WO2015170835A1 - Préparation liquide plus stable comprenant du montélukast ou un sel de montélukast pharmaceutiquement acceptable, et procédé de préparation associé - Google Patents

Préparation liquide plus stable comprenant du montélukast ou un sel de montélukast pharmaceutiquement acceptable, et procédé de préparation associé Download PDF

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Publication number
WO2015170835A1
WO2015170835A1 PCT/KR2015/003529 KR2015003529W WO2015170835A1 WO 2015170835 A1 WO2015170835 A1 WO 2015170835A1 KR 2015003529 W KR2015003529 W KR 2015003529W WO 2015170835 A1 WO2015170835 A1 WO 2015170835A1
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Prior art keywords
liquid formulation
montelukast
pharmaceutically acceptable
electrolyte compound
acceptable salt
Prior art date
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Ceased
Application number
PCT/KR2015/003529
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English (en)
Inventor
Young Hun Kim
Taek Kwan Kwon
Seung Bin YOUN
Jae Hyun Park
Jong Soo Woo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Publication of WO2015170835A1 publication Critical patent/WO2015170835A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to a liquid formulation comprising montelukast or a pharmaceutically acceptable salt thereof and a method for preparing the formualtion. More particularly, the present invention relates to a syrup formulation for the prevention and treatment of asthma, which is a liquid formulation comprising montelukast or a pharmaceutically acceptable salt thereof in a solution state, having enhanced stability. The present invention also relates to a method for preparing the above syrup formulation.
  • Asthma is an inflammatory airway obstructive disease with symptoms of dyspnea and severe cough caused by swelling of bronchial mucosa due to bronchial inflammation, and bronchial obstruction due to bronchial muscle spasm.
  • Patients with asthma show symptoms such as wheezing, dyspnea and cough etc. due to airway obstruction, and the symptoms tend to get worse at night than in daytime. Also, they may have difficulties in breathing due to excessive sputum production. In severe cases, asthmatic attacks may be life-threatening.
  • Asthma is a problematic disease prevalent worldwide, and about 300 million asthma patients are estimated to be present. A half of childhood asthma cases persists until adulthood and continues as adult asthma. The prevalence of asthma among children and adults confirmed by a standard survey method amounts to 1 to 18%, albeit with differences among countries.
  • Therapeutic agents of asthma are mainly divided into disease-controlling agents and symptom-alleviating agents.
  • the disease-controlling agents are used for controlling symptoms of asthma mainly by anti-inflammatory effects.
  • the symptom- alleviating agents are medications used in order to alleviate symptoms in a short time period by rapidly dilating airway.
  • Montelukast one of the disease-controlling agents, is an antagonist that inhibits cysteinyl leukotriene CysLTl receptor, and has been used for the treatment and prevention of leukotriene-mediated diseases and disorders.
  • montelukast is known to be effective for allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyps, chronic obstructive pulmonary disease, conjunctivitis including rhino- conjunctivitis, migraine, cystic fibrosis, and viral bronchiolitis, etc. (SE Dahlen, Eur. J. Pharmacol., 533 (1-3), 40-56 (2006)).
  • montelukast has a great advantage that it is effective for aspirin-sensitive asthma patients and has very few side effects.
  • SingulairTM an agent employing sodium montelukast as its pharmacologically active ingredient, is approved for the treatment of asthma for adults and children over 6 months of age, and commercially available.
  • SingulairTM is commercially available with dosage forms of 10 mg tablets to be taken once a day by adults agaed over 15 years, 4 to 5 mg chewable tablets to be chewed and taken once a day by children aged 2 to 14 years, and 4 mg fine granules to be taken once a day by children aged 6 months to 2 years.
  • the fine granule has a disadvantage that it should be taken orally itself, or mixed in small amount (e.g. 5 mL or less) of soft foods such as baby food, mother's milk or porridge which is colder than room temperature and be taken immediately (i.e., within 15 minutes).
  • montelukast produces degradation products such as montelukast sulfoxide (as shown in Formula 1 below) and montelukast cis-isomer (as shown in Formula 2 below) when it is degraded.
  • SingulairTM employing sodium montelukast as its main ingredient to sunlight
  • montelukast sulfoxide increases up to 2.4% in 3 weeks
  • montelukast st in 0.1 M solution of hydrochloric acid to sodium, etc. for 6 hours montelukast cis-isomer increases up to 14.6% (M. M. Al Omari et al., J. Pharm. and Biomed. Anal, 45, 465-471 (2007)).
  • oral liquid formulations such as syrups, suspensions, elixirs, and spirits
  • solid formulations such as tablets, chewable tablets and granules
  • the bioavailability of the oral liquid formulations can be increased and individual variations can be decreased.
  • medication compliance of patients can be enhanced by improving taste and flavor by addition of sweeteners and flavoring agents.
  • Montelukast has high solubility in water, but it has disadvantage in that its pharmacological component can be degraded rapidly and produce related substances when dissolved in water, making it difficult to maintain the feature of montelukast. As such, there have been difficulties in developing a liquid formulation comprising montelukast or a pharmaceutically acceptable salt thereof, and there is no product commercially available or developed yet.
  • the present inventors have endeavored to develop a liquid formulation comprising montelukast with improved stability, bioavailability and medication compliance, and without decrease of dissolution over time, by employing a stabilizer thereto.
  • a liquid formulation comprising an electrolyte compound, and montelukast or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a method for preparing a liquid formulation comprising: (1) adding at least one pharmaceutically acceptable additive selected from the group consisting of a sweetener, a flavoring agent, a preservative, a solubilizing agent, an emulsifying agent, a pH adjusting agent, an antioxidant and a coloring agent, to purified water and then stirring them to prepare solution 1 ; (2) adding at least one electrolyte compound to purified water and stirring them, and then adding montelukast or its pharmaceutically acceptable salt thereto and stirring them to prepare solution 2; and (3) mixing solution 1 with solution 2, and adding purified water thereto to adjust the concentration.
  • a pharmaceutically acceptable additive selected from the group consisting of a sweetener, a flavoring agent, a preservative, a solubilizing agent, an emulsifying agent, a pH adjusting agent, an antioxidant and a coloring agent
  • the liquid formulation comprising montelukast or a pharmaceutically acceptable salt thereof according to the present invention allows its pharmacological ingredients to be substantially dissolved and present in a solution state, thereby preventing decrease of dissolution over time and increasing its bioavailability. Further, owing to superior taste, flavor and easy dosage control, the liquid formulation of the present invention can be easily taken by patients and its medication compliance can be enhanced. And, due to the addition of an electrolyte compound it shows improvement in stability and homogeneity of drug effect by preventing recrystallization, precipitation, separation of layers or production of related substances does not take place even when stored for a long time, and can be effectively used for asthma and allergic rhinitis patients. BRIEF DESCRIPTION OF THE DRAWING
  • Fig. 1 shows the amount of montelukast sulfoxide produced in the liquid formulations in Examples 1 to 3 and Comparative Examples 1 to 8 when stored under the accelerated conditions;
  • Fig. 2 shows the amount of total montelukast related substances of the liquid formulations in Examples 1 to 3 and Comparative Examples 1 to 8 when stored under the accelerated conditions.
  • the liquid formulation according to the present invention comprises an electrolyte compound, and montelukast or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the active ingredient can be selected from the group consisting of montelukast, montelukast sodium, montelukast potassium, montelukast strontium, montelukast calcium, montelukast magnesium, montelukast ammonium, and a mixture thereof, among which montelukast sodium is preferred.
  • the active ingredient can be employed in the liquid formulation in an amount of
  • montelukast in the active ingredient is employed in the above preferred amount.
  • montelukast in the above preferred range
  • a patient can avoid the inconvenience of taking too large or small amount of liquid formulation, and the quality test and analysis of a prepared liquid formulation can be performed more easily.
  • the liquid formulation comprising montelukast or a pharmaceutically acceptable salt thereof can be used for the treatment or prevention of asthma, allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyps, chronic obstructive pulmonary disease, conjunctivitis including rhino-conjunctivitis, migraine, cystic fibrosis, and viral bronchiolitis, etc.
  • the liquid formulation can comprise at least one electrolyte compound which can function as a stabilizer.
  • the stabilizer may be a property stabilizer.
  • the term “property” refers to a physicochemical feature or characteristics of a liquid formulation or a pharmacologically active ingredient comprised therein.
  • “property stability” means that a stable solution state is maintained over time without deterioration change of the physicochemical feature or characteristics of the liquid formulation or the pharmacologically active ingredient employed therein.
  • “property stabilizer” refers to an agent to improve the property stability.
  • the “solution state” in the present invention means that the solubility of the montelukast or a pharmaceutically acceptable salt thereof measured at room temperature is 70 to 100%, specifically 80 to 100%, more specifically 90 to 100%, and more specifically 95 and 100%.
  • room temperature in the present invention refers to a temperature range of approximately 15 °C to 25 °C.
  • the electrolyte compound may be neutral or weak alkaline by being dissociated in a solvent.
  • the electrolyte compound can have pKa of 6.0 to 12.0, more specifically pKa of 6.5 to 11.0, and more specifically pKa of 7.0 to 10.0.
  • pKa of the electrolyte compound being within the above preferred range, the stimulation imposed on the active ingredient by the electrolyte compound can be minimized, which is advantageous in preventing deterioration of the characteristics of the active ingredient.
  • the solubility of the electrolyte compound at room temperature can be 100 to 900 g/L.
  • the solubility of the liquid formulation in a solvent at room temperature can be 200 to 750 g/L, more specifically 300 to 600 g/L.
  • the electrolyte compound is at least one selected from the group consisting of alkali metal chloride and alkali earth metal chloride.
  • the electrolyte compound can be selected from the group consisting of potassium chloride, sodium chloride, calcium chloride and a mixture thereof.
  • the electrolyte compound can be employed in the liquid formulation in an amount of 0.5 to 20 parts by weight, preferably 1 to 15 parts by weight, more preferably 2 to 10 parts by weight based on 1 part by weight of montelukast. With the content of the electrolyte compound being within the above preferred range, a pharmacologically active ingredient in liquid formulation can be solubilized with its solubility effectively maintained, while the increase of related substances in the liquid formulation is prevented.
  • the liquid formulation of the present invention can further comprise a pharmaceutically acceptable additive.
  • the pharmaceutically acceptable additive can be, for example, at least one selected from a group consisting of a sweetener, a flavoring agent, a preservative, a solubilizing agent, an emulsifying agent, a pH adjusting agent, an antioxidant and a coloring agent.
  • the sweetener improves taste of the liquid formulation, which may be, for example, at least one substance selected from the group consisting of white sugar, high fructose, sorbitol, mannitol, xylitol, aspartame, steviol glycosides, sucralose, acesulfame potassium and glycerin.
  • the sweetener can be employed in an amount of 0.001 to 50 weight%, preferably 0.005 to 30 weight% based on the total weight of the liquid formulation.
  • the flavoring agent makes patients feel a scent when taking the liquid formulation, which improves the medication compliance. It can be, for example, at least one substance selected from the group consisting of a general fruit flavor or various fruit flavors such as apple flavor, cherry flavor, orange flavor, strawberry flavor, banana flavor, grape flavor, mango flavor and peach flavor; vanilla flavor; mint flavor; and honey flavor.
  • the flavoring agent can be employed in an amount of 0.1 to 5 weight%, preferably 0.2 to 3 weight% based on the total weight of the liquid formulation.
  • the preservative is inhibits the growth of microorganisms during storage of the liquid formulation, which may be, for example, at least one substance selected from the group consisting of paraoxybenzoates such as paraoxybenzoic acid methyl, paraoxybenzoic acid ethyl, paraoxybenzoic acid propyl and paraoxybenzoic acid butyl; benzoates such as benzoic acid and sodium benzoate; and sorbates such as sorbic acid and potassium sorbate.
  • the preservative can be employed in an amount of 0.01 to 2 weight%, preferably 0.02 to 1 weight% based on the total weight of the liquid formulation.
  • the solubilizing agent plays the role of improving the solubility of an active ingredient and the like in the liquid formulation, which may be, for example, at least one substance selected from the group consisting of meglumine, arginine, and lysine.
  • the solubilizing agent can be employed in an amount of 0.001 to 1.0 weight%, preferably 0.005 to 0.5 weight% based on the total weight of the liquid formulation.
  • the liquid formulation can also employ an emulsifying agent to improve the feature of the liquid formulation, and a pH adjusting agent to adjust the acidity of the liquid formulation to an appropriate level.
  • the liquid formulation can comprise a solvent to dissolve an active ingredient and the like.
  • the solvent may be, but not limited to, a polar solvent, preferably a polar aqueous solvent, for example.
  • the solvent can be water (purified water).
  • the liquid formulation can be alkaline, e.g., neutral or weakly alkaline.
  • the liquid formulation can have a pH range of 6.0 to 12.0, more specifically 8.0 to 12.0.
  • the property of the liquid formulation can be improved in terms of property stability by preventing precipitations of montelukast or pharmaceutically acceptable salt thereof.
  • the active ingredient solubilized in the liquid formulation can show a solubility of 70% to 100%, specifically 80% to 100%, more specifically 90% to 100%, even more specifically 95% to 100% under the accelerated conditions of 40 °C, 75% of relative humidity and 3 month period.
  • the amount of montelukast sulfoxide produced may be 0.9% or less, specifically 0.7% or less, more specifically 0.5% or less, even more specifically 0.4% or less, while the amount of total related substancess produced may be 1%) or less, specifically 0.8% or less, more specifically 0.6% or less, even more specifically 0.5% or less.
  • the above liquid formulation can be a liquid formulation for oral administration, such as, but not limited to, a syrup, a suspension, an elixir, and a spirit, preferably a syrup.
  • the liquid formulation of the present invention allows its pharmacological ingredients to be substantially dissolved and present in a solution state, thereby preventing decrease of dissolution over time and increasing its bioavailability. Further owing to superior taste, flavor and easy dosage control, the liquid formulation of the present invention can be easily taken by patients and its medication compliance can be enhanced. And, due to the addition of an electrolyte compound it shows improvement in stability and homogeneity of drug effect by preventing recrystallization, precipitation, separation of layers or production of related substances even when stored for a long time, and can be effectively used for asthma and allergic rhinitis patients.
  • liquid formulation of the present invention can be prepared by a method comprising the steps of:
  • the pharmaceutically acceptable additive may be one of the additives exemplified above.
  • a sweetener and an antioxidant can be sequentially added thereto and stirred to prepare solution 1.
  • step (1) can comprise the steps of:
  • a solubilizing agent e.g., meglumine
  • purified water 30 °C or less, preferably 15 °C to 30 °C in a preparation tank, and stirring them
  • a sweetener to the solution obtained in the step i) and stirring them;
  • step (2) the pharmacologically active ingredient is montelukast or a pharmaceutically acceptable salt thereof, specific examples of which have been described above.
  • step (2) can comprise the steps of:
  • the liquid formulation can be prepared by mixing the prepared solution 1 with solution 2 and adding purified water thereto to adjust the concentration, as stated above.
  • the liquid formulation can be prepared by adding solution 2 to solution 1, and then adding sterilized purified water cooled in room temperature thereto until reaching a preferred volume, followed by stirring them. It is preferable for the liquid formulation prepared as above to be subjected to the step of filtration through 1 /m filter and the like.
  • the final liquid formulation prepared can be stored in a storage tank or an appropriate container.
  • Example 1 Preparation of a liquid formulation comprising montelukast
  • solution 1 0.20 g of meglumine was dissolved in 50 mL of sterile purified water in a preparation tank with stirring. After cooling the preparation tank to 30 °C or lower, 0.50 g of sucralose was added thereto and stirred, and then 0.01 g of sodium edetate was added thereto, to prepare solution 1. Separately, after preparing a solution by adding 0.2 g of potassium chloride to purified water at 25 °C, 0.104 g of montelukast sodium (equivalent to 0.100 g of montelukast alone) was added thereto and stirred, to prepare solution 2. Solution 2 was mixed with solution 1, and sterile purified water was added thereto to prepare a solution with a final volume of 100 mL.
  • Liquid formulations were prepared by the same method as Example 1 , except for the addition of potassium chloride or sodium chloride as a stabilizer in the amount described in Table 1.
  • Liquid formulations were prepared by the same method as Example 1, except that the stabilizer was either excluded or potassium chloride, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate or glucose was added as a stabilizer in the amount described in Table 2.
  • Examples 1 to 8 was measured with a pH meter. The results are shown in Table 3 below.
  • pHs of the liquid formulations of Comparative Examples were in the range of 9 to 11, except for Comparative Example 5.
  • the liquid formulation of Comparative Example 5 showed pH out of a preferred range due to strong alkalinity of potassium hydroxide, although potassium hydroxide was employed in the same amount as potassium chloride in Example 1.
  • the liquid formulations of Examples 1 to 3 generated no precipitations and showed transparent properties during 3 months of accelerated conditions.
  • the liquid formulation of Comparative Example 1 in which no electrolyte compound was added, showed precipitation and opaque property on day 7 of acceleration.
  • the ionizing capacity on the active ingredient decreased, resulting in opaque property along with precipitation formation.
  • the liquid formulations of Comparative Examples 4 to 6 although their pHs were within the range of 8.0-12.0, showed precipitation and browning phenomenon upon 3 month acceleration, due to the addition of strong alkaline electrolyte compounds which imposed strong stimulation to the main ingredient.
  • the liquid formulation of Comparative Example 7 showed precipitation due to low ionizing capacity of the electrolyte compound..
  • the liquid formulation of Comparative Example 8 showed precipitation on day 7 of acceleration, due to the addition of non-electrolyte component.
  • montelukast sodium was added at a concentration of 1 ,040 ⁇ g/mL, which corresponds to a concentration of 1 ,000 ⁇ g/mL of montelukast, assuming that the entire amount of inputted montelukast has been dissolved.
  • Test timing initial, after 1 and 3 months
  • Detector ultraviolet absorption spectrophotometer (wavelength: 238 nm) Column: stainless steel column (inner diameter: about 4.6 mm; length: about 25 cm) packed with octylsilyl silica gel (particle diameter: 5 ⁇ ) for liquid chromatography (Zorbax SB-Phenyl, Agilent)

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Abstract

La présente invention concerne une préparation liquide comprenant un composé d'électrolyte, ainsi que du montélukast ou un sel de montélukast pharmaceutiquement acceptable en tant que principe actif. L'invention concerne également un procédé de préparation associé. Selon la présente invention, le montélukast ou le sel de montélukast pharmaceutiquement acceptable est sensiblement dissous et présent à l'état de solution, ce qui améliore sa stabilité dans le temps, évite la baisse de dissolution et la perte de stabilité dans le temps et augmente sa biodisponibilité. La plus grande stabilité de la préparation liquide, son goût meilleur et son arôme plus développé lui permettent d'être plus facilement acceptée par le patient, et d'être utilisée efficacement pour le traitement de l'asthme et de la rhinite allergique.
PCT/KR2015/003529 2014-05-07 2015-04-08 Préparation liquide plus stable comprenant du montélukast ou un sel de montélukast pharmaceutiquement acceptable, et procédé de préparation associé Ceased WO2015170835A1 (fr)

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KR1020140054401A KR102391494B1 (ko) 2014-05-07 2014-05-07 몬테루카스트 또는 이의 약제학적으로 허용가능한 염을 포함하는 안정성이 개선된 액상 제제 및 이의 제조방법
KR10-2014-0054401 2014-05-07

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Cited By (1)

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GB2577248A (en) * 2018-09-13 2020-03-25 Syri Ltd A pharmaceutical liquid composition of leukotriene receptor antagonist

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KR20200138556A (ko) 2019-05-31 2020-12-10 지엘팜텍주식회사 몬테루카스트 또는 그의 약제학적으로 허용가능한 염을 포함하는 시럽 조성물
CN121532170A (zh) * 2023-07-18 2026-02-13 三亚制药株式会社 含普仑司特的药物组合物的制备方法以及通过所述制备方法制备的药物组合物

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WO2003101434A2 (fr) * 2001-12-21 2003-12-11 Sampad Bhattacharya Compositions pharmaceutiques intranasales comprenant un antihistaminique et un inhibiteur de leucotrienes
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WO2012066401A1 (fr) * 2010-11-16 2012-05-24 Lupin Limited Compositions pharmaceutiques orales stables de montélukast
KR20120089958A (ko) * 2010-12-31 2012-08-16 주식회사 드림파마 안정성 및 복약 순응도가 향상된 경구투여용 몬테루카스트 시럽제제

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030066753A1 (en) * 2001-09-26 2003-04-10 Pfirrmann Rolf W. Stable taurolidine electrolyte solutions
WO2003101434A2 (fr) * 2001-12-21 2003-12-11 Sampad Bhattacharya Compositions pharmaceutiques intranasales comprenant un antihistaminique et un inhibiteur de leucotrienes
WO2007126865A2 (fr) * 2006-03-30 2007-11-08 Patrin Pharma Administration nasale d'antagonistes de leukotriènes
KR20100093428A (ko) * 2009-02-16 2010-08-25 서울대학교산학협력단 항알러지성 약물을 활성성분으로 함유하는 비강투여용 액상제제
WO2012066401A1 (fr) * 2010-11-16 2012-05-24 Lupin Limited Compositions pharmaceutiques orales stables de montélukast
KR20120089958A (ko) * 2010-12-31 2012-08-16 주식회사 드림파마 안정성 및 복약 순응도가 향상된 경구투여용 몬테루카스트 시럽제제

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2577248A (en) * 2018-09-13 2020-03-25 Syri Ltd A pharmaceutical liquid composition of leukotriene receptor antagonist

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