WO2017078008A1 - ゲムシタビンリポソーム組成物を含む腫瘍治療剤およびキット - Google Patents
ゲムシタビンリポソーム組成物を含む腫瘍治療剤およびキット Download PDFInfo
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- WO2017078008A1 WO2017078008A1 PCT/JP2016/082415 JP2016082415W WO2017078008A1 WO 2017078008 A1 WO2017078008 A1 WO 2017078008A1 JP 2016082415 W JP2016082415 W JP 2016082415W WO 2017078008 A1 WO2017078008 A1 WO 2017078008A1
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
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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
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- 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 tumor therapeutic agent comprising a combination of a liposomal composition encapsulating gemcitabine or a salt thereof in a liposome and a taxane antitumor agent, and a liposomal composition encapsulating gemcitabine or a salt thereof in a liposome and a taxane antitumor agent.
- the present invention relates to a tumor treatment kit.
- Gemcitabine is used as a useful drug in chemotherapy for malignant tumors.
- the response rate to a tumor with gemcitabine alone is as low as 10%, and the survival time of cancer patients is short (median survival time 6.7 months) (Non-patent Document 1).
- taxane antitumor agents such as paclitaxel and nabupaclitaxel are also used as useful drugs.
- the tumor response rate with a taxane antitumor agent alone is as low as 10 to 25%, and the survival time of cancer patients is short (survival time 12 to 15 months) (Non-patent Document 2).
- multi-drug combination therapy is performed for the purpose of compensating for the difference in sensitivity of each anti-tumor agent to the tumor and enhancing the drug efficacy.
- the combined use of gemcitabine and Abraxane the combined use of gemcitabine and paclitaxel, the combined use of gemcitabine and nabupaclitaxel, etc. are known.
- the response rate for breast cancer patients in combination with gemcitabine and paclitaxel is 41.4%
- the median survival is 18.6 months
- the response rate for pancreatic cancer patients with the combination of gemcitabine and nabupaclitaxel is 23%, and the median survival time is 8.5 months (Non-patent Document 1).
- Liposomes are closed vesicles formed by lipid bilayers using lipids, and their application as carriers in drug delivery systems has been studied. It is known that encapsulating a drug in a liposome can improve the reachability to a target tissue by changing the blood stability and biodistribution of the drug (Non-patent Document 4). Further, it is known that liposomes having a particle size of 100 to 200 nm are likely to accumulate in cancer tissues (Non-patent Document 5).
- One of the causes of the low antitumor effect of gemcitabine alone is the short residence time of gemcitabine in blood.
- Gemcitabine has a strong drug effect in a time-dependent manner, but it has a short residence time in blood of 20 minutes, so that it cannot exert a sufficient antitumor effect.
- Another cause of the low antitumor effect of gemcitabine alone is the low selectivity of gemcitabine for tumor tissues.
- an antitumor agent When an antitumor agent is administered, it may disappear quickly from the blood or be distributed to organs other than the target, and it does not always effectively accumulate in the tumor tissue. For this reason, many of the antitumor agents cannot sufficiently exert an antitumor effect on the tumor tissue, and often have an undesirable effect on normal tissues (side effects), causing serious toxicity.
- An object of the present invention is to provide a tumor therapeutic agent and a tumor treatment kit superior in antitumor effect as compared with commercially available gemcitabine, a taxane antitumor agent and a combination therapy thereof.
- the present inventors have found that the antitumor effect is enhanced by using a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome together with a taxane antitumor agent, and the present invention has been completed. It came to do.
- the present invention provides the following.
- a tumor therapeutic agent comprising a combination of a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a taxane antitumor agent.
- a taxane antitumor agent is paclitaxel or a salt thereof or nabupaclitaxel.
- the taxane antitumor agent is nabupaclitaxel.
- the cholesterol content relative to the total amount of lipids constituting the liposome is 10 mol% to 35 mol%, and the osmotic pressure of the inner aqueous phase of the liposome is 2 to 8 times the osmotic pressure of the outer aqueous phase of the liposome.
- the tumor therapeutic agent according to any one of (1) to (3) which is doubled.
- the tumor therapeutic agent according to any one of (1) to (5), wherein the release rate of gemcitabine or a salt thereof from the liposome composition in plasma is 10% by mass / 24 hr to 70% by mass / 24 hr. .
- a tumor treatment kit comprising a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a taxane antitumor agent.
- the present invention also provides the following.
- An anti-tumor composition comprising a liposome composition containing gemcitabine or a salt thereof encapsulated in a liposome, wherein the anti-tumor agent is used in combination with one or more antitumor agents selected from taxane antitumor agents Tumor effect enhancer.
- the cholesterol content relative to the total amount of lipids constituting the liposome is 10 mol% to 35 mol%, and the osmotic pressure of the inner aqueous phase of the liposome is 2 to 8 times the osmotic pressure of the outer aqueous phase of the liposome.
- the present invention provides the following.
- a therapeutically effective dose when a liposome composition containing gemcitabine or a salt thereof encapsulated in a liposome is used in combination therapy, and a therapeutically effective dose when a taxane antitumor agent is used in combination therapy, and administered to a subject
- a method for treating a tumor comprising: (19) A therapeutically effective dose when a liposome composition containing gemcitabine or a salt thereof encapsulated in a liposome is used in combination therapy, and a therapeutically effective dose when a taxane antitumor agent is used in combination therapy, simultaneously and separately.
- a method for treating a tumor comprising administering to a subject continuously or at intervals.
- the present invention provides the following. (20) Gemcitabine or a liposome thereof for producing a tumor therapeutic agent comprising a combination of a liposome composition containing gemcitabine or a salt thereof in a liposome and one or more antitumor agents selected from taxane antitumor agents Use of a liposome composition encapsulating a salt. (21) Gemcitabine or a salt thereof is encapsulated in a liposome for tumor treatment, wherein the liposome is used in combination with one or more antitumor agents selected from taxane antitumor agents Liposome composition.
- the tumor therapeutic agent and tumor treatment kit of the present invention have superior tumor regression and tumor growth delaying effects compared to gemcitabine alone, a taxane antitumor agent or a combination of gemcitabine and a taxane antitumor agent. Have.
- a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
- % means mass percentage.
- the amount of each component in the composition means the total amount of the plurality of substances present in the composition unless there is a specific notice when there are a plurality of substances corresponding to each component in the composition. To do.
- “Release” means that the drug encapsulated in the liposome passes through the lipid membrane constituting the liposome and exits from the liposome. “Release rate” means the amount of drug encapsulated in the liposome per unit time through the lipid membrane constituting the liposome and out of the liposome. “Retention in the blood” means the property that a drug encapsulated in liposomes exists in blood in a subject administered with a liposome composition.
- the “average particle diameter of the liposome” means the volume average particle diameter of the liposome present in the liposome composition. The average particle size of the liposomes contained in the liposome composition of the present invention is measured using a dynamic light scattering method.
- Examples of commercially available measuring apparatuses using dynamic light scattering include a dense particle analyzer FPAR-1000 (manufactured by Otsuka Electronics Co., Ltd.), Nanotrack UPA (manufactured by Nikkiso Co., Ltd.), and nanosizer (manufactured by Malvern).
- the “subject” is a mammal such as a human, a mouse, a monkey, a domestic animal or the like in need of the prevention or treatment, and preferably a human in need of the prevention or treatment.
- tumor examples include breast cancer, endometrial cancer, ovarian cancer, prostate cancer, lung cancer, stomach (gastric gland) cancer, non-small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the head and neck, esophageal cancer, bladder cancer, melanoma, Examples include colon cancer, renal cell carcinoma, non-Hodgkin lymphoma, and urothelial cancer.
- Taxane antitumor agent examples include pharmaceutical compositions containing a taxane ring or a compound having a similar structure as an active ingredient.
- Specific examples of the taxane antitumor agent include paclitaxel, docetaxel, cabazitaxel, tesetaxel and ortataxel, and salts or derivatives thereof.
- Examples of the salt include generally known salts in basic groups such as amino groups, and acidic groups such as hydroxyl groups and carboxyl groups.
- Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
- mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
- formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
- salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
- alkali metals such as sodium and potassium
- salts with alkaline earth metals such as calcium and magnesium
- ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
- paclitaxel derivative examples include nabu paclitaxel (albumin-bound paclitaxel) and the like.
- paclitaxel or a salt thereof or nabupaclitaxel is preferable, and nabupaclitaxel is more preferable.
- Taxane antitumor agents are usually excipients, binders, lubricants, disintegrants, colorants, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents used for formulation. , Additives such as isotonic agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
- Examples of routes of administration of taxane antitumor agents include intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration, and suppositories. Can be mentioned.
- the dose and frequency of administration are, for example, 1 to 0.01 to 1000 mg / kg per day by oral or parenteral (for example, injection, infusion, administration to the rectal site, etc.) for adults.
- the dose can be divided into several times.
- dosage forms include tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches Agents, ointments and injections.
- a liposome is a closed vesicle formed of a lipid bilayer membrane using lipid, and has an aqueous phase (inner aqueous phase) in the space of the closed vesicle.
- the inner water phase includes water and the like.
- Liposomes usually exist in a dispersed state in an aqueous solution outside the closed vesicles (outer aqueous phase).
- Liposomes are single lamellae (also called single-layer lamellae or unilamellar, and double-layer membranes have a single structure.)
- it is a single-lamellar liposome. Is preferred.
- the form of the liposome is not particularly limited as long as it is a liposome capable of encapsulating a drug.
- “Encapsulation” means that the drug is in a form in which the drug is contained in the inner aqueous phase and the membrane itself.
- a form in which a drug is enclosed in a closed space formed of a film, a form in which the drug is included in the film itself, and the like may be used.
- the average particle size of the liposome is not particularly limited, but is preferably 2 nm to 200 nm, more preferably 5 nm to 150 nm, still more preferably 5 nm to 120 nm, and most preferably 5 nm to 100 nm.
- Liposomes preferably take a spherical shape or a form close thereto.
- the component constituting the lipid bilayer of the liposome is selected from lipids.
- lipid any lipid that can be dissolved in a mixed solvent of a water-soluble organic solvent and an ester-based organic solvent can be arbitrarily used.
- lipids include phospholipids, lipids other than phospholipids, cholesterols, and derivatives thereof. These components may be composed of a single type or multiple types of components.
- the phospholipid examples include phosphatidylcholine (lecithin), phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cardiolipin, and hydrogenated ones ( Examples thereof include hydrogenated soybean phosphatidylcholine (HSPC). Among these, hydrogenated phospholipid such as hydrogenated soybean phosphatidylcholine or sphingomyelin is preferable, and hydrogenated soybean phosphatidylcholine is more preferable.
- the “phospholipid” includes phospholipid derivatives obtained by modifying phospholipids.
- lipids other than phospholipids include lipids that do not contain phosphoric acid, such as glycerolipids that do not have a phosphate moiety in the molecule, and sphingolipids that do not have a phosphate moiety in the molecule.
- lipid other than phospholipid includes derivatives of lipids other than phospholipids obtained by modifying lipids other than phospholipids.
- the lipid In the case of a substance in which a compound having a basic functional group is bound to a lipid, the lipid is called a cationized lipid.
- the cationized lipid for example, can modify the liposome membrane, and can improve the adhesion to the cell that is the target site.
- cholesterols examples include cholesterol having cyclopentahydrophenanthrene as a basic skeleton, and part or all of which are hydrogenated, and derivatives thereof.
- An example is cholesterol.
- the curvature of the lipid membrane increases. Since the distortion of the membrane arranged in the liposome is also increased, the water-soluble drug is more likely to leak.
- it is effective to add cholesterol or the like in order to fill the strain of the membrane caused by lipid (membrane stabilization effect).
- the addition of cholesterols is expected to lower the fluidity of the liposome membrane, such as by filling gaps in the liposome membrane.
- the amount of cholesterol is desirably contained in an amount usually up to about 50 mol% in the total (total lipid) mol of lipid components.
- the content of cholesterol with respect to the total amount of lipids constituting the liposome according to the present invention is 10 mol% to 35 mol%, preferably 15 mol% to 25 mol%, more preferably 17 mol% to 21 mol%.
- the liposome may be added with a hydrophilic polymer or the like for the purpose of improving blood retention, fatty acid or diacetyl phosphate as a membrane structure stabilizer, and ⁇ -tocopherol as an antioxidant. Good.
- additives such as dispersion aids that are not approved for intravenous use in pharmaceutical applications, such as surfactants.
- phospholipids, lipids other than phospholipids, cholesterols, and derivatives thereof are preferably modified with hydrophilic polymers such as phospholipids, lipids other than phospholipids, or cholesterols.
- hydrophilic polymer examples include polyethylene glycols, polyglycerins, polypropylene glycols, polyvinyl alcohol, styrene-maleic anhydride alternating copolymer, polyvinyl pyrrolidone, and synthetic polyamino acid. Said hydrophilic polymer can be used individually or in combination of 2 types or more, respectively.
- polyethylene glycols, polyglycerols and polypropylene glycols are preferable from the viewpoint of blood retention of the preparation, and polyethylene glycol (PEG), polyglycerol (PG) and polypropylene glycol (PPG) are more preferable. From the viewpoint of versatility and blood retention, polyethylene glycol (PEG) is more preferable.
- the molecular weight of PEG is not particularly limited, but is 500 to 10,000 daltons, preferably 1,000 to 7,000 daltons, and more preferably 2,000 to 5,000 daltons.
- lipid modified with PEG PEG-modified lipid
- PEG-modified lipid examples include 1,2-distearoyl-3-phosphatidylethanolamine-PEG2000 (manufactured by NOF Corporation), 1,2-distearoyl-3-phosphatidylethanolamine-PEG5000 (manufactured by NOF Corporation) and Examples include 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol such as distearoylglycerol-PEG2000 (manufactured by NOF Corporation).
- PEG-modified lipids may be added so as to contain 0.3 to 50% by mass, preferably 0.5 to 30% by mass, more preferably 1 to 20% by mass with respect to the total lipid amount.
- lipid used in combination with main lipid
- lipid of cholesterol lipid used in combination with main lipid
- the liposome according to the present invention preferably does not contain an anionic polymer (polyanion).
- the liposome according to the present invention includes at least gemcitabine or a salt thereof as a drug.
- the salt of gemcitabine include a salt of a commonly known basic group such as an amino group and an acidic group such as a hydroxyl group and a carboxyl group.
- Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
- mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
- formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
- Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
- As the salt of gemcitabine hydrochloride is preferable.
- the content of gemcitabine is preferably 0.1 to 2.0 mg / ml, more preferably 0.2 to 1.0 mg / ml with respect to the liposome composition.
- the drug (gemcitabine or a salt thereof) encapsulated in the liposome according to the present invention exists in a dissolved state in the internal aqueous phase of the liposome.
- the dissolved state is considered to be encapsulated in the dissolved state when the amount of the drug filled with respect to the volume of the liposome is equal to or lower than the saturated solubility of the drug in the composition solution of the inner aqueous phase.
- the liposome composition according to the present invention can include a liposome encapsulating gemcitabine or a salt thereof and an aqueous solution in which the liposome is dispersed.
- the osmotic pressure of the inner aqueous phase of the liposome is preferably 2 to 8 times, more preferably 2.5 to 6 times the osmotic pressure of the outer aqueous phase of the liposome. More preferably, it is 3 to 5 times.
- the liposome composition may comprise at least one of pharmaceutically acceptable isotonic agents, stabilizers, antioxidants, and pH adjusters, related to the route of administration.
- the isotonic agent is not particularly limited, but for example, inorganic salts such as sodium chloride, potassium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerol, mannitol, sorbitol, etc.
- inorganic salts such as sodium chloride, potassium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerol, mannitol, sorbitol, etc.
- examples include polyols, sugars such as glucose, fructose, lactose, or sucrose.
- the stabilizer is not particularly limited, and examples thereof include saccharides such as glycerol, mannitol, sorbitol, lactose, or sucrose.
- antioxidant For example, ascorbic acid, uric acid, a tocopherol homologue (For example, four isomers of vitamin E, tocopherol alpha, beta, gamma, and delta) cysteine, EDTA (ethylenediaminetetraacetic acid), etc. Is mentioned.
- the stabilizer and the antioxidant can be used alone or in combination of two or more.
- pH adjusters examples include sodium hydroxide, citric acid, acetic acid, triethanolamine, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like.
- Liposome composition is pharmaceutically acceptable organic solvent, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methylcellulose , Ethyl cellulose, xanthan gum, gum arabic, casein, gelatin, agar, diglycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin (HSA), mannitol, sorbitol, lactose, PBS, sodium chloride Contains sugars, biodegradable polymers, serum-free media, and excipients that are acceptable as pharmaceutical additives It may be.
- HSA human serum albumin
- the liposome composition according to the present invention preferably contains ammonium sulfate, L-histidine, purified sucrose, sodium hydroxide, hydrochloric acid or the like.
- the container for filling the liposome composition is not particularly limited, but is preferably a material having low oxygen permeability.
- gas barrier layer made of plastic container, glass container, aluminum foil, aluminum vapor deposition film, aluminum oxide vapor deposition film, silicon oxide vapor deposition film, polyvinyl alcohol, ethylene vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, etc.
- a back using a colored glass, an aluminum foil, an aluminum vapor-deposited film, or the like can be used to shield the light.
- the gas in the container space and the chemical solution it is preferable to replace the gas in the container space and the chemical solution with an inert gas such as nitrogen in order to prevent oxidation due to oxygen present in the space in the container.
- an inert gas such as nitrogen
- the injection solution may be bubbled with nitrogen and the container is filled in a nitrogen atmosphere.
- the release rate of the drug is preferably 10% by mass / 24 hr to 70% by mass / 24 hr, more preferably 20% by mass / 24 hr to 60% by mass / 24 hr, More preferably, the content is from mass% / 24 hr to 50 mass% / 24 hr.
- the release rate depends on the temperature, it is preferable to measure under a constant temperature condition.
- the temperature is not particularly limited, but it is preferably measured within the range of body temperature (35 ° C. to 38 ° C.).
- the release rate of the drug is less than 15% by mass / 24 hr, sufficient exposure time in the body cannot be obtained, and the expected efficacy is often not obtained.
- the liposome containing the drug may remain in the body for an unnecessarily long time, and may accumulate in a tissue that is difficult to be distributed, such as the skin, thereby causing unexpected toxicity.
- the dose is greater than 70% by mass / 24 hr, the amount of drug to be exposed per unit time increases, so that the maximum blood concentration increases, resulting in increased toxicity. It is not preferable because the retention in the blood decreases due to distribution or rapid metabolism.
- the method for measuring the drug release rate is not particularly limited, but after administration to the target mammal, model system, etc., blood or plasma, etc. is collected from the mammal or model system every unit time. Pre-processing is performed accordingly.
- the target drug can be measured by a method such as liquid high-speed chromatograph or mass spectrum.
- the liposome composition according to the present invention comprises: An emulsification step in which a lipid is dissolved in an organic solvent to form liposomes without going through a drying and solidification step.
- Drug loading step in which gemcitabine or a salt thereof is encapsulated in the liposome obtained in the emulsification step, and osmotic pressure for adjusting the osmotic pressure of the inner aqueous phase of the liposome to 2 to 8 times the osmotic pressure of the outer aqueous phase of the liposome It can be manufactured by a method including an adjusting step.
- the method for producing a liposome composition may include other steps such as an evaporation step for evaporating the organic solvent used in the emulsification step, aseptic filtration, and aseptic filling, as necessary.
- an oil phase in which at least one kind of lipid is dissolved in an organic solvent and an aqueous phase are mixed, and an aqueous solution containing the lipid can be stirred and emulsified.
- an emulsion in which the oil phase and the aqueous phase are emulsified in the O / W type is prepared.
- liposomes are formed by removing part or all of the organic solvent derived from the oil phase by the evaporation step described below. Alternatively, part or all of the organic solvent in the oil phase evaporates in the course of stirring and emulsification to form liposomes.
- ultrasonic waves or mechanical shearing force is used for particle refinement.
- an extruder process or a microfluidizer process through a filter having a fixed pore diameter can be performed. If an extruder or the like is used, the secondary vesicle liposomes can be separated into single vesicle liposomes.
- it is preferable from the viewpoint of simplifying the production process that the liposome in a state in which no drug is loaded is used in the next step without being subjected to the extrusion treatment.
- the average particle size of the prepared liposome can be controlled by arbitrarily selecting the stirring speed and time. From the viewpoint of obtaining liposomes having safety and stability, it is preferable to apply shear to the aqueous solution containing lipids at a peripheral speed of 20 m / sec or more.
- the shearing is not limited, but specifically, it is preferable to give a shear of 20 m / sec to 35 m / sec, and more preferably a shear of 23 m / sec to 30 m / sec.
- the emulsification step is not limited as long as it is an emulsification step, but is preferably a step in which high shear is applied and fine particles are formed in an emulsification step containing an organic solvent. If necessary, liposomes can be formed by evaporating (desolving) the organic solvent used in the emulsification step.
- the liquid temperature in the emulsification step in producing the liposome can be adjusted as appropriate, but the liquid temperature at the time of mixing the oil phase and the aqueous phase is preferably equal to or higher than the phase transition temperature of the lipid, For example, when a lipid having a phase transition temperature of 35 to 40 ° C. is used, the temperature is preferably 35 to 70 ° C.
- Oil phase As the organic solvent used as the oil phase, a mixed solvent of a water-soluble organic solvent and an ester organic solvent is used. In the present invention, it is preferable that substantially no organic solvents such as chloroform, methylene chloride, hexane, and cyclohexane are used as the organic solvent, and it is more preferable that these organic solvents are not used at all.
- the water-soluble organic solvent is preferably an organic solvent having a property of being arbitrarily mixed with water.
- the water-soluble organic solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol, glycols such as glycerin, ethylene glycol and propylene glycol, and polyethylene glycol. Examples include polyalkylene glycols. Among these, alcohols are preferable.
- the alcohol is preferably at least one selected from ethanol, methanol, 2-propanol and t-butanol, more preferably at least one selected from ethanol, 2-propanol and t-butanol, More preferably, it is ethanol.
- the ester organic solvent is preferably an ester obtained from a reaction between an organic acid and an alcohol.
- the ester organic solvent include ethyl acetate, methyl acetate, isopropyl acetate, t-butyl acetate and methyl propionate, and are at least one selected from ethyl acetate, isopropyl acetate and methyl propionate. Preferably, it is ethyl acetate.
- the mixing ratio of the water-soluble organic solvent and the ester-based organic solvent can be, for example, 90:10 to 30:70, preferably 80:20 to 40:60, more preferably 80: 20-70: 30.
- the mixed solvent of the water-soluble organic solvent and the ester organic solvent may further contain an aqueous solvent such as water or a buffer solution.
- the aqueous solvent can be added, for example, in the range of 1 to 30% by mass.
- the pH of the mixed solvent can be 3 to 10, for example, and is preferably 4 to 9.
- the ester organic solvent may contain physiologically active substances such as various drugs soluble in these solvents.
- the mixing ratio of ethanol and ethyl acetate can be, for example, 80:20 to 70:30 in terms of mass ratio.
- the concentration of the lipid is not particularly limited and can be appropriately adjusted.
- the solution containing a mixed solution of a water-soluble organic solvent and an ester-based organic solvent as a solvent may be 40 g / L to 250 g / L. It is preferably 100 g / L to 200 g / L.
- the aqueous phase means an outer aqueous phase and an inner aqueous phase.
- the outer aqueous phase in the present invention means an aqueous solution in which liposomes are dispersed.
- a solution occupying the outside of the liposome in a dispersion of liposomes stored in a vial or prefilled syringe package is the outer aqueous phase.
- the solution occupying the outside of the liposome in the liposome dispersion is the outer aqueous phase of the dispersion dispersed at the time of administration using the attached dispersion or other solution.
- the inner aqueous phase in the present invention means an aqueous phase in a closed vesicle separated by a lipid bilayer of a liposome.
- the aqueous solution (outer aqueous phase) in which the liposomes are dispersed in the production of liposomes includes water (distilled water, water for injection, etc.), physiological saline, various buffer solutions or aqueous solutions of saccharides, and mixtures thereof (aqueous solvent).
- aqueous solvent aqueous solvent
- the buffer is not limited to organic or inorganic, but a buffer having a buffering action near the hydrogen ion concentration close to the body fluid is preferably used.
- Phosphate buffer, Tris buffer, citric acid examples include a buffer solution, an acetate buffer solution, and a good buffer.
- the pH of the aqueous phase can be, for example, 5 to 9, and preferably 7 to 8.
- the internal aqueous phase of the liposome may be an aqueous solution in which the liposome is dispersed when the liposome is produced, or water, physiological saline, various buffer solutions or aqueous solutions of saccharides and a mixture thereof newly added. There may be.
- the physiological saline means an inorganic salt solution adjusted to be isotonic with the human body, and may further have a buffer function.
- examples of the physiological saline include saline containing 0.9 w / v sodium chloride, phosphate buffered saline (hereinafter also referred to as PBS), Tris buffered saline, and the like.
- the aqueous solution containing liposomes prepared through the emulsification process is subjected to centrifugation, ultrafiltration, dialysis, gel filtration, lyophilization, etc. to remove components not contained in the liposomes or to adjust the concentration or osmotic pressure. You may post-process by the method.
- the extrusion treatment means a step of applying physical shearing force and atomizing by passing the liposome through a filter having pores.
- the liposome dispersion liquid and the filter can be rapidly atomized by keeping the temperature at a temperature higher than the phase transition temperature of the membrane constituting the liposome.
- an evaporation step may be provided as necessary.
- the organic solvent is evaporated from the aqueous solution containing the liposomes obtained in the emulsification step.
- the evaporation step is a step in which part or all of the organic solvent derived from the oil phase is forcibly removed as an evaporation step, and a portion or all of the organic solvent in the oil phase is a process of stirring and emulsification. Including at least one of the steps of spontaneous evaporation.
- the method for evaporating the organic solvent in the evaporation step is not particularly limited.
- the step of evaporating the organic solvent by heating, the step of continuing static stirring or gentle stirring after emulsification, and the step of performing vacuum deaeration Do at least one.
- the concentration of the organic solvent contained in the aqueous solution containing the liposome is preferably 15% by mass or less within 30 minutes after the start of the step of evaporating the organic solvent.
- the drug when the drug (gemcitabine or a salt thereof) is encapsulated in the liposome, the drug is dissolved in an aqueous medium to be hydrated and swollen, and the drug is obtained by a method such as heating above the phase transition temperature, sonication or extrusion. Can be encapsulated in the internal aqueous phase of the liposome. Alternatively, the drug can be dissolved in the aqueous phase during lipid emulsification and encapsulated in the inner aqueous phase.
- the osmotic pressure adjusting step means a step of adjusting the osmotic pressure of the inner aqueous phase and the outer aqueous phase of the liposome.
- the release rate can be controlled by adjusting the osmotic pressure of the inner aqueous phase and the outer aqueous phase of the liposome.
- Dialysis etc. are mentioned.
- the solutes of the outer aqueous phase and the inner aqueous phase are homogenized, and the osmotic pressure at that time can be defined as the osmotic pressure of the inner aqueous phase of the completed liposome.
- the heating operation is limited to the case where the solute of the inner aqueous phase is sufficiently retained, for example, by suppressing it to a phase transition of lipid or less.
- the osmotic pressure of the outer aqueous phase can be defined by the osmotic pressure of the dialysate used in the final dialysis step.
- the solute composition concentration of the outer aqueous phase and the solute composition concentration of the inner aqueous phase are quantified and the osmotic pressure of the composition solution is measured.
- the osmotic pressure of the inner aqueous phase and the outer aqueous phase can be obtained.
- the osmotic pressure of the inner aqueous phase of the liposome is preferably adjusted to 2 to 8 times, more preferably adjusted to 2.5 to 6 times the osmotic pressure of the outer aqueous phase of the liposome, more preferably 3 to It is more preferable to adjust to 5 times.
- the measurement of osmotic pressure may be performed according to the osmotic pressure measuring method described in the 16th revision Japanese Pharmacopoeia. Specifically, the osmolality can be obtained by measuring the degree of freezing point (freezing point) of water.
- the freezing point depression degree of water is defined by the solute molar concentration, and the osmolality can be obtained from the solute molar concentration.
- the osmotic pressure of the external water phase has an important effect on the living body during administration.
- the osmotic pressure of the outer aqueous phase is preferably 200 mOsmol / L to 400 mOsmol / L, more preferably 250 mOsmol / L to 350 mOsmol / L, and still more preferably isotonic with the body fluid.
- the liposome composition is preferably subjected to aseptic filtration.
- As a filtration method an unnecessary thing can be removed from the aqueous solution containing a liposome using a hollow fiber membrane, a reverse osmosis membrane, or a membrane filter.
- the aseptic filtration step and the aseptic filling step described below are preferably performed at a phase transition temperature or lower of the lipid constituting the liposome.
- the phase transition temperature of the lipid is around 50 ° C., it is preferably about 0 ° C. to 40 ° C., and more specifically, it is preferably produced at about 5 ° C. to 30 ° C.
- the liposome composition obtained after aseptic filtration is preferably aseptically filled for medical use.
- a known method can be applied for aseptic filling.
- a liposome composition suitable for medical use can be prepared by filling the container aseptically.
- the tumor therapeutic agent of the present invention is usually an excipient, binder, lubricant, disintegrant, coloring agent, flavoring agent, emulsifier, surfactant, solubilizing agent, suspending agent used for formulation.
- Additives such as agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
- the tumor therapeutic agent of the present invention includes a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a liposomal composition in which gemcitabine or a salt thereof is encapsulated in a liposome, even if it is a one-part preparation containing a taxane antitumor agent. It may be a two-drug preparation of a product and a taxane antitumor agent. Preferably, it is a two-drug preparation comprising a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a taxane antitumor agent as separate preparations.
- each formulation is simultaneously, separately, sequentially, or spaced apart. Can be administered to a subject with a gap.
- Examples of the administration route of the tumor therapeutic agent of the present invention include intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration, and suppository. Is mentioned.
- parenteral administration is preferable.
- intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection
- Examples of the administration method include administration by syringe or infusion.
- the administration route of the taxane antitumor agent is preferably oral administration.
- a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome can be administered parenterally, and a taxane antitumor agent can be administered orally.
- the dosage and administration frequency of gemcitabine or a salt thereof contained in the liposome composition can be administered in 1 to 4 mg / kg divided into 1 to several times per day.
- 60 mg to 240 mg, preferably 120 mg to 240 mg, more preferably 180 mg to 240 mg per day is administered by intravenous injection in a human (patient; weight 60 kg).
- the dose and the number of administration are not limited.
- 0.01 mg / kg to 1000 mg / kg can be divided into 1 to several times per day for an adult.
- Examples of the dosage form of the tumor therapeutic agent of the present invention include tablets, capsules, suspensions, emulsions, solutions, eye drops, nasal drops, ear drops and injections.
- the tumor for which the tumor therapeutic agent of the present invention can be effectively used is not particularly limited as long as it is a carcinoma or sarcoma.
- breast cancer, endometrial cancer, ovarian cancer, prostate cancer, lung cancer, stomach (gastric gland) cancer, non-small cell Examples include lung cancer, pancreatic cancer, and squamous cell carcinoma of the head and neck, with pancreatic cancer being preferred.
- the kit of the present invention is a kit comprising a combination of (a) a liposome composition encapsulating gemcitabine or a salt thereof and (b) a taxane antitumor agent.
- (a) a liposome composition encapsulating gemcitabine or a salt thereof and (b) a taxane antitumor agent can each be in various known dosage forms, and depending on the dosage form, Housed in various containers used.
- (a) the liposome composition containing gemcitabine or a salt thereof and (b) the taxane antitumor agent may be contained in separate containers, or may be mixed and contained in the same container. Also good. It is preferable that (a) a liposome composition containing gemcitabine or a salt thereof and (b) a taxane antitumor agent are contained in separate containers.
- the antitumor effect potentiator of the present invention is usually an excipient, a binder, a lubricant, a disintegrant, a colorant, a flavoring agent, an emulsifier, a surfactant, a solubilizing agent, a suspension, Additives such as turbidity agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
- the antitumor effect potentiator of the present invention can be administered to a subject simultaneously with the taxane antitumor agent, separately, continuously or at intervals.
- parenteral administration is preferable.
- intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection
- administration method include administration by syringe or infusion.
- the dose and frequency of administration of gemcitabine or a salt thereof contained in the antitumor effect potentiator of the present invention can be administered from 1 mg / kg to 4 mg / kg divided from 1 to several times per day.
- the antitumor effect potentiator of the present invention is not limited to these doses and administration frequency.
- the tumor for which the antitumor effect potentiator of the present invention can be used effectively is not particularly limited as long as it is a carcinoma and sarcoma in which a taxane antitumor agent is used.
- Pancreatic cancer is preferred.
- the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples.
- the sample was diluted 1000 times with 1 ⁇ PBS (Nippon Gene), and the volume average particle size was measured by a dynamic light scattering method using Nanotrac UPA-UT (Nikkiso Co., Ltd.).
- the tumor volume was calculated by the following formula, measuring the tumor major axis (a) and minor axis (b) with calipers.
- Mixing was performed at a speed of 20 m / s at 13000 rpm for 30 minutes. Thereafter, the organic solvent and water are evaporated by supplying nitrogen while heating above the phase transition temperature, and concentrated to about 1/10 of the volume before emulsification. Got. The average particle size at this time was 68.0 nm.
- Gemcitabine hydrochloride was used as a drug.
- Gemcitabine hydrochloride was purchased from TEVA. 81.63 g of sodium chloride, 29.01 g of disodium hydrogen phosphate dodecahydrate and 2.29 g of sodium dihydrogen phosphate dihydrate were dissolved in 948 g of water for injection to obtain PBS. In each of the two containers, 12.98 g of gemcitabine hydrochloride, 54.01 g of PBS, 75.74 g of JP injection water, and 2.71 mL of 8M sodium hydroxide were mixed to obtain a drug solution.
- a 275 mM sucrose / 10 mM histidine aqueous solution was prepared as a finished dialysate of the liposome composition by dialysis.
- the osmotic pressure determined from the solute molar concentration of this solution was 285 mOsm / L.
- Dialysis was performed using this dialysate at room temperature to remove unencapsulated gemcitabine hydrochloride and each solute present in the outer aqueous phase of the drug loading solution, and the outer aqueous phase was replaced with the dialysate.
- gemcitabine hydrochloride concentration 0.81 mg / mL, average particle diameter 74.9 nm, inner aqueous phase osmotic pressure 1039 mOsm / L, outer aqueous phase osmotic pressure 285 mOsm / L, osmotic pressure of inner aqueous phase with respect to outer aqueous phase Obtained a 3.6 times larger gemcitabine-encapsulating liposome composition.
- the content of cholesterol with respect to the total amount of lipid constituting the liposome was 19.3 mol%.
- the osmotic pressure was calculated from the solute molar concentration.
- Example 1 Medicinal effect test in Capan-1 subcutaneous transplantation tumor-bearing model mouse
- gemcitabine hereinafter also referred to as Gem
- abraxane hereinafter also referred to as Abx
- gemcitabine-encapsulating liposome composition hereinafter also referred to as composition A
- gemcitabine hydrochloride manufactured by TEVA
- Abx was prepared by dissolving Abraxane (Celgene) in physiological saline.
- the gemcitabine-encapsulating liposome composition the one prepared in Reference Example 1 was used.
- Capan-1 cells a human pancreatic cancer cell line, were transplanted subcutaneously into the flank of female nude mice to form subcutaneous tumors. Using the tumor volume as an index, the subcutaneous tumor suppressive effect of the combined administration of Abx and Composition A was evaluated.
- group 1 used sucrose solution
- group 2 used Gem
- group 3 used composition A
- groups 4 and 5 used Abx and Gem
- group 6 and group 7 used Abx and composition A.
- Groups 1 to 5 are comparative examples
- groups 6 and 7 are examples. All test substances were administered via the caudal vein once a week from the 17th day after transplantation for a total of 3 weeks. The dose of each drug was set such that the weight loss rate did not exceed 20% as a dose that would not reach a serious minimum body weight so that MTD (maximum tolerated dose) recovery was not observed.
- Table 1 shows the group composition and dosage.
- the change in tumor volume is shown in FIG.
- Table 2 shows the tumor volume average value on the 38th day after transplantation, the tumor volume standard deviation on the 38th day after transplantation, the tumor regression rate from the start of administration, and the number of days to reach the tumor volume average value of 2000 mm 3 .
- Tukey's multiple comparisons test was performed, and a P value of less than 5% was determined to be statistically significant between groups.
- Graphpad Prism version 5.03 was used for data processing.
- a is P ⁇ 0.001 by comparison with Group 1
- b is P ⁇ 0.001 by comparison with Group 2
- c is by comparison with Group 4.
- R. Indicates no retraction.
- the tumor volume was smaller at 38 days after transplantation compared to group 4 or group 5, and group 6 showed a statistically significant difference from group 4 (P ⁇ 0.05). ).
- the tumor regression rate from the start of administration no tumor regression was observed in Group 4, and the tumor regression rate in Group 5 was 31%, whereas the tumor regression rate in Group 6 was 47%. %, The tumor regression rate in group 7 was 86%, and group 6 and group 7 showed an excellent tumor regression effect.
- the arrival time to a tumor volume average of 2000 mm 3 is 69 days after transplantation in group 4 and 80 days after transplantation in group 5, whereas it is> 87 days in group 6 and group 7, which is delayed. It was. From the above results, composition A has a growth inhibitory effect on Capan-1 tumor cells transplanted subcutaneously in nude mice in combination with Abx, and the growth inhibitory effect is higher than that in combination with Gem and Abx. Indicated.
Abstract
Description
タキサン系抗腫瘍剤単剤での抗腫瘍効果が低い原因の一つとして、腫瘍ごとのタキサン感受性が大きく異なり、治療患者の奏効率が上がらないことが挙げられる。そのため、タキサン系抗腫瘍剤に加えて、メカニズムが異なる抗腫瘍剤との併用が必要である。
また、非特許文献3および非特許文献1に記載されている併用療法についても、治療効果として十分に高いとは言えない。
本発明の課題は、上市されているゲムシタビン、タキサン系抗腫瘍剤およびそれらの併用療法と比較して、抗腫瘍効果に優れた腫瘍治療剤および腫瘍治療用キットを提供することである。
(2)タキサン系抗腫瘍剤がパクリタキセルもしくはその塩またはナブパクリタキセルである、(1)に記載の腫瘍治療剤。
(3)タキサン系抗腫瘍剤がナブパクリタキセルである、(1)または(2)に記載の腫瘍治療剤。
(4)リポソームを構成する脂質の合計量に対するコレステロール類の含有率が10mol%~35mol%であり、リポソームの内水相の浸透圧がリポソームの外水相の浸透圧に対して2倍~8倍である、(1)~(3)のいずれか一に記載の腫瘍治療剤。
(5)リポソームがシングルラメラである(1)~(4)のいずれか一に記載の腫瘍治療剤。
(6)血漿中におけるリポソーム組成物からのゲムシタビンまたはその塩の放出速度が10質量%/24hr~70質量%/24hrである、(1)~(5)のいずれか一に記載の腫瘍治療剤。
(7)リポソームを構成する脂質が水素添加大豆ホスファチジルコリン、1、2-ジステアロイル-3-ホスファチジルエタノールアミン-ポリエチレングリコール、およびコレステロールを含む、(1)~(6)のいずれか一に記載の腫瘍治療剤。
(8)リポソームの平均粒子径が2nm~200nmである、(1)~(7)のいずれか一に記載の腫瘍治療剤。
(9)リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物およびタキサン系抗腫瘍剤を含む腫瘍治療用キット。
(10)タキサン系抗腫瘍剤から選択される1以上の抗腫瘍剤と組み合わせて併用投与されるように用いられることを特徴とする、リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物を含む抗腫瘍効果増強剤。
(11)タキサン系抗腫瘍剤がパクリタキセルもしくはその塩またはナブパクリタキセルである、(10)に記載の抗腫瘍効果増強剤。
(12)タキサン系抗腫瘍剤がナブパクリタキセルである、(10)または(11)に記載の抗腫瘍効果増強剤。
(13)リポソームを構成する脂質の合計量に対するコレステロール類の含有率が10mol%~35mol%であり、リポソームの内水相の浸透圧がリポソームの外水相の浸透圧に対して2倍~8倍である、(10)~(12)のいずれか一に記載の抗腫瘍効果増強剤。
(14)リポソームがシングルラメラである、(10)~(13)のいずれか一に記載の抗腫瘍効果増強剤。
(15)血漿中におけるリポソーム組成物からのゲムシタビンまたはその塩の放出速度が10質量%/24hr~70質量%/24hrである、(10)~(14)のいずれか一に記載の抗腫瘍効果増強剤。
(16)リポソームを構成する脂質が水素添加大豆ホスファチジルコリン、1、2-ジステアロイル-3-ホスファチジルエタノールアミン-ポリエチレングリコール、およびコレステロールを含む、(10)~(15)のいずれか一に記載の抗腫瘍効果増強剤。
(17)リポソームの平均粒子径が2nm~200nmである、(10)~(16)のいずれか一項に記載の抗腫瘍効果増強剤。
(18)リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物を併用治療に用いる場合の治療有効用量、および、タキサン系抗腫瘍剤を併用治療に用いる場合の治療有効用量を組み合わせて、対象に投与することを特徴とする、腫瘍の治療方法。
(19)リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物を併用治療に用いる場合の治療有効用量、および、タキサン系抗腫瘍剤を併用治療に用いる場合の治療有効用量を、同時に、別々に、連続して、あるいは間隔をあけて、対象に投与することを特徴とする、腫瘍の治療方法。
(20)リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物とタキサン系抗腫瘍剤から選択される1以上の抗腫瘍剤とを組み合わせてなる腫瘍治療剤を製造するための、リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物の使用。
(21)タキサン系抗腫瘍剤から選択される1以上の抗腫瘍剤と組み合わせて併用投与されるように用いられることを特徴とする、腫瘍治療のための、リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物。
本発明において、特にことわらない限り、%は、質量百分率を意味する。
本明細書において組成物中の各成分の量は、組成物中に各成分に該当する物質が複数存在する場合、特に断らない限り、組成物中に存在する当該複数の物質の合計量を意味する。
「放出速度」とは、単位時間あたりに、リポソームに内包された薬物が、リポソームを構成する脂質膜を通過して、リポソームの外部へ出る量を意味する。
「血中滞留性」とは、リポソーム組成物を投与した対象において、リポソームに内包された状態の薬物が血液中に存在する性質を意味する。
「リポソームの平均粒子径」とは、リポソーム組成物中に存在するリポソームの体積平均粒子径を意味する。本発明のリポソーム組成物中に含まれるリポソームの平均粒子径は動的光散乱法を用いて測定する。動的光散乱を用いた市販の測定装置としては、濃厚系粒子アナライザーFPAR-1000(大塚電子社製)、ナノトラックUPA(日機装社製)およびナノサイザー(マルバーン社製)等が挙げられる。
「対象」とは、その予防若しくは治療を必要とするヒト、マウス、サル、家畜等の哺乳動物であり、好ましくは、その予防若しくは治療を必要とするヒトである。
「腫瘍」としては、例えば、乳癌、子宮体癌、卵巣癌、前立腺癌、肺癌、胃(胃腺)癌、非小細胞肺癌、膵臓癌、頭頚部扁平上皮癌、食道癌、膀胱癌、メラノーマ、大腸癌、腎細胞癌、非ホジキンリンパ腫および尿路上皮癌等が挙げられる。
タキサン系抗腫瘍剤としては、タキサン環またはその類縁構造を有する化合物を有効成分とする医薬組成物が挙げられる。
タキサン系抗腫瘍剤としては、具体的には、パクリタキセル、ドセタキセル、カバジタキセル、テセタキセルおよびオルタタキセル等ならびにそれらの塩または誘導体が挙げられる。
塩としては、通常知られているアミノ基などの塩基性基、ヒドロキシル基およびカルボキシル基などの酸性基における塩を挙げることができる。
塩基性基における塩としては、例えば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩;ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩;ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が挙げられる。
酸性基における塩としては、例えば、ナトリウムおよびカリウムなどのアルカリ金属との塩;カルシウムおよびマグネシウムなどのアルカリ土類金属との塩;アンモニウム塩;ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、N、N-ジメチルアニリン、N-メチルピペリジン、N-メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、N-ベンジル-β-フェネチルアミン、1-エフェナミンおよびN、N'-ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などが挙げられる。
パクリタキセルの誘導体としては、例えば、ナブパクリタキセル(アルブミン結合パクリタキセル)等が挙げられる。
タキサン系抗腫瘍剤としては、パクリタキセルもしくはその塩またはナブパクリタキセルが好ましく、ナブパクリタキセルがより好ましい。
リポソームとは、脂質を用いた脂質二重膜で形成される閉鎖小胞体であり、その閉鎖小胞の空間内に水相(内水相)を有する。内水相には、水等が含まれる。リポソームは通常、閉鎖小胞外の水溶液(外水相)に分散した状態で存在する。リポソームはシングルラメラ(単層ラメラまたはユニラメラとも呼ばれ、二重層膜が一重の構造である。)であっても、多層ラメラ(マルチラメラとも呼ばれ、タマネギ状の形状の多数の二重層膜の構造である。個々の層は水様の層で仕切られている。)であってもよいが、本発明では、医薬用途での安全性および安定性の観点から、シングルラメラのリポソームであることが好ましい。
本発明に係るリポソームを構成する脂質の合計量に対するコレステロール類の含有率は10mol%~35mol%であり、好ましくは15mol%~25mol%、より好ましくは17mol%~21mol%である。リポソームを構成する脂質の合計量に対するコレステロール類の含有率を10mol%~35mol%とすることにより、薬物の放出し易さと保管安定性とを両立できるリポソーム組成物を得ることができる。
これらの中でも、製剤の血中滞留性の観点から、ポリエチレングリコール類、ポリグリセリン類およびポリプロピレングリコール類が好ましく、ポリエチレングリコール(PEG)、ポリグリセリン(PG)およびポリプロピレングリコール(PPG)がより好ましい。汎用性および血中滞留性の観点から、ポリエチレングリコール(PEG)がさらに好ましい。
本発明に係るリポソームは、薬物として少なくともゲムシタビンまたはその塩を内包する。
ゲムシタビンの塩としては、通常知られているアミノ基などの塩基性基、ヒドロキシル基およびカルボキシル基などの酸性基における塩を挙げることができる。
塩基性基における塩としては、例えば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩;ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩;ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が挙げられる。
酸性基における塩としては、例えば、ナトリウムおよびカリウムなどのアルカリ金属との塩;カルシウムおよびマグネシウムなどのアルカリ土類金属との塩;アンモニウム塩;ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、N、N-ジメチルアニリン、N-メチルピペリジン、N-メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、N-ベンジル-β-フェネチルアミン、1-エフェナミンおよびN、N'-ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などが挙げられる。
ゲムシタビンの塩としては、塩酸塩が好ましい。
ゲムシタビンの含有量は、リポソーム組成物に対して0.1~2.0mg/mlであることが好ましく、0.2~1.0mg/mlであることがより好ましい。
本発明に係るリポソームに内包された薬物(ゲムシタビンまたはその塩)は、リポソームの内水相に溶解状態で存在している。ここで、溶解状態とは、リポソームの体積に対して充填した薬物の量が、その内水相の組成液での薬物の飽和溶解度以下の場合、溶解状態で内包されたものとみなす。また、飽和溶解度以上においても、Cryo-TEMで薬物結晶が観察されない、またはXRD測定で結晶格子に起因する回折パターンが観察されない場合、リポソームに内包された薬物の大部分が溶解し、溶解状態で内包されたものとみなす。この場合、脂質膜が作る物理化学的な環境による溶解促進、または一部薬物が脂質膜に取り込み等が起きていると推測する。
本発明に係るリポソーム組成物は、ゲムシタビンまたはその塩を内包するリポソームおよびそのリポソームを分散する水溶液を含むことができる。
本発明に係るリポソーム組成物において、薬物(ゲムシタビンまたはその塩)の放出速度は10質量%/24hr~70質量%/24hrが好ましく、20質量%/24hr~60質量%/24hrがより好ましく、20質量%/24hr~50質量%/24hrがさらに好ましい。
本発明に係るリポソーム組成物は、
乾燥固化工程を経ずに、有機溶媒に溶解した脂質を乳化してリポソームを形成する乳化工程、
乳化工程で得られたリポソームにゲムシタビンまたはその塩を内包させる薬物ローディング工程、および
リポソームの内水相の浸透圧をリポソームの外水相の浸透圧に対して2倍~8倍に調整する浸透圧調整工程
を含む方法により製造することができる。
リポソーム組成物の製造方法は、必要に応じて、乳化工程で用いた有機溶媒を蒸発させる蒸発工程、無菌ろ過、無菌充填等の他の工程を含んでもよい。
乳化工程では、少なくとも1種の脂質が有機溶媒に溶解している油相と水相とを混合して脂質を含む水溶液を攪拌して乳化することができる。脂質が有機溶媒に溶解している油相および水相を混合し撹拌し、乳化することで、油相および水相がO/W型に乳化した乳化液が調製される。混合後、油相由来の有機溶媒の一部または全部を後述する蒸発工程によって除去することにより、リポソームが形成される。または、油相中の有機溶媒の一部または全部が撹拌・乳化の過程で蒸発して、リポソームが形成される。
油相として用いられる有機溶媒として、水溶性有機溶媒およびエステル系有機溶媒の混合溶媒を用いる。本発明では、有機溶媒として、クロロホルム、塩化メチレン、ヘキサン、およびシクロヘキサン等の有機溶剤を実質的に用いないことが好ましく、これらの有機溶剤をまったく用いないことがより好ましい。
水相とは、外水相および内水相を意味する。
本発明における外水相とは、リポソームを分散する水溶液を意味する。例えば注射剤の場合においては、バイアル瓶またはプレフィルドシリンジ包装されて保管されたリポソームの分散液のリポソームの外側を占める溶液が外水相となる。また、添付された分散用液またはその他溶解液により投与時に用時分散した液についても同様に、リポソームの分散液のリポソームの外側を占める溶液が外水相となる。
本発明における内水相とは、リポソームの脂質二重膜を隔てた閉鎖小胞内の水相を意味する。
リポソームを製造する際に、リポソームを分散する水溶液(外水相)としては、水(蒸留水、注射用水等)、生理食塩水、各種緩衝液または糖類の水溶液およびこれらの混合物(水性溶媒)が好ましく用いられる。緩衝液としては、有機系、無機系に限定されることはないが、体液に近い水素イオン濃度付近に緩衝作用を有する緩衝液が好適に用いられ、リン酸緩衝液、トリス緩衝液、クエン酸緩衝液、酢酸緩衝液およびグッドバッファー等があげられる。水相のpHは、例えば、5~9とすることができ、7~8であることが好ましい。リポソームを分散する水溶液(外水相)としては、リン酸緩衝液(例えば、pH=7.4)を用いることが好ましい。リポソームの内水相は、リポソームを製造する際に、リポソームを分散する水溶液であってもよいし、新たに添加される、水、生理食塩水、各種緩衝液または糖類の水溶液およびこれらの混合物をあってもよい。外水相または内水相として用いる水は、不純物(埃、化学物質等)を含まないことが好ましい。
生理食塩水とは、人体と等張になるように調整された無機塩溶液を意味し、さらに緩衝機能を持っていてもよい。生理食塩水としては、塩化ナトリウムを0.9w/v%含有する食塩水、リン酸緩衝生理食塩水(以下、PBSともいう)およびトリス緩衝生理食塩水等が挙げられる。
エクストリュージョン処理とは、細孔を有するフィルターにリポソームを通過させることで、物理的なせん断力を施し、微粒化する工程を意味する。リポソームを通過させる際、リポソーム分散液およびフィルターを、リポソームを構成する膜の相転移温度以上の温度に保温することで、速やかに微粒化することができる。
リポソーム組成物の製造方法においては、必要に応じて蒸発工程を設けてもよい。蒸発工程では、乳化工程で得られたリポソームを含む水溶液から有機溶媒を蒸発させる。本発明において、蒸発工程とは、油相由来の有機溶媒の一部または全部を蒸発工程として強制的に除去する工程、および油相中の有機溶媒の一部または全部が撹拌・乳化の過程で自然に蒸発する工程の少なくとも一つを含む。
有機溶剤を蒸発させる工程において、リポソームを含む水溶液に含まれる有機溶媒の濃度を、有機溶剤を蒸発させる工程の開始後から30分以内に、15質量%以下にすることが好ましい。
薬物ローディング工程では、リポソームに薬物(ゲムシタビンまたはその塩)を内包させる場合、水和・膨潤させる水性媒体に薬物を溶解し、相転移温度以上の加熱、超音波処理またはエクストルージョン等の方法により薬物をリポソームの内水相に内包させることができる。また、脂質乳化時の水相に薬物を溶解させ内水相に内包させることもできる。
浸透圧調整工程とは、リポソームの内水相および外水相の浸透圧を調整する工程を意味する。リポソームの内水相および外水相の浸透圧を調整することにより、放出速度を制御することができる。浸透圧調整工程としては、特に限定されないが、透析等が挙げられる。本発明の製造方法では、核酸アナログ抗癌剤をリポソームに内包させる工程および浸透圧調整工程を同時に行うことが、生産効率の観点から好ましい。
リポソームの内水相の浸透圧をリポソームの外水相の浸透圧に対して2倍~8倍に調整することが好ましく、2.5倍~6倍に調整することがより好ましく、3倍~5倍に調整することがさらに好ましい。
リポソーム組成物は、無菌ろ過を行うことが好ましい。ろ過の方法としては、中空糸膜、逆浸透膜またはメンブレンフィルター等を用いて、リポソームを含む水溶液から不要な物を除去することができる。本発明では、滅菌できる孔径をもつフィルター(好ましくは0.2μmのろ過滅菌フィルター)によってろ過することが好ましい。
無菌ろ過の後に得られたリポソーム組成物は、医療用途として無菌充填することが好ましい。無菌充填の方法は公知のものが適用できる。容器に無菌的に充填することで医療用として好適なリポソーム組成物が調製できる。
本発明の腫瘍治療剤は、通常、製剤化に使用される賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤および吸収促進剤などの添加剤を含んでいてもよい。
リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物とタキサン系抗腫瘍剤とが別個の製剤からなる腫瘍治療剤を用いる場合には、各製剤は、同時に、別々に、連続して、あるいは間隔をあけて対象に投与することができる。
リポソーム組成物の投与経路としては、非経口投与が好ましい。例えば、点滴等の静脈内注射(静注)、筋肉内注射、腹腔内注射、皮下注射、眼内注射および髄腔内注射を挙げることができる。投与方法としては、シリンジまたは点滴による投与が挙げられる。
タキサン系抗腫瘍剤の投与経路としては、経口投与が好ましい。
本発明の腫瘍治療剤においては、例えば、リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物を非経口投与し、タキサン系抗腫瘍剤を経口投与することができる。
タキサン系抗腫瘍剤の投与量および投与回数は、例えば、成人に対しては、1日あたり、0.01mg/kg~1000mg/kgを1回から数回に分割して投与することができる。
本発明のキットは、(a)ゲムシタビンまたはその塩を内包したリポソーム組成物および(b)タキサン系抗腫瘍剤の組み合わせからなるキットである。
本発明のキットでは、(a)ゲムシタビンまたはその塩を内包したリポソーム組成物および(b)タキサン系抗腫瘍剤は各々公知の各種の製剤形態とすることができ、その製剤形態に応じて、通常用いられる各種の容器に収容される。
本発明のキットでは、(a)ゲムシタビンまたはその塩を内包したリポソーム組成物および(b)タキサン系抗腫瘍剤は各々別の容器に収容されてもよいし、混合されて同じ容器に収容されてもよい。(a)ゲムシタビンまたはその塩を内包したリポソーム組成物および(b)タキサン系抗腫瘍剤が各々別の容器に収容されていることが好ましい。
本発明の抗腫瘍効果増強剤は、通常、製剤化に使用される賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤および吸収促進剤などの添加剤を含んでいてもよい。
平均粒子径は、試料を1×PBS(ニッポンジーン社製)で1000倍質量に希釈し、ナノトラックUPA-UT(日機装社製)を用い、動的光散乱法で体積平均粒子径を測定した。
腫瘍体積は、腫瘍長径(a)および短径(b)をノギスで測定し、以下の式で算出した。
式:(a×b2)×0.5(式中、“a”は長径であり、“b”は短径である。)
a)油相の調製
水素添加大豆ホスファチジルコリン、コレステロールおよびN-(カルボニル-メトキシポリエチレングリコール2000)-1、2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミンナトリウム塩(以下、DSPE-PEGともいう)を76/19/5のモル比となるようにそれぞれ16.6g、2.0g、4.3g取り、次いで有機溶媒(エタノール/酢酸エチル=3/1)405mlを加えて70℃に加温して脂質を溶解し油相とした。
4mMリン酸緩衝液(pH7.78)を調製し水相とした。
水相を70℃に加温し、水相/油相=8/3の容積比となるように油相を添加した後、回転かき混ぜ式乳化機にて、周速20m/s、13000rpmにて30分間混合した。その後、相転位温度以上に加温しながら窒素を送気することで有機溶剤と水とを蒸発させ、乳化前の容積に対して約1/10の体積になるまで濃縮し、薬物未内包リポソームを得た。このときの平均粒子径は68.0nmであった。
上記c)で調製した薬物未内包リポソーム2バッチを混合した。
薬物として、ゲムシタビン塩酸塩を用いた。ゲムシタビン塩酸塩はTEVA社から購入した。塩化ナトリウム81.63g、リン酸水素二ナトリウム十二水和物29.01g、リン酸二水素ナトリウム二水和物2.29gを注射用水948gで溶解し、PBSとした。二つの容器にそれぞれゲムシタビン塩酸塩12.98g、PBS54.01g、日局注射用水75.74g、8M水酸化ナトリウム2.71mLを混合し、薬物溶液とした。それぞれの薬物溶液に、薬物未封入リポソーム141.4mL、8M水酸化ナトリウム2.71mLを加え、混合した。この液の浸透圧は1039mOsm/Lであり、これが完成するリポソーム組成物の内水相の浸透圧となる。次にこの液を70℃で10分間加熱した後40℃まで冷却し、1016mMスクロース/37mMヒスチジン溶液で希釈した。希釈後、一つにまとめ、薬物ローディング液とした。透析によるリポソーム組成物の完成透析液として275mMスクロース/10mMヒスチジン水溶液を調製した。この液の溶質モル濃度より求めた浸透圧は285mOsm/Lであった。この透析液を用いて室温にて透析を行い、薬物ローディング液の外水相に存在する未封入のゲムシタビン塩酸塩と各溶質を除去し、透析液で外水相を置換した。以上の工程により、ゲムシタビン塩酸塩濃度0.81mg/mL、平均粒子径74.9nm、内水相浸透圧1039mOsm/L、外水相浸透圧285mOsm/L、内水相の外水相に対する浸透圧が3.6倍のゲムシタビン内包リポソーム組成物を得た。リポソームを構成する脂質の合計量に対するコレステロール類の含有率は19.3mol%であった。
なお、浸透圧は、溶質モル濃度から算出した。
血漿中の放出速度の測定
リポソーム組成物50μLをマウス血漿で20倍希釈(体積)し、37℃で24時間インキュベートし、24時間の時点で100μL採取した。続いて、限外ろ過フィルター(アミコンウルトラ-0.5 10kDa、ミリポア社製)を用い7400×g、30分、4℃の条件で遠心ろ過を行った。回収したろ液に含まれる薬物量をHPLCにて定量し、放出速度を次の式により算出した。
式:放出速度(%/24hr)=(インキュベーション24時間後のろ液中の薬物量)×20÷リポソーム組成物の全相に含まれる薬量×100
結果は24%/24hrであった。
Capan-1皮下移植担がんモデルマウスでの薬効試験
被験物質として、ゲムシタビン(以下、Gemともいう)、アブラキサン(以下、Abxともいう)およびゲムシタビン内包リポソーム組成物(以下、組成物Aともいう)を用いた。
Gemは、ゲムシタビン塩酸塩(TEVA社製)を生理食塩水に溶解させたものを用いた。Abxは、アブラキサン(Celgene社製)を生理食塩水に溶解させたものを用いた。ゲムシタビン内包リポソーム組成物は、参考例1で作製したものを用いた。
ヒト膵臓癌細胞株であるCapan-1細胞1×107個を雌性ヌードマウスの脇腹部皮下に移植し皮下腫瘍を形成させた。腫瘍体積を指標としてAbxおよび組成物Aの併用投与における皮下腫瘍の抑制効果を評価した。被験物質として、群1はスクロース溶液、群2はGem、群3は組成物A、群4および群5はAbxおよびGem、群6および群7はAbxおよび組成物Aを用いた。群1~5が比較例、群6および群7が実施例である。被験物質はいずれも移植後17日目から週1回、計3週間、尾静脈投与した。
なお、各薬剤の投与量は、体重減少率が20%を超えない量をMTD(最大耐用量)回復が認められないような重篤な最低体重に達しないと思われる用量として設定した。
群構成および投与量を表1に示す。
統計学的解析として、Tukeyの多重比較検定(Tukey's multiple comparisons test)を実施し、群間でP値5%未満を統計学的有意差ありと判定した。データ処理にはGraphpad Prism version 5.03を用いた。
表2において、aは群1との比較によりP<0.001であったものを、bは群2との比較によりP<0.001であったものを、cは群4との比較によりP<0.05であったものを示し、N.R.は退縮なしを示す。
以上の結果から、組成物AはAbxとの併用においてヌードマウスの皮下に移植したCapan-1腫瘍細胞の増殖抑制効果を有し、その増殖抑制効果はGemとAbxとの併用よりも上回ることが示された。
Claims (9)
- リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物とタキサン系抗腫瘍剤とを組み合わせてなる腫瘍治療剤。
- タキサン系抗腫瘍剤がパクリタキセルもしくはその塩またはナブパクリタキセルである、請求項1に記載の腫瘍治療剤。
- タキサン系抗腫瘍剤がナブパクリタキセルである、請求項1または2に記載の腫瘍治療剤。
- リポソームを構成する脂質の合計量に対するコレステロール類の含有率が10mol%~35mol%であり、リポソームの内水相の浸透圧がリポソームの外水相の浸透圧に対して2倍~8倍である、請求項1~3のいずれか一項に記載の腫瘍治療剤。
- リポソームがシングルラメラである請求項1~4のいずれか一項に記載の腫瘍治療剤。
- 血漿中におけるリポソーム組成物からのゲムシタビンまたはその塩の放出速度が10質量%/24hr~70質量%/24hrである、請求項1~5のいずれか一項に記載の腫瘍治療剤。
- リポソームを構成する脂質が水素添加大豆ホスファチジルコリン、1、2-ジステアロイル-3-ホスファチジルエタノールアミン-ポリエチレングリコール、およびコレステロールを含む、請求項1~6のいずれか一項に記載の腫瘍治療剤。
- リポソームの平均粒子径が2nm~200nmである、請求項1~7のいずれか一項に記載の腫瘍治療剤。
- リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物およびタキサン系抗腫瘍剤を含むキット。
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DK3372232T3 (da) | 2021-06-07 |
US20210275453A1 (en) | 2021-09-09 |
CN108348538A (zh) | 2018-07-31 |
US20180243214A1 (en) | 2018-08-30 |
US20200197305A1 (en) | 2020-06-25 |
JPWO2017078008A1 (ja) | 2018-08-09 |
US11166913B2 (en) | 2021-11-09 |
KR102084340B1 (ko) | 2020-03-03 |
PL3372232T3 (pl) | 2021-09-27 |
ES2869283T3 (es) | 2021-10-25 |
CN111437259A (zh) | 2020-07-24 |
RU2018119680A3 (ja) | 2019-12-05 |
CN111632030A (zh) | 2020-09-08 |
MA43183A (fr) | 2018-09-12 |
CN108348538B (zh) | 2021-06-22 |
RU2020137385A3 (ja) | 2021-03-31 |
EP3372232A1 (en) | 2018-09-12 |
RU2761620C2 (ru) | 2021-12-13 |
US11166914B2 (en) | 2021-11-09 |
RU2020137384A3 (ja) | 2021-03-31 |
RU2018119680A (ru) | 2019-12-05 |
RU2738365C2 (ru) | 2020-12-11 |
EP3372232B1 (en) | 2021-04-14 |
JP6602886B2 (ja) | 2019-11-06 |
RU2020137384A (ru) | 2020-12-03 |
EP3372232A4 (en) | 2018-11-14 |
RU2768178C2 (ru) | 2022-03-23 |
CN111632030B (zh) | 2023-01-17 |
RU2020137385A (ru) | 2020-12-03 |
KR20180054873A (ko) | 2018-05-24 |
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