WO2020098563A1 - Composition pharmaceutique comprenant un composé polypeptidique, procédé de préparation et utilisation correspondante - Google Patents

Composition pharmaceutique comprenant un composé polypeptidique, procédé de préparation et utilisation correspondante Download PDF

Info

Publication number
WO2020098563A1
WO2020098563A1 PCT/CN2019/116533 CN2019116533W WO2020098563A1 WO 2020098563 A1 WO2020098563 A1 WO 2020098563A1 CN 2019116533 W CN2019116533 W CN 2019116533W WO 2020098563 A1 WO2020098563 A1 WO 2020098563A1
Authority
WO
WIPO (PCT)
Prior art keywords
pain
pharmaceutical composition
sodium
adjusting agent
composition according
Prior art date
Application number
PCT/CN2019/116533
Other languages
English (en)
Chinese (zh)
Inventor
王梦馨
黎晓龙
周丹
王亚华
赵栋
宋宏梅
蔡家强
曾宏
赵曦
王利春
薛彤彤
王晶翼
Original Assignee
四川科伦博泰生物医药股份有限公司
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 四川科伦博泰生物医药股份有限公司 filed Critical 四川科伦博泰生物医药股份有限公司
Priority to CN201980060343.8A priority Critical patent/CN112739709A/zh
Publication of WO2020098563A1 publication Critical patent/WO2020098563A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition containing a polypeptide compound and a preparation method thereof, wherein the polypeptide compound has peripheral ⁇ opioid receptor agonistic activity, therefore, the present application also relates to the pharmaceutical composition Use in the preparation of a medicament for the prevention or treatment of diseases associated with kappa opioid receptors.
  • Peripheral kappa opioid receptor agonists can bind to kappa opioid receptors, causing the opioid receptor-coupled Gi / Go protein to be activated, and then reduce cAMP by inhibiting adenylate cyclase activity or by inhibiting calcium channels
  • Ca 2+ influx decreases and K + efflux increases, causing hyperpolarization of membrane potential, reducing neurotransmitter release, and reducing the excitability of neurons transmitting pain information, thereby inhibiting the transmission of pain signals.
  • WO 2018/059331 A1 a polypeptide compound having peripheral kappa opioid receptor agonistic activity represented by the following formula, which has a brand-new structure, clear pharmacological effects and important clinical value.
  • An object of the present application is to provide a pharmaceutical preparation of a polypeptide compound having peripheral kappa opioid receptor agonistic activity, which is compatible with the clinical administration route and can simultaneously ensure the safety of the polypeptide compound in the clinical use process Sex.
  • the present application provides a pharmaceutical composition containing an active ingredient, a buffer, a pH adjuster, and water for injection, and optionally, it further contains a stabilizer; wherein,
  • the active ingredient is selected from the compounds described in WO2018059331A1, or their stereoisomers, polymorphs, solvates, or their metabolites or pharmaceutically acceptable salts or esters;
  • the content of the pH adjusting agent is such that the pH of the pharmaceutical composition is 3.5-5.5.
  • WO2018059331A1 is hereby incorporated by reference in its entirety.
  • the active ingredient in the pharmaceutical composition described in this application refers to any compound, stereoisomer, polymorph, solvate, or metabolite of WO2018059331A1. Or a pharmaceutically acceptable salt or ester.
  • the active ingredient is selected from the following compounds of formula I, or their stereoisomers, polymorphs, solvates, or their metabolites or pharmaceutically acceptable salts or esters:
  • the pharmaceutically acceptable salt is an acid addition salt. In some preferred embodiments, the pharmaceutically acceptable salt is selected from formate, acetate, hydrochloride and trifluoroacetate. In some preferred embodiments, the pharmaceutically acceptable salt is acetate or hydrochloride. In some preferred embodiments, the pharmaceutically acceptable salt is an acetate salt. In some preferred embodiments, the molar ratio of the compound of formula I to acid in the pharmaceutically acceptable salt is 1: (0.5-3), for example, 1: (0.5-2.5), 1: (0.5-2), 1: (0.5-1.5) or 1: (0.5-1). In some preferred embodiments, the active ingredient is an acetate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to acetic acid is 1: (0.5-1).
  • the content of the pH adjusting agent is such that the pH of the pharmaceutical composition is 3.5-5.0, 4.0-5.5, 4.0-5.0, or 4.3-4.7, such as 4.5.
  • the pH of the pharmaceutical composition is 4.0-5.0
  • the impurity content generated at the beginning of storage (for example, 0 days) is less than 0.1%
  • the impurity content hardly changes when left at 40 ° C for 10 days, for example, the change in impurity content is less than 0.05%, for example 0.01%, 0.02%, 0.03%, 0.04%.
  • the content of the active ingredient is 0.01-0.1% (w / v), for example 0.01-0.02% (w / v).
  • the buffering agent is selected from the group consisting of carbonate, phosphate, citrate, acetate, barbiturate, trishydroxymethylaminomethane, and borate.
  • the buffer is selected from phosphate, citrate and acetate, such as sodium dihydrogen phosphate, sodium citrate and sodium acetate.
  • the buffering agent is sodium acetate or sodium acetate trihydrate. The sodium acetate buffer system has good compatibility with the pharmaceutical composition.
  • the sodium acetate buffer system allows the pharmaceutical composition to produce fewer impurities at the beginning of storage (eg, 0 days), less than the detection limit of the instrument, and the impurities increase less when stored at 60 ° C for 10 days, for example, the amount of impurities changes less than 10 .
  • the molar concentration of the buffer is 1-5 mM, such as 1, 2, 3, 4 or 5 mM, preferably 2 mM.
  • concentration of the buffering agent for example, sodium acetate or sodium acetate trihydrate
  • the pharmaceutical composition is left at 60 ° C for 15 days or 30 days with less increase in impurities.
  • the pH adjusting agent is selected from one or more of hydrochloric acid, phosphoric acid, citric acid, glacial acetic acid, barbituric acid, boric acid, sodium hydroxide, and potassium hydroxide. In some preferred embodiments, the pH adjusting agent is glacial acetic acid, hydrochloric acid or sodium hydroxide.
  • the pharmaceutical composition also contains an osmotic regulator.
  • the osmotic pressure adjusting agent is selected from one or more of sodium chloride, glucose, glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, and xylitol. In some preferred embodiments, the osmotic pressure adjusting agent is sodium chloride.
  • the amount of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is 250-350 mOsm / kg, such as 260-330 mOsm / kg, 290-310 mOsm / kg.
  • the content of the osmotic pressure adjusting agent is 0.80-1.05% (m / v), for example 0.90-0.95% (m / v).
  • the stabilizer is an antioxidant or a metal ion chelating agent.
  • the antioxidant is selected from sodium bisulfite, sodium thiosulfate and sodium metabisulfite.
  • the metal ion chelating agent is selected from disodium edetate and sodium calcium edetate.
  • the stabilizer is selected from sodium thiosulfate and sodium calcium edetate.
  • the stabilizer is calcium sodium edetate.
  • the content of the stabilizer is 0.05-0.2% (w / v), preferably 0.05-0.1% (w / v).
  • composition consists of the following ingredients:
  • the pH adjusting agent is selected from hydrochloric acid, sodium acetate and sodium hydroxide;
  • the stabilizer is selected from sodium thiosulfate and calcium sodium edetate.
  • composition consists of the following ingredients:
  • the pH adjusting agent is selected from hydrochloric acid, sodium acetate and sodium hydroxide;
  • the stabilizer is selected from sodium thiosulfate and calcium sodium edetate.
  • the pharmaceutical composition consists of an active ingredient, sodium acetate or sodium acetate trihydrate, sodium chloride, pH adjuster, water for injection, and optional stabilizer, wherein the stabilizer is selected From sodium thiosulfate and sodium calcium edetate, the pH of the pharmaceutical composition is 4.0-5.5.
  • the pharmaceutical composition is selected from formulas (1)-(3):
  • the pharmaceutical composition is an injection, emulsion or suspension.
  • the present application provides a method for preparing the pharmaceutical composition, which includes the following steps:
  • the preparation method further includes the step of sterilizing the pharmaceutical composition
  • the step method further includes the step of adjusting the pH value of the solution 1 to 3.5-5.5 with a pH adjusting agent after step (1);
  • a step of nitrogen filling is further included;
  • a filling step is also included.
  • step (3) the solution 2 is adjusted to pH 3.5-5.0, 4.0-5.5, 4.0-5.0, or 4.3-4.7 with the pH adjusting agent.
  • step (1) and step (2) are performed at a temperature of 15-40 ° C. In some preferred embodiments, step (1) and step (2) are performed at a temperature of 15-25 ° C.
  • the above-mentioned sterilization refers to filtration sterilization, for example, sterilization through a 0.22 ⁇ m filter membrane.
  • a 0.22 ⁇ m polyethersulfone filter is used for filtration and sterilization.
  • the present application provides an injectable product comprising the above pharmaceutical composition and a closed container containing the pharmaceutical composition, wherein the volume of the pharmaceutical composition is less than or equal to the volume of the closed container, when the When the volume of the pharmaceutical composition is smaller than the volume of the closed container, the remaining space of the closed container is filled with an inert gas.
  • the airtight container is a glass or plastic airtight container, such as an ampoule or a vial (such as a medium borosilicate glass controlled injection bottle).
  • the inert gas is nitrogen.
  • the present application provides the use of the pharmaceutical composition in the preparation of a medicament for preventing or treating a disease associated with a kappa opioid receptor.
  • the present application provides the pharmaceutical composition for preventing or treating diseases associated with kappa opioid receptors.
  • the present application provides a method of preventing or treating a disease associated with a kappa opioid receptor, which includes the step of administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof.
  • the disease associated with a kappa opioid receptor is selected from pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma.
  • the disease associated with kappa opioid receptors is pain.
  • the pain is selected from neuropathic pain, somatic pain, visceral pain and skin pain.
  • the pain is selected from arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, post-medical pain, ocular pain, otitis pain , Cancer pain and pain related to gastrointestinal disorders.
  • w / v and m / v refer to Kg / L.
  • the water for injection described herein generally refers to water suitable for in vivo injection, that is, it should meet the requirements of the product for injection for bacterial endotoxin test.
  • the water for injection may be distilled water of pure water.
  • the present application provides a pharmaceutical composition containing a polypeptide compound, a preparation method and use thereof.
  • the pharmaceutical composition of the present application can achieve at least one of the following technical effects:
  • the pharmaceutical composition improves the stability of the polypeptide compound on the premise of ensuring the sterility level, thereby improving the application safety.
  • the pH of the pharmaceutical composition meets the requirements of injectables (pH 4-9), enhancing its exploitability as an intravenous injection preparation.
  • the active ingredients used in the following examples and comparative examples are acetate salts of the compound of formula I, wherein the molar ratio of the compound of formula I and acetic acid in the active ingredients used in examples 1-2 and comparative examples 1-2 The ratio was 1: 0.8, and the molar ratio of the compound of formula I to acetic acid in the active ingredients used in Examples 3-6 and Comparative Examples 3-4 was 1: 0.6.
  • glacial acetic acid, hydrochloric acid and / or sodium hydroxide are used in each embodiment to adjust the pH of the system.
  • Sodium acetate refers specifically to sodium acetate trihydrate.
  • the active ingredient and sodium acetate are weighed into a drug solution with a concentration of 1 mg / ml.
  • the pH value is adjusted to 4.5 with glacial acetic acid, filtered through a 0.22 ⁇ m filter membrane and filled into ampoules to obtain sample.
  • Each sample was placed at a high temperature of 60 ° C for 10 days to detect changes in related substances.
  • samples 1-4 According to the prescription composition of samples 1-4 (see Table 4), weigh the prescribed amount of sodium acetate, sodium chloride, sodium thiosulfate and calcium edetate sodium into the water, stir and dissolve, Use hydrochloric acid to adjust the pH to 4.3, add the active ingredient to prepare a drug solution with a concentration of 0.1mg / ml, use hydrochloric acid to adjust the pH to 4.5, filter it through a 0.22 ⁇ m filter membrane and fill it in a medium borosilicate glass control injection bottle. Samples 1-3 were prepared. In the same way, a drug solution with an active ingredient concentration of 0.1 mg / ml without stabilizer was prepared, and the headspace was filled with nitrogen before filling to prepare sample 4.
  • the purpose of the experiment to investigate the effect of different preparation temperature and preparation time on the stability of the solution.
  • Experimental content according to the prescription composition in Table 6, weigh sodium chloride and sodium acetate in water, stir and dissolve, adjust the pH to 4.3 with hydrochloric acid, add active ingredients, prepare a drug solution with a concentration of 0.1 mg / ml, use hydrochloric acid Adjust the pH value to 4.5, stir at 25 °C, 30 °C, and 40 °C for 0h, 2h, 5h, and 8h, and then take samples to observe the properties of the solution. At the same time, detect the related substances and pH. The test results are shown in Table 7.
  • Experimental content According to the prescription composition in Table 8, weigh sodium chloride and sodium acetate trihydrate (final concentrations are 1 mM and 2 mM respectively) in water, stir and dissolve, adjust the pH to 4.3 with hydrochloric acid, add active ingredients, and prepare the concentration It is a 0.1mg / ml drug solution, adjusted to pH 4.5 with hydrochloric acid, filtered through a 0.22 ⁇ m filter membrane and filled in a medium borosilicate glass control injection bottle, stoppered, capped, and placed at 60 ° C for 15 days and 30 days. Test related substances and pH value. The test results are shown in Table 9.
  • Experimental content According to the prescription composition in Table 10, weigh sodium chloride and sodium acetate in water, stir and dissolve, adjust the pH to 4.3 with hydrochloric acid, add active ingredients, and prepare a drug solution with a concentration of 0.1 mg / ml, using hydrochloric acid Adjust the pH value to 4.5, filter it through a 0.22 ⁇ m filter membrane, and fill it in a medium borosilicate glass controlled injection bottle, stopper it, and check the osmotic pressure. The test results are shown in Table 11.
  • the active ingredients sodium citrate and sodium dihydrogen phosphate monohydrate (calculated based on the weight of sodium dihydrogen phosphate) are weighed into a drug solution with a concentration of 1 mg / ml.
  • Phosphoric acid was adjusted to pH 4.5, filtered through a 0.22 ⁇ m filter membrane and filled in ampoules to prepare samples.
  • Experimental content Prepare a drug solution containing 0.2% cysteine, 0.2% sodium thiosulfate, 0.2% sodium bisulfite, 0.05% calcium edetate active ingredient concentration of 1mg / ml, adjust the pH value After 7.5, it is filled in medium borosilicate glass controlled injection bottles to prepare samples 1-4. In the same way, a drug solution with an active ingredient concentration of 1 mg / ml without stabilizer was prepared, and the headspace was filled with nitrogen before filling to prepare sample 5.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Ophthalmology & Optometry (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique qui comprend un composé polypeptidique et son procédé de préparation, le composé polypeptidique ayant une activité agoniste du récepteur opioïde kappa périphérique. Par conséquent, la présente invention concerne également l'utilisation de la composition pharmaceutique dans la préparation d'un médicament pour la prévention ou le traitement de maladies associées au récepteur opioïde kappa.
PCT/CN2019/116533 2018-11-15 2019-11-08 Composition pharmaceutique comprenant un composé polypeptidique, procédé de préparation et utilisation correspondante WO2020098563A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980060343.8A CN112739709A (zh) 2018-11-15 2019-11-08 含有多肽类化合物的药物组合物及其制备方法和用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811357621.X 2018-11-15
CN201811357621 2018-11-15

Publications (1)

Publication Number Publication Date
WO2020098563A1 true WO2020098563A1 (fr) 2020-05-22

Family

ID=70731290

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/116533 WO2020098563A1 (fr) 2018-11-15 2019-11-08 Composition pharmaceutique comprenant un composé polypeptidique, procédé de préparation et utilisation correspondante

Country Status (2)

Country Link
CN (1) CN112739709A (fr)
WO (1) WO2020098563A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107098871A (zh) * 2016-02-23 2017-08-29 江苏恒瑞医药股份有限公司 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用
WO2018059331A1 (fr) * 2016-09-27 2018-04-05 四川科伦博泰生物医药股份有限公司 Composé polyamide et son utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107098871A (zh) * 2016-02-23 2017-08-29 江苏恒瑞医药股份有限公司 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用
WO2018059331A1 (fr) * 2016-09-27 2018-04-05 四川科伦博泰生物医药股份有限公司 Composé polyamide et son utilisation

Also Published As

Publication number Publication date
CN112739709A (zh) 2021-04-30

Similar Documents

Publication Publication Date Title
US8759401B2 (en) Aqueous gel formulation and method for inducing topical anesthesia
JP2021120404A (ja) アトロピン含有水性組成物
EA034839B1 (ru) Офтальмологический раствор
US10813900B2 (en) Baclofen formulations and methods for making same
TW200932285A (en) Topical ophthalmic or otic solution formulations containing moxifloxacin hydrochloride and dexamethasone phosphate
CN103747786A (zh) 比马前列素和溴莫尼定的固定剂量组合
SA516380321B1 (ar) مستحضرات للعين لتوصيل الدواء إلى الجزء الخلفي من العين
JP6178028B1 (ja) ドルゾラミドとチモロールと界面活性剤を含有する医薬組成物
CN107810000B (zh) 来氟米林的可注射药物组合物
JP2022003099A (ja) ジクアホソルまたはその塩、およびポリビニルピロリドンを含有する水性眼科用組成物
WO2016072440A1 (fr) Composition ophtalmique aqueuse
JP2022516099A (ja) 眼科用医薬組成物及び癌表面疾患の処置方法
CN112294756A (zh) 一种苯磺顺阿曲库铵注射液及其制备方法
JP2016522257A (ja) 安定なブロムフェナク溶液
WO2020098563A1 (fr) Composition pharmaceutique comprenant un composé polypeptidique, procédé de préparation et utilisation correspondante
US11969403B2 (en) Topical formulations of chloroprocaine and methods of using same
CN116897046A (zh) 含有熊去氧胆酸或其盐的水性医药组合物
CN105769756B (zh) 一种富马酸西他沙星注射剂及其制备方法
RU2716164C2 (ru) Стабильные композиции нейроактивных пептидов
JPH08231403A (ja) アルギニンバソプレシン拮抗薬を含有する安定な水溶液
WO2024034592A1 (fr) Composition pharmaceutique aqueuse contenant de l'udca ou un sel de celui-ci
CN113197848B (zh) 一种重酒石酸间羟胺药物组合物及其制备方法
RU2781022C2 (ru) Офтальмологические композиции, содержащие простамид, высвобождающий окись азота
CN108853015B (zh) 一种地佐辛注射液组合物
CA3228588A1 (fr) Composition pharmaceutique, sa methode de preparation et son application

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: 19885669

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: 19885669

Country of ref document: EP

Kind code of ref document: A1