WO2015062466A1 - Composition particulaire, procédé de préparation et formulation de ladite composition - Google Patents

Composition particulaire, procédé de préparation et formulation de ladite composition Download PDF

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WO2015062466A1
WO2015062466A1 PCT/CN2014/089649 CN2014089649W WO2015062466A1 WO 2015062466 A1 WO2015062466 A1 WO 2015062466A1 CN 2014089649 W CN2014089649 W CN 2014089649W WO 2015062466 A1 WO2015062466 A1 WO 2015062466A1
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montelukast sodium
granules
levocetirizine hydrochloride
binder
preparation
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PCT/CN2014/089649
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English (en)
Chinese (zh)
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闫学文
杨慧君
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北京韩美药品有限公司
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Publication of WO2015062466A1 publication Critical patent/WO2015062466A1/fr

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    • 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

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a granular composition, a preparation method thereof and a preparation.
  • Allergic rhinitis a multifactorial disease induced by the interaction of genes and the environment, is a medium mainly mediated by IgE after atopic individuals are exposed to allergens. (mainly histamine) release, and a variety of immune-active cells and cytokines involved in the non-infectious inflammatory diseases of the nasal mucosa. There are three necessary conditions for its occurrence: 1 specific antigen is the substance that causes the body's immune response; 2 atopic individual is called individual difference, allergic constitution; 3 specific antigen meets with the atopic individual.
  • Specific antigens are derived from animals, plants, insects, fungi or occupational substances such as alfalfa, pollen, animal dander, fungal allergens, mite allergens, food allergens, etc., and their constituents are proteins or glycoproteins. Very few are polysaccharides.
  • the typical symptoms of allergic rhinitis are paroxysmal sneezing, clear watery nose, nasal congestion and nasal itching, some with olfactory hypothyroidism. Moderate or severe allergic rhinitis can affect the quality of life of patients, which can lead to many other diseases. The patient is incapacitated.
  • Montelukast is a highly selective cysteine leukotriene (Cys-LT) receptor antagonist developed by Merck in recent years, which competitively antagonizes leukotriene D4 Binding to the Cys-LT1 receptor. It was first used as a new type of non-steroidal anti-asthma drug in clinical practice and has achieved positive results in the clinic. With the deeper understanding of leukotrienes (LT) and its receptor antagonists, it has been found that montelukast sodium can not only improve the lung function of asthma patients, but also has important application value in many aspects such as anti-inflammation and immunity. For example, montelukast sodium can be used for the treatment of allergic rhinitis.
  • LT leukotrienes
  • Levocetirizine is a selective H1 receptor antagonist. In vitro binding characteristics studies found that levocetirizine (Xyzal) has twice the affinity for H1 receptor than cetirizine, and levocetirizine is effective in relieving allergic rhinitis in adult and children over 6 years old. symptom.
  • the pharmaceutical form of levocetirizine is levocetirizine hydrochloride. In a randomized, double-blind, placebo-controlled, randomized controlled trial in France, 470 patients with allergic rhinitis were randomized into 4 groups of oral levocetirizine 2.5 mg, 5 mg, 10 mg, and placebo. 2 weeks.
  • montelukast sodium and levocetirizine hydrochloride are more effective than the corresponding unilateral in relieving nasal discharge, sneezing, itchy nose, etc., and montelukast sodium is also mainly used.
  • Relieve the therapeutic effect of nasal congestion while levocetirizine hydrochloride can only relieve symptoms such as itchy nose and sneezing. It can not relieve the symptoms of nasal congestion in patients with moderate to severe allergic rhinitis with nasal congestion.
  • the compound preparation can play a role in the curative effect. Complementary role.
  • montelukast sodium levocetirizine hydrochloride is not as effective as corticosteroids, but it can be used as a long-term treatment for patients with moderate to severe rhinitis who are unwilling to use or are intolerant to corticosteroids.
  • montelukast sodium levocetirizine hydrochloride there are mainly two factors that hinder the development of the compound preparation.
  • montelukast sodium is very easy to absorb moisture, and it is unstable in light, humidity, heat, oxygen and acid. It is found that montelukast sodium and levocetirizine hydrochloride react quickly after contact. Yellow indicates that there is a contraindication between montelukast sodium and levocetirizine hydrochloride.
  • sugar-free pharmaceutical preparations are very necessary for diabetic patients.
  • mannitol Since mannitol is completely non-hygroscopic and has a sweet taste, it can be used instead of glucose or sucrose, so mannitol is used as a filler (or sweetener).
  • a strong advantage is shown in sugar-free pharmaceutical preparations.
  • mannitol and levocetirizine hydrochloride were very unstable under high temperature conditions. It was found that the related substances of levocetirizine hydrochloride containing mannitol were significantly increased, indicating that mannitol and hydrochloric acid There is also a contraindication between telizine. In the preparation of a pharmaceutical preparation containing levocetirizine hydrochloride, the use of mannitol is limited. So far, no effective solution has been found for the incompatibility between montelukast sodium and levocetirizine hydrochloride and the limited use of the preferred excipient mannitol in sugar-free preparations.
  • the present invention provides a granular composition, a preparation method thereof, and a preparation.
  • the granular composition solves the incompatibility problem between montelukast sodium and levocetirizine hydrochloride through the addition of meglumine, improves the stability of montelukast sodium, and improves the left oxime hydrochloride.
  • the stability of the alkazine makes mannitol can be used as an auxiliary in the compound preparation; the addition of hydroxypropyl- ⁇ -cyclodextrin can improve the stability of montelukast sodium, reduce the production of oxidation products, and improve the drug.
  • the uniformity of the active ingredients are examples of the active ingredients.
  • the present invention provides the following technical solutions:
  • the present invention provides a granule composition comprising montelukast sodium granules and levocetirizine hydrochloride granules;
  • the montelukast sodium granules include montelukast sodium, a filler, a stabilizer, and a binder;
  • the levocetirizine hydrochloride granules include levocetirizine hydrochloride, a filler, a stabilizer, and a binder;
  • the stabilizer is meglumine
  • the binder is hydroxypropyl- ⁇ -cyclodextrin.
  • meglumine can keep the surrounding of montelukast sodium alkaline, eliminate the effect of levocetirizine hydrochloride on montelukast sodium, and improve the stability of montelukast sodium. Overcome the incompatibility between montelukast sodium and levocetirizine hydrochloride; it can effectively improve the incompatibility between levocetirizine hydrochloride and mannitol, and fully exert the preference of mannitol as a sugar-free preparation. The advantages of accessories.
  • hydroxypropyl- ⁇ -cyclodextrin can effectively improve the stability of montelukast sodium, solve the problem of excessive oxidation of montelukast sodium in general preparations; improve Montelux
  • the degree of dispersion of sodium is greatly improved in the uniformity and dissolution of montelukast sodium; it can effectively improve the bitterness of levocetirizine hydrochloride; the compressibility of mannitol is not good, hydroxypropyl- ⁇ - Cyclodextrin can increase the compressibility of the granules, allowing the high mannitol content of the granules to be smoothly compressed.
  • the montelukast sodium particles include 0.5 to 5 parts of montelukast sodium, 85 to 98 parts of a filler, 0.1 to 1 part of a stabilizer, and 1 to 7.2 of a binder.
  • the levocetirizine hydrochloride granule comprises 0.1 to 5 parts of levocetirizine hydrochloride, 89.96 to 98 parts of a filler, 0.1 to 2.9 parts of a stabilizer, and 1 to 5 parts of a binder;
  • the mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was (0.5-2):1.
  • the montelukast sodium particles comprise 0.8 to 3.6 parts of montelukast sodium, 89.1 to 97 parts of a filler, 0.14 to 0.2 parts of a stabilizer, and 2 to 7.2 parts of a binder, in parts by weight;
  • the levocetirizine hydrochloride granules include 0.5-3.6 parts of levocetirizine hydrochloride, 89.96-97.1 parts of a filler, 0.4-2.9 parts of a stabilizer, and 2-3.6 parts of a binder;
  • the mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was (0.99-1.04):1.
  • the montelukast sodium particles in the granular composition comprise 0.8 parts of montelukast sodium, 97 parts of filler, 0.2 parts of stabilizer, 2 parts of binder. ;
  • the levocetirizine hydrochloride granules include 0.5 parts of levocetirizine hydrochloride, 97.1 parts of a filler, 0.4 parts of a stabilizer, and 2 parts of a binder;
  • the mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was 1:1.
  • the montelukast sodium particles in the granular composition comprise 3.6 parts of montelukast sodium, 89.1 parts of filler, 0.14 parts of stabilizer, binder 7.2.
  • the levocetirizine hydrochloride granules include 3.6 parts of levocetirizine hydrochloride, 89.96 parts of a filler, 2.9 parts of a stabilizer, and 3.6 parts of a binder;
  • the mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was 0.99:1.
  • the filler refers to a substance which accounts for a major portion of the preparation in terms of volume, such as mannitol, starch, microcrystalline fibers, sorbitol, and the like.
  • the filler in the present invention is one or a mixture of two or more of mannitol, lactose or microcrystalline cellulose.
  • the filler is mannitol, and the mannitol has a good mouthfeel and improves patient compliance.
  • the invention also provides a preparation method of the granular composition, comprising the following steps:
  • montelukast sodium Mixing montelukast sodium, stabilizer, binder, filler with water to obtain montelukast sodium
  • the solution is granulated, dried, and granulated to obtain montelukast sodium granules;
  • levocetirizine hydrochloride Taking levocetirizine hydrochloride, a stabilizer, a binder, a filler and water to obtain a levocetirizine hydrochloride solution, which is granulated, dried, and granulated to obtain levocetirizine hydrochloride granules;
  • the montelukast sodium granules are mixed with the levocetirizine hydrochloride granules, that is, obtained;
  • the stabilizer is meglumine
  • the binder is hydroxypropyl- ⁇ -cyclodextrin.
  • the mass ratio of montelukast sodium, filler, stabilizer, binder to water in the montelukast sodium solution is (0.5 to 5): (85 ⁇ 98): (0.1 to 1): (1 to 7.2): (8 to 17.2);
  • the mass ratio of levocetirizine hydrochloride, a filler, a stabilizer, a binder to water is (0.1 to 5): (89.96 to 98): (0.1 to 2.9) :(1 ⁇ 5): (5 ⁇ 15);
  • the mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was (0.5-2):1.
  • the mass ratio of montelukast sodium, filler, stabilizer, binder to water in the montelukast sodium solution is (0.8 to 3.6): (89.1 ⁇ 97): (0.14 to 0.2): (2 to 7.2): (8 to 17.2);
  • the mass ratio of levocetirizine hydrochloride, filler, stabilizer, binder to water is (0.5 to 3.6): (89.96 to 97.1): (0.4 to 2.9): 2 to 3.6): (7.0 to 7.2);
  • the mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was (0.99-1.04):1.
  • the mass ratio of montelukast sodium, filler, stabilizer, binder to water in the montelukast sodium solution is 0.8:97:0.2:2:8;
  • the mass ratio of levocetirizine hydrochloride, filler, stabilizer, binder to water in levocetirizine hydrochloride solution is 0.5:97.1:0.4:2:7;
  • the mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was 1:1.
  • the montelukast sodium solution comprises 3.6 parts of montelukast sodium, 89.1 parts of filler, 0.14 parts of stabilizer, 7.2 parts of binder, and 17.2 parts of water in parts by weight. ;
  • the levocetirizine hydrochloride solution includes 3.6 parts of levocetirizine hydrochloride and 89.96 parts of a filler. 2.9 parts stabilizer, 3.6 parts of binder, 7.2 parts of water;
  • the mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was 0.99:1.
  • the filler is one or a mixture of two or more of mannitol, lactose or microcrystalline cellulose.
  • the present invention also provides a combination preparation comprising the granular composition provided by the present invention and a pharmaceutically acceptable excipient composition.
  • the formulations provided by the present invention are oral formulations, and in some embodiments provided herein, the dosage forms of the combination formulations are granules or tablets.
  • the oral preparations which are considered to be feasible by those skilled in the art are all within the scope of the present invention.
  • the type of the oral preparation is not limited thereto, and the present invention is not limited thereto.
  • the dosage form of the combination preparation is a granule
  • the pharmaceutically acceptable excipient in the granule is a lubricant
  • Lubricant refers to an auxiliary material which can reduce the friction between the particles or the surface of the tablet and the die wall, so as to prevent the friction from being large and the tableting is difficult; the lubricant can make the pressure distribution uniform during tableting and make the density of the tablet uniform; The force required to push the tablet out of the die hole is reduced.
  • the lubricant is magnesium stearate.
  • the lubricants that are considered to be feasible by those skilled in the art are all within the scope of the present invention.
  • the type of the lubricant is not limited thereto, and the present invention is not limited thereto.
  • the mass ratio of the particulate composition to the pharmaceutically acceptable excipient in the granule is (99 to 99.9): (0.1 to 1).
  • the granule composition and the pharmaceutically acceptable excipient produce granules.
  • the mass ratio of the granule composition to the pharmaceutically acceptable excipient is 800:1.
  • the pharmaceutically acceptable excipient in the tablet is a mixture of a sweetener, a disintegrant, a fragrance, a pigment, and a lubricant.
  • Sweeteners and flavors can improve the taste of the drug and improve the patient's compliance; the disintegrant can increase the dissolution rate of the drug; the pigment can improve the appearance of the drug; the lubricant can reduce the friction and make the tableting smooth.
  • the mass ratio of the granular composition to the pharmaceutically acceptable excipient is (90 to 99): (1 to 10).
  • the granular composition and the pharmaceutically acceptable excipient Chewable tablets are prepared (including sweeteners, disintegrants, flavors, colors, lubricants).
  • the mass ratio of the granular composition to the pharmaceutically acceptable excipient is 18.7:1.
  • the mass ratio of the sweetener, the disintegrant, the essence, the pigment and the lubricant is (0.1 to 1): (0.5 to 6): (0.01 to 0.5): (0.1 to 1): (0.1 to 2).
  • the pharmaceutically acceptable excipients have a mass ratio of sweetener, disintegrant, flavor, pigment to lubricant of 1:4.5:0.25:0.25:1.6.
  • the sweetener is sucralose.
  • the sweeteners that are considered to be feasible by those skilled in the art are all within the scope of the present invention.
  • the type of the sweetener is not limited thereto, and the present invention is not limited thereto.
  • the disintegrant is one of sodium carboxymethyl starch, hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and croscarmellose sodium. kind or a mixture of two or more.
  • the disintegrators which are considered to be feasible by those skilled in the art are all within the scope of the present invention.
  • the type of disintegrant is not limited thereto, and the present invention is not limited thereto.
  • the method of adding the disintegrating agent may be selected from any one of three ways of adding, adding, and adding the inside and the outside, and the present invention is not limited thereto.
  • the fragrance is a cherry flavor.
  • flavors that are considered to be feasible by those skilled in the art are all within the scope of the present invention, and the types of flavors are not limited thereto, and the present invention is not limited thereto.
  • the pigment is red iron oxide.
  • the pigments that are considered to be feasible by those skilled in the art are all within the scope of the present invention.
  • the type of the pigment is not limited thereto, and the present invention is not limited thereto.
  • the lubricant is magnesium stearate.
  • the lubricants that are considered to be feasible by those skilled in the art are all within the scope of the present invention.
  • the type of the lubricant is not limited thereto, and the present invention is not limited thereto.
  • the invention provides a granular composition, a preparation method thereof and a preparation.
  • the granular composition comprises montelukast sodium particles and levocetirizine hydrochloride particles; montelukast sodium particles include montelukast sodium, a filler, a stabilizer, a binder; levocetirizine hydrochloride particles Including levocetirizine hydrochloride, a filler, a stabilizer, a binder; the stabilizer is meglumine; the binder is hydroxypropyl- ⁇ -cyclodextrin.
  • the stability test under accelerated conditions, the results show that the content of the pharmaceutically active ingredient related substance in the granular composition and the preparation thereof provided by the present invention slightly increases or does not increase, and the content of the related substance in the reference preparation increases greatly. It is indicated that the preparation provided by the invention has stable properties; the stability test by long-term conditions shows that the indexes of the preparations provided by the invention have no significant change, and the impurities in the reference substance of the montelukast sodium particle reference preparation are determined. The increase indicates that the preparation provided by the present invention has good stability; the research further indicates that the pharmaceutical formulation of the present invention solves the incompatibility problem between montelukast sodium and levocetirizine hydrochloride, and improves montelukast sodium.
  • Figure 1 shows the dissolution profile of montelukast sodium when the granules provided in Example 7 were placed for 0 days;
  • Figure 2 is a graph showing the dissolution profile of montelukast sodium when the granules provided in Example 7 were placed at 60 ° C for 10 days;
  • Figure 3 shows the dissolution profile of the commercially available reference formulation Shun Ning
  • Figure 4 is a graph showing the dissolution profile of levocetirizine hydrochloride when the granules provided in Example 7 were placed for 0 days;
  • Figure 5 is a graph showing the dissolution profile of levocetirizine hydrochloride when the granules provided in Example 7 were allowed to stand at 60 ° C for 10 days.
  • the invention discloses a granular composition, a preparation method thereof and a preparation thereof, and those skilled in the art can learn from the contents of the present invention and appropriately improve the process parameters. Special mention is that all classes Such substitutions and modifications will be apparent to those skilled in the art and are considered to be included in the invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the granule composition provided by the present invention, a preparation method thereof, and a drug substance or an auxiliary material used in the preparation are commercially available.
  • Preparation of montelukast sodium granules Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl- ⁇ -cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used.
  • the mannitol was placed in a wet granulator after passing through a 26 mesh sieve, and the prepared first binder solution was placed in a wet granulator to prepare a soft material, and the soft material was sieved through a 26 mesh sieve, and dried at 45 ° C.
  • the granules were sieved through a 26 mesh sieve, and drying was continued until the loss on drying was ⁇ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium granules.
  • the montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.
  • Preparation of montelukast sodium granules Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl- ⁇ -cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used.
  • the mannitol and microcrystalline cellulose 101 are respectively passed through a 26 mesh sieve, uniformly mixed, placed in a wet granulator, and the first binder solution is placed in a wet granulator to prepare a soft material and a soft material.
  • the granules were sieved at 26 ° C, dried at 45 ° C for 15 minutes, sieved through a 26 mesh sieve, and dried until the loss on drying was ⁇ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium. Particles.
  • Preparation of levocetirizine hydrochloride granules adding purified water to a stainless steel tank, adding hydroxypropyl- ⁇ -cyclodextrin to dissolve until dissolved; stirring and adding levocetirizine hydrochloride to dissolve; finally adding meglumine Stir until dissolved to obtain a second binder solution, which is ready for use.
  • the mannitol and microcrystalline cellulose 101 are respectively passed through a 26 mesh sieve, uniformly mixed, placed in a wet granulator, and the prepared second binder solution is placed in a wet granulator to prepare a soft material and a soft material.
  • the granules of 26 mesh sieves were dried at 45 ° C for 15 minutes, then sieved through a 26 mesh sieve, and dried until the loss on drying was ⁇ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride. Pyrazine particles.
  • the montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.
  • Preparation of montelukast sodium granules Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl- ⁇ -cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used.
  • the mannitol was placed in a wet granulator after passing through a 26 mesh sieve, and the prepared first binder solution was placed in a wet granulator to prepare a soft material, and the soft material was sieved through a 26 mesh sieve, and dried at 45 ° C.
  • the granules were sieved through a 26 mesh sieve, and drying was continued until the loss on drying was ⁇ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium granules.
  • the montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.
  • Preparation of montelukast sodium granules Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl- ⁇ -cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used. Mannitol and lactose were sieved through a 26 mesh sieve, mixed uniformly and placed in a wet granulator. The first binder solution was placed in a wet granulator to make a soft material. The soft material was sieved through a 26 mesh screen. The granules were dried at 45 ° C for 15 minutes and then sieved through a 26 mesh sieve. The granules were further dried to a loss on drying ⁇ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve. The montelukast sodium granules are obtained.
  • the granules were dried at 45 ° C for 15 minutes, sieved through a 26 mesh sieve, and dried to a loss on drying ⁇ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride granules.
  • the montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.
  • Preparation of montelukast sodium granules Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl- ⁇ -cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used.
  • the mannitol was placed in a wet granulator after passing through a 26 mesh sieve, and the prepared first binder solution was placed in a wet granulator to prepare a soft material, and the soft material was sieved through a 26 mesh sieve, and dried at 45 ° C.
  • the granules were sieved through a 26 mesh sieve, and drying was continued until the loss on drying was ⁇ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium granules.
  • the montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.
  • Preparation of montelukast sodium granules Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl- ⁇ -cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used.
  • the mannitol and microcrystalline cellulose 101 are respectively passed through a 26 mesh sieve, uniformly mixed, placed in a wet granulator, and the first binder solution is placed in a wet granulator to prepare a soft material and a soft material.
  • 26 mesh sieve granules dried at 45 ° C for 15 minutes The whole mesh was sieved by 26 mesh, and drying was continued until the loss on drying was less than or equal to 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium particles.
  • Preparation of levocetirizine hydrochloride granules adding purified water to a stainless steel tank, adding hydroxypropyl- ⁇ -cyclodextrin to dissolve until dissolved; stirring and adding levocetirizine hydrochloride to dissolve; finally adding meglumine Stir until dissolved to obtain a second binder solution, which is ready for use.
  • the mannitol and microcrystalline cellulose 101 are respectively passed through a 26 mesh sieve, uniformly mixed, placed in a wet granulator, and the prepared second binder solution is placed in a wet granulator to prepare a soft material and a soft material.
  • the granules of 26 mesh sieves were dried at 45 ° C for 15 minutes, then sieved through a 26 mesh sieve, and dried until the loss on drying was ⁇ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride. Pyrazine particles.
  • the montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.
  • Example 1 The granule composition obtained in Example 1 was mixed with magnesium stearate in a mixer for 5 minutes, and after the air bag airtightness was confirmed, the filling was started, and the granules were obtained by loading 1 g/bag.
  • the prescription for chewing tablets is shown in Table 8.
  • the granule composition prepared in Example 2 was mixed with sucralose, sodium carboxymethyl starch, cherry flavor, red iron oxide, magnesium stearate in a mixer for 5 minutes, and tableted to obtain a chewable tablet.
  • the granule composition obtained in Example 3 was mixed with magnesium stearate in a mixer for 5 minutes, and after the air bag airtightness was confirmed, the filling was started, and the granules were obtained by loading 1 g/bag.
  • the prescription for chewing tablets is shown in Table 10.
  • Prescription amount Granular composition Granular composition prepared in Example 4 20820 Sweetener Sucralose 34 Disintegrator Hydroxypropyl cellulose 2041 essence Cherry flavor 170 pigment Red iron oxide 34 Lubricant Magnesium stearate 34
  • the granule composition prepared in Example 4 was mixed with sucralose, hydroxypropylcellulose, cherry flavor, red iron oxide, magnesium stearate in a mixer for 5 minutes, and tableted to obtain a chewable tablet.
  • the granule composition obtained in Example 5 was mixed with magnesium stearate in a mixer for 5 minutes, and after the air bag airtightness was confirmed, the filling was started, and the granules were obtained by loading 1 g/bag.
  • the prescription for chewing tablets is shown in Table 12.
  • the granule composition prepared in Example 6 was mixed with sucralose, crospovidone, cherry flavor, red iron oxide, magnesium stearate in a mixer for 5 minutes, and tableted to obtain a chewable tablet.
  • Example 7 Take the three batches of granules obtained in Example 7 (product batch number: 20121101, 20121102, 20121103) and the commercially available Shun Ning (from Merck East Pharmaceutical Company, the trade name is The batch number is 0000148425A, which is a reference preparation for the related substances of montelukast sodium, and the stability test is carried out. Stability tests include accelerated tests, long-term tests, and intermediate tests.
  • the accelerated test was as follows: the granules and the reference preparation prepared in Example 7 were respectively measured at 0, 1, 2 under accelerated test conditions of a temperature of 40 ⁇ 2 ° C and a relative humidity of 75 ⁇ 5% RH for 6 months. At 3 and 6 months, the content of cetirizine hydrochloride, water, dissolution, labeling content and related substances were investigated for stability.
  • the long-term test is: take the three batches of granules obtained in Example 7 (product batch number: 20121101, 20121102, 20121103) and the commercially available Shun Ning (from Merck East Pharmaceutical Company, the trade name is Batch number 0000148425A, as a reference preparation for montanukast sodium related substances) stored in a constant temperature and humidity chamber, controlled temperature and relative humidity conditions of 25 ⁇ 2 ° C and 60 ⁇ 10% RH, in 3, 6, 18 Samples were taken after the month and compared with the 0 month data and map. The montelukast sodium fraction was compared with the reference preparation Shun Ning, and levocetirizine hydrochloride was partially compared with its own 0-day data because there was no reference preparation.
  • the intermediate test was: taking the three batches of granules obtained in Example 7 (product batch number: 20121101, 20121102, 20121103) and the commercially available Shun Ning (from Merck East Pharmaceutical Company, the trade name is Batch number 0000148425A, as a reference preparation for montelukast sodium related substances) stored in a constant temperature and humidity chamber, controlled temperature and relative humidity conditions of 30 ⁇ 2 ° C and 65 ⁇ 5% RH, in 3, 6, 18 Samples were taken after the month and compared with the 0 month data and map. The montelukast sodium fraction was compared with the reference preparation Shun Ning, and levocetirizine hydrochloride was partially compared with its own 0-day data because there was no reference preparation.
  • the moisture is determined by the moisture measurement method (Chinese Pharmacopoeia 2010 edition two appendix VIIIM first method A).
  • the content determination, related substances, levocetirizine hydrochloride and dissolution were determined by HPLC.
  • the microbial limit test method is improved according to the Chinese Pharmacopoeia 2010 edition two appendix microbial limit test method.
  • Montelukast sodium related substance detection method in the dark operation, take 2500mg of granules prepared in Example 7, add 10mL volumetric flask, montelukast sodium concentration is 1mg / mL, add solvent [methanol-water (9 :1)] Appropriate amount, sonicate for 10 minutes, dilute to the mark with solvent [methanol-water (9:1)], shake well, filter, and take the filtrate as the test solution.
  • Di-p-chlorobenzyl piperazine, levocetirizine, p-chlorophenol and di-p-chlorophenylmethanol were sequentially peaked, and di-p-chlorobenzoyl was obtained.
  • the relative retention times of piperazine, p-chlorophenol and di-p-chlorophenylmethanol are about 0.9, 1.1 and 3.8, respectively.
  • the resolution of di-p-chlorobenzyl piperazine peak and levocetirizine peak should be in accordance with the regulations. Adjust the detection sensitivity so that the peak of di-p-chlorobenzyl piperazine is about 20% of full scale.
  • the area of other single unknown impurity peaks should not be greater than the levocetirizine peak in the control solution. Area (0.5%), the total impurities should not exceed 1.0%.
  • the impurity peak in the chromatogram of the test solution which is less than 0.1 times the area of the levocetirizine in the control solution is negligible.
  • Microbial limit detection method 10 g of the granules prepared in Example 7 were aseptically weighed, and a pH 7.0 sterile sodium chloride-peptone buffer solution containing 0.3% egg yolk lecithin and 3% polysorbate 80 was added to 100 mL. Shake until the test sample is evenly dispersed to make a 1:10 test solution. Count bacteria, mold and yeast, take 1:10 test solution 1.0mL, evenly dispense into 2 dishes, 0.5mL per dish, check according to law (Chinese Pharmacopoeia 2010 edition second appendix XI J).
  • test solution 10 mL
  • test solution 10 mL
  • add to 100 mL of bile salt lactose medium and check according to law (Chinese Pharmacopoeia 2010 Edition Part II Appendix XI J).
  • the test standard is: 1g of the test sample, the number of bacteria should not exceed 1000 CFU, the number of molds and yeasts should not exceed 100 CFU, and Escherichia coli should not be detected.
  • the accelerated test results are shown in Tables 17 and 18.
  • the long-term test results are shown in Tables 19 and 20.
  • the intermediate test results are shown in Table 21 and Table 22.
  • ND means not detected.
  • ND means not detected.
  • ND means not detected.
  • the three batches of chewable tablets (product lot number: 13050039, 13060051, 13060052) prepared in Example 8 were subjected to a stability test. Stability tests include accelerated tests, long-term and intermediate tests.
  • the accelerated test was: the chewable tablet prepared in Example 8 and the reference preparation were measured at 0 and 6 months under accelerated test conditions of a temperature of 40 ⁇ 2 ° C and a relative humidity of 75 ⁇ 5% RH for 6 months.
  • the stability of the content of dextrozartrazin hydrochloride, water, dissolution, labeling content and related substances were investigated.
  • the long-term test was as follows: the three batches of chewable tablets prepared in Example 8 (product batch number: 13050039, 13060051, 13060052) were stored in a constant temperature and humidity chamber, and the controlled temperature and relative humidity conditions were 25 ⁇ 2 ° C and 60 ⁇ 10% RH, sampled after 3, 6, and 12 months and compared with the 0 month data and map.
  • the intermediate test was as follows: the three batches of chewable tablets prepared in Example 8 (product batch number: 13050039, 13060051, 13060052) were stored in a constant temperature and humidity chamber, and the controlled temperature and relative humidity conditions were 30 ⁇ 2° C. and 65 ⁇ . 5% RH was sampled after 3, 6, and 12 months and compared with the 0 month data and map.
  • the test method refers to the test method for detecting the related substances of the granules of the present invention, and the accelerated test results are shown in Table 23 and Table 24.
  • the long-term test results are shown in Table 25 and Table 26.
  • the intermediate condition test results are shown in Table 27 and Table 28. .
  • ND means not detected.
  • ND means not detected.
  • ND means not detected.
  • the compound preparation provided by the invention has stable properties and can overcome the incompatibility between montelukast sodium and levocetirizine hydrochloride, and can overcome the incompatibility between mannitol and levocetirizine hydrochloride. .
  • Example 7 The granules obtained in Example 7 and the chewable tablets prepared in Example 8 were each placed at 60 ° C for 10 days, and the contents of the relevant substances were measured for stability investigation. The results are shown in Tables 29 to 32.
  • the results show that the montelukast sodium component in the granules provided in Example 7 is very stable under high temperature conditions, the related substances are not substantially increased, and the quality of the drug completely conforms to the national standard; from Table 30, the results show examples. 7
  • the granules provided in the granules are very stable under high temperature conditions, the related substances are slightly increased, and the quality of the drugs is in full compliance with the national standard. quasi. It can be seen that the granules provided in Example 7 are stable in nature and the quality of the drug is in full compliance with national standards.
  • the results show that the amount of montelukast sodium-related substance in the chewable tablet provided in Example 8 is slightly increased, and the quality of the drug completely conforms to the national standard; as can be seen from Table 32, the results show that hydrochloric acid in the chewable tablet provided in Example 8 The substance related to levocetirizine is slightly increased, and the quality of the drug is in full compliance with national standards. It can be seen that the chewable tablet provided in Example 8 is stable in nature and the quality of the drug is in full compliance with national standards.
  • the compound preparation provided by the invention has stable properties and can overcome the incompatibility between montelukast sodium and levocetirizine hydrochloride, and can overcome the incompatibility between mannitol and levocetirizine hydrochloride. .
  • the granules prepared in Example 7 were allowed to stand at 60 ° C for 10 days, and then with the commercially available Shun Ning [from Merck East Pharmaceutical Company, the trade name is The batch number was 0000148425A, and the dissolution test was carried out as a reference preparation of the dissolution rate (dissolution amount) of the montelukast sodium.
  • the granules obtained in Example 7 were obtained and placed at 0 days and 10 days, montelukast sodium and levocetine hydrochloride.
  • the dissolution method is determined by the paddle method in the second method of Appendix 2C of the Chinese Pharmacopoeia 2010 edition.
  • the dissolution conditions of montelukast sodium are: 0.5% SDS aqueous solution: 5.0 g SDS dissolved in water and diluted to 1000 mL, shake well , that is; medium volume: 900mL; device: paddle method; speed: 50 rpm; medium temperature: 37 ° C; sampling time: 5, 10, 15, 30, 45, 60 min.
  • the dissolution conditions of levocetirizine hydrochloride were: dissolution medium: water; medium volume: 900 mL; device: paddle method; rotation speed: 50 rpm; medium temperature: 37 ° C; sampling time: 5, 10, 15, 30, 45, 60 min .
  • test results are shown in Figs. 1 to 5, Table 29, and Table 30, wherein the test data of Figs. 1 to 3 are shown in Table 33, and the test data of Figs. 4 and 5 are shown in Table 34.
  • Example 7 1 to 3 and Table 33, the granules prepared in Example 7 were left to stand at 60 ° C for 10 days, and the dissolution rate of montelukast sodium was almost unchanged from 0 days, and the dissolution of the reference preparation Shun Ning was observed. The degree is similar. 4, 5, and 34, the granules obtained in Example 7 were left to stand at 60 ° C for 10 days, and the dissolution rate of levocetirizine hydrochloride was almost unchanged from 0 days.
  • Example 7 From this, it was found that the granules obtained in Example 7 were left unaffected for 10 days under high temperature conditions, and the elution effect was hardly affected, and it was found that the dissolution rate of the granule composition provided in Example 1 was not easily affected by high temperature conditions.
  • the preparations prepared in Examples 8 to 12 were subjected to a dissolution test, and the results were similar to those of the granules provided in Example 7, indicating that the preparations prepared in Examples 8 to 12 were left to stand under high temperature for 10 days, and the dissolution effect was almost Without being affected, it can be inferred that the dissolution of the granular compositions provided in Examples 2 to 6 is not easily affected by high temperature conditions.
  • the dissolution rate of the granular composition and the preparation thereof provided by the present invention is not easily affected by high temperature conditions.

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Abstract

La présente invention concerne une composition particulaire et son procédé de préparation. Ladite composition particulaire comprend des particules de montélukast sodique et des particules de lévocétirizine. Les particules de montélukast sodique comprennent du montélukast sodique , une charge, un stabilisant et un adhésif. Les particules de lévocétirizine comprennent de la lévocétirizine, une charge, un stabilisant et un adhésif. Les stabilisants sont de la méglumine et les adhésifs sont de l'hydroxypropyl-β-cyclodextrine.
PCT/CN2014/089649 2013-10-29 2014-10-28 Composition particulaire, procédé de préparation et formulation de ladite composition WO2015062466A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3222279A1 (fr) 2016-03-21 2017-09-27 Invest Bielany Spolky z Ograniczona Odpowiedzialnoscia Préparation pharmaceutique orale de montélukast et de lévocétirizine et procédé pour sa production
EP3505172A1 (fr) * 2017-12-31 2019-07-03 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique comprenant du montélukast et de la lévocétirizine
WO2019197939A1 (fr) * 2018-04-11 2019-10-17 Hetero Healthcare Limited Formulation à dissolution buccale de montélukast sodique et de chlorhydrate de lévocétirizine, au goût masqué,
CN111110679A (zh) * 2018-10-31 2020-05-08 长春海悦药业股份有限公司 一种含有孟鲁司特钠的药物组合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105193743B (zh) * 2015-11-05 2018-05-08 石家庄市华新药业有限责任公司 一种孟鲁司特钠颗粒制剂及其制备方法
CN109833302A (zh) * 2017-11-29 2019-06-04 扬子江药业集团有限公司 一种稳定的孟鲁司特钠咀嚼片及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010021607A2 (fr) * 2008-08-22 2010-02-25 Mahmut Bilgic Préparation pharmaceutique
WO2010107404A1 (fr) * 2009-03-16 2010-09-23 Mahmut Bilgic Combinaisons pharmaceutiques stables
CN102038645A (zh) * 2009-10-12 2011-05-04 杭州赛利药物研究所有限公司 一种地氯雷他定颗粒及其制备方法
CN102258531A (zh) * 2011-04-12 2011-11-30 宁辉 一种含有环磷腺苷与葡甲胺的药物组合物及其制备方法
CN102688238A (zh) * 2012-06-18 2012-09-26 重庆康刻尔制药有限公司 一种用于治疗哮喘的孟鲁斯特钠组合药物颗粒剂及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009288006B2 (en) * 2008-09-05 2014-07-17 Mcneil-Ppc, Inc. Method for making cetirizine tablets

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010021607A2 (fr) * 2008-08-22 2010-02-25 Mahmut Bilgic Préparation pharmaceutique
WO2010107404A1 (fr) * 2009-03-16 2010-09-23 Mahmut Bilgic Combinaisons pharmaceutiques stables
CN102038645A (zh) * 2009-10-12 2011-05-04 杭州赛利药物研究所有限公司 一种地氯雷他定颗粒及其制备方法
CN102258531A (zh) * 2011-04-12 2011-11-30 宁辉 一种含有环磷腺苷与葡甲胺的药物组合物及其制备方法
CN102688238A (zh) * 2012-06-18 2012-09-26 重庆康刻尔制药有限公司 一种用于治疗哮喘的孟鲁斯特钠组合药物颗粒剂及其应用

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3222279A1 (fr) 2016-03-21 2017-09-27 Invest Bielany Spolky z Ograniczona Odpowiedzialnoscia Préparation pharmaceutique orale de montélukast et de lévocétirizine et procédé pour sa production
EP3505172A1 (fr) * 2017-12-31 2019-07-03 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique comprenant du montélukast et de la lévocétirizine
WO2019197939A1 (fr) * 2018-04-11 2019-10-17 Hetero Healthcare Limited Formulation à dissolution buccale de montélukast sodique et de chlorhydrate de lévocétirizine, au goût masqué,
CN111110679A (zh) * 2018-10-31 2020-05-08 长春海悦药业股份有限公司 一种含有孟鲁司特钠的药物组合物

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