WO2022022656A1 - 一种冻干口服制剂 - Google Patents

一种冻干口服制剂 Download PDF

Info

Publication number
WO2022022656A1
WO2022022656A1 PCT/CN2021/109414 CN2021109414W WO2022022656A1 WO 2022022656 A1 WO2022022656 A1 WO 2022022656A1 CN 2021109414 W CN2021109414 W CN 2021109414W WO 2022022656 A1 WO2022022656 A1 WO 2022022656A1
Authority
WO
WIPO (PCT)
Prior art keywords
freeze
oral preparation
dried oral
water
sodium
Prior art date
Application number
PCT/CN2021/109414
Other languages
English (en)
French (fr)
Inventor
张严源
吴龙昊
李鹏飞
梁莹莹
Original Assignee
北京兴源祥生物科技（集团）有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 北京兴源祥生物科技（集团）有限公司 filed Critical 北京兴源祥生物科技（集团）有限公司
Publication of WO2022022656A1 publication Critical patent/WO2022022656A1/zh

Links

Classifications

    • 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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • 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

Definitions

  • the invention relates to the field of freeze-dried preparations in the field of biomedicine, in particular to a freeze-dried oral preparation.
  • Montelukast sodium is a representative drug in the class of leukotriene receptor antagonists and has a wide range of therapeutic applications.
  • Montelukast sodium has poor stability and exhibits a strong degradation trend under light, heat and humidity conditions, and light sensitivity is the dominant factor.
  • Montelukast sodium can be degraded rapidly under light conditions, and the degradation under other conditions can often be traced back to light.
  • the main degradation impurities are oxidation products (sulfoxide and cis-sulfoxide) and light products ( cis isomer). Therefore, in the production of pharmaceutical preparations with montelukast sodium as the active ingredient, it is very important to solve the problem of light sensitivity, and it is necessary to provide a freeze-dried oral preparation with stable pharmaceutical active ingredients.
  • a lyophilized oral formulation includes a pharmaceutical active ingredient and a light stabilizer; the pharmaceutical active ingredient is montelukast or a pharmaceutically acceptable salt thereof, and the light stabilizer is a water-soluble pigment.
  • the water-soluble pigment is an anthocyanin, an anthocyanin, or a catechin oxidation product.
  • the water-soluble pigment is selected from the group consisting of sunset yellow, quinoline yellow, tartrazine, brilliant blue, indigo, patent blue, carmine, allura red, amaranth, cochineal, carmine, bean green, and One or more of the fruit greens.
  • the water-soluble pigment is allura red and/or tartrazine.
  • the lyophilized oral formulation further contains excipients.
  • the excipients are selected from one or more of thickeners, pH adjusters, flavoring agents, and backbone proppants.
  • the backbone proppant is selected from one or more of sugars, sugar alcohols, amino acids, small molecule salts and small molecule organic acids.
  • the backbone proppant is selected from the group consisting of sucrose, glucose, fructose, xylose, lactose, maltose, mannose, sorbose, malttooligosaccharides, fructooligosaccharides, dextran, xylitol, sorbose Alcohol, isosorbide, mannitol, erythritol, maltitol, isomalt, lactitol, glycine, sodium glycinate, sodium chloride, sodium phosphate, citrate, citric acid and tartaric acid one or more.
  • the thickening agent is selected from one or more of gelatin, pullulan, water-soluble cellulose, and povidone.
  • the flavoring agent is a non-sugar sweetener.
  • the flavoring agent is selected from one or more of saccharin and its sodium salt, aspartame, cyclamate, sucralose, sucralose, and acesulfame potassium.
  • the pH adjusting agent is sodium citrate or sodium hydroxide.
  • the weight ratio of the active pharmaceutical ingredient to the water-soluble pigment is 2.5-1000.
  • the weight ratio of the active pharmaceutical ingredient to the water-soluble pigment is 35-200.
  • the lyophilized oral formulation is an orally disintegrating tablet.
  • a water-soluble pigment as a light stabilizer in the preparation of a freeze-dried oral preparation of montelukast.
  • pharmaceutically acceptable salt refers to the form of a pharmaceutically active ingredient, including pharmaceutically acceptable salts of organic acids and bases or inorganic acids and bases.
  • unit dose refers to a single dose which can be administered to a subject and which is easy to handle and package.
  • a unit dose can be a single tablet, pill, capsule, lozenge, suppository, cachet, drops, ampoules, and the like.
  • the present application also provides a freeze-dried oral preparation having stable pharmaceutical active ingredients.
  • the lyophilized oral formulation of this embodiment includes a pharmaceutical active ingredient and a light stabilizer.
  • the freeze-dried oral preparations include, but are not limited to, oral preparations in the form of tablets, pills, granules and the like.
  • the lyophilized oral formulation is a lyophilized orally disintegrating tablet.
  • the active pharmaceutical ingredient contained in the freeze-dried oral formulation is montelukast or a pharmaceutically acceptable salt thereof.
  • Montelukast and its pharmaceutically acceptable salts are used as active pharmaceutical ingredients, and the content of the active pharmaceutical ingredients in the unit dose of the freeze-dried oral preparation can be in the range of 0-50 mg.
  • the pharmaceutically active ingredient contained in the freeze-dried oral preparation is a pharmaceutically acceptable salt of montelukast, such as montelukast sodium
  • the content of the pharmaceutically active ingredient is carried out according to montelukast. discount.
  • the content of the pharmaceutically active ingredient in a unit dose of the lyophilized oral formulation may be about 2-10 mg.
  • the lyophilized oral formulation may contain about 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of the active pharmaceutical ingredient in a unit dose of the lyophilized oral formulation. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here.
  • the light stabilizer contained in the lyophilized oral formulation is a water-soluble pigment.
  • the water-soluble pigment may be anthocyanin, anthocyanin, or catechin oxidation product.
  • Non-limiting examples of water-soluble pigments that can be used as light stabilizers include, but are not limited to, sunset yellow, quinoline yellow, tartrazine, brilliant blue, indigo, patent blue, carmine, allura red, amaranth, cochineal , Carmine, bean green, fruit green and so on.
  • the water-soluble pigment may be selected from one or more of allura red pigment, tartrazine pigment, bright blue pigment, fruit green pigment, and pea green pigment. In some embodiments, the water-soluble pigment may be allura red and/or tartrazine.
  • the content of the water-soluble pigment in a unit dose of the lyophilized oral formulation may be about 0.004-6 mg. In some embodiments, the content of water-soluble pigments in a unit dose of the lyophilized oral formulation may be about 0.004 mg, 0.006 mg, 0.008 mg, 0.01 mg, 0.03 mg, 0.05 mg, 0.07 mg, 0.09 mg, 0.1 mg , 0.3mg, 0.5mg, 0.5mg, 0.7mg, 0.9mg, 1mg, 1.2mg, 1.4mg, 1.6mg, 1.8mg, 2mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3mg, 3.2mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.4 mg, 5.6 mg, 5.8 mg or 6 mg. It also includes any range characterized by a combination of the above-menti
  • the weight ratio of the active pharmaceutical ingredient to the water-soluble pigment may be about 2.5-1000. In some embodiments, the weight ratio of pharmaceutically active ingredient to water-soluble pigment may be about 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 , 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350 , 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here.
  • the lyophilized oral formulation may also include one or more of thickeners, matrix proppants, flavoring agents, pH adjusters, preservatives, and antioxidants .
  • the thickening agent contained in the freeze-dried oral formulation may be selected from one or more of gums, sugars, water-soluble cellulose and povidone.
  • useful thickeners include, but are not limited to, gelatin, pectin, collagen, gellan gum, carob gum, locust bean gum, carrageenan, alginate, agar, guar gum , Xanthan gum, kelp gum, pullulan, transparent starch, microcrystalline cellulose, carboxymethyl cellulose, ethyl cellulose, PVPk30, etc.
  • the thickening agent is selected from one or more of gelatin, pullulan, water-soluble cellulose, and povidone.
  • the content of the thickening agent in a unit dose of the lyophilized oral formulation may be about 0.3-20 mg. In some embodiments, the content of the thickening agent in a unit dose of the lyophilized oral formulation may be about 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg or 20 mg. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here.
  • the backbone proppant is selected from one or more of sugars, sugar alcohols, amino acids, small molecule salts, and small molecule organic acids.
  • scaffolding proppants include, but are not limited to, glucose, sucrose, fructose, xylose, lactose, galactose, maltose, isomalt, mannose, sorbose, trehalose, raffinose, pullulan Polysaccharide, Dextran, Hydroxypropyl Cyclodextrin, Xylitol, Sorbitol, Isosorbide, Mannitol, Erythritol, Maltitol, Isomalt, Lactitol, Glycine, Sodium Glycinate, Alanine, Vale Amino acid, proline, serine, cysteine, asparagine, glutamine, threonine, lysine, arginine, histidine, glutamic acid, hydroxy
  • the backbone proppant is selected from the group consisting of sucrose, glucose, fructose, xylose, lactose, maltose, mannose, sorbose, malttooligosaccharides, fructooligosaccharides, dextran, xylitol, sorbose
  • sucrose glucose, fructose, xylose, lactose, maltose, mannose, sorbose, malttooligosaccharides, fructooligosaccharides, dextran, xylitol, sorbose
  • the scaffolding proppant is mannitol.
  • the flavoring agent in the lyophilized oral formulation includes a non-saccharide sweetener.
  • Non-sugar sweeteners that can be used as flavoring agents include, but are not limited to, aspartame, sodium cyclamate, saccharin, calcium saccharin, sodium saccharin, sucralose, aspartame, acesulfame potassium, alitame, Sweet, stevioside, thaumatin, mogrosin, thomastin, etc.
  • the flavoring agent may be selected from one or more of saccharin and its sodium or calcium salts, aspartame, cyclamate, sucralose, sucralose, and acesulfame potassium.
  • the lyophilized oral formulation may contain a biocompatible pH adjusting agent.
  • pH adjusters include, but are not limited to, hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, phosphoric acid, citric acid, sodium citrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dihydrogen phosphate Potassium, disodium hydrogen phosphate, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, potassium citrate, potassium metaphosphate, sodium lactate solution, sodium carbonate, etc.
  • the pH adjusting agent may be sodium citrate or sodium hydroxide.
  • the application also provides the use of water-soluble pigments as light stabilizers in the preparation of montelukast freeze-dried oral preparations.
  • Non-limiting examples of formulations that can be administered orally include, but are not limited to, tablets, pills, powders, granules, and the like.
  • the lyophilized oral formulation is an orally disintegrating tablet.
  • Water-soluble pigments that can act as light stabilizers include anthocyanins, anthocyanins, and catechin oxidation products.
  • the water-soluble pigment is selected from the group consisting of sunset yellow, quinoline yellow, tartrazine, brilliant blue, indigo, patent blue, carmine, allura red, amaranth, cochineal, carmine, bean green, and One or more of the fruit greens. Details on water-soluble pigments can be found elsewhere in this disclosure.
  • test materials in the following examples are conventional methods unless otherwise specified.
  • the test materials used in the following examples were purchased from conventional biochemical reagent companies unless otherwise specified.
  • Appearance evaluation Take the orally disintegrating tablet upwards from the bottom of the blister with your fingers, and observe the appearance, smoothness, depression, cracks, sticking to the bottom, shrinkage, etc. with the naked eye.
  • the orally disintegrating tablet meltability test was performed to simulate its release in the oral cavity according to USP standards. Put the sample into 2 mL of water at 37°C, observe the phenomenon still, and measure the time for complete disintegration. Measurements were repeated in 6 independent experiments and results are given as mean values in seconds.
  • the samples were placed under a fluorescent lamp with an illuminance of 450 ⁇ 50Lux (simulating natural illuminance), and after 0 hours, 6 hours, 24 hours, and 72 hours, samples were taken for substance content detection, so as to analyze the stability of the samples under illumination conditions. .
  • test solution Take an appropriate amount of the montelukast sodium orally disintegrating tablet sample of the corresponding embodiment (approximately equivalent to 41.5 mg of montelukast), put it in a 100 mL brown volumetric flask, add 70 mL of diluent, ultrasonicate for 30 minutes to dissolve, and let it cool to room temperature , add diluent to volume to the mark, filter with 0.45 ⁇ m filter membrane, discard the initial filtrate, and take the subsequent filtrate as the test solution.
  • step 3 Add the mixed solution obtained in step 1) to the mixed solution obtained in step 2), add or not add a pH adjuster according to the formula table of different embodiments, add water to make the volume to 100 mL, and stir evenly.
  • step 4) The mixed solution obtained in step 4) is divided into tablet blister molds and placed in a freeze dryer; set to -50°C for rapid cooling, vacuum degree 0.1500mbar, duration 90min; from -50°C to - 30°C, hold for 150min; from -30°C to -15°C, hold for 90min; from -15°C to 0°C, hold for 20min; from 0°C to 20°C, hold for 20min; from 20°C to 35°C, Hold for 20min.
  • Embodiment 1 Montelukast sodium orally disintegrating tablet
  • a control sample of the oral formulation of montelukast sodium containing iron oxide red colorant was prepared.
  • Montelukast sodium was passed through a 100-mesh sieve, and iron oxide red was passed through an 80-mesh sieve.
  • Table 1.2 weigh the iron oxide red, microcrystalline cellulose, croscarmellose sodium, PVP k30 of the formula amount and mix well, then add the montelukast sodium of the formula amount and the above mixture in equal amounts for 3 times Mix uniformly, pass through an 80-mesh sieve for dry granulation, add the formula amount of colloidal silicon dioxide and magnesium stearate, mix well, and press into tablets to obtain the oral preparation of montelukast sodium containing colored iron oxide colorant, namely Control sample 3.
  • Illumination stability test was carried out on samples 1 to 2 of the montelukast orally disintegrating tablet and samples 1 to 3 of the control group using the aforementioned light test and substance content detection methods, and the test results are shown in Table 1.3.
  • the montelukast orally disintegrating tablet samples 1 and 2 are montelukast orally disintegrating tablets containing different kinds of water-soluble pigments.
  • Sample 1 of the control group is an orally disintegrating tablet of montelukast without water-soluble pigments, and the other components and their contents are the same as those of sample 1 except that they do not contain water-soluble pigments.
  • Sample 2 of the control group is montelukast sodium singnarin tablet, which can protect from light by adding red iron oxide, yellow iron oxide and other substances in the coating to reduce the light risk of the drug wrapped in the coating.
  • sample 3 of the control group is an oral formulation of montelukast sodium containing a colored iron oxide colorant, which is prepared by mixing the powdered iron oxide colorant with other drug powders including montelukast sodium. Tablets to protect from light.
  • test results of physical and chemical properties of samples 1, 2 and control sample 1 are shown in Table 1.4. According to the test results, the montelukast sodium oral disintegrating tablet sample 1 and sample 2 were in good molding state, and the disintegration time was extremely short, which met the requirements of various quality indicators for the oral disintegrating tablet.
  • Embodiment 2 Montelukast sodium orally disintegrating tablet
  • the cis-isomer and total impurity content and the content of montelukast sodium in samples 3 to 8 of montelukast sodium orally disintegrating tablet have little difference after exposure to light for different periods of time; Impurities of cis isomers can be controlled within 0.1% after 72 hours of continuous exposure under the light.
  • test results of physical and chemical properties of samples 3 to 8 are shown in Table 2.3. According to the test results, the montelukast sodium oral disintegrating tablet samples 3 to 8 are in good molding state, and the disintegration time is extremely short, which meets the requirements of various quality indicators for the oral disintegrating tablet.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本申请实施例公开了一种冻干口服制剂，所述冻干口服制剂包括药物活性成分和光稳定剂；所述药物活性成分为孟鲁司特或其药学上可接受的盐，所述光稳定剂为水溶性色素。所述冻干口服制剂具有稳定的药物活性成分。

Description

一种冻干口服制剂
交叉引用
本申请请求2020年7月29日提交的中国申请号202010744103.4的优先权，全部内容通过引用并入本文。
技术领域
本发明涉及生物医药领域中的冻干制剂领域，特别涉及一种冻干口服制剂。
背景技术
孟鲁司特钠是白三烯受体拮抗剂类中的代表性药物，具有广泛的治疗应用。孟鲁司特钠稳定性差，在光、热、湿的条件下都呈现较强的降解趋势，而其中光敏感是主导因素。孟鲁司特钠可在光照条件下降解迅速，并且其他条件下的降解归结原因，经常也会回溯到光照上面，主要的降解杂质为氧化产物(亚砜及顺式亚砜)及光照产物(顺式异构体)。因此，在药物活性成分为孟鲁司特钠的药品制剂生产中，如何解决光照敏感的问题至关重要，有必要提供一种具有稳定的药物活性成分的冻干口服制剂。
发明内容
根据本申请的一方面，提供了一种冻干口服制剂。所述冻干口服制剂包括药物活性成分和光稳定剂；所述药物活性成分为孟鲁司特或其药学上可接受的盐，所述光稳定剂为水溶性色素。
在一些实施例中，所述水溶性色素为花黄素、花青素或儿茶素氧化产物。
在一些实施例中，所述水溶性色素选自日落黄、喹啉黄、柠檬黄、亮蓝、靛蓝、专利蓝、胭脂红、诱惑红、苋菜红、胭脂虫红、胭脂红、豆绿和果绿中的一种或多种。
在一些实施例中，所述水溶性色素为诱惑红和/或柠檬黄。
在一些实施例中，所述冻干口服制剂还含有赋形剂。
在一些实施例中，所述赋形剂选自增稠剂、pH调节剂、矫味剂、骨架支撑剂中的一种或多种。
在一些实施例中，所述骨架支撑剂选自糖、糖醇、氨基酸、小分子盐和小分子有机酸中的一种或多种。
在一些实施例中，所述骨架支撑剂选自蔗糖、葡萄糖、果糖、木糖、乳糖、麦芽糖、甘露糖、山梨糖、低聚麦芽糖、低聚果糖、葡聚糖、木糖醇、山梨糖醇、异山梨醇、甘露糖醇、赤藓糖醇、麦芽糖醇、异麦芽糖醇、乳糖醇、甘氨酸、甘氨酸钠、氯化钠、磷酸钠盐、枸橼酸盐、枸橼酸和酒石酸中的一种或多种。
在一些实施例中，所述增稠剂选自明胶、普鲁兰多糖、水溶性纤维素和聚维酮中的一种或多种。
在一些实施例中，所述矫味剂为非糖类甜味剂。
在一些实施例中，所述矫味剂选自糖精及其钠盐、阿司帕坦、甜蜜素、蔗糖素、三氯蔗糖和安赛蜜中的一种或多种。
在一些实施例中，所述pH调节剂为枸橼酸钠或氢氧化钠。
在一些实施例中，所述冻干口服制剂中，所述药物活性成分与所述水溶性色素的重量比为2.5-1000。
在一些实施例中，所述药物活性成分与水溶性色素的重量比为35-200。
在一些实施例中，所述冻干口服制剂为口腔崩解片。
根据本申请的另一方面，提供了水溶性色素作为光稳定剂在制备孟鲁司特冻干口服制剂中的用途。
具体实施方式
以下是对本申请中一些术语的定义。
如本申请中所使用的，术语“药学上可接受的盐”是指药物活性成分的形 式，包括药学上可接受的有机酸和有机碱或者无机酸和无机碱的盐。
术语“单位剂量”是指能够施用于受试者并且易于处理和包装的单一剂量。例如，单位剂量可以为单一片剂、丸剂、胶囊、锭剂、栓剂、扁囊剂、滴剂、安瓿装等。
本申请还提供了一种冻干口服制剂，所述冻干口服制剂具有稳定的药物活性成分。
本实施例的冻干口服制剂包括药物活性成分和光稳定剂。所述冻干口服制剂包括但不限于片剂、丸剂、颗粒剂等形式的口服制剂。在一些实施例中，所述冻干口服制剂为冻干口腔崩解片。
在一些实施例中，所述冻干口服制剂所含的药物活性成分为孟鲁司特或其药学上可接受的盐。孟鲁司特及其药学上可接受的盐作为药物活性成分，在所述冻干口服制剂的单位剂量内药物活性成分的含量适用范围可在0-50mg之间。需要说明的是，若所述冻干口服制剂所含的药物活性成分为孟鲁司特的药学上可接受的盐，如孟鲁司特钠，则药物活性成分的含量按照孟鲁司特进行折算。在一些实施例中，所述冻干口服制剂的单位剂量内药物活性成分的含量可为约2-10mg。在一些实施例中，所述冻干口服制剂的单位剂量内药物活性成分的含量可为约2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg或10mg。还包括以上述端值的组合为特征的任一范围，在此不再赘述。
在一些实施例中，所述冻干口服制剂所含的光稳定剂为水溶性色素。在一些实施例中，所述水溶性色素可以为花黄素、花青素或儿茶素氧化产物。可用作光稳定剂的水溶性色素的非限制性实施例包括但不限于日落黄、喹啉黄、柠檬黄、亮蓝、靛蓝、专利蓝、胭脂红、诱惑红、苋菜红、胭脂虫红、胭脂红、豆绿、果绿等。
在一些实施例中，所述水溶性色素可选自诱惑红色素、柠檬黄色素、亮蓝色素、果绿色素、豆绿色素中的一种或多种。在一些实施例中，所述水溶性色素可为诱惑红和/或柠檬黄。
在一些实施例中，所述冻干口服制剂的单位剂量内水溶性色素的含量可约为0.004-6mg。在一些实施例中，所述冻干口服制剂的单位剂量内水溶性色素的含量可约为0.004mg、0.006mg、0.008mg、0.01mg、0.03mg、0.05mg、0.07mg、0.09mg、0.1mg、0.3mg、0.5mg、0.5mg、0.7mg、0.9mg、1mg、1.2mg、1.4mg、1.6mg、1.8mg、2mg、2.2mg、2.4mg、2.6mg、2.8mg、3mg、3.2mg、3.4mg、3.6mg、3.8mg、4mg、4.2mg、4.4mg、4.6mg、4.8mg、5mg、5.2mg、5.4mg、5.6mg、5.8mg或6mg。还包括以上述端值的组合为特征的任一范围，在此不再赘述。
在一些实施例中，所述冻干口服制剂中，药物活性成分与水溶性色素的重量比可为约2.5-1000。在一些实施例中，药物活性成分与水溶性色素的重量比可为约2.5、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、11、12、13、14、15、16、17、18、19、20、22、24、26、28、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、350、400、450、500、550、600、650、700、750、800、850、900、950或1000。还包括以上述端值的组合为特征的任一范围，此处不再赘述。
除上述讨论的药物活性成分及光稳定剂以外，所述冻干口服制剂还可以包括增稠剂、骨架支撑剂、矫味剂、pH调节剂、防腐剂、抗氧化剂中的一种或多种。
在一些实施例中，所述冻干口服制剂所含的增稠剂可选自胶类、糖类、水溶性纤维素和聚维酮中的一种或多种。可用作增稠剂的非限制性实施例包括但不限于明胶、果胶、胶原蛋白、结冷胶、角豆胶、刺槐豆胶、角叉菜胶、海藻酸盐、琼脂、瓜尔胶、黄原胶、红藻胶、普鲁兰多糖、透明淀粉、微晶纤维素、羧甲基纤维素、乙基纤维素、PVPk30等。在一些实施例中，所述增稠剂选自明胶、普鲁兰多糖、水溶性纤维素和聚维酮中的一种或多种。
在一些实施例中，所述冻干口服制剂的单位剂量内增稠剂的含量可为约0.3-20mg。在一些实施例中，所述冻干口服制剂的单位剂量内增稠剂的含量可为 约0.3mg、0.5mg、0.7mg、0.9mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、12mg、14mg、16mg、18mg或20mg。还包括以上述端值的组合为特征的任一范围，在此不再赘述。
在一些实施例中，所述骨架支撑剂选自糖、糖醇、氨基酸、小分子盐、小分子有机酸中的一种或多种。可作为骨架支撑剂的非限制性实施例包括但不限于葡萄糖、蔗糖、果糖、木糖、乳糖、半乳糖、麦芽糖、异麦芽糖、甘露糖、山梨糖、海藻糖、棉子糖、普鲁兰多糖、右旋糖酐、羟丙基环糊精、木糖醇、山梨醇、异山梨醇、甘露醇、赤藓糖醇、麦芽糖醇、异麦芽糖醇、乳糖醇、甘氨酸、甘氨酸钠、丙氨酸、缬氨酸、脯氨酸、丝氨酸、半胱氨酸、天冬酰胺、谷氨酰胺、苏氨酸、赖氨酸、精氨酸、组氨酸、谷氨酸、羟脯胺酸、异亮氨酸、亮氨酸、苯丙氨酸等。在一些实施例中，所述骨架支撑剂选自蔗糖、葡萄糖、果糖、木糖、乳糖、麦芽糖、甘露糖、山梨糖、低聚麦芽糖、低聚果糖、葡聚糖、木糖醇、山梨糖醇、异山梨醇、甘露糖醇、赤藓糖醇、麦芽糖醇、异麦芽糖醇、乳糖醇、甘氨酸、甘氨酸钠中的一种或多种。在一些实施例中，所述骨架支撑剂为甘露醇。
在一些实施例中，所述冻干口服制剂中的矫味剂包括非糖类甜味剂。可作为矫味剂的非糖类甜味剂包括但不限于阿司帕坦、甜蜜素、糖精、糖精钙、糖精钠、三氯蔗糖、天冬甜素、安赛蜜、阿力甜、纽甜、甜菊苷、奇异果素、罗汉果素、索马甜等。在一些实施例中，所述矫味剂可选自糖精及其钠盐或钙盐、阿司帕坦、甜蜜素、蔗糖素、三氯蔗糖和安赛蜜中的一种或多种。
所述冻干口服制剂中可包含具有生物相容性的pH调节剂。可作为pH调节剂的非限制性实施例包括但不限于盐酸、氢氧化钠、醋酸、醋酸钠、磷酸、枸橼酸、枸橼酸钠、磷酸二氢钾、磷酸二氢钠、磷酸氢二钾、磷酸氢二钠、碳酸铵、磷酸铵、硼酸、乳酸、枸橼酸钾、偏磷酸钾、乳酸钠溶液、碳酸钠等。在一些实施例中，所述pH调节剂可为枸橼酸钠或氢氧化钠。
本申请还提供了水溶性色素作为光稳定剂在制备孟鲁司特冻干口服制剂中的用途。
可作为口服制剂的非限制性实施例包括但不限于片剂、丸剂、散剂、颗粒剂等。在一些实施例，所述冻干口服制剂为口腔崩解片。
可作为光稳定剂的水溶性色素包括花黄素、花青素和儿茶素氧化产物。在一些实施例中，所述水溶性色素选自日落黄、喹啉黄、柠檬黄、亮蓝、靛蓝、专利蓝、胭脂红、诱惑红、苋菜红、胭脂虫红、胭脂红、豆绿和果绿中的一种或多种。关于水溶性色素的详细内容，可在本披露的其他部分中找到。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂公司购买得到的。
口腔崩解片外观的检测
外观评价：将口腔崩解片用手指从泡罩底部用力向上取出，肉眼观察外观形貌、光滑度、是否凹陷、裂纹、粘底、萎缩等。
崩解时间的检测
可以使用两种方法：
1.根据USP标准，进行口腔崩解片的溶化性实验用以模拟其在口腔中的释放。将样品放入37℃的2mL水中，静止观察现象，测定完全崩解的时间。在6个独立实验中重复测定，结果用平均值给出，以秒为单位表示。
2.根据《中国药典》2015版四部通则0921崩解时限检查法中的口崩片测试法。
光照试验
把样品放置在照度为450±50Lux(模拟自然光照度)的日光灯下，经过0小时、6小时、24小时、72小时之后，分别取样品进行物质含量检测，从而分析在光照条件下样品的稳定性。
有关物质含量的检测(顺式异构体，总杂)
避光操作，在72小时内进行测定。采用高效液相色谱法(中国药典2015年版四部通则0512)对样品进行检测。色谱条件及系统适用性试验用苯基键合硅胶为填充剂，柱温30℃；检测波长为238nm；流动相流速为1.2mL/min；进样 体积10μL；采用线性梯度洗脱，流动相和洗脱程序见下表。流动相A为0.15％的三氟乙酸水溶液；流动相B为0.15％的三氟乙酸乙腈溶液；稀释剂为75％甲醇水溶液。
时间/min 流动相A/％ 流动相B/％
0 60 40
3 60 40
16 49 51
35 49 51
50 60 40
制备系统适用性溶液。称取孟鲁司特钠原料13.36mg，加入稀释剂稀释至25mL，加入过氧化氢10μL，混匀，于自然光下放置1h即得。
制备供试品溶液。取对应实施例的孟鲁司特钠口腔崩解片样品适量(约相当于孟鲁司特41.5mg)，置100mL棕色量瓶中，加稀释剂70mL，超声30分钟使溶解，放冷至室温，加稀释剂定容至刻度，0.45μm滤膜过滤，弃去初滤液，取续滤液作为供试品溶液。
制备自身对照溶液。取供试品溶液0.2mL，加入稀释剂定容至20mL。
孟鲁司特钠含量的检测
避光操作，按照前述有关物质含量检测的方法，取供试品溶液及对照品溶液分别进样，记录色谱图，外标法以峰面积计算，即得孟鲁司特钠含量。
冻干口服制剂的制备方法
1)称取配方量的增稠剂，添加水，于60℃水浴搅拌使其完全溶解，放冷至室温。
2)另取适量水，根据不同实施例的配方表，称取配方量的药物活性成分和其他组分，加入水中搅拌均匀。
3)将步骤1)所得混合液添加到步骤2)所得混合液中，根据不同实施例的配方表，添加或不添加pH调节剂，加水定容至100mL，搅拌均匀。
4)将步骤3)所得混合液脱气。
5)将步骤4)所得混合液分装于片剂泡罩模具中，置于冻干机中；设定-50℃ 快速降温，真空度0.1500mbar，持续时间90min；由-50℃升至-30℃，保持150min；由-30℃升至-15℃，保持90min；由-15℃升至0℃，保持20min；由0℃升至20℃，保持20min；由20℃升至35℃，保持20min。
6)取出产品，铝塑密封保存。
实施例1.孟鲁司特钠口腔崩解片
利用前述冻干口腔制剂的制备方法，按照如表1.1所示的配方制备含柠檬黄色素的孟鲁司特口腔崩解片样品1；制备含诱惑红色素的孟鲁司特口腔崩解片样品2；制备不含水溶性色素的孟鲁司特口腔崩解片，即对照组样品1。选用市售制剂顺尔宁孟鲁司特钠片作为对照组样品2，购自MSD MERCK CO公司。
表1.1配方表
Figure PCTCN2021109414-appb-000001
制备含氧化铁红着色剂的孟鲁司特钠口服制剂对照组样品。
孟鲁司特钠过100目筛，氧化铁红过80目筛。按照表1.2称取配方量的氧化铁红、微晶纤维素、交联羧甲基纤维素钠、PVP k30混合均匀，然后将配方量的孟鲁司特钠与上述混合物等量递加3次混合均匀，过80目筛干法制粒，外加配方量的胶态二氧化硅和硬脂酸镁，混匀，压片，制得含有色氧化铁着色剂的孟鲁司特钠口服制剂，即对照组样品3。
表1.2配方表
组分 重量百分比/％ 配方量/g
孟鲁司特钠(钠盐需折算) 2.5 0.83
微晶纤维素(pH101型) 84.8 27.136
PVP k30 4.0 1.28
交联羧甲基纤维素钠 7.5 2.40
胶态二氧化硅 0.5 0.16
氧化铁红 0.2 0.064
硬脂酸镁 0.5 0.16
共 100 32
表1.3稳定性试验结果
Figure PCTCN2021109414-appb-000002
注：“ND”表示未检出。
用前述光照试验及物质含量的检测方法对孟鲁司特口腔崩解片样品1至2以及对照组样品1至3进行光照稳定性试验，试验结果见表1.3。
表1.3中，孟鲁司特口腔崩解片样品1和2为含不同种类水溶性色素的孟鲁司特口腔崩解片。对照组样品1为不含水溶性色素的孟鲁司特口腔崩解片，除不含水溶性色素外，其余组分及其含量与样品1相同。对照组样品2为顺尔宁孟鲁司特钠片，其通过在包衣中添加红色铁氧化物、黄色铁氧化物等物质达到避光效果，降低包衣内包裹的药物的光照风险。相似的，对照组样品3为含有色氧化铁着色剂的孟鲁司特钠口服制剂，其通过将粉末状的氧化铁着色剂与包含孟鲁司特钠在内的其他药物粉末进行混合制成片剂来达到避光效果。
由试验结果可知：在经过不同时长的光照之后，与对照组样品1相比，孟鲁司特口腔崩解片样品1和2中，孟鲁司特钠的顺式异构体和总杂含量均受到有效控制，孟鲁司特钠含量变化小。由此可见，含有水溶性色素的孟鲁司特钠口腔崩解片中，药物活性成分孟鲁司特钠的稳定性显著提高。孟鲁司特口腔崩解片样品1和2在药物活性成分孟鲁司特钠的稳定性方面明显优于对照组样品2和对照组样品3。
表1.4理化性能检测结果
Figure PCTCN2021109414-appb-000003
注：“/”表示未检测崩解时间。
样品1、2和对照组样品1的理化性能检测结果见表1.4。根据检测结果可知，孟鲁司特钠口腔崩解片样品1和样品2的成型状态良好，崩解时间极短，符合口腔崩解片的各项质量指标要求。
实施例2.孟鲁司特钠口腔崩解片
用前述冻干口腔制剂的制备方法制备含水溶性色素的孟鲁司特钠口腔崩解片，即样品3至8。其中，口腔崩解片的配方见表2.1。
表2.1配方表
Figure PCTCN2021109414-appb-000004
前述光照试验及物质含量的检测方法对孟鲁司特钠口腔崩解片样品3至8进行光照稳定性试验，试验结果见表2.2。
表2.2稳定性试验结果
Figure PCTCN2021109414-appb-000005
Figure PCTCN2021109414-appb-000006
注：“ND”表示未检出。
从试验结果上看，在经过不同时长的光照之后，孟鲁司特钠口腔崩解片样品3至8中的顺式异构体和总杂含量以及孟鲁司特钠含量差异较小；在目光灯下连续暴露72h后顺式异构体杂质均可控制在0.1％以内。
表2.3理化性能检测结果
Figure PCTCN2021109414-appb-000007
样品3至8的理化性能检测结果见表2.3。根据检测结果可知，孟鲁司特 钠口腔崩解片样品3至样品8的成型状态良好，崩解时间极短，符合口腔崩解片的各项质量指标要求。
上文已对基本概念做了描述，显然，对于本领域技术人员来说，上述详细披露仅仅作为示例，而并不构成对本说明书的限定。虽然此处并没有明确说明，本领域技术人员可能会对本说明书进行各种修改、改进和修正。该类修改、改进和修正在本说明书中被建议，所以该类修改、改进、修正仍属于本说明书示范实施例的精神和范围。

Claims (19)

  1. 一种冻干口服制剂，其特征在于，所述冻干口服制剂包括药物活性成分和光稳定剂；所述药物活性成分为孟鲁司特或其药学上可接受的盐，所述光稳定剂为水溶性色素。
  2. 如权利要求1所述的冻干口服制剂，其特征在于，所述水溶性色素为花黄素、花青素或儿茶素氧化产物。
  3. 如权利要求2所述的冻干口服制剂，其特征在于，所述水溶性色素选自日落黄、喹啉黄、柠檬黄、亮蓝、靛蓝、专利蓝、胭脂红、诱惑红、苋菜红、胭脂虫红、胭脂红、豆绿和果绿中的一种或多种。
  4. 如权利要求3所述的冻干口服制剂，其特征在于，所述水溶性色素为诱惑红和/或柠檬黄。
  5. 如权利要求1所述的冻干口服制剂，其特征在于，所述冻干口服制剂还含有赋形剂。
  6. 如权利要求5所述的冻干口服制剂，其特征在于，所述赋形剂选自增稠剂、pH调节剂、矫味剂、骨架支撑剂中的一种或多种。
  7. 如权利要求6所述的冻干口服制剂，其特征在于，所述骨架支撑剂选自糖、糖醇、氨基酸、小分子盐和小分子有机酸中的一种或多种。
  8. 如权利要求7所述的冻干口服制剂，其特征在于，所述骨架支撑剂选自蔗糖、葡萄糖、果糖、木糖、乳糖、麦芽糖、甘露糖、山梨糖、低聚麦芽糖、低聚果糖、葡聚糖、木糖醇、山梨糖醇、异山梨醇、甘露糖醇、赤藓糖醇、麦芽糖醇、异麦芽糖醇、乳糖醇、甘氨酸、甘氨酸钠、氯化钠、磷酸钠盐、枸橼酸盐、 枸橼酸和酒石酸中的一种或多种。
  9. 如权利要求6所述的冻干口服制剂，其特征在于，所述增稠剂选自明胶、普鲁兰多糖、水溶性纤维素和聚维酮中的一种或多种。
  10. 如权利要求6所述的冻干口服制剂，其特征在于，所述矫味剂为非糖类甜味剂。
  11. 如权利要求10所述的冻干口服制剂，其特征在于，所述矫味剂选自糖精及其钠盐、阿司帕坦、甜蜜素、蔗糖素、三氯蔗糖和安赛蜜中的一种或多种。
  12. 如权利要求6所述的冻干口服制剂，其特征在于，所述pH调节剂为枸橼酸钠或氢氧化钠。
  13. 如权利要求1所述的冻干口服制剂，其特征在于，所述冻干口服制剂中，所述药物活性成分与水溶性色素的重量比为2.5-1000。
  14. 如权利要求13所述的冻干口服制剂，其特征在于，所述药物活性成分与水溶性色素的重量比为35-200。
  15. 如权利要求1-14中任一项所述的冻干口服制剂，其特征在于，所述冻干口服制剂为口腔崩解片。
  16. 水溶性色素作为光稳定剂在制备孟鲁司特冻干口服制剂中的用途。
  17. 如权利要求16所述的用途，其特征在于，所述冻干口服制剂为口腔崩解片。
  18. 如权利要求17所述的用途，其特征在于，所述水溶性色素为花黄素、花青素或儿茶素氧化产物。
  19. 如权利要求18所述的用途，其特征在于，所述水溶性色素选自日落黄、喹啉黄、柠檬黄、亮蓝、靛蓝、专利蓝、胭脂红、诱惑红、苋菜红、胭脂虫红、胭脂红、豆绿和果绿中的一种或多种。
PCT/CN2021/109414 2020-07-29 2021-07-29 一种冻干口服制剂 WO2022022656A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010744103.4A CN114053231A (zh) 2020-07-29 2020-07-29 一种有色的孟鲁司特钠冻干口腔崩解片
CN202010744103.4 2020-07-29

Publications (1)

Publication Number Publication Date
WO2022022656A1 true WO2022022656A1 (zh) 2022-02-03

Family

ID=80037664

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/109414 WO2022022656A1 (zh) 2020-07-29 2021-07-29 一种冻干口服制剂

Country Status (2)

Country Link
CN (1) CN114053231A (zh)
WO (1) WO2022022656A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101732268A (zh) * 2010-01-09 2010-06-16 鲁南制药集团股份有限公司 一种孟鲁司特钠片剂及其制备方法
CN101773481A (zh) * 2010-01-09 2010-07-14 鲁南制药集团股份有限公司 一种含有孟鲁司特钠的咀嚼片
CN105769825A (zh) * 2014-12-24 2016-07-20 广州朗圣药业有限公司 一种孟鲁司特钠的口腔膜剂及其制备方法
CN108888602A (zh) * 2018-08-16 2018-11-27 海南锦瑞制药有限公司 一种孟鲁司特钠制剂及其制备方法
EP3505172A1 (en) * 2017-12-31 2019-07-03 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. A pharmaceutical composition comprising montelukast and levocetirizine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017052718A (ja) * 2015-09-09 2017-03-16 沢井製薬株式会社 モンテルカスト含有口腔内崩壊錠
CN111000813B (zh) * 2020-01-06 2021-10-29 国药集团致君（深圳）坪山制药有限公司 孟鲁司特钠咀嚼片及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101732268A (zh) * 2010-01-09 2010-06-16 鲁南制药集团股份有限公司 一种孟鲁司特钠片剂及其制备方法
CN101773481A (zh) * 2010-01-09 2010-07-14 鲁南制药集团股份有限公司 一种含有孟鲁司特钠的咀嚼片
CN105769825A (zh) * 2014-12-24 2016-07-20 广州朗圣药业有限公司 一种孟鲁司特钠的口腔膜剂及其制备方法
EP3505172A1 (en) * 2017-12-31 2019-07-03 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. A pharmaceutical composition comprising montelukast and levocetirizine
CN108888602A (zh) * 2018-08-16 2018-11-27 海南锦瑞制药有限公司 一种孟鲁司特钠制剂及其制备方法

Also Published As

Publication number Publication date
CN114053231A (zh) 2022-02-18

Similar Documents

Publication Publication Date Title
EP3024442B1 (en) Formulations containing amorphous dapagliflozin
DK1886678T3 (en) STABLE TABLET CONTAINING DROXIDOPA
RU2725074C1 (ru) Композиция таблетки леналидомида для перорального приема
JP6133786B2 (ja) エスリカルバゼピンアセテート含有顆粒
BRPI0708108B1 (pt) Composição farmacêutica compreendendo fosfato de oseltamivir
IL274625B (en) A pharmaceutical preparation with excellent properties in terms of resistance to light and the property of disintegration
BR112012023654B1 (pt) Método para produzir grânulos contendo agente anticoagulante e método para produzir uma composição farmacêutica contendo o dito agente
US11925648B2 (en) Solid dosage form having excellent stability
EA036982B1 (ru) Способ получения лиофилизированной фармацевтической композиции, содержащей митомицин с
TWI808349B (zh) 含有芳基烷基胺化合物之醫藥組合物
WO2022022656A1 (zh) 一种冻干口服制剂
US10583087B2 (en) Pharmaceutical composition for oral administration
US10952968B2 (en) Preparation containing 6,7-unsaturated-7-carbamoyl morphinan derivatives
KR20100053449A (ko) 안정한 에구알렌나트륨 고형 제제
AU2023201826B2 (en) Solid formulation having excellent stability
CN113950324A (zh) 微型软胶囊萘普生组合物
KR20080071557A (ko) 고형 제제 및 제제 조성물
ES2958158T3 (es) Composición farmacéutica para administración oral
ES2409730T3 (es) Comprimidos de indapamida prensados directamente con liberación retardada de principio activo
TW202038918A (zh) 醫藥組合物
TWI836051B (zh) 錠劑及其製造方法
KR20110104903A (ko) 안정성이 개선된 프라미펙솔을 함유하는 약제학적 조성물 및 이의 제조방법
TW202103702A (zh) 醫藥組成物
KR20220131186A (ko) L-세린 또는 이의 약제학적으로 허용가능한 염의 액상 제제 및 이의 제조방법
TW202342054A (zh) 經口固形製劑

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21850239

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21850239

Country of ref document: EP

Kind code of ref document: A1