WO2019242051A1 - Liposome multivésiculaire d'acétate de glatiramère et son procédé de préparation - Google Patents

Liposome multivésiculaire d'acétate de glatiramère et son procédé de préparation Download PDF

Info

Publication number
WO2019242051A1
WO2019242051A1 PCT/CN2018/095405 CN2018095405W WO2019242051A1 WO 2019242051 A1 WO2019242051 A1 WO 2019242051A1 CN 2018095405 W CN2018095405 W CN 2018095405W WO 2019242051 A1 WO2019242051 A1 WO 2019242051A1
Authority
WO
WIPO (PCT)
Prior art keywords
liposome
glatiramer acetate
liposomes
acetate
phospholipid
Prior art date
Application number
PCT/CN2018/095405
Other languages
English (en)
Chinese (zh)
Inventor
张伟明
秦超
陶安进
袁建成
Original Assignee
深圳翰宇药业股份有限公司
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 深圳翰宇药业股份有限公司 filed Critical 深圳翰宇药业股份有限公司
Publication of WO2019242051A1 publication Critical patent/WO2019242051A1/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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P37/02—Immunomodulators

Definitions

  • the invention relates to a composition of glatiramer, in particular to a slow-release glatiramer polycystic liposome and a preparation method thereof, and belongs to the field of pharmaceutical preparations.
  • Glatiramer acetate is a synthetic peptide preparation composed of four amino acids, glutamic acid, alanine, tyrosine, and lysine, for the treatment of multiple sclerosis.
  • Glatiramer acetate (commercial name: Copaxone) was developed by TEVA, a world-renowned Israeli pharmaceutical company. It was first approved for marketing in Israel in 1996, and was approved by the FDA for marketing in the United States in the same year. It is currently available in 43 major countries. In western countries with more patients with multiple sclerosis, the efficacy and tolerability of glatiramer acetate has been fully affirmed.
  • TEVA's 2013 annual report shows that glatiramer acetate sales reached $ 4.3 billion in that year. According to the IMS report, glatiramer acetate in 2013 ranked 15th in the global drug market sales.
  • Glatiramer acetate injection is a white to off-white sterilized frozen crystal powder. It is packaged with water for injection to prepare an injection solution. Mainly as a single subcutaneous injection to treat multiple sclerosis.
  • Glatiramer acetate Consists of 4 amino acids L-glutamic acid, L-alanine, L-lysine and L-tyrosine
  • the molecular formula is: C25H45N5O13, the average molecular weight is about 7,000daltons.
  • Copaxone In western countries with more patients with multiple sclerosis, the efficacy and tolerability of Copaxone has been fully affirmed. In addition to many studies and clinical experience, it can significantly reduce the recurrence rate of patients, improve the condition of disability, and reduce brain damage. The incidence of side effects of Copaxone is small, which helps to improve the tolerance of patients. In addition, related studies also show that Copaxone can significantly reduce the recurrence rate, prevent further damage and deterioration of nerves, and has better tolerance than interferon. In other long-term efficacy studies (ranging from 6 years to a maximum of 12 years), Copaxone has also been shown to continuously delay the deterioration of the patient's neurological course or maintain a stable condition, reduce brain damage and prevent nerves.
  • Copaxone regulates the immune process in patients with multiple sclerosis to achieve the purpose of treatment. After entering the body, Copaxone combines with regulatory factors in the immune system and enters the central nervous system. Through a series of immune effects, it reverses the autoimmune process of multiple sclerosis patients; that is, it stimulates the conversion of harmful or pre-inflammatory T cells into beneficial ones. Or anti-inflammatory T cells. Copaxone works directly at the site of nerve cell damage and directly reduces inflammation. These benefits help reduce the recurrence rate of patients with multiple sclerosis and effectively reduce their further damage.
  • Multiple sclerosis is a chronic, inflammatory, demyelination of the central nervous system disease. Can cause a variety of symptoms, including sensory changes, visual impairment, muscle weakness, depression, difficulty coordinating and speaking, severe fatigue, cognitive impairment, balance disorders, body heat and pain, etc. Severe can lead to mobility disorders and disability. Multiple sclerosis affects nerve cells in the brain and spinal cord-neurons. Neurons transmit information to form thoughts and feelings that enable the brain to control the body. The fat layer that protects these neurons is Myelin Sheath, which assists neurons in transmitting electrical signals. Multiple sclerosis gradually causes the plaqueous nerve myelin sheath of the brain and spinal cord to be destroyed (demyelination). Scar formation of the myelin sheath affects the signal transmission of axons, so as to lose control of the brain and spinal cord to the periphery, and at most Site stiffness or loss of function.
  • the average age of onset of multiple sclerosis is generally 20 to 40 years old, with twice as many women as men.
  • the etiology of multiple sclerosis is unclear, and it is often considered an autoimmune disease. A few people think it is a metabolic dependent neurodegenerative disease.
  • MS global multiple sclerosis market
  • CAGR compound annual growth rate
  • the only recommended route of administration is subcutaneous injection, which should not be done intravenously.
  • the recommended dosage is 20 mg per day subcutaneous (subcutaneous fat layer) injection; because it needs to be injected once a day, it is not convenient for clinical use; weekly injection Copaxone, a three-time long-acting version, was approved by the FDA, making it easier for patients to use.
  • Polycystic liposomes are favored because of their natural biofilm structure and their good sustained release effect.
  • Multivesicular liposome (trade name DepoFoam) is a non-concentric liposome.
  • the liposome was first discovered by American scientist Kim S and others in 1983. At that time, they researched the preparation of a liposome with a cell size similar to that used in biofilm simulation.
  • the liposome was prepared by the double milk method, and glycerol trioleate was added to the prescription. There are many small bubble compartments in a large soap bubble. It was later discovered that the liposomes can be used for sustained and controlled release of drugs, and the sustained release time can reach several days to several weeks. After years of research and development, there are now two products available.
  • Depomorphine TM is mainly used for the treatment of lymph meningitis. After cytarabine was made into Depocyt TM , the number of administrations was reduced from once every 2d to once every 3 weeks, which greatly improved patient compliance. Depomorphine TM is mainly used to relieve pain after surgery. Traditional morphine preparations require multiple administrations due to their short duration of action. The effect of Depomorphine TM can last for 48 hours, which is the peak period of pain after surgery.
  • microspheres and microcapsules can also be used for slow and controlled release.
  • polycystic liposomes have the following advantages: higher drug encapsulation and recovery rates, which are related to the larger volume of the internal aqueous phase; no burst release phenomenon when the drug is released; the raw material is phospholipids , Cholesterol, triglyceride and other materials, have good biocompatibility and biodegradability; relatively mild preparation conditions, not only can be used for the encapsulation of small molecule drugs, but also can be used for large molecule drugs such as proteins, peptides Encapsulation.
  • drugs that have been studied in polycystic liposomes include amikacin, methotrexate, gentamicin, cisplatin, morphine and other small molecule drugs, bone marrow cell growth factor (myelopoietin), and hematopoietic Protein peptide drugs such as growth factor (progenipoietin), apolipoprotein E (apolipoprotein E), and human interferon ⁇ -2b.
  • polycystic liposomes are currently known as unique lipid drug depots.
  • Polycystic liposomes are different from ordinary single-compartment and multi-compartment liposomes, and are mainly reflected in three aspects: morphology, composition and particle size.
  • morphology in addition to phospholipids and cholesterol, polycystic liposomes also require the use of triglycerides.
  • particle size the particle size of typical polycystic liposomes is generally 5-50 ⁇ m, while the typical ordinary single-chamber and multi-chamber liposomes are generally 0.1-5 ⁇ m, and the particle size of polycystic liposomes is more common.
  • Liposomes are one to two orders of magnitude larger. Unlike single-chamber and multi-chamber liposomes, which have the same circle center structure, polycystic liposomes do not have the same circle center (non-concentric). There are many small capsules of different sizes and irregular shapes inside. These vesicles are tightly packed together. The capsular and vesicles are separated by a lipid bilayer membrane. Its internal structure is similar to foam. This may also be its trade name DepFoam (depot-foam). s reason. This structure gives the lipid membrane a strong mechanical strength, making it more stable than ordinary liposomes. Polycystic liposomes can achieve the slow and controlled release of drugs because of its unique structure.
  • drugs are prepared as injections, which have a shorter action time in the body; while polycystic liposomes are relatively slow to release and have a longer action in the body.
  • glatiramer acetate polycysteum liposome which is a liposome membrane material composed of common phospholipids, triglycerides and charged phospholipids, and also contains active ingredients in the polycysteum liposome. Glatiramer acetate.
  • the liposome membrane material further includes cholesterol.
  • the present invention aims to provide a polycystic liposome capable of effectively prolonging the release time of glatiramer acetate in vivo.
  • the composition contains the active ingredient glatiramer acetate, and a composition suitable for the needs of patients is obtained by selecting an appropriate prescription and process. .
  • the common phospholipid is selected from the group consisting of soy phospholipid, lecithin, dipalmitoylphosphatidylcholine (DPPC), hydrogenated phospholipid (HSPC), or a combination thereof.
  • the triglyceride is selected from glyceryl trioleate, glyceryl tricaprylate, glyceryl tripalmitate, glyceryl trilaurate, glyceryl tridecanoate, glyceryl tricaprylate, glyceryl trihexanoate, or a combination thereof.
  • the charged phospholipid is selected from the group consisting of phosphatidylglycerol, phosphatidylserine, cardiolipin, phosphatidylinositol, etc., or a combination thereof.
  • the internal / external aqueous phase can be selected from sucrose, mannitol, lactose, sorbitol, glucose, citric acid, and chlorinated Sodium, arginine, lysine, PBS buffer salts, etc .; cholesterol can be optionally added or not to regulate the fluidity of the liposome phospholipid bilayer membrane.
  • the mass ratio of glatiramer acetate to the liposome membrane is 1:10 to 1: 300. It is preferably 1:30 to 1: 250, and more preferably 1: 36.5 to 1: 224.
  • the mass ratio of the charged phospholipid and triglyceride is 0.8-1.2, preferably 0.9-1.1.
  • the mass ratio of phospholipid, charged phospholipid to triglyceride is 3-10: 1: 0.8-1.2.
  • the organic solvent is selected from volatile solvents, preferably chloroform, acetone, chloroform, ether or a mixture thereof, and more preferably a mixed solvent of chloroform and ether.
  • glatiramer acetate based on parts by mass, 1 part of glatiramer acetate is dissolved in water to obtain an aqueous phase.
  • 100 parts of soybean phospholipid, 100 parts of cholesterol, 12 parts of phosphatidylserine, and 12 parts of tri-oil Glyceryl acid is dissolved in an organic solvent to obtain an oil phase, and an aqueous phase is added to the oil phase to prepare a colostrum; the obtained colostrum is added to the same volume of external water, and emulsification is continued to obtain a double milk; the obtained double milk is blow-dried organic solvent , Ie, multivesicular liposomes.
  • glatiramer acetate is dissolved in water to obtain an aqueous phase, 25 parts of lecithin, 6 parts of phosphatidylserine, and 5.5 parts of trioctyl glyceride are dissolved.
  • An oil phase is obtained from an organic solvent, and the aqueous phase is added to the same volume of oil phase to prepare colostrum; the obtained colostrum is added to the same volume of external water, and the emulsification is continued to obtain a double milk; the obtained double milk is blown to dry the organic solvent, that is, Multi-vesicle liposomes.
  • a method for preparing glatiramer acetate polysome is provided:
  • the organic solvent in the organic phase is generally a volatile solvent, usually chloroform or a mixed solution of chloroform and ether.
  • Lipids are phospholipids, neutral lipids (often triglycerides), cholesterol, and the like.
  • the method for preparing colostrum can be selected from the methods for preparing emulsions, including ultrasonic, high-speed dispersion, milk homogenizer, and nozzle atomization. Laboratory preparation often uses a high-speed disperser or vortex mixer for emulsification; W / O colostrum is mixed with a second aqueous phase buffer solution to prepare a double milk; organic solvents in the double milk are removed to form polycystic liposomes.
  • the method of removal is usually nitrogen. Nitrogen can be passed on the surface, or a nitrogen tube can be inserted into the bottom of the polycystic liposome container; suitable for storage and physiologically acceptable salt solution to replace the second aqueous phase to remove Encapsulated drug, concentrated.
  • each of these steps includes a process for preparing a double milk.
  • the lipids for the preparation of polycystic liposomes must contain neutral lipids, otherwise only ordinary liposomes can be obtained.
  • lipids also contain triglycerides.
  • the main factor that affects the release rate of polycystin liposomes is the ratio of long-chain triglycerides to short-chain triglycerides in triglycerides. Using long-chain triglycerides, drug release The rate is slow; the opposite is true for short-chain triglycerides. The desired drug release rate can be obtained by adjusting the ratio between the two.
  • the triglyceride is not uniformly contained in the lipid bilayer membrane, but a part of it is dispersed as small oil droplets in the internal aqueous phase of the polycystic liposome, and the other part is filled between the capsule and the capsule In the gap of the lipid membrane cross-linking site, it plays the role of connecting, bridging, and stabilizing the internal vesicles.
  • the triglyceride is filled in the gap between the polycystic liposome vesicles and the vesicles, and plays a role of connecting, bridging, and stabilizing the internal vesicles.
  • Different chain lengths of triglycerides have different degrees of stabilization, resulting in different release rates of the drug in vivo and in vitro.
  • the drug release rate is slow; short-chain triglycerides are the opposite.
  • long-chain and short-chain triglycerides are mixed, and the drug release rate is adjusted by adjusting their ratios. The larger the proportion of long-chain triglycerides, the slower the release rate.
  • the reason that affects the stability of liposomes is mainly related to the potential of liposomes.
  • Charged phospholipids are included in the prescription to prevent aggregation between liposomes.
  • the lower charge is shielded, resulting in easy aggregation of liposomes.
  • the internal water phase / external water phase can be selected from sucrose, mannitol, sorbitol, glucose, citric acid, sodium chloride, arginine, lysine, PBS buffer salt, sodium hydroxide, Sodium bicarbonate, sodium carbonate, amine sulfate, etc.
  • Cholesterol that regulates the fluidity of the liposome phospholipid bilayer membrane can also be optionally added or not added.
  • the embodiment of the invention discloses a glatiramer polycystic liposome and a preparation method thereof.
  • Those skilled in the art can draw on the content of this article and appropriately improve the formulation formulation implementation.
  • all similar replacements and modifications will be apparent to those skilled in the art, and they are all considered to be included in the present invention.
  • the method of the present invention has been described by the preferred embodiments. It is obvious that relevant persons can implement or apply the prescription or process described herein or make appropriate changes and combinations without departing from the content, spirit, and scope of the present invention. Invention technology.
  • glatiramer acetate 50 mg was dissolved in 30 mL of water phase, 5 g of soybean phospholipid, 5 g of cholesterol, 0.6 g of phosphatidylserine, and 0.6 g of glyceryl trioleate were dissolved in 30 mL of chloroform-ether (1: 1) (oil phase).
  • the water phase was added to the oil phase, and the vortex mixer was emulsified for 8 minutes to prepare colostrum.
  • the obtained colostrum is added to the same volume of the external aqueous phase, and the vortex mixer is emulsified for 1 to 240 seconds, usually 20 to 80 seconds.
  • the resulting double milk was blown dry with an organic solvent, i.e., a polycystic liposome.
  • the particle size of the obtained polycystic liposomes is related to the length of secondary emulsification. The longer the time, the smaller the particle size. After centrifugation, the supernatant was removed, and the polycystic liposomes were resuspended in physiological saline.
  • glatiramer acetate 200 mg was dissolved in 100 mL of water phase, 5 g of lecithin, 1.2 g of phosphatidylserine, and 1.1 g of glyceryl tricaprylate were dissolved in 120 mL (oil phase) of chloroform or a mixed solvent of chloroform and ether.
  • oil phase 120 mL
  • the obtained colostrum was added to the external volume of the same volume, and emulsified for 30-120s at a high speed disperser 4500-5000r / min.
  • the resulting double milk was blown dry with an organic solvent, i.e., a polycystic liposome. After centrifugation, the supernatant was removed, and the polycystic liposomes were resuspended in physiological saline.
  • an organic solvent i.e., a polycystic liposome.
  • glatiramer acetate 50 mg was dissolved in 30 mL of water phase, 5 g of soybean phospholipid, 5 g of cholesterol, 0.6 g of phosphatidylserine, and 0.1 g of glyceryl trioleate were dissolved in 30 mL of chloroform-ether (1: 1) (oil phase).
  • the water phase was added to the oil phase, and the vortex mixer was emulsified for 8 minutes to prepare colostrum.
  • the obtained colostrum is added to the same volume of the external aqueous phase, and the vortex mixer is emulsified for 1 to 240 seconds, usually 20 to 80 seconds.
  • the resulting double milk was blown dry with an organic solvent, i.e., a polycystic liposome.
  • the resulting double milk was blown dry with an organic solvent, i.e., a polycystic liposome. After centrifugation, the supernatant was removed, and the liposomes were resuspended in physiological saline.
  • glatiramer acetate 200 mg was dissolved in 100 mL of water phase, 5 g of lecithin, 3 g of phosphatidylserine, and 1.1 g of glyceryl tricaprylate were dissolved in 120 mL (oil phase) of chloroform or a mixed solvent of chloroform and ether.
  • the aqueous phase was added to In the same volume of oil phase, high-speed disperser 8000-15000r / min is emulsified for 6-12min to prepare colostrum.
  • the obtained colostrum was added to the external volume of the same volume, and emulsified for 30-120s at a high speed disperser 4500-5000r / min.
  • the resulting double milk was blown dry with an organic solvent, i.e., a polycystic liposome. After centrifugation, the supernatant was removed, and the liposomes were resuspended in physiological saline.
  • an organic solvent i.e., a polycystic liposome.
  • Example 1 was 19.43 ⁇ 7.63um
  • the particle size of Example 2 was 16.39 ⁇ 3.45um
  • the particle size of Example 3 It is 18.67 ⁇ 5.83um
  • the particle size of Example 4 is 14.45 ⁇ 5.75um.
  • Examples 1, 2, 3 and 4 are significantly different from ordinary liposomes, but the particle sizes formed by Examples 3 and 4 Relatively small.
  • the obtained polycystic liposomes were placed in a stoppered test tube, 4 ml of human plasma containing 0.01% NaN3 was added, fixed on the stirring slurry of the dissolution apparatus and immersed in the water of the dissolution cup, the temperature of the water was maintained at 37 ° C, and stirred The pulp was rotated at 100 rpm.
  • Sample 0.5ml at the set time add the obtained sample to 4.5ml physiological saline, centrifuge at 10,000 * g for 10min, discard the supernatant, dissolve the precipitate in an appropriate amount of acidified methanol, and filter and HPLC to obtain polycysts at each time point.
  • the amount of unreleased drug in the liposome The following formula calculates the percentage of drug released at each time point:
  • Drug release (%) (total amount of drug encapsulated in polycysteum liposome-amount of drug not released) / amount of drug encapsulated in polycyste liposome x 100%.
  • Example 3-4 are relatively faster than the polycystic liposomes prepared in Example 1-2.
  • the neutral phospholipid trioleate is relatively low, and the charged phospholipid phosphatidylserine in the prescription of Example 4 is relatively high.
  • the drug-loaded liposome solution was placed in a centrifuge, centrifuged at 10,000 * g for 10 minutes, the supernatant was discarded, and the liposomes were washed and collected to determine the encapsulation efficiency.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un liposome multivésiculaire d'acétate de glatiramère, une membrane de liposome étant formée par un phospholipide normal, un triglycéride et un phospholipide chargé, et l'acétate de glatiramère en tant que principe actif étant également encapsulé dans le liposome multivésiculaire. La membrane de liposome comprend également du cholestérol. Le rapport massique du phospholipide normal au phospholipide chargé par rapport au triglycéride est de 3-10 : 1 : 0,8-1,2.
PCT/CN2018/095405 2018-06-21 2018-07-12 Liposome multivésiculaire d'acétate de glatiramère et son procédé de préparation WO2019242051A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810642538.0A CN110624099A (zh) 2018-06-21 2018-06-21 一种醋酸格拉替雷多囊脂质体及其制备方法
CN201810642538.0 2018-06-21

Publications (1)

Publication Number Publication Date
WO2019242051A1 true WO2019242051A1 (fr) 2019-12-26

Family

ID=68966285

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/095405 WO2019242051A1 (fr) 2018-06-21 2018-07-12 Liposome multivésiculaire d'acétate de glatiramère et son procédé de préparation

Country Status (2)

Country Link
CN (1) CN110624099A (fr)
WO (1) WO2019242051A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113976052B (zh) * 2021-11-03 2022-06-10 健进制药有限公司 一种多囊脂质体制备系统及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102274183A (zh) * 2010-06-13 2011-12-14 上海现代药物制剂工程研究中心有限公司 一种多囊脂质体制备方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101780039A (zh) * 2010-03-05 2010-07-21 南京海陵中药制药工艺技术研究有限公司 曲马多多囊泡脂质体及其制备方法
CN103169670B (zh) * 2013-03-22 2016-07-06 深圳翰宇药业股份有限公司 一种醋酸格拉替雷微球及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102274183A (zh) * 2010-06-13 2011-12-14 上海现代药物制剂工程研究中心有限公司 一种多囊脂质体制备方法和应用

Also Published As

Publication number Publication date
CN110624099A (zh) 2019-12-31

Similar Documents

Publication Publication Date Title
RU2632433C2 (ru) Липидный преконцентрат с замедленным высвобождением фармакологически активного вещества и фармацевтическая композиция, содержащая его
US10206876B2 (en) Depot formulations of a local anesthetic and methods for preparation thereof
JP2848583B2 (ja) アルファトコフェロールをベースにした小胞体
JP2518605B2 (ja) 水不溶性薬剤を含む微小滴
JPH10501534A (ja) 強化されたドラッグ・デリバリーのためのスフィンゴソーム
BR112015015518B1 (pt) Composição farmacêutica e uso da mesma
WO2011066684A1 (fr) Liposome d'irinotécan ou son hydrochlorure et son procédé d'obtention
CN107427482A (zh) 凝血酸的多囊脂质体制剂
BR112014018393B1 (pt) Composição farmacêutica adequada para liberação ocular de um esteroide e uso da mesma para a fabricação de um medicamento para tratar uma doença oftálmica
WO2014127245A1 (fr) Traitement de klebsiella pneumoniae au moyen de glutathion de formulation liposomale
WO2019242051A1 (fr) Liposome multivésiculaire d'acétate de glatiramère et son procédé de préparation
JPS63502899A (ja) リポソームおよびβ↓２‐レセプター活性物質の組成物
CN113509440B (zh) 一种高包封率酮咯酸多囊脂质体制备及提高其稳定性方法
JP2003512313A (ja) ６，９−ビス−［（２−アミノエチル）−アミノ］ベンゾ［ｇ］イソキノリン−５，１０−ジオンジマレエートのリポソーム製剤
AU2020295730A1 (en) Liposomal doxorubicin formulation, method for producing a liposomal doxorubicin formulation and use of a liposomal doxorubicin formulation as a medicament
JP2002535359A (ja) グルタチオン類縁体を含有する治療用組成物
JP2911550B2 (ja) リポソーム製剤
TW202220668A (zh) 用於疼痛控制之關節內皮質類固醇的藥學組成物
WO2020206314A1 (fr) Liposomes encapsulant de l'adénosine
AU2019214872A1 (en) Method of administering emulsion formulations of an NK-1 receptor antagonist
MXPA96001033A (en) Nanosuspensions for intraven administration

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: 18923156

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: 18923156

Country of ref document: EP

Kind code of ref document: A1