusitena and levo-cetirizine hydrochloride when the obtained granule of embodiment 7 places 0 day, 10 days, and the dissolution of Singulair.Dissolution determination method measures with reference to the paddle method in Chinese Pharmacopoeia version in 2010 two annex XC second methods, and wherein, Menglusitena leaching condition is: 0.5%SDS aqueous solution: 5.0g SDS is dissolved in water and is diluted to 1000mL, shakes up, and to obtain final product; Medium volume: 900mL; Device: paddle method; Rotating speed: 50 turns; Medium temperature: 37 DEG C; Sample time: 5,10,15,30,45,60min.Levo-cetirizine hydrochloride leaching condition is: dissolution medium: water; Medium volume: 900mL; Device: paddle method; Rotating speed: 50 turns; Medium temperature: 37 DEG C; Sample time: 5,10,15,30,45,60min.
Result of the test is as shown in Fig. 1 to Fig. 5, table 25, table 26, and wherein, the test data of Fig. 1 to Fig. 3 is in table 25, and the test data of Fig. 4, Fig. 5 is in table 26.
Table 25 Menglusitena dissolution (%) measurement result
Table 26 levo-cetirizine hydrochloride dissolution (%) measurement result
From Fig. 1 to Fig. 3, table 25, have almost no change when the obtained granule of embodiment 7 places the dissolution of Menglusitena after 10 days and 0 day at 60 DEG C, similar to the dissolution of reference preparation Singulair.From Fig. 4, Fig. 5, table 26, have almost no change when the obtained granule of embodiment 7 places the dissolution of levo-cetirizine hydrochloride after 10 days and 0 day at 60 DEG C.It can thus be appreciated that after the granule that embodiment 7 obtains places 10 days under the high temperature conditions, result of extraction is not almost affected, and the dissolution can knowing the particulate composition that embodiment 1 provides by inference is not subject to the impact of hot conditions.
The preparation that Example 8 to 12 obtains carries out dissolution test, the stripping result of the granule that result and embodiment 7 provide is close, after showing that the obtained preparation of embodiment 8 to 12 places 10 days under the high temperature conditions, result of extraction is not also almost affected, and the dissolution can knowing the particulate composition that embodiment 2 to 6 provides by inference is not subject to the impact of hot conditions.
As can be seen here, the dissolution of particulate composition provided by the invention and preparation thereof is not subject to the impact of hot conditions.
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 (9)
1. a particulate composition, is characterized in that, it comprises Menglusitena granule and levocetirizine dihydrochloride granule;
Described Menglusitena granule comprises Menglusitena, filler, stabilizing agent, binding agent;
Described levocetirizine dihydrochloride granule comprises levo-cetirizine hydrochloride, filler, stabilizing agent, binding agent;
Described stabilizing agent is meglumine;
Described binding agent is HP-β-CD.
2. particulate composition according to claim 1, is characterized in that, with parts by weight, described Menglusitena granule comprises Menglusitena 0.5 ~ 5 part, filler 85 ~ 98 parts, stabilizing agent 0.1 ~ 1 part, binding agent 1 ~ 7.2 part;
Described levocetirizine dihydrochloride granule comprises levo-cetirizine hydrochloride 0.1 ~ 5 part, filler 89.96 ~ 98 parts, stabilizing agent 0.1 ~ 2.9 part, binding agent 1 ~ 5 part;
The mass ratio of described Menglusitena granule and described levocetirizine dihydrochloride granule is (0.5 ~ 2): 1.
3. particulate composition according to claim 1, is characterized in that, described filler is a kind of or both the above mixture in mannitol, lactose or microcrystalline Cellulose.
4. a preparation method for particulate composition as claimed any one in claims 1 to 3, is characterized in that, comprises the steps:
Getting Menglusitena, stabilizing agent, binding agent, filler mix with water, obtain montelukast sodium solution, through granulating, dry, granulate, obtaining Menglusitena granule;
Getting levo-cetirizine hydrochloride, stabilizing agent, binding agent, filler mix with water, obtain levo-cetirizine hydrochloride solution, through granulating, dry, granulate, obtaining levocetirizine dihydrochloride granule;
Get described Menglusitena granule to mix with described levocetirizine dihydrochloride granule, to obtain final product;
Described stabilizing agent is meglumine;
Described binding agent is HP-β-CD.
5. preparation method according to claim 4, it is characterized in that, with parts by weight, in described montelukast sodium solution, the mass ratio of Menglusitena, filler, stabilizing agent, binding agent and water is (0.5 ~ 5): (85 ~ 98): (0.1 ~ 1): (1 ~ 7.2): (8 ~ 17.2);
In described levo-cetirizine hydrochloride solution, the mass ratio of levo-cetirizine hydrochloride, filler, stabilizing agent, binding agent and water is (0.1 ~ 5): (89.96 ~ 98): (0.1 ~ 2.9): (1 ~ 5): (5 ~ 15);
The mass ratio of described Menglusitena granule and described levocetirizine dihydrochloride granule is (0.5 ~ 2): 1.
6. a compound preparation, is characterized in that, it comprises particulate composition as claimed any one in claims 1 to 3 and pharmaceutically acceptable adjuvant composition.
7. compound preparation according to claim 6, is characterized in that, the dosage form of described compound preparation is granule or tablet.
8. compound preparation according to claim 6, is characterized in that, in described granule, described pharmaceutically acceptable adjuvant is lubricant.
9. compound preparation according to claim 6, is characterized in that, in described tablet, described pharmaceutically acceptable adjuvant is the mixture of sweeting agent, disintegrating agent, essence, pigment and lubricant.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310521523.6A CN104546851B (en) | 2013-10-29 | 2013-10-29 | A kind of particulate composition and preparation method thereof, preparation |
| PCT/CN2014/089649 WO2015062466A1 (en) | 2013-10-29 | 2014-10-28 | Particle composition, preparation method and formulation therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310521523.6A CN104546851B (en) | 2013-10-29 | 2013-10-29 | A kind of particulate composition and preparation method thereof, preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104546851A true CN104546851A (en) | 2015-04-29 |
| CN104546851B CN104546851B (en) | 2018-01-02 |
Family
ID=53003340
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310521523.6A Active CN104546851B (en) | 2013-10-29 | 2013-10-29 | A kind of particulate composition and preparation method thereof, preparation |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN104546851B (en) |
| WO (1) | WO2015062466A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193743A (en) * | 2015-11-05 | 2015-12-30 | 石家庄市华新药业有限责任公司 | Montelukast sodium granular preparation and preparation method thereof |
| CN109833302A (en) * | 2017-11-29 | 2019-06-04 | 扬子江药业集团有限公司 | A kind of stable Montelukast sodium chewable tablet and preparation method thereof |
| CN111110679A (en) * | 2018-10-31 | 2020-05-08 | 长春海悦药业股份有限公司 | Pharmaceutical composition containing montelukast sodium |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL3222279T3 (en) | 2016-03-21 | 2022-05-09 | Invest Bielany Spółka Z Ograniczoną Odpowiedzialnością | Oral pharmaceutical formulation of montelukast and levocetirizine and method for its production |
| EP3505172A1 (en) * | 2017-12-31 | 2019-07-03 | Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. | A pharmaceutical composition comprising montelukast and levocetirizine |
| WO2019197939A1 (en) * | 2018-04-11 | 2019-10-17 | Hetero Healthcare Limited | Taste masked mouth dissolving formulation of montelukast sodium and levocetirizine hydrochloride |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010021607A2 (en) * | 2008-08-22 | 2010-02-25 | Mahmut Bilgic | Pharmaceutical formulation |
| WO2010107404A1 (en) * | 2009-03-16 | 2010-09-23 | Mahmut Bilgic | Stable pharmaceutical combinations |
| CN102038645A (en) * | 2009-10-12 | 2011-05-04 | 杭州赛利药物研究所有限公司 | Desloratadine grain and preparation method thereof |
| CN102143737A (en) * | 2008-09-05 | 2011-08-03 | 麦克内尔-Ppc股份有限公司 | Method for making cetirizine tablets |
| CN102258531A (en) * | 2011-04-12 | 2011-11-30 | 宁辉 | Medicinal composition containing adenosine cyclophosphate and meglumine and preparation method thereof |
| CN102688238A (en) * | 2012-06-18 | 2012-09-26 | 重庆康刻尔制药有限公司 | Montelukast sodium combination drug granules for treating asthma, and application thereof |
-
2013
- 2013-10-29 CN CN201310521523.6A patent/CN104546851B/en active Active
-
2014
- 2014-10-28 WO PCT/CN2014/089649 patent/WO2015062466A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010021607A2 (en) * | 2008-08-22 | 2010-02-25 | Mahmut Bilgic | Pharmaceutical formulation |
| CN102143737A (en) * | 2008-09-05 | 2011-08-03 | 麦克内尔-Ppc股份有限公司 | Method for making cetirizine tablets |
| WO2010107404A1 (en) * | 2009-03-16 | 2010-09-23 | Mahmut Bilgic | Stable pharmaceutical combinations |
| CN102038645A (en) * | 2009-10-12 | 2011-05-04 | 杭州赛利药物研究所有限公司 | Desloratadine grain and preparation method thereof |
| CN102258531A (en) * | 2011-04-12 | 2011-11-30 | 宁辉 | Medicinal composition containing adenosine cyclophosphate and meglumine and preparation method thereof |
| CN102688238A (en) * | 2012-06-18 | 2012-09-26 | 重庆康刻尔制药有限公司 | Montelukast sodium combination drug granules for treating asthma, and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 罗明生等: "《药剂辅料大全》", 31 January 2006, 四川科学技术出版社 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193743A (en) * | 2015-11-05 | 2015-12-30 | 石家庄市华新药业有限责任公司 | Montelukast sodium granular preparation and preparation method thereof |
| CN105193743B (en) * | 2015-11-05 | 2018-05-08 | 石家庄市华新药业有限责任公司 | A kind of Montelukast Sodium granular preparation and preparation method thereof |
| CN109833302A (en) * | 2017-11-29 | 2019-06-04 | 扬子江药业集团有限公司 | A kind of stable Montelukast sodium chewable tablet and preparation method thereof |
| CN111110679A (en) * | 2018-10-31 | 2020-05-08 | 长春海悦药业股份有限公司 | Pharmaceutical composition containing montelukast sodium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104546851B (en) | 2018-01-02 |
| WO2015062466A1 (en) | 2015-05-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104546851A (en) | Particle composition as well as preparation method and preparation thereof | |
| Dey et al. | Orodispersible tablets: A new trend in drug delivery | |
| CN101695480B (en) | Olopatadine hydrochloride dispersible tablets, preparation method thereof and quality control method thereof | |
| CN106539768B (en) | A kind of Lurasidone HCl oral disnitegration tablet and preparation method thereof | |
| CN103181923B (en) | Pharmaceutical preparation comprising Repaglinide and preparation method thereof | |
| CN103156819A (en) | Benzoic acid alogliptin composition troche and preparation method thereof | |
| CN103463130A (en) | Preparation method of compound paracetamol and amantadine hydrochloride capsule | |
| EP2612659B1 (en) | Panaxatriol saponins enteric pellet, capsule comprising same and method for preparing same | |
| CN103585641A (en) | Lipid coating and cyclodextrin inclusion synergic flavoring method and related preparation thereof | |
| CN104644578A (en) | Sitagliptin phosphate composition tablet and preparation method thereof | |
| CN105213335A (en) | Glipizide tablet and preparation method thereof and application | |
| CN102349877A (en) | Hydroxychloroquine sulfate capsule, hydroxychloroquine sulfate dispersible tablet and application thereof | |
| Kim et al. | Novel montelukast sodium-loaded stable oral suspension bioequivalent to the commercial granules in rats | |
| CN103675135B (en) | A kind of content assaying method of Chinese medicine composition | |
| CN102813699B (en) | Pharmaceutical composition having effects of heat clearing, detoxifying and anti-inflammation and preparation method thereof | |
| CN1957987B (en) | Medicine preparation for treating infectious diseases, preparation method, and quality detection method | |
| CN104666302A (en) | Composition and preparation method thereof as well as oral liquid and preparation method of oral liquid | |
| CN103385863B (en) | Sodium azulene sulfonate sustained-release preparation | |
| CN106404953B (en) | A kind of quality determining method of penicillin skin test freeze dried powder | |
| CN109846905A (en) | A kind of preparation method of infant paracetamol and amantadine hydrochloride particles | |
| CN111096949A (en) | Cetirizine hydrochloride oral drop and preparation method thereof | |
| Morshed | Comparative evaluation of prednisolone 5MG tablets marketed in Bangladesh | |
| CN101874792A (en) | Phloroglucinol orally disintegrating tablets and preparation method thereof | |
| CN110604726B (en) | Sofosbuvir composition and application thereof | |
| CN106860405B (en) | Faropenem sodium granules and preparation method thereof |
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 |