WO2013097266A1 - Préparation pharmaceutique enrobant le ly294002. - Google Patents

Préparation pharmaceutique enrobant le ly294002. Download PDF

Info

Publication number
WO2013097266A1
WO2013097266A1 PCT/CN2012/000500 CN2012000500W WO2013097266A1 WO 2013097266 A1 WO2013097266 A1 WO 2013097266A1 CN 2012000500 W CN2012000500 W CN 2012000500W WO 2013097266 A1 WO2013097266 A1 WO 2013097266A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical preparation
acid
oil
preparation
phospholipid
Prior art date
Application number
PCT/CN2012/000500
Other languages
English (en)
Chinese (zh)
Inventor
张文芳
戴杰
陆翔
谢日清
Original Assignee
苏州纳晶医药技术有限公司
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 苏州纳晶医药技术有限公司 filed Critical 苏州纳晶医药技术有限公司
Priority to CN201280064823.XA priority Critical patent/CN104010628A/zh
Publication of WO2013097266A1 publication Critical patent/WO2013097266A1/fr

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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the field of pharmacy, in particular to a pharmaceutical preparation for wrapping LY294002, which is packaged in the pharmaceutical auxiliary material selected for the research of the invention, effectively controls the release of LY294002, and can be used as a medicine for clinical use.
  • LY294002 is also written as LY-294, 002, LY-294002 or LY 294002, CAS No.: 154447- 36- 6 Molecular Weight: 307. 343, Structural Formula C19H17N03, is a cell signaling pathway that blocks the phosphatidylinositol kinase Protein kinase inhibitor. LY294002 can penetrate cells, specifically inhibit PI3K, and inhibit PI3K/Akt signaling pathways, including common inhibition of Akt phosphorylation. It is widely used in the study of the characteristics of the signal transduction pathway of phosphatidylinositol kinase.
  • LY294002 is one of the most widely studied PI3K/niT0RC inhibitors.
  • a large number of literatures have proved its unique efficacy, broad-spectrum inhibition of tumor cell growth, but due to the short half-life of this compound, the basic metabolism is complete in half an hour, leading to serious Acute toxicity, it is impossible to make a general pharmaceutical preparation for clinical use.
  • LY294002 is a sensitizer for chemotherapeutic drugs, and can also reverse the body's resistance to chemotherapeutic drugs. If it is made into a pharmaceutical preparation that can control the release of LY294002 molecules, it can inhibit the growth of tumor cells and improve the therapeutic effect of chemotherapeutic drugs. It is very meaningful in clinical treatment.
  • the molecule has been discovered for nearly 15 years now, and a large number of literature reports on its unique PI3K kinase inhibitor. Under the current research trend of kinase inhibitors, no researchers have made this molecule into a pharmaceutical preparation for clinical use. It can be seen that it is very difficult to prepare a pharmaceutical preparation capable of controlling release without producing an acute toxicity reaction.
  • albumin conjugate preparations which can theoretically achieve enrichment of tumor cells and increase the local concentration of drugs in tumor cells, thereby increasing the therapeutic effect of tumor cells, especially For the treatment of lymphoma.
  • the invention encapsulates the pharmaceutical preparation of LY294002, wherein LY294002 can be effectively wrapped in the pharmaceutical auxiliary material, and the weight ratio of the medicine to the auxiliary material is 1: 1 - 1 : 20.
  • the presence of LY294002 can be either solid or liquid, either intravenous or local, including intramuscular or intratumoral or peripheral injections, including embolization.
  • the pharmaceutical excipient of the present invention is selected from the group consisting of protein, phospholipid, oil, poloxamer 188, vitamin strontium, cholesterol, cyclodextrin and its derivatives, polyethylene glycol, glycerin, propylene glycol, and lyophilized support. Or two or more.
  • the pharmaceutical preparation of the invention wrapped with LY294002 can also be prepared into a mixture preparation together with anti-tumor chemotherapy drugs, wherein the anti-tumor chemotherapy drug is selected from the group consisting of doxorubicin and its derivatives, paclitaxel and its derivatives, Taxotere and its derivatives, Ring amide, actinomycin, bleomycin, gentamicin, methotrexate, fluorouracil, carboplatin, carmustine, methyl-carbamide, cisplatin, podophyllotoxin, interferon, camptothecin and A derivative thereof, one or more selected from the group consisting of benzoic acid, alcohol, vinblastine, vincristine, tamoxifen, etoposide, and piperazine.
  • the anti-tumor chemotherapy drug is selected from the group consisting of doxorubicin and its derivatives, paclitaxel and its derivatives, Taxotere and its derivatives, Ring amide, actin
  • the protein in the pharmaceutical excipient is selected from the group consisting of albumin or an amino acid polymer, wherein the albumin is selected from one of human albumin, recombinant human albumin and animal serum albumin or a mixture thereof; From polyamino acids containing cysteine/dithio groups, free thiol groups and/or dithio-modified polyethanols, free sulfhydryl groups and/or dimercapto-modified polyhydroxyethyl methacrylates, free sulfhydryl groups and/or Or disulfide-modified polyacrylic acid, free sulfhydryl and/or disulfide-modified polyethyloxazoline, free sulfhydryl and/or disulfide-modified polyacrylamide, free thiol and/or disulfide-modified Polyglycolide An acid lactone or a copolymer thereof, and a mixture of any two or more of them.
  • Phospholipids and phospholipids in the pharmaceutical excipients are exemplified by, for example, lecithin (soy lecithin, egg yolk lecithin, dilauroyl phospholipid, dimyristoyl phospholipid, dipalmitoyl phospholipid or distearoyl phospholipid), phospholipids Acylethanolamine (dilauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine or distearoylphosphatidylethanolamine, etc.) phosphatidylserine (dilauroylphosphatidylserine, dimyristoyl phospholipid) Phosphatidic acid, phosphatidylglycerol (dilauroyl phosphatidylglycerol, dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol or
  • the lyophilized support agent is selected from one or more of a small molecule amino acid, a polysaccharide and a polyol, and the small molecule amino acid refers to one or more of 20 natural amino acids, and the polysaccharide refers to trehalose and sucrose.
  • the polysaccharide refers to trehalose and sucrose.
  • lactose and maltose the polyhydric alcohol being one or more of mannitol and sorbitol.
  • Examples of 20 natural amino acids are as follows, such as 20 alpha-amino acids including, eight non-polar amino acids: alanine, valine, leucine, isoleucine, valine, tryptophan, phenylalanine Acid, methionine; seven polar, uncharged amino acids: serine, glycine, threonine, cysteine, asparagine, glutamine, tyrosine; two acidic amino acids: aspartame Acid, glutamic acid; three basic amino acids: arginine, lysine, histidine.
  • the pharmaceutical preparation for wrapping LY294002 may further comprise a pH adjusting agent, wherein the pH adjusting agent is a biocompatible acid or a buffer salt, and the biocompatible acid means hydrochloric acid, phosphoric acid or a metal sodium salt thereof, citric acid or a metal thereof.
  • the buffer salt being referred to as a phosphate buffer salt and a citrate buffer salt a mixture of one or several.
  • buffer salts are as follows: sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, dihydrogen phosphate-dihydrogen phosphate A sodium buffer, a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, or a disodium hydrogen phosphate-citric acid buffer may be a buffer of potassium dihydrogen phosphate-dipotassium hydrogen phosphate.
  • the pharmaceutical preparation for wrapping LY294002 may further comprise an antioxidant, wherein the antioxidant is selected from the group consisting of vitamin E, vitamins (:, sulfites, ethylenediaminetetraacetic acid and its derivatives, and cysteine hydrochloride). Or several.
  • the fat in the pharmaceutical excipient of the present invention is selected from the group consisting of soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, sesame oil, orange oil, lemon oil, fatty acid having 2-30 carbon atoms, and containing 2-30 carbon atoms.
  • the cyclodextrin and its derivative in the pharmaceutical excipient of the present invention are one selected from the group consisting of hydroxypropyl ⁇ -cyclodextrin and decyl butyl-cyclodextrin.
  • the present invention contains a pharmaceutical preparation of LY294002 for treating disorders associated with ⁇ 3 ⁇ activity, such as: cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine disorders, and neurological disorders.
  • disorders associated with ⁇ 3 ⁇ activity such as: cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine disorders, and neurological disorders.
  • the present invention studies the prepared albumin conjugate preparation, wherein the weight ratio of LY294002 to albumin is 1: 5 - 1: 20, and may also contain phospholipids and lyophilized support agents, wherein LY294002, albumin, phospholipids and lyophilized support
  • the weight ratio of the agent is: 1 : 3: 1: 3 - 1: 20: 20: 30 ⁇
  • the preparation method comprises the following steps: dissolving LY294002 in an organic solvent, dissolving human albumin and hydrazine regulator in water, stirring into an emulsion, evaporating the solvent under reduced pressure, and forming nanoparticles by high pressure homogenization to form white Protein-coated LY294002 nanoparticles with a particle size range of less than 1000 nm.
  • the present invention investigates a liposome preparation prepared by the method wherein the weight ratio of LY294002, cholesterol and phospholipid is 1: 0. 5: 5 - 1: 1 : 20, and may also contain a buffer salt and a lyophilized support.
  • the preparation method comprises the steps of: dissolving LY294002, cholesterol and phospholipid in an organic solvent, evaporating the organic solvent through a thin film evaporator under reduced pressure, adding a phosphate buffer solution, fully stirring into an emulsion, and preparing the nanometer by high pressure homogenization method. Particles.
  • the present invention investigates a prepared nanoemulsion preparation, wherein LY294002, cholesterol (vitamin E), phospholipid or poloxamer or a mixture of the two, the weight ratio thereof is: 1: 0: 1 : 3- 1 : 5: 20, It may contain a buffer salt and a lyophilized support.
  • the preparation method comprises the following steps: dissolving LY294002, cholesterol (vitamin E) or phospholipid In an organic solvent, an organic phase is formed, a phospholipid or a poloxamer is dissolved in an aqueous phase, an organic phase is added to the aqueous phase, the mixture is thoroughly stirred to form an emulsion, and the solvent is evaporated under reduced pressure to form a nanoparticle by a high pressure homogenization method.
  • the cyclodextrin inclusion compound prepared by the present invention comprises the following steps: LY294002 is dissolved in an organic solvent to form an organic phase, and hydroxypropyl ⁇ -cyclodextrin or oxime butyl-cyclodextrin is dissolved in water. The organic phase is slowly added to the aqueous phase, stirred well, and the organic solvent is evaporated to form the clathrate.
  • the high pressure homogenization method may be selected from, for example, a high pressure homogenizer, a high shear mixer, an ultrasonic processor, a high shear agitator, and the like.
  • the reduced pressure evaporator is selected from the group consisting of a rotary evaporator, a falling film evaporator, a spray dryer, a freeze dryer, and the like.
  • the organic solvent includes one or more of dichloromethane, trichloromethane, ethanol, ethyl acetate, diethyl ether and acetone.
  • the nanoparticles have an average particle diameter of less than 0.5 um, and the obtained powder preparation and water for injection, glucose and physiological saline are reformed to form an injectable aqueous solution having a pH of from 5.0 to 7.0.
  • the nanoparticles have an average particle diameter of less than 0.2 um, and the obtained powder preparation and injection water, glucose and physiological saline are reformed to form an injectable aqueous solution having a pH of between 5.5 and 6.5.
  • the beneficial effects of the invention are as follows:
  • the formula of the component of the invention is reasonable, can effectively control the distribution and slow release of LY294002, and reduce the toxicity thereof, thereby being able to be used for clinical medicine.
  • Figure 1 is a graph showing the blood concentration-time line of a preferred embodiment of a pharmaceutical preparation of LY294002;
  • FIG. 2 is a diagram showing the concentration of a drug at each time point in the YR1103 nanoparticle tissue of a preferred embodiment of the pharmaceutical preparation of LY294002;
  • Fig. 3 is a diagram showing the in vitro release of YR1103 nanoparticles within 80 hours of a preferred embodiment of the pharmaceutical preparation of LY294002.
  • Prescription amount LY294002 50mg human albumin 500mg
  • LY294002 50mg in 3ml machine solvent such as chloroform and ethanol
  • human albumin dissolved
  • the organic solvent is removed under reduced pressure, and the nanoparticles are prepared by repeated homogenization under high pressure by a high pressure homogenization method, and the pressure in the microjet or high pressure homogenization method is 600-1500 bar.
  • the obtained average particle diameter was 150 nm, and the organic solvent was evaporated by a thin film evaporator under reduced pressure, and sterilized by filtration and freeze-dried.
  • Prescription amount LY294002 50mg albumin 400mg phospholipid (E80) 0.6g
  • Dissolve 50mg of LY294002 and 0.6g of phospholipid in 3ml organic solvent such as chloroform and ethanol
  • organic solvent such as chloroform and ethanol
  • the nanoparticle is prepared by repeated hooking treatment, the pressure in the microjet or high pressure homogenization method is 600-1500 bar, the average particle diameter is 105 nm, and lyophilized support trehalose or maltose 2.5 g is added, and the pressure is reduced after dissolution.
  • the organic solvent is evaporated by evaporation, sterilized by filtration, and lyophilized.
  • LY294002 50mg Paclitaxel 50mg Albumin 900mg Phospholipid (E80) l.Og Dissolve the prescribed amount of LY294002, paclitaxel and phospholipid in 4ml machine solvent (such as chloroform and ethanol), recombinant human albumin dissolved in sterile water 25ml
  • machine solvent such as chloroform and ethanol
  • the nanoparticle is prepared by repeated homogenization under high pressure by a high pressure homogenization method.
  • the pressure in the microjet or high pressure homogenization method is 600-1500 bar, and the average particle diameter is obtained.
  • 2.5 g of lyophilized support trehalose or maltose was added, dissolved, and the organic solvent was evaporated under reduced pressure, and the mixture was filtered and lyophilized.
  • Prescription amount LY294002 50mg cholesterol 50mg phospholipid (PC98) 0.9g
  • Dissolve the prescribed amount of LY294002, cholesterol and phospholipid in an organic solvent such as chloroform and ethanol
  • evaporate the organic solvent through a thin film evaporator under reduced pressure, add 25 ml of phosphate buffer of pH 7.4, and stir well to form an emulsion.
  • the organic solvent is removed by pressure, and the nanoparticle is prepared by repeated homogenization treatment under high pressure by a high pressure homogenization method.
  • the pressure in the microjet or high pressure homogenization method is 600-1500 bar, and the average particle diameter is 160 nm, and the sterilization filtration is performed. Got it.
  • Prescription amount LY294002 50mg cholesterol 50mg phospholipid (PC98) 0.9g PEG- DSPE 50mg
  • LY294002 Dissolve the prescribed amount of LY294002, cholesterol and phospholipids in organic solvents such as chloroform and ethanol.
  • organic solvents such as chloroform and ethanol.
  • the organic solvent was evaporated by a thin film evaporator under reduced pressure, and PEG-DSPE was added to 25 ml of a phosphate buffer of pH 7.4, thoroughly stirred to form an emulsion, and subjected to high-pressure homogenization to repeat the homogenization under high pressure to prepare nanoparticles.
  • the pressure in the microjet or high pressure homogenization method is 600-1500 bar, and the average particle diameter obtained is 135 nm, which is obtained by sterilization filtration.
  • LY294002 50mg Cholesterol (vitamin E) 25mg Phospholipid (PC98) 0.6g Poloxamer 1.2g Glycerin 0.75g
  • the prescription amount of LY294002, cholesterol (vitamin E) or phospholipid (0.3g) is dissolved in an organic solvent (such as chloroform and ethanol) to form an organic phase, and phospholipids (0.3g), glycerol and poloxamer are dissolved in the aqueous phase.
  • the organic phase is added to the aqueous phase, stirred well to form an emulsion, and the organic solvent is removed under reduced pressure.
  • the nanoparticles are prepared by a high pressure homogenization method, and the organic solvent is evaporated by a thin film evaporator under reduced pressure.
  • LY294002 50mg Hydroxypropyl ⁇ -cyclodextrin (p-butyl-cyclodextrin) 1.25g Dissolve the prescribed amount of LY294002 in an organic solvent (such as chloroform and ethanol), and dissolve the cyclodextrin in 25ml of sterile water. The organic phase is slowly added to the aqueous phase while stirring in the aqueous phase, stirred well, and the organic solvent is heated and evaporated while stirring to obtain a clathrate.
  • an organic solvent such as chloroform and ethanol
  • YR1103 (batch number 63038-1; purity 99.8%), made by our company.
  • LY294002 High purity sample (batch number 63038-2; purity >99.9%), made by our company.
  • Methanol and acetonitrile were chromatographically pure, American sigma company; other reagents were of analytical grade and purchased from Sinopharm Chemical Reagent Factory.
  • Eight healthy SD rats weighing 220 g were randomly divided into 4 groups.
  • the first three groups were administered YR1103-20120106 nanoparticles, the first group was treated with 10.5 mg/kg of the inferior femoral vein cannula, and the second group was administered with 21 mg/kg.
  • the third group was administered 42 mg/kg.
  • the fourth group was administered 25 mg/kg of SF1126 physiological saline solution. The administration time was 20 min. Numbered 1-8 in order.
  • Another 6 SD rats were randomly divided into two groups. The first group was administered with nanoparticles of 70 nm particle size, and the second group was administered with nanoparticles of 40 nm particle size, number 1-8, and the dose was 10.5 mg.
  • tissue homogenate One male and one female were killed at 0h, 0.5h, lh, 2h, and 6h after administration, and the abdominal aorta was drained and the saline was perfused for 5 minutes. Immediately dissect the tissue organs such as heart, liver, spleen, lung, kidney, brain, mesenteric lymph nodes, etc. After washing the surface blood and contents with normal saline, the filter paper is blotted, placed in a ziplock bag, and cut, as follows Prepare tissue homogenate:
  • Heart, liver, spleen, lung, kidney, brain tissue Take 0.5 g, force ⁇ 2.0 ⁇ 150% aqueous methanol, homogenate, supersonic for 10 min, centrifugation (5000 g) lO min, remove the supernatant at 20 ° C.
  • lymph nodes were weighed for their actual mass, 2.0 ml of 50% aqueous methanol solution, homogenized, sonicated for 10 min, centrifuged (5000 g) for 10 min, and the supernatant was stored at 20 °C.
  • tissue drug concentration data table of YR1103 nanoparticles at each time point and the results are shown in Fig. 2
  • YR1103 nanoparticles were slowly administered intravenously (20 min), and YR1103 was rapidly distributed in the kidney, spleen, lung and kidney organs.
  • the concentration of YR1103 decreased rapidly, and the half-life of drug concentration was much lower than the half-life of blood concentration. .
  • the YR1103 content in other tissues could not be determined and was almost zero.
  • the YR1103 nanoparticles were distributed slowly after administration, reached Cmax at about 2 hours, and then began to slowly decrease. By 6 hours, the blood concentration had dropped to 1/10 Cmax, while the YR1103 in the lymph nodes remained unchanged. High concentration. YR1103 nanoparticles accumulate in the lymphatic system and are slowly eliminated.
  • YR1103 powder Take 10mg of YR1103 powder in a 100ml volumetric flask, add water to volume and shake vigorously for 5min, and the amount is not dissolved. After electromagnetic stirring for 40 minutes in a 40-degree water bath, it was placed in an ultrasound system for 40 minutes for 5 minutes. After 0.22 um nylon membrane, 20 ul of injection was taken. The YR1103 peak could not be detected in the chromatogram, indicating that YR1103 is insoluble in water.
  • the invention can effectively control the distribution and slow release of LY294002. Since LY294002 is not intravenously injected by the wrapping technique, the half-life in the body is only 15 minutes, and the drug for clinical use cannot be made. In view of the good antitumor activity of the molecule, many scholars adopt Various methods have been used to study the molecule. It has not been found that some people have made it into a clinically applicable and industrialized drug through the wrapping technology. The present invention not only controls the slow release of the preparation, but also achieves a passive distribution of the lymphatic system, which is expected to produce an effective drug for successfully treating lymphoma and controlling lymphatic metastasis of cancer cells, thereby producing good economic and social benefits.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une préparation pharmaceutique enrobant le LY294002. Le LY294002 est enrobé dans un médicament et un adjuvant, et la proportion pondérale du médicament à celle de l'adjuvant vaut : 1:1 à 1:20, de manière à contrôler efficacement la libération du LY294002. Un médicament destiné au traitement clinique d'une maladie associée à des troubles liée à une activité de PI3K peut être préparé et en particulier peut être utilisé pour le traitement d'une tumeur lymphocytaire et le traitement de métastases de tumeur lymphocytaire.
PCT/CN2012/000500 2011-12-30 2012-04-13 Préparation pharmaceutique enrobant le ly294002. WO2013097266A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201280064823.XA CN104010628A (zh) 2011-12-30 2012-04-13 一种包裹ly294002的药物制剂

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110453641 2011-12-30
CN201110453641.9 2011-12-30

Publications (1)

Publication Number Publication Date
WO2013097266A1 true WO2013097266A1 (fr) 2013-07-04

Family

ID=48696307

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2012/000500 WO2013097266A1 (fr) 2011-12-30 2012-04-13 Préparation pharmaceutique enrobant le ly294002.

Country Status (2)

Country Link
CN (1) CN104010628A (fr)
WO (1) WO2013097266A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111514317B (zh) * 2020-04-09 2022-08-19 温州医科大学附属第一医院 一种淋巴系统双模态成像造影剂

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005051229A2 (fr) * 2003-11-24 2005-06-09 Avantec Vascular Corporation Dispositifs et procedes d'administration d'agents therapeutiques
CN1846679A (zh) * 2006-01-23 2006-10-18 济南帅华医药科技有限公司 含氨甲喋呤及其增效剂的缓释注射剂
WO2007120897A2 (fr) * 2006-04-13 2007-10-25 The Trustees Of Columbia University In The City Of New York Compositions et dispositifs intraluminaux permettant d'inhiber la stenose vasculaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005051229A2 (fr) * 2003-11-24 2005-06-09 Avantec Vascular Corporation Dispositifs et procedes d'administration d'agents therapeutiques
CN1846679A (zh) * 2006-01-23 2006-10-18 济南帅华医药科技有限公司 含氨甲喋呤及其增效剂的缓释注射剂
WO2007120897A2 (fr) * 2006-04-13 2007-10-25 The Trustees Of Columbia University In The City Of New York Compositions et dispositifs intraluminaux permettant d'inhiber la stenose vasculaire

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HARFOUCHE, R. ET AL.: "Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis", ANGIOGENESIS, vol. 12, no. 4, 30 April 2009 (2009-04-30), pages 325 - 338, XP019745622, DOI: doi:10.1007/s10456-009-9154-4 *
XIE, XIA ET AL.: "Drug resistance reversing effects on gastric carcinoma cell line by inhibition of PI3K/PKB signal pathway and its mechanism", CHONGQING MEDICINE, vol. 39, no. 21, 30 November 2010 (2010-11-30), pages 2875 - 2877 *
YANG, XUEFENG ET AL.: "Application of the nanoemulsion administration system", GUANGDONG AGRICULTURAL SCIENCES, 31 July 2011 (2011-07-31), pages 125 - 127 *

Also Published As

Publication number Publication date
CN104010628A (zh) 2014-08-27

Similar Documents

Publication Publication Date Title
CN103002877B (zh) 作为缓解疾病的抗风湿性药（dmard）和抗癌药剂的甲氨蝶呤的持续释放制剂
JP4885715B2 (ja) イリノテカン製剤
KR101943230B1 (ko) 항암제로서 라파마이신 및 알부민을 포함하는 나노입자
CN102188377B (zh) 包载药物脂质体的制备方法
WO2008080367A1 (fr) Composition de liposome et son procédé de préparation
KR20160140992A (ko) 이리노테칸 또는 그의 하이드로클로라이드의 리포좀 및 그의 제조 방법
JP2009507049A (ja) リン脂質のポリエチレングリコール誘導体に包み込まれたビンカアルカロイド系制癌剤のナノミセル製剤
Xin et al. PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: In vitro and in vivo investigations
CN106474064B (zh) 一种蒿甲醚纳米脂质体及其制备方法与应用
BRPI0619565A2 (pt) composições lipossÈmicas
CN109730998A (zh) 米铂白蛋白纳米粒组合物及其制法
WO2023030524A1 (fr) Système d'administration de nanoporteurs de liposomes ciblant l'athérosclérose et son procédé de préparation
KR101395858B1 (ko) 다당류 리포솜, 이의 제조 방법 및 용도
CN103585106B (zh) 一种pH敏感性修饰脂质体及其制备方法
Maddiboyina et al. Perspectives on cutting‐edge nanoparticulate drug delivery technologies based on lipids and their applications
CN103622909A (zh) 一种含心磷脂的脂质体新制剂及其在抗肿瘤药物中的应用
CN106913882B (zh) 一种聚乙二醇-藤黄酸脂质体和制备方法及其在治疗恶性肿瘤中的应用
WO2005123078A1 (fr) Préparation de liposome contenant du camptothecin legérement soluble dans l'eau
JP2006273812A (ja) リポソーム製剤の製造方法
CN100350912C (zh) 一种新型的聚乙二醇衍生化磷脂包载前列腺素e1的纳米微粒给药系统
Sankar et al. Comparative studies of lamivudine-zidovudine nanoparticles for the selective uptake by macrophages
CN114712514B (zh) 用于局部和全身性减脂的纳米制剂及其应用
JP2018527289A (ja) リン脂質でコーティングされた治療薬ナノ粒子および関連する方法
WO2013097266A1 (fr) Préparation pharmaceutique enrobant le ly294002.
CN101849915A (zh) 异长春花碱隐形脂质体冻干粉针剂及其制备方法

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: 12863701

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: 12863701

Country of ref document: EP

Kind code of ref document: A1