US20110002977A1 - Liposomal pharmaceutical preparation and method for manufacturing the same - Google Patents

Liposomal pharmaceutical preparation and method for manufacturing the same Download PDF

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US20110002977A1
US20110002977A1 US12/521,357 US52135707A US2011002977A1 US 20110002977 A1 US20110002977 A1 US 20110002977A1 US 52135707 A US52135707 A US 52135707A US 2011002977 A1 US2011002977 A1 US 2011002977A1
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liposome
liposomal
drug
liposomal drug
phospholipid
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Chunlei Li
Jinxu Wang
Caixia Wang
Yanhui Li
Dongmin Shen
Wenmin Guo
Li Zhang
Lan Zhang
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Shijiazhuang Pharma Group Zhongqi Pharmaceutical Technology Co Ltd
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Shijiazhuang Pharma Group Zhongqi Pharmaceutical Technology Co Ltd
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Assigned to SHIJIAZHUANG PHARMA. GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD reassignment SHIJIAZHUANG PHARMA. GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GUO, WENMIN, LI, CHUNLEI, LI, YANHUI, SHEN, DONGMIN, WANG, CAIXIA, WANG, JINXU, ZHANG, LAN, ZHANG, LI
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    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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 present invention relates to a liposomal preparation and a drug-encapsulating liposomal pharmaceutical preparation, especially to a liposomal pharmaceutical preparation of mitoxantrone.
  • the present invention further relates to methods for manufacturing the liposome, liposomal pharmaceutical preparation and uses thereof.
  • Liposomes can be used as a carrier for many drugs, especially for antitumor drugs (in particular chemotherapeutic drugs). Liposomes can reduce the distribution of drug in normal tissues, but increase the accumulation of drug in tumor tissues, thereby improving the therapeutic index of drug. The reason why a liposome can target passively to a tumor relates to the physiological properties of tumor tissue. Tumor blood vessels may have a pore size of up to 100-780 nm due to its rapid growth, while normal vascular endothelial cells have a typical space of about 2 nm.
  • liposomes can accumulate passively in tumor region if they can circulate for a relatively long period in blood and have a size of less than 200 nm, because after liposomes with small size are administered via intravenous injection, they can not enter normal tissues but can penetrate blood vessel of tumor region and arrive at treatment area.
  • the drug can be encapsulated in liposome in a good encapsulation efficiency and a sufficient drug loading; (2) the drug will not be released from the liposome during storage period in vitro; (3) there is not a notable drug leakage during blood circulation of liposomal drug; and (4) the drug can be released effectively and thereby exerting its therapeutic effects when liposomes are accumulated in the tumor region.
  • the former three problems have been solved well, therefore, the rational release in vivo of liposomal drug draws more attentions.
  • One critical technical problem to be solved for developing some liposomal drugs is to effectively control the rational release of liposomal drugs after targeting to a tumor region. This is especially important for some drugs, such as mitoxantrone.
  • a liposome formulation having a size of about 100 nm which was prepared by using hydrogenated soybean phosphatidylcholine (HSPC) and cholesterol as phospholipid bilayer and loading drug by a 300 mM citric acid gradient, was not as good as free mitoxantrone.
  • HSPC hydrogenated soybean phosphatidylcholine
  • the group finally changed the composition of phospholipid bilayer into dimyristoyl phosphatidylcholine (DMPC) and cholesterol, and obtained a preparation with improved therapeutic indexes.
  • DMPC dimyristoyl phosphatidylcholine
  • the leakage of drug may increase during the storage period because the phase transition temperature of DMPC is about 21° C., so that the preparation may not be stable (Liposomal formulations of mitoxantrone, U.S. Pat. No. 5,858,397).
  • Neopharm Corporation of USA used another technique to develop a liposome formulation of mitoxantrone, in which a cardiolipin carrying negative charge was added to phospholipid bilayer. Due to the intensive interaction between cardiolipin and mitoxantrone, mitoxantrone could be inserted into the phospholipid bilayer in a passive loading mode. This passive loading technique is different from active loading technique. By virtue of active loading technique, a drug would deposit in the intraliposomal aqueous phase in a form of precipitation. The Phase I clinical study on the product of Neopharm indicated that liposome drugs could increase the possibility of occasional infection, compared with free drug. The development of this product was ceased in view of safety (Liposomal preparations of mitoxantrone, CN01817424.8).
  • the size of liposomes is usually controlled in the range of 80 ⁇ 150 nm, since there is a consensus in the field of liposome that a liposome with a size of about 100 nm would have the best targeting efficiency (Pharmacol. Rev. 1999 51: 691-744.).
  • a liposome should not only have an excellent targeting efficiency, but also a sufficient release from liposome to exert its effect.
  • the leakage of drug during blood circulation should be essentially avoid so that the drug could be effectively transferred to tumors, but this requirement also results in a difficulty of releasing the drug from the liposome when it is targeted to tumor region.
  • a drug is usually encapsulated by a active loading technique, in which the drug encapsulated in the liposome is present in a colloid precipitate form having no bioactivity, so that only when the drug is released effectively from the liposome, it can change into a therapeutic drug with bioactivity. If the release rate of drug is too slow, the drug can hardly exert its therapeutic actions even though it has been targeted effectively to the tumor region, and its therapeutic effect may be even inferior to an unencapsulated drug.
  • the present inventors surprisingly found by chance that some drugs having a plurality of dissociable groups and a liability of forming compact precipitate with multivalent counter ion, could be processed to form a small unilamellar liposomal preparation with an effectively improved therapeutic index, so that the above technical problem could be solved.
  • the present invention provides a liposomal preparation with a size of about 30-80 nm having a phospholipid with a Tm higher than body temperature in phospholipid bilayer, so that the phase transition temperature of liposome is higher than the body temperature.
  • phospholipid include but are not limited to phosphatidylcholine, hydrogenated soybean phosphatidylcholine (HSPC), hydrogenated egg-yolk phosphatidylcholine, dipalmitoyl phosphatidylcholine (DPPC) or distearoyl phosphatidylcholine (DSPC) or any combination thereof.
  • the phospholipid with a Tm higher than body temperature in the phospholipid bilayer represents 50-100 mol/mol %, preferably 55-95 mol/mol %, and more preferably 55-95 mol/mol % of the total content of phospholipids.
  • the phospholipid bilayer of the liposomal preparation of the present invention further comprises additional phospholipids, for example, a phospholipid with a Tm not higher than the body temperature, such as dimyristoyl phosphatidylcholine (DMPC) and the like.
  • a phospholipid with a Tm not higher than the body temperature such as dimyristoyl phosphatidylcholine (DMPC) and the like.
  • DMPC dimyristoyl phosphatidylcholine
  • the amount of the phospholipid in the liposomal preparations of the present invention can be conventionally determined by those of ordinary skilled in the field, provided that the Tm value of the liposomal preparation is not markedly reduced to a value lower than the body temperature.
  • the liposomal preparation of the present invention can also optionally comprise cholesterol in order to regulate the fluidity of liposome membrane.
  • the liposomal preparation of the present invention can also optionally comprise additional excipients, especially excipients for further modifying surface characteristics of liposome to confer the liposome better behavior in vivo.
  • excipients include, for example, lipids and the like modified with hydrophilic polymers.
  • the present invention provides a liposomal pharmaceutical preparation, which comprises a drug of interest, especially a multivalent ionic drug, in a liposomal preparation of the present invention. Therefore, the present invention relates to a liposomal pharmaceutical preparation having a size of 30-80 nm, wherein: (1) the liposomal pharmaceutical preparation comprises a multivalent ionic drug as active ingredient; (2) the phospholipid bilayer comprises a phospholipid with a Tm higher than body temperature so that the phase transition temperature of the liposome is higher than the body temperature; and optionally (3) the liposomal pharmaceutical preparation comprises additional drugs and/or additional excipients acceptable in the liposomal pharmaceutical preparation.
  • the main peaks of size of the liposomal pharmaceutical preparation are centered around 35-75 nm, especially around 40-60 nm.
  • the present invention provides a method for preparing the above liposomal pharmaceutical preparation, the method comprising the following steps: (1) preparing a liposome using a phospholipid with a Tm higher than body temperature and optionally additional phospholipids and/or cholesterol; and (2) encapsulating a drug of interest, especially a multivalent ionic drug in the liposome.
  • the present invention also provides a method for treatment of disease, comprising administering a liposomal pharmaceutical preparation of the present invention to a subject in need of the treatment.
  • the subject is a mammal, especially a human being.
  • FIG. 1 is the in vivo pharmacokinetics of PLM60 in Kunming mice and the comparison thereof with the in vivo pharmacokinetics of free mitoxantrone, in which PLM represents PEGylated mitoxantrone liposome, FM represents free mitoxantrone, the abscissa represents time (hour) and the ordinate represents plasma level of mitoxantrone ( ⁇ g mitoxantrone/mL plasma).
  • FIG. 2 is the profile of PLM60 and FM in mice tumor, in which PLM60 represents PEGylated mitoxantrone liposome, FM represents free mitoxantrone, the abscissa represents time (hour) and the ordinate represents the concentration of mitoxantrone in tumor tissues ( ⁇ g mitoxantrone/g tumor tissue).
  • FIG. 3 is the comparison of in vivo pharmacokinetics in mice of different formulations, in which the abscissa represents time (hour) and ordinate represents the plasma level of mitoxantrone ( ⁇ g mitoxantrone/mL plasma), and the dosages of different formulations are all 4 mg/kg.
  • liposomes are formed with phospholipids and cholesterol as membrane materials. These two ingredients not only are the basic materials for forming liposome bilayer, but also have very important physiological functions.
  • the physical properties of liposomal membrane are closely related to the temperature.
  • acyl side chains of lipid bilayer change form ordered array into unordered array. This kind of change can result in many changes of physical properties of lipid membrane.
  • “gel” state may change into “liquid crystal” state, the cross section of membrane may increase, the thickness of bilayer may decrease, the membrane fluidity may increase.
  • the temperature at which such changes happen is called phase transition temperature.
  • the phase transition temperature of lipid membrane can be determined by Differential Scanning Calorimertry, Electron Spins Resonance (ESR) and the like.
  • ESR Electron Spins Resonance
  • the phase transition temperature of liposome membrane depends on the kinds of phospholipids. Generally, the longer the acyl side chain, the higher the phase transition temperature; and vice versa.
  • the phase transition temperature of dimyristoyl phosphatidylcholine is 24° C.
  • those of dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine are 41° C. and 58° C., respectively.
  • Membrane fluidity is an important property of liposome. At phase transition temperature, membrane fluidity will increase, and the drug encapsulated in the liposome has the maximum release rate. Thus the membrane fluidity affects directly the stability of liposome.
  • the present invention provides a liposome preparation having a size of about 30-80 nm and a phospholipid with a Tm higher than body temperature in phospholipid bilayer, so that the phase transition temperature of liposome is higher than the body temperature.
  • the liposomal pharmaceutical preparation of the present invention is prepared by using phospholipids with a relatively high phase transition temperature Tm, such as phosphatidylcholine. If the Tm of phosphatidylcholine is higher than the body temperature, the length of its hydrocarbon chain is preferably not less than 16 carbons.
  • the phospholipids of the present invention include but not limited to hydrogenated soybean phosphatidylcholine, hydrogenated egg-yolk phosphatidylcholine, dipalmitoyl phosphatidylcholine (DPPC) or distearoyl phosphatidylcholine (DSPC), or any combination thereof.
  • the phospholipids with a Tm higher than the body temperature in phospholipid bilayer represent about 50-100 mol/mol %, preferably about 55-95 mol/mol %, more preferably about 60-90 mol/mol % relative to the total content of all phospholipids.
  • the phospholipid bilayer may comprise additional phospholipids, for example, phospholipids with a Tm not higher than the body temperature, such as dimyristoyl phosphatidylcholine (DMPC) and the like.
  • DMPC dimyristoyl phosphatidylcholine
  • Such phospholipids may be present in the liposome in any suitable amount, provided that it does not render the phase transition temperature of the liposomal preparation below the body temperature. The suitable amount can be determined according to conventional techniques by those of ordinary skilled in the field.
  • the liposomal preparation of the present invention may further comprise cholesterol.
  • Cholesterol has a function of regulating membrane fluidity. When the liposome membrane comprises 50% (mol/mol) cholesterol, the phase transition of liposome membrane may disappear. Cholesterol is called “fluidity buffer” by Papahadjopoulos et al., because the addition of cholesterol to phospholipids under phase transition temperature can reduce the ordered array of membrane and increase membrane fluidity, while the addition of cholesterol to phospholipids above the phase transition temperature can increase the ordered array of membrane and reduce the membrane fluidity.
  • the content of cholesterol can be 2-60 mol/mol %, 5-55 mol/mol % or 10-50 mol/mol % relative to the total amount of ingredients of liposome. More specifically, the content of cholesterol can be 15-45 mol/mol %, for example 20-40 mol/mol % relative to the total amount of ingredients of liposome.
  • the content of cholesterol in the liposome of the present invention can be determined easily according to conventional techniques by those of ordinary skilled in the field.
  • the phospholipid bilayer in the liposome of the present invention can also comprise additional excipients, especially excipients for further modifying surface characteristics of the liposome to confer better in vivo behaviors to the liposome.
  • excipients include, for example, lipid substances modified with hydrophilic polymers, and the examples thereof are PEG-modified distearoyl phosphatidyl ethanolamine (DSPE-PEG), PEG-modified distearoyl phosphatidyl glycerol (DSPG-PEG), PEG-modified cholesterol (chol-PEG), polyvidone-modified distearoyl phosphatidyl ethanolamine (DSPE-PVP), polyvidone-modified disteroyl phosphatidyl glycerol (DSPG-PVP), or polyvidone-modified cholesterol (chol-PVP).
  • DSPE-PEG PEG-modified distearoyl phosphatidyl ethanolamine
  • DSPG-PEG PEG-
  • Said excipients can also be membrane materials modified with a specific antibody or ligand.
  • the amount of such excipients in the liposome of the present invention can be determined according to conventional techniques by those of ordinary skilled in the field, for example, can be 0.1-20 mol/mol %, preferably 0.3-18 mol/mol %, more preferably 0.5-15 mol/mol %, especially 0.8-12 mol/mol %, for example 1-10 mol/mol %, or 2-8 mol/mol %, 2.5-7 mol/mol %, 3-6 mol/mol %, etc. relative to the mole number of phospholipids.
  • the molecular weight of PEG moiety can be, for example, 400-20000 Dalton, preferably 600-15000 Dalton, more preferably 800-10000 Dalton, especially 1000-8000 Dalton, for example 1200-5000 Dalton.
  • the use of PEG in the present invention can also be determined easily according to conventional trails by those of ordinary skilled in the field.
  • the liposomal preparation of the present invention is a small unilamellar liposomal preparation, and should have a suitable size.
  • the size of the preparation is 30-80 nm, more preferably 35-70 nm, especially preferably 40-60 nm.
  • the size of liposome can be determined by particle size analyzer or electron microscope or other means. It should be understood that the liposome particles in the present invention can not have a completely uniform size, but span a size range, due to the nature of liposome per se and properties of manufacture process. Therefore, in the liposomal preparation of the present invention, the presence of liposome particles out of the stated size range may not be excluded, provided that they do not evidently affect the characters of the liposomal preparation or pharmaceutical preparation of the present invention.
  • the liposome in the present invention can be prepared by various suitable methods, including, for example, film dispersion method, injection method, ultrasonic dispersion method, freeze-drying method, freeze-thaw method and the like.
  • the methods can be divided into: (1) methods based on dry lipid membrane, lipid powder; (2) methods based on emulsifying agents; (3) liposome preparation methods based on mixed micelles; and (4) liposome preparation methods based on a triple phase mixture of ethanol, phospholipids and water.
  • the encapsulation of drug can be implemented by either passive loading mode or active loading mode. These methods can be found in many review articles about liposomes.
  • Suitable methods can be used to encapsulate a drug in liposome and form a liposomal pharmaceutical preparation.
  • Suitable methods include for example active loading methods and passive loading methods.
  • Active loading method is usually performed by gradient methods, for example an ammonium sulfate gradient method, i.e., using an ammonium sulfate solution as aqueous phase to firstly prepare a liposome comprising ammonium sulfate in both intraliposomal and extraliposomal phase, then forming a concentration gradient of ammonium sulfate between the intraliposomal and extraliposomal phase by removing extraliposomal ammonium sulfate.
  • gradient methods for example an ammonium sulfate gradient method, i.e., using an ammonium sulfate solution as aqueous phase to firstly prepare a liposome comprising ammonium sulfate in both intraliposomal and extraliposomal phase, then forming
  • Intraliposomal NH 4 + dissociates into NH 3 and H + which leads to a concentration difference of H + (i.e. pH gradient) between intraliposomal and extraliposomal phase, so that after an extraliposomal drug in molecular state enters into the intraliposomal aqueous phase, it changes into ionic state, thereby the drug can not return to the extraliposomal aqueous phase and the liposome has less leakage of drug and is more stable.
  • Passive loading method can be performed by organic solvent injection method, film dispersion method, freeze-thaw method, and the like.
  • the active pharmaceutical ingredient in the liposomal pharmaceutical preparation of the present invention is a multivalent ionic drug.
  • multivalent ionic drug means a drug having two or more dissociable groups with a dissociation constant pKa of 4.5 ⁇ 9.5, so that the drug has more positive charges or more negative charges in the ranges of pKa.
  • said dissociation constant is in the range of 5.0-9.5. More preferably, said dissociation constant is in the range of 5.5-9.5. Especially preferably, said dissociation constant is in the range of 6.0-9.0 m, especially 6.5-9.0.
  • the pKa value of each dissociable group of ion drug can be determined easily according conventionally techniques by those of ordinary skilled in the field.
  • the multivalent ionic drugs can include but are not limited to anticancer drugs, for example, drugs useful for prevention or treatment of the following cancers: lung cancers (such as non-small cell lung cancer), pancreas cancer, breast cancer, rectum cancer or multiple myeloma, liver cancer, cervical carcinoma, gastric carcinoma, carcinoma of prostate, renal carcinoma and/or carcinoma of bladder. Therefore, in one embodiment of the present invention, the multivalent ionic drug is a multivalent ion anticancer drug.
  • the multivalent ionic drug is mitoxantrone, vincristine, vinorelbine or vinblastine.
  • said multivalent ionic drug is mitoxantrone and can optionally combine with at least one of additional drugs, which can for example be an antitumor drug, such as vincristine, vinorelbine or vinblastine, and the like.
  • additional drugs can for example be an antitumor drug, such as vincristine, vinorelbine or vinblastine, and the like.
  • the multivalent ionic drug can also be a combination of any one or two or more of the above drugs, for example, a combination of two anticancer drugs, a combination of one or more anticancer drugs with additional drugs such as immunopotentiator, and a combination of two or more other kinds of drugs.
  • the liposomal drugs of the present invention can also optionally comprise one or more of additional non-multivalent ionic drugs besides the multivalent ionic drugs mentioned above, which can be administered in combination with the multivalent ionic drugs as mentioned above.
  • the combinatory administration comprises the administration with all the components in one preparation, also comprises the combinatory administration in separate unit dosage form.
  • the drug as active ingredient as mentioned herein comprises not only its original form, but also its derivatives, for example solvates (such as hydrates and alcohol addition products), prodrugs and other physiologically acceptable derivatives, as well as active metabolites, and the like.
  • solvates such as hydrates and alcohol addition products
  • prodrugs and other physiologically acceptable derivatives as well as active metabolites of a drug are all well known to those of ordinary skilled in the field.
  • the liposomal pharmaceutical preparation of the present invention can further comprise two or more multivalent counter ions with charges opposite to that of active ingredient.
  • the multivalent counter ions include but are not limited to organic acid anions, such as acid anions of the following saturated or unsaturated organic acids: citric acid, tartaric acid, fumaric acid, oxalic acid, malonic acid, succinic acid, malic acid and maleic acid, and the like; inorganic acid anions, such as sulfate anion, phosphate anion and the like. Among them citrate anion, sulfate anion or phosphate anion are preferred.
  • said multivalent counter ions can also be amino acids, such as cystine and the like.
  • the multivalent counter ion is able to form an insoluble precipitate with a drug of interest (e.g., multivalent ionic drug) encapsulated in the liposome, thereby the existence of the multivalent ionic drug in the liposome is stabilized.
  • a drug of interest e.g., multivalent ionic drug
  • the liposomal pharmaceutical preparation of the present invention further comprises optionally additional excipients and carriers commonly known in the pharmaceutical field, such as sucrose, histidine, antioxidants, stabilizers, dispersants, preservatives, diluents, solvents, salts for altering osmotic pressure, and the like.
  • excipients and carriers commonly known in the pharmaceutical field, such as sucrose, histidine, antioxidants, stabilizers, dispersants, preservatives, diluents, solvents, salts for altering osmotic pressure, and the like.
  • the present invention provides a method for preparing the liposomal pharmaceutical preparation of the present invention, comprising: firstly preparing the liposomal preparation of the present invention as mentioned above, and subsequently incubating a drug of interest with the liposomal preparation in a suitable condition.
  • the method for preparing the liposomal pharmaceutical preparation of the present invention comprises the following steps: (1) dissolving lipid excipients suitable for preparing a liposome in a suitable organic solvent, such as tert-butyl alcohol or cyclohexane, then lyophilizing to obtain a lyophilized powder; (2) hydrating the lyophilized powder with a solution containing a counter ion of the drug active ingredient of interest to form an empty liposome; (3) removing the extraliposomal counter ion by a suitable means such as dialysis or column chromatography and the like in order to form a counter ion gradient between the intraliposomal phase and extraliposomal phase; and (4) incubating the drug with the liposome to obtain the liposome drug.
  • a suitable organic solvent such as tert-butyl alcohol or cyclohexane
  • the lipid is a phospholipid, especially a lipid with a relatively high phase transition temperature, for example, phosphatidylcholine, hydrogenated soybean phosphatidylcholine, hydrogenated egg yolk phosphatidylcholine, dipalmitoyl phosphatidylcholine (DPPC) or distearoyl phosphatidylcholine (DSPC), or any combination thereof.
  • said lipid can also comprise cholesterol in an amount of, for example, 2-60 mol/mol %, 5-55 mol/mol % or 10-50 mol/mol %.
  • the amount of cholesterol can be 15-45 mol/mol %, for example 20-40 mol/mol % relative to the total mole number of all ingredients in the liposome.
  • Those of ordinary skilled in the field can determine the cholesterol amount depending on specific requirements for the phase transition temperature of liposome to be obtained and the desired properties.
  • the encapsulation efficiency of drug in liposome can be determined by conventional techniques. Methods for determining the encapsulation efficiency of liposome includes ultrafiltration, dialysis, column chromatography, minicolumn centrifugation, and the like.
  • Ultrafiltration is not used due to the high requirements for experiment device; column chromatography is not used because the dilution requires a large amount of eluent, and the content of drug is very low, so that it is difficult to conduct content determination, moreover, the dilution of a large amount of eluent can also lead to leakage of drug in liposome, it can be known from trial data that the encapsulation efficiency for dialysis is lower (perhaps due to the breakage of liposome after dilution) and the time for dialysis is long, thus the method is not suitable. Determination of encapsulation efficiency by minicolumn centrifugation has the following advantages: short time consuming, small dilution rate for solution of liposome, and no need for expensive instruments.
  • the liposomal pharmaceutical preparation of the present invention ensures not only sufficient encapsulation efficiency and sufficient drug loading, but also no release of drug from liposome during in vitro storage, no notable leakage of drug from liposome during blood circulation to increase toxicity.
  • An important notable effect of the liposome drug of the present invention is that the release rate of drug is accelerated efficiently, the therapy index of liposome is improved, the half-life period is significantly prolonged, the toxicity is reduced markedly in comparison with the current products in the field, and thus the effective therapeutic effects of drug are achieved.
  • HSPC hydrogenated soybean phosphatidylcholine
  • DPPC dipalmitoyl phosphatidylcholine
  • the toxicity thereof is markedly reduced and the therapeutic index thereof is significantly improved.
  • the phospholipid bilayer is composed of dimyristoyl phosphatidylcholine (DMPC)
  • DMPC dimyristoyl phosphatidylcholine
  • the small unilamellar liposomal preparation of the present invention can accelerate the release of drug because the small unilamellar liposomal preparation may contain more liposome particles in which drug precipitation with a small particle size is contained, in comparison with a larger unilamellar liposome preparation, if the drug/lipid ratio is fixed. Drug precipitation with a small particle size would have a relatively great specific surface area, and thus have a more rapid dissolution rate under same conditions.
  • the liposomal pharmaceutical preparation of the present invention should be prepared using suitable phospholipids in order to achieve an effective release of drug in target tissues, especially in tumors.
  • the phospholipid bilayer of the liposomal pharmaceutical preparation of the present invention is composed of phospholipids with a relatively high phase transition temperature.
  • HSPC hydrogenated soybean phosphatidylcholine
  • DPPC dipalmitoyl phosphatidylcholine
  • the phospholipid bilayer is composed of dimyristoyl phosphatidylcholine (DMPC), the release of drug would be too fast and would lead to a notable toxicity, even the safety would not be as good as an unencapsulated drug.
  • the liposomal pharmaceutical preparation of the present invention can be administered to a patient in need thereof in an administration route commonly used in the field.
  • the liposome drug is formulated into a preparation for parenteral administration.
  • the liposome drug is administered by injection.
  • the present invention also provides a method for the treatment of disease, especially tumors in a patient, the method comprising administering a liposomal pharmaceutical preparation of the present invention to the patient in need of the treatment.
  • a thermotherapy method (such as a radioactive thermotherapy method) can also be applied in combination to a tumor patient in order to enhance the therapeutic effect of the liposomal pharmaceutical preparation.
  • the patient can be a mammal, preferably a human.
  • the present invention also relates to a use of the liposomal preparation or liposomal pharmaceutical preparation as mentioned above in the manufacture of a medicament for treatment of a tumor patient.
  • Phospholipid e.g., hydrogenated soy phosphatidylcholine (HSPC), dipalmitoyl phosphatidylcholine (DPPC) or dimyristoyl phosphatidylcholine (DMPC)
  • cholesterol molar ratio of 1:1 to 10:1
  • HSPC hydrogenated soy phosphatidylcholine
  • DPPC dipalmitoyl phosphatidylcholine
  • DMPC dimyristoyl phosphatidylcholine
  • cholesterol molar ratio of 1:1 to 10:1
  • the solution is treated by conventional lyophilization to obtain a lyophilized powder.
  • the lyophilized powder is hydrated at 60-65° C.
  • a mitoxantrone hydrochloride solution (10 mg/mL) is added to the empty liposomes at a suitable liposome/drug ratio, and the loading of drug is conducted at 60-65° C. After incubation for about 1 hour, a gel exclusion chromatography is employed to determine encapsulation efficiency (EE).
  • Phospholipid e.g., hydrogenated soy phosphatidylcholine (HSPC), dipalmitoyl phosphatidylcholine (DPPC) or dimyristoyl phosphatidylcholine (DMPC)
  • cholesterol molar ratio of 1:1 to 10:1
  • HSPC hydrogenated soy phosphatidylcholine
  • DPPC dipalmitoyl phosphatidylcholine
  • DMPC dimyristoyl phosphatidylcholine
  • DSPE-PEG polyethylene glycol-modified distearoyl phosphatidylethanolamine
  • the obtained mixture is dissolved in an organic solvent, such as t-butyl alcohol or cyclohexane, to form a clear solution.
  • the solution is treated by conventional lyophilization to obtain a lyophilized powder.
  • the lyophilized powder is hydrated at 60-65° C. with (50-1000 mM) ammonium sulfate solution, citric acid solution or transition metal sulfate (e.g., nickel sulfate) solution and shaken for about 1 hour to obtain heterogenous multilamellar vesicles.
  • the size of the obtained vesicles is reduced by a microfluidizer or a high pressure extrusion apparatus to obtain liposomes.
  • a sample of the obtained liposomes is diluted by 200 times with 0.9% NaCl solution and detected by NanoZS.
  • the extraliposomal buffer solution is removed by ultrafiltration apparatus to form a dynamic transmembrane gradient.
  • a mitoxantrone hydrochloride solution (10 mg/mL) is added to the empty liposomes at a suitable liposome/drug ratio, and the loading of drug is conducted at 60-65° C. After incubation for about 1 hour, a gel exclusion chromatography is employed to determine encapsulation efficiency (EE).
  • HSPC, cholesterol and DSPE-PEG2000 at a weight ratio of 3:1:1 were dissolved in 95% t-butyl alcohol to form a clear solution.
  • the solution was treated by lyophilization to obtain a lyophilized powder.
  • the lyophilized powder was hydrated with an ammonium sulfate solution (300 mM) at 60-65° C. and shaken for about 1 hour to obtain heterogenous multilamellar vesicles having a final concentration of phospholipid of 96 mg/mL
  • the size of vesicles was reduced by a microfluidizer to obtain liposomes.
  • a sample of the obtained liposomes was diluted by 200 times with 0.9% NaCl and detected by NanoZS, having an average size of about 60 nm and a main peak between 40 nm and 60 nm.
  • the extraliposomal ammonium sulfate solution was removed by an ultrafiltration apparatus and substituted by a solution with 250 mM sucrose and 50 mM glycine to form a dynamic transmembrane gradient.
  • a mitoxatrone hydrochloride solution (10 mg/mL) was added to the empty liposomes at a liposome/drug ratio of 16:1, and the loading of drug was conducted at 60-65° C. After incubation for about 1 hour, the encapsulation efficiency (EE) was determined as 100% by a gel exclusion chromatography.
  • the obtained liposomes were named as PLM60.
  • HSPC, cholesterol and DSPE-PEG2000 at a weight ratio of 3:1:1 were dissolved in 95% t-butyl alcohol to form a clear solution.
  • the solution was treated by lyophilization to obtain a lyophilized powder.
  • the lyophilized powder was hydrated with an ammonium sulfate solution (300 mM) at 60-65° C. and shaken for about 1 hour to obtain heterogenous multilamellar vesicles having a final concentration of phospholipid of 96 mg/mL
  • the size of vesicles was reduced by a high pressure extrusion apparatus to obtain liposomes.
  • a sample of the obtained liposomes was diluted by 200 times with NaCl solution and detected by NanoZS, having an average size of about 85 nm
  • the extraliposomal ammonium sulfate solution was removed by an ultrafiltration apparatus and substituted by a solution with 250 mM sucrose and 50 mM glycine to form a dynamic transmembrane gradient.
  • a mitoxatrone hydrochloride solution (10 mg/mL) was added to the empty liposomes at a liposome/drug ratio of 16:1, and the loading of drug was conducted at 60-65° C. After incubation for about 1 hour, the encapsulation efficiency (EE) was determined as 100% by a gel exclusion chromatography.
  • the obtained liposomes were named as PLM85.
  • DPPC, cholesterol and DSPE-PEG2000 at a weight ratio of 3:1:1 were mixed, and other steps were identical to those of Example 2.
  • the obtained liposomes were named as PLM60-dppc.
  • DMPC DMPC, cholesterol and DSPE-PEG2000 at a weight ratio of 3:1:1 were mixed, and other steps were identical to those of Example 2.
  • the obtained liposomes were named as PLM60-dmpc.
  • DMPC DMPC, cholesterol and DSPE-PEG2000 at a weight ratio of 3:1:0.1 were mixed, and other steps were identical to those of Example 2.
  • the obtained liposomes were named as PLM60-dmpc-0.1.
  • the release media were isotonic, had a pH of 7.4, and had a concentration of ammonium chloride of 2, 10 and 40 mM, respectively.
  • the diluted liposomes were placed in dialysis tubings, and dialysis was performed on 2 mL diluted liposome by 400 mL of release medium at 37° C. Samples were taken at different time points for analysis until 96 hours later.
  • the obtained data were subjected to an regression analysis.
  • the drug-release half-life periods of PLD60 were 94.3, 31.9 and 11.2 hours, respectively.
  • PLM60 no obvious release was observed in the three release media. Since PLD60 and PLM60 have no difference in composition and size, the difference of drug release kinetic characteristic could be attributed to their different pharmaceutical features.
  • a drug with multi-dissociable groups such as mitoxantrone can form a complex precipitation with counter-ions when an active loading method is employed, so that the in vitro release of drug is significantly slowed down.
  • a drug with uni-dissociable group such as adriamycin could be released too quickly even in a release medium without plasma when a small size liposome is employed.
  • Release condition 1 a liposome was diluted by 25 times with a release medium.
  • the release medium contained 50% human plasma, was adjusted to be isotonic by glucose and had a pH of 7.4. Other conditions were identical to those of Example 9. The obtained data were subjected to a regression analysis. The result showed that the release half-life period of PLM60 was 56.4 hours, while PLM85 was not significantly released under the same conditions.
  • Release condition 2 a release medium containing 50% human plasma and 20 mM ammonium chloride was used, and other conditions were identical to those of Example 9. The obtained data were subjected to a regression analysis. The result showed that the release half-life period of PLM60 was 26.2 hours, while the release half-life period of PLM85 was 36.7 hours.
  • mice Male Kunming mice having a body weight about 20 g were used in the present example. The mice were inoculated in right oxter with S-180 sarcoma cells at a ration of 5 ⁇ 10 5 . Drugs were injected through vein in mice when tumor grew to 0.4-0.7 g. After the administration of drugs, mice were executed at various time points and their tissues were taken out to determine the concentration of mitoxantrone. The tissues included hearts, livers, spleens, lungs, kidneys, intestines, bone marrow and tumors. The results showed that PLM60 had a very clear targeting to tumor tissues. The detailed data were shown in Table 2 and FIG. 2 .
  • PLM60-DPPC, PLM60-DMPC-0.1 and PLM60-DMPC at 4 mg/kg were injected through tail vein in mice.
  • the data were shown in Table 3 and FIG. 3 . It was shown that pharmacokinetics of liposomal drugs changed significantly with the change of liposome membrane composition.
  • the MRT values of PLM60-DPPC, PLM60-DMPC-0.1 and PLM60-DMPC in vivo were 14.22, 7.914 and 10.123 hours, respectively.
  • the length of acyl chain could significantly influence the membrane permeability of phospholipid bilayer.
  • the phase transition temperature of DPPC was 41° C. and the phase transition temperature of DMPC was 23° C.
  • the release of liposomal drug in plasma depends on two factors: one is the release of liposomal drug across phospholipid bilayer and the other is the clearance by lipoprotein and reticuloendothelial system (RES). Since the PEGylation of PLM60-DMPC-0.1 was not complete, the release caused by plasma components had more influences on it.
  • RES reticuloendothelial system
  • mice with a body weight of 18-22 g were divided into 9 groups, each group had 10 mice.
  • the mice of group 1 were administered with FM at 6 mg/kg, while mice of other 8 groups were administered with PLM60, PLM60-DPPC and PLM60-DMPC-0.1 and PLM60-DMPC at 6 and 12 mg/kg, respectively.
  • Body weight changes were observed and the death time of each animal was recorded. The dead animals were dissected and autopsied.
  • the results of death of mice of FM group and liposomal drug groups were shown in Table 5. This experiment showed that the order of acute toxicity was: PLM60 ⁇ PLM60-DPPC ⁇ PLM60-DMPC-0.1 FM ⁇ PLM60-DMPC.
  • PLM60-DMPC-0.1 with incomplete PEGylation would release drug earlier in comparison with PLM60-DMPC and would not release suddenly in important tissues, thereby exhibiting a lower toxicity, but the toxicity of PLM60-DMPC-0.1 was still nearly equivalent to that of free mitoxantrone.
  • mice(day) Formulary and dose(mg/kg) 1 2 3 4 5 6 7 8 9 10 FM-6 NA NA NA NA NA NA NA NA NA NA NA NA PLM60-6 NA NA NA NA NA NA NA NA NA NA NA PLM60-12 NA NA NA NA NA NA 10 NA NA NA NA 11 Plm60DPPC-6 NA NA NA NA NA NA NA NA NA Plm60DPPC-12 10 10 12 11 NA NA NA 13 NA 14 Plm60-DMPC-6 4 NA NA 3 6 7 7 6 NA NA Plm60DMPC-12 3 3 5 3 3 3 4 3 3 3 3 Plm60DMPC-0.1-6 NA NA NA NA NA NA NA NA NA NA Plm60DMPC-0.1-12 10 12 10 12 10 10 10 10 11 10 10 NA: No animal died at the end of experimental observation
  • mice with a body weight of 18-22 g were used in toxicity comparison of PLM60, PLM85 and PLM100.
  • the dose was 9 mg/kg.
  • body weight varieties caused by the three liposome formulations were equivalent, which confirmed that the three liposome formulations had no significant difference in toxicity under the experimental conditions.
  • the body weight decreased over 30% and about 20% mice died.
  • Ascitic tumor-bearing mice which were inoculated with S180 tumor cells 7 days ago were executed by decollation, and milky viscous ascitic fluid was extracted and diluted with RPMI 1640 medium. After dilution, the tumor cell number was adjusted to 2.5 ⁇ 10 6 cells/ml. 0.2 mL of the tumor cell suspension containing about 5 ⁇ 10 5 tumor cells was inoculated into forward limb oxter tissues of male KM mice with a body weight of 18-22 g. After inoculation, the cells in the residual tumor cell suspension were counted under light microscope, and living tumor cells were greater than 95%. The number of inoculated mice was 80.
  • mice with clear-cut tumors having a diameter of about 5 mm were selected and divided into 5 groups by both tumor volume and body weight, i.e., 7 mice in blank control group, 8 mice in each of 4 mg/kg PLM60 group, 6 mg/kg PLM60 group, 4 mg/kg FM group and 6 mg/kg FM group.
  • the mice were administered by intravenous injection.
  • Table 6 showed that the growth of S180 solid tumor was significantly suppressed in the 4 mg/kg PLM60 group and 6 mg/kg PLM60 group.
  • Ascitic tumor BDF1 mice which were inoculated with L1210 ascitic tumor cells 7 days ago were executed by decollation, and milky viscous ascitic fluid was extracted under aseptic condition and diluted by RPMI 1640 medium. After dilution, the tumor cell number was adjusted to 2.5 ⁇ 10 6 cells/ml. 0.2 mL of the tumor cell suspension containing about 5.0 ⁇ 10 5 tumor cells was inoculated into the abdominal cavity of a 7-8 week-old female BDF1 mouse. After inoculation, the cells in the residual tumor cell suspension were counted under light microscope, and living tumor cells were greater than 95%.
  • mice 24 hours later, the mice were divided into 8 groups by body weight, and were administered with FM at 2, 4 and 8 mg/kg, and PLM60 at 2, 4, and 6 mg/kg by injection in a volume of 20 ml/kg through tail vein in mice, respectively. After administration, the mice were bred normally. Their body weights were measured 3 times per week, the death time of each mouse was observed and recorded, and survival time was calculated. Mean survival time (MST) and median survival time were employed to evaluate the survival time of each group. Experimental observation was kept for 60 days after the inoculation.
  • Ascitic tumor BDF1 mice which were inoculated L1210 ascitic tumor cells 7 days ago were executed by decollation, and milky viscous ascitic fluid was extracted under aseptic condition and diluted with RPMI 1640 medium. After dilution, the tumor cell number was adjusted to 2.5 ⁇ 10 5 cells/ml. 0.2 mL of the tumor cell suspension containing about 5.0 ⁇ 10 4 tumor cells was intravenously inoculated into a 7-8 week-old male BDF1 mouse. After inoculation, the cells in the residual tumor cell suspension were counted under light microscope, and living tumor cells were greater than 95%. Total 62 mice were inoculated.
  • mice 24 hours later, the mice were grouped and administered. After administration, the mice were bred normally. The body weights of mice were measured 3 times per week, the death time of each mouse was observed and recorded every day, and survival time was calculated. Experimental observation was kept for 60 days after the inoculation.
  • mice in the control group died between the 11 th and 14 th day after inoculation
  • all mice in the three FM dose level groups died between the 11 th and 17 th day after inoculation
  • all mice in the 2 mg/kg PLM60 group died between the 15 th and 29 th day after inoculation
  • only one mouse in the 6 mg/kg PLM60 group died on the 39 th day after inoculation
  • no mouse in the 8 mg/kg PLM60 group died during the observation.
  • the experimental scheme and data process mode were the same as Example 19. Five groups were setup, including control group, FM group, PLM60 group, PLM85 group and PLM100 group. The administration dosage for mice in each group was 4 mg/kg. The results were shown in Table 9. The results showed that liposome with smaller size had better treatment effects.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110223675A1 (en) * 2008-11-20 2011-09-15 Terumo Kabushiki Kaisha Drug release means from liposomes and method for evaluating releasability
US20150283272A1 (en) * 2010-10-27 2015-10-08 Vikas Kundra Dual mode gadolinium nanoparticle contrast agents
US20170042810A1 (en) * 2014-04-30 2017-02-16 Fujifilm Corporation Liposome composition and method for producing same
US20170042811A1 (en) * 2014-04-30 2017-02-16 Fujifilm Corporation Liposome composition and method for producing same
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
RU2728976C2 (ru) * 2018-03-22 2020-08-03 Зули Холдингз, Лтд. Липосомный состав и его получение
US11166913B2 (en) 2015-11-02 2021-11-09 Fujifilm Corporation Tumor therapeutic agent and kit containing gemcitabine liposome composition
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US20110059549A1 (en) 2007-05-09 2011-03-10 Coleman Matthew A Methods and systems for producing nanolipoprotein particles
WO2010113983A1 (ja) 2009-03-30 2010-10-07 エーザイ・アール・アンド・ディー・マネジメント株式会社 リポソーム組成物の製造方法
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JP2013526533A (ja) * 2010-05-10 2013-06-24 シュミット，マイケル，エー． 治療用リポソーム、並びにこれらを製造及び使用する方法
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CA2853316C (en) 2011-10-25 2018-11-27 The University Of British Columbia Limit size lipid nanoparticles and related methods
US9644038B2 (en) 2011-12-21 2017-05-09 The Regents Of The University Of California Apolipoprotein nanodiscs with telodendrimer
MX2015005992A (es) * 2012-11-20 2016-03-07 Spectrum Pharmaceuticals Inc Metodo mejorado para la preparacion de la vincristina liposomal encapsulada para el uso terapeutico.
JP6605446B2 (ja) 2013-03-15 2019-11-13 ザ ユニバーシティ オブ ブリティッシュ コロンビア 形質移入用の脂質ナノ粒子および関連方法
US10220095B2 (en) 2013-03-15 2019-03-05 Taiwan Liposome Company, Ltd Controlled drug release liposome compositions and methods thereof
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US11279749B2 (en) 2015-09-11 2022-03-22 Lawrence Livermore National Security, Llc Synthetic apolipoproteins, and related compositions methods and systems for nanolipoprotein particles formation
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MA47319A (fr) * 2017-01-18 2019-11-27 Temasek Life Sciences Laboratory Ltd Liposomes hyperstabilisés augmentant le ciblage de cellules mitotiques
WO2018204495A1 (en) * 2017-05-02 2018-11-08 Synthetic Genomics, Inc. Nanolipoprotein particles and related compositions methods and systems for loading rna
US11207422B2 (en) 2017-05-02 2021-12-28 Lawrence Livermore National Security, Llc MOMP telonanoparticles, and related compositions, methods and systems
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US12036204B2 (en) 2019-07-26 2024-07-16 Eisai R&D Management Co., Ltd. Pharmaceutical composition for treating tumor
US11083705B2 (en) 2019-07-26 2021-08-10 Eisai R&D Management Co., Ltd. Pharmaceutical composition for treating tumor
AU2021218871B2 (en) * 2020-02-10 2024-04-11 Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Use of mitoxantrone hydrochloride liposome for treating breast cancer
WO2021180184A1 (zh) * 2020-03-12 2021-09-16 石药集团中奇制药技术（石家庄）有限公司 盐酸米托蒽醌脂质体的用途
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Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5169635A (en) * 1989-11-17 1992-12-08 Fuji Photo Film Co., Ltd. Photoresponsive liposome
US5356633A (en) * 1989-10-20 1994-10-18 Liposome Technology, Inc. Method of treatment of inflamed tissues
US5858397A (en) * 1995-10-11 1999-01-12 University Of British Columbia Liposomal formulations of mitoxantrone
US5939096A (en) * 1995-04-18 1999-08-17 Yissum Research Development Company Of The Hebrew University Of Jerusalem Liposome drug-loading method and composition
US20020102298A1 (en) * 1998-06-18 2002-08-01 David Needham Temperature-sensitive liposomal formulation
US6465008B1 (en) * 1998-09-16 2002-10-15 Alza Corporation Liposome-entrapped topoisomerase inhibitors
US20030219476A1 (en) * 2000-10-16 2003-11-27 Neopharm, Inc. Liposomal formulation of mitoxantrone
US6740335B1 (en) * 1997-09-16 2004-05-25 Osi Pharmaceuticals, Inc. Liposomal camptothecin formulations
US20050100590A1 (en) * 2000-10-10 2005-05-12 Duena Antonio P. Liposomes encapsulating anticancer drugs and use thereof in the treatment of malignant tumours
US20060034906A1 (en) * 2004-05-21 2006-02-16 Transave, Inc. Treatment of lung diseases and pre-lung disease conditions
US20060241076A1 (en) * 2005-04-26 2006-10-26 Coley Pharmaceutical Gmbh Modified oligoribonucleotide analogs with enhanced immunostimulatory activity
US20070116753A1 (en) * 2004-05-03 2007-05-24 Hermes Biosciences, Inc. Liposomes useful for drug delivery
US20070196461A1 (en) * 2005-12-08 2007-08-23 Jeff Weers Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US20140044777A1 (en) * 2009-03-30 2014-02-13 Eisai R&D Management Co., Ltd. Liposome Composition

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995026185A1 (fr) * 1994-03-28 1995-10-05 Daiichi Pharmaceutical Co., Ltd. Liposome a capacite de retention accrue
US6214388B1 (en) * 1994-11-09 2001-04-10 The Regents Of The University Of California Immunoliposomes that optimize internalization into target cells
BR9812316A (pt) * 1997-09-16 2001-03-20 Nexstar Pharmaceuticals Inc Formulações de camptotecina lipossÈmica
PT1196144E (pt) * 1999-07-16 2004-12-31 Alza Corp Composicao de liposomas com resistencia ao dano da congelacao/descongelacao
US7850990B2 (en) * 2001-10-03 2010-12-14 Celator Pharmaceuticals, Inc. Compositions for delivery of drug combinations
US7179484B2 (en) * 2002-11-06 2007-02-20 Azaya Therapeutics, Inc. Protein-stabilized liposomal formulations of pharmaceutical agents
WO2004047800A2 (en) * 2002-11-26 2004-06-10 Gilead Sciences, Inc. Method of drug loading in liposomes by gradient
US7205299B2 (en) * 2003-06-05 2007-04-17 Zentaris Gmbh Indole derivatives having an apoptosis-inducing effect
US7288396B2 (en) * 2003-09-11 2007-10-30 Kosan Biosciences Incorporated Biosynthetic gene cluster for leptomycins
RU2258530C1 (ru) * 2004-04-27 2005-08-20 Генкин Дмитрий Дмитриевич Способ профилактики и коррекции изменений кожи
CN1242740C (zh) * 2004-08-05 2006-02-22 常州太平洋药物研究所有限公司 米托蒽醌或盐酸米托蒽醌脂质体注射剂及其制备工艺
JP2006248978A (ja) * 2005-03-10 2006-09-21 Mebiopharm Co Ltd 新規なリポソーム製剤
JP2006298844A (ja) * 2005-04-21 2006-11-02 Konica Minolta Medical & Graphic Inc リポソーム内に医薬化合物を内包するリポソーム含有製剤
US8246983B2 (en) * 2005-09-02 2012-08-21 Northwestern University Encapsulated arsenic drugs
US7703945B2 (en) 2006-06-27 2010-04-27 Cree, Inc. Efficient emitting LED package and method for efficiently emitting light
CN101209243B (zh) 2006-12-29 2010-12-08 石药集团中奇制药技术（石家庄）有限公司 一种脂质体药物及其制备方法
JP5480867B2 (ja) * 2011-10-07 2014-04-23 住友ゴム工業株式会社 空気入りタイヤ

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5356633A (en) * 1989-10-20 1994-10-18 Liposome Technology, Inc. Method of treatment of inflamed tissues
US5169635A (en) * 1989-11-17 1992-12-08 Fuji Photo Film Co., Ltd. Photoresponsive liposome
US5939096A (en) * 1995-04-18 1999-08-17 Yissum Research Development Company Of The Hebrew University Of Jerusalem Liposome drug-loading method and composition
US5858397A (en) * 1995-10-11 1999-01-12 University Of British Columbia Liposomal formulations of mitoxantrone
US6740335B1 (en) * 1997-09-16 2004-05-25 Osi Pharmaceuticals, Inc. Liposomal camptothecin formulations
US20020102298A1 (en) * 1998-06-18 2002-08-01 David Needham Temperature-sensitive liposomal formulation
US6465008B1 (en) * 1998-09-16 2002-10-15 Alza Corporation Liposome-entrapped topoisomerase inhibitors
US20050100590A1 (en) * 2000-10-10 2005-05-12 Duena Antonio P. Liposomes encapsulating anticancer drugs and use thereof in the treatment of malignant tumours
US20030219476A1 (en) * 2000-10-16 2003-11-27 Neopharm, Inc. Liposomal formulation of mitoxantrone
US20070116753A1 (en) * 2004-05-03 2007-05-24 Hermes Biosciences, Inc. Liposomes useful for drug delivery
US20060034906A1 (en) * 2004-05-21 2006-02-16 Transave, Inc. Treatment of lung diseases and pre-lung disease conditions
US20060241076A1 (en) * 2005-04-26 2006-10-26 Coley Pharmaceutical Gmbh Modified oligoribonucleotide analogs with enhanced immunostimulatory activity
US20070196461A1 (en) * 2005-12-08 2007-08-23 Jeff Weers Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US20140044777A1 (en) * 2009-03-30 2014-02-13 Eisai R&D Management Co., Ltd. Liposome Composition

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Trosco J.E., Mutation Research, 480-481, pp. 219-229, 2001 *
Zhu ea al, in Cancer Chemother Pharmacol, vol. 39, pp. 138-142 (1996) *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110223675A1 (en) * 2008-11-20 2011-09-15 Terumo Kabushiki Kaisha Drug release means from liposomes and method for evaluating releasability
US20150283272A1 (en) * 2010-10-27 2015-10-08 Vikas Kundra Dual mode gadolinium nanoparticle contrast agents
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
US11633357B2 (en) 2013-03-14 2023-04-25 Zuli Holdings, Ltd. Liposome formulation and manufacture
US10265269B2 (en) 2013-03-14 2019-04-23 Biorest Ltd. Liposome formulation and manufacture
US10646442B2 (en) * 2014-04-30 2020-05-12 Fujifilm Corporation Liposome composition and method for producing same
JPWO2015166986A1 (ja) * 2014-04-30 2017-04-20 富士フイルム株式会社 リポソーム組成物及びその製造方法
US10391057B2 (en) * 2014-04-30 2019-08-27 Fujifilm Corporation Liposome composition and method for producing same
US20170042811A1 (en) * 2014-04-30 2017-02-16 Fujifilm Corporation Liposome composition and method for producing same
US10898435B2 (en) 2014-04-30 2021-01-26 Fujifilm Corporation Liposome composition and method for producing same
US20170042810A1 (en) * 2014-04-30 2017-02-16 Fujifilm Corporation Liposome composition and method for producing same
US11684575B2 (en) 2014-04-30 2023-06-27 Fujifilm Corporation Liposome composition and method for producing same
US11166913B2 (en) 2015-11-02 2021-11-09 Fujifilm Corporation Tumor therapeutic agent and kit containing gemcitabine liposome composition
US11166914B2 (en) 2015-11-02 2021-11-09 Fujifilm Corporation Tumor therapeutic agent and kit containing gemcitabine liposome composition
US11433143B2 (en) * 2017-05-18 2022-09-06 The Regents Of The University Of California Nano-enabled immunotherapy in cancer
RU2728976C2 (ru) * 2018-03-22 2020-08-03 Зули Холдингз, Лтд. Липосомный состав и его получение
CN113876711A (zh) * 2020-07-01 2022-01-04 江苏长泰药业有限公司 一种盐酸阿霉素脂质体的制备工艺
WO2022247921A1 (zh) * 2021-05-28 2022-12-01 石药集团中奇制药技术（石家庄）有限公司 盐酸米托蒽醌脂质体用于制备治疗晚期实体瘤的药物的用途

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