WO2011081430A2 - 향상된 수용해도를 갖는 라파마이신 함유 고분자나노입자 주사제형 조성물 및 그 제조방법, 및 방사선 요법과 병용하기 위한 항암 조성물 - Google Patents
향상된 수용해도를 갖는 라파마이신 함유 고분자나노입자 주사제형 조성물 및 그 제조방법, 및 방사선 요법과 병용하기 위한 항암 조성물 Download PDFInfo
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- WO2011081430A2 WO2011081430A2 PCT/KR2010/009476 KR2010009476W WO2011081430A2 WO 2011081430 A2 WO2011081430 A2 WO 2011081430A2 KR 2010009476 W KR2010009476 W KR 2010009476W WO 2011081430 A2 WO2011081430 A2 WO 2011081430A2
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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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
- A61K31/395—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a rapamycin-containing polymer nanoparticle injectable composition having improved water solubility, and more particularly, to a rapamycin-containing injectable composition having a water solubility improved by solubilizing low-water-soluble rapamycin into polymer nanoparticles and a method for preparing the same. And anti-cancer compositions for use in combination with radiation therapy.
- Rapamycin (molecular formula: C 51 H 79 NO 13 , molecular weight: 914.2) is a macrolide lactone compound, also known as sirolimus, which has immunosuppressive activity and commercialized as a transplant rejection inhibitor (Rapamune) in organ transplant patients. It is. Rapamycin is also used to suppress organ transplant rejection. It can also be used to treat ocular inflammation, restenosis and rheumatoid arthritis.
- rapamycin has not only an immunosuppressive function but also an anticancer agent that destroys cancer cells by inducing apoptosis as an inhibitor of mammalian target of rapamycin (mTOR).
- mTOR mammalian target of rapamycin
- rapamycin has a very low solubility in water (1-2 ⁇ g / ml), so the absorption rate is very low when administered orally, and the change in bioavailability between individuals is very severe.
- Rapamune tablets are introduced as a formulation containing rapamycin.
- the tablet contains excipients such as sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, Povidone, poloxamer 188, and glyceryl monooleate.
- Rapamune® oral solutions also include Phosal 50 PG (phosphatitylcholine, propylene glycol, mono-glycerides, di-glycerides, ethanol, soybean fatty acids, ascorbyl palmitate) and polysorbate 80. Contains 2.5% ethanol.
- the bioavailability (absolute bioavailability) is about 14%
- the Rapamune tablet is orally administered
- the Rapamune® solution is about 25% higher than the oral administration of the Rapamune® solution. Show utilization.
- the bioavailability of both agents is low, below 20%, due to the low solubility of rapamycin in water.
- U.S. Patent 5,559,121 discloses a capsule composition containing a solution in which rapamycin is dissolved in a mixed solution comprising surfactant polysorbate 80, N, N-dimethylacetamide and one of lecithin or phospholipid.
- Patent 5,616, 588 discloses an injectable aqueous solution composition in which rapamycin is dissolved in an aqueous solution of propylene glycol at a concentration of 0.1 to 4 mg / ml and does not contain a nonionic surfactant.
- the conventional rapamycin injectable aqueous solution there is a disadvantage in that the administration of the rapamycin injection solution is performed in a short time. At present there are no commercially available injection formulations.
- Korean Patent 0160957 discloses a composition for inhibiting organ or tissue transplant rejection, which contains rapamycin in an amount effective to inhibit transplant rejection of an organ or tissue of a mammal.
- this patent discloses the use of rapamycin in combination with oils such as olive oil, alcohols, propylene glycol and polyethylene glycols and surfactants such as cremopoa EL and polysorbate 80.
- the present invention is to solve the problems of the prior art as described above, rapamycin-containing polymer nanoparticles that can be intravenous injection, subcutaneous / muscle injection using only an organic solvent, excellent biocompatibility, biodegradable polymers It is a technical subject to provide a particle injection composition, its manufacturing method, and anticancer composition for use in combination with radiation therapy.
- the present invention to solve the above technical problem, (i) AB-type diblock copolymer composed of a hydrophilic block (A) and a hydrophobic block (B), (ii) a polylactic acid containing at least one carboxyl group at the terminal or Alkali metal salt of the derivative and (iii) Rapamycin as an active ingredient, wherein the rapamycin is enclosed in the micelle formed by the AB-type diblock copolymer and the alkali metal salt of polylactic acid or a derivative thereof. It provides a rapamycin-containing polymer nanoparticle injectable composition.
- AB type diblock copolymer composed of hydrophilic block (A) and hydrophobic block (B), (ii) polylactic acid comprising at least one carboxyl group at the end or Alkali metal salts of derivatives and (iii) solubilizing rapamycin as an active ingredient in an organic solvent; (b) removing the organic solvent from the result of step (a); And (c) adding an aqueous medium to the resultant of step (b), a method for preparing a rapamycin-containing polymer nanoparticle injectable composition.
- the AB-type diblock copolymer consisting of a hydrophilic block (A) and a hydrophobic block (B), (ii) a polylactic acid or derivative thereof containing at least one carboxyl group at the end Radiation therapy comprising an alkali metal salt and (iii) rapamycin as an active ingredient, wherein rapamycin is enclosed within nanoparticles formed by the AB-type diblock copolymer and the alkali metal salt of the polylactic acid or derivatives thereof.
- An anticancer composition for use in combination with is provided.
- the injectable composition may provide an injection solution having a solubility of rapamycin of 0.1 mg / ml or more upon reconstitution in an aqueous solution after drying.
- a rapamycin injection composition capable of solubility of rapamycin of 0.1 mg / ml or more, containing no organic solvent, having excellent biocompatibility, and enabling intravenous injection and subcutaneous / muscle injection using only biodegradable polymers It can be obtained, the effect of significantly increasing the anticancer efficacy when administered in combination with the composition of the present invention can be expected.
- Rapamycin-containing injectable compositions of the present invention can maximize the radiation effect by synergism, thereby reducing the toxicity caused during radiation treatment.
- Rapamycin is a drug that has strong pharmacological activity such as immunosuppressive effect as well as radiosensitizing effect. It is one of the drugs with severe side effects, and because it is insoluble in water, it should be formulated using a solubilizer. Although most of the surfactants have the same toxicity as the hypersensitivity reaction, the rapamycin-containing injectable composition of the present invention does not cause toxicity of the solubilizer, and minimizes the dose of rapamycin to reduce side effects while minimizing side effects. Can be exercised.
- FIG. 1 is an NMR spectrum of D, L-PLA-COONa according to Preparation Example 1.
- FIG. 2 is an NMR spectrum of mPEG-PLA according to Preparation Example 2.
- Figure 3 is a graph showing the body dynamic evaluation of the rapamycin-containing polymer nanoparticles obtained in Experimental Example 1.
- Figure 4 is a graph showing the radiation sensitivity effect test results of the rapamycin-containing polymer nanoparticle composition obtained in Experimental Example 2.
- FIG. 6 is a graph showing the results of in vivo kinetics of rapamycin-containing polymer nanoparticles obtained in Experimental Example 4.
- FIG. 6 is a graph showing the results of in vivo kinetics of rapamycin-containing polymer nanoparticles obtained in Experimental Example 4.
- rapamycin in the present invention includes both rapamycin, derivatives or analogs thereof and pharmaceutically acceptable salts thereof.
- Derivatives or analogs of rapamycin specifically include, but are not limited to, benzoyl rapamycin, everolirimus, temsirolimus, pimetriomus, biolimus, and the like.
- nanoparticle is a concept that collectively refers to particles of the nanometer level of the particle diameter, and includes micelles, mixed micelles, nanocapsules or nanospheres, the size level is not limited thereto, for example, 1 to 500nm It may be a particle diameter.
- amphiphilic diblock copolymer (i) is an AB-type diblock copolymer composed of a hydrophilic block (A) and a hydrophobic block (B), and the hydrophilic block (A) is polyethylene glycol, and the hydrophobic Block (B) may be polylactic acid or a derivative thereof.
- the polyethylene glycol of the hydrophilic block (A) may be polyethylene glycol, methoxy polyethylene glycol, and the like, but is not limited thereto, and specifically, methoxy polyethylene glycol.
- the number average molecular weight of the hydrophilic block (A) is preferably 500 to 20,000 Daltons, more preferably 1,000 to 10,000 Daltons, even more preferably 1,000 to 5,000 Daltons. When the number average molecular weight of the hydrophilic block (A) is less than 500 Daltons, the hydrophilic portion may be smaller than the hydrophobic portion, so that the composition of the present invention may not be dissolved in water.
- the content of the hydrophilic block (A) in the amphiphilic diblock copolymer is preferably 40 to 70% by weight, more preferably 50 to 65% by weight based on 100% by weight of the total diblock copolymer, It is advantageous in that it can stably maintain micelles of the amphiphilic diblock copolymer.
- the polylactic acid or derivative thereof of the hydrophobic block (B) is, for example, polylactic acid, polylactide, polyglycolide, polymandelic acid, polycaprolactone, polydioxan-2-one, polyamino acid, poly At least one selected from the group consisting of orthoesters, polyanhydrides and copolymers thereof, and more specifically, polylactic acid, polylactide, polyglycolide, polymandelic acid, polycaprolactone or polydioxane It can be -2 degrees.
- the polylactic acid or derivative thereof of the hydrophobic block (B) is a polylactic acid, polylactide, polycaprolactone, a copolymer of lactic acid and mandelic acid, a copolymer of lactic acid and glycolic acid, It may be at least one selected from the group consisting of a copolymer of lactic acid and caprolactone and a copolymer of lactic acid and 1,4-dioxane-2one.
- the number average molecular weight of the hydrophobic block (B) is preferably 500 to 10,000 Daltons, more preferably 500 to 5,000 Daltons.
- the content of the hydrophobic block (B) in the amphiphilic diblock copolymer is preferably 30 to 60% by weight, more preferably 35 to 50% by weight based on 100% by weight of the total diblock copolymer, It is advantageous in that it can stably maintain micelles of the amphiphilic diblock copolymer.
- the alkali metal salt of polylactic acid or a derivative thereof containing at least one carboxyl group at the terminal serves to enhance the encapsulation efficiency of the drug by hardening the core inside the micelle containing the drug.
- polylactic acid or derivative thereof including at least one carboxyl group at the terminal examples include polylactic acid, polylactide, polyglycolide, polymandelic acid, polycaprolactone, polyanhydride and copolymers thereof. One or more selected may be used. More specifically, the polylactic acid or derivatives thereof is polylactide, polyglycolide, polycaprolactone or copolymers thereof. According to a preferred embodiment of the present invention, the polylactic acid or derivative thereof is selected from the group consisting of polylactic acid, copolymers of lactic acid and mandelic acid, copolymers of lactic acid and glycolic acid, and copolymers of lactic acid and caprolactone There may be more than one.
- the alkali metal salt of polylactic acid or a derivative thereof refers to a form in which the terminal carboxylic acid anion and the alkali metal ion of the polylactic acid or the derivative thereof are bonded by an ionic bond.
- the alkali metal is preferably a monovalent metal selected from the group consisting of sodium, potassium and lithium, more preferably sodium.
- the opposite terminal of the carboxyl group which is ion-bonded with the alkali metal ion is substituted with one selected from the group consisting of hydroxy, acetoxy, benzoyloxy, decanoyloxy, palmitoyloxy and alkoxy.
- the opposite terminal of the carboxyl group which is ion-bonded with the alkali metal ion is substituted with one selected from the group consisting of hydroxy, acetoxy, benzoyloxy, decanoyloxy, palmitoyloxy and alkoxy.
- polylactic acid alkali metal salt including at least one carboxyl group at the terminal of the present invention may be represented by the formula (1).
- R is hydrogen, acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group or ethyl group,
- Z and Y are hydrogen, methyl group or phenyl group
- M is sodium, potassium or lithium
- n is an integer from 1 to 30,
- n is an integer of 0 to 20
- the salt of the polylactic acid or a derivative thereof may be represented by the following formula (2).
- R is hydrogen, acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group or ethyl group,
- X is a methyl group
- Y ' is hydrogen or a phenyl group
- Z is hydrogen, methyl or phenyl
- M is sodium, potassium or lithium
- p is an integer from 0 to 25,
- q is an integer from 0 to 25,
- the alkali metal salt of the polylactic acid or derivatives thereof preferably has a water solubility of 20 mg / ml or more, and when dissolved in an aqueous medium, the hydrophilic portion of the carboxylic acid anion present in the molecule and the hydrophobic portion of the polylactic acid are balanced to form micelles. Get involved. Therefore, if the molecular weight is too large, the hydrophobic portion becomes large, so that it is difficult to associate hydrophilic anionic carboxylate anions, and micelles may not be formed well. On the contrary, if the molecular weight is too small, it is completely dissolved in water, making it difficult to form micelles themselves. .
- the number average molecular weight of the alkali metal salt of the polylactic acid or derivatives thereof is 500 to 2,500 Daltons, specifically 1,000 to 2,000 Daltons. If the molecular weight is less than 500 Daltons may be completely dissolved in water to make the micelle formation difficult, and if the molecular weight exceeds 2,500 Daltons, the hydrophobicity is increased, so that it is difficult to dissolve in an aqueous solution, it may not be able to form micelles.
- the rapamycin-containing polymer nanoparticle injectable composition of the present invention is 0.1 to 10% by weight of rapamycin, preferably 0.2 to 5% by weight, hydrophilic block (A) and hydrophobic block (B). 40 to 90% by weight, preferably 45 to 74% by weight, and 10 to 50% by weight of an alkali metal salt of polylactic acid or a derivative thereof containing at least one carboxyl group at the end, preferably Comprises 25 to 45% by weight.
- the weight ratio of the AB-type diblock copolymer and the alkali metal salt of polylactic acid or a derivative thereof including at least one carboxyl group at the terminal thereof is from 9: 1 to 3: 7, more specifically 5: 1. ⁇ 1: 2.
- divalent or trivalent metal ions may be further added to further improve the stability of the nanoparticles.
- the divalent or trivalent metal ion reacts with the terminal monovalent alkali metal cation of the alkali metal salt of polylactic acid or a derivative thereof in the polymer nanoparticle to form a stronger ionic bond with the carboxyl group at the terminal of the polylactic acid or derivative.
- an AB-type diblock copolymer composed of a hydrophilic block (A) and a hydrophobic block (B), and (ii) at least one carboxyl group at the terminal, the carboxy terminal A polylactic acid or a derivative thereof fixed with a divalent or trivalent metal ion and (iii) a rapamycin as an active ingredient, wherein the AB-type diblock copolymer and the polylactic acid or a derivative thereof form nanoparticles
- a rapamycin-containing polymer nanoparticle injectable composition wherein the rapamycin is encapsulated inside.
- polylactic acid or derivative thereof including at least one carboxyl group at the terminal those as described above may be used.
- the divalent or trivalent metal ion is preferably a divalent or trivalent cation of a metal selected from the group consisting of calcium, magnesium, barium, chromium, iron, manganese, nickel, copper, zinc and aluminum, more preferably Is a divalent cation of calcium or magnesium.
- the equivalent amount of divalent or trivalent metal ions may be adjusted according to the release rate of the drug encapsulated inside the polymer nanoparticles. Specifically, when the divalent or trivalent metal ions are contained in less than 1 equivalent to the equivalent of the carboxyl group of the polylactic acid alkali metal salt in the polymer nanoparticle composition, the number of the carboxyl terminal groups of the polylactic acid salt is less likely to be released. When it is included in an amount exceeding 1 equivalent, the number of carboxyl terminal groups of the polylactic acid salts is increased, thereby delaying the release rate of the drug.
- the composition of the invention is preferably 0.1 to 10% by weight, more preferably rapamycin, based on the total weight of the composition 0.2 to 5 weight percent; 40 to 90% by weight of the aforementioned amphiphilic block copolymer, more preferably 45 to 74% by weight; And 10 to 50% by weight of polylactic acid or a derivative thereof containing at least one carboxyl group at the terminal, more preferably 25 to 45% by weight, wherein the divalent or trivalent metal ions are added to the polylactic acid or derivatives thereof. 0.01 to 10 equivalents, more preferably 1 to 2 equivalents, based on the terminal carboxyl equivalents.
- the relative proportion of the amphiphilic block copolymer is too large, it has a micelle property rather than that of the polymer nanoparticles, which causes a problem in stability during dilution. If the relative ratio of the metal salt of polylactic acid or its derivative is too large, a divalent or trivalent metal is present. When ions are added, a uniformly dispersed nanoparticle solution cannot be obtained due to precipitation with a divalent or trivalent metal salt of polylactic acid or a derivative thereof.
- the use of divalent or trivalent metal ions results in the drug being incorporated into the nanoparticles comprising the amphiphilic block copolymer and the polylactic acid or derivative thereof having the carboxy terminus fixed with a divalent or trivalent metal ion.
- Encapsulated compositions can be obtained.
- the composition of the invention may be in lyophilized or spray dried dry form. That is, the micelles are formed in an aqueous solution containing the above components, and then dried by freeze drying, spray drying, or the like to obtain a solid polymer nanoparticle composition.
- the lyophilized composition it may further include polysaccharides, mannitol, sorbitol, lactose and the like as a lyophilization aid.
- the lyophilization aid one or more selected from the group consisting of mannitol, sorbitol, lactose, trehalose and sucrose may be preferably used, more preferably mannitol and lactose.
- rapamycin is physically associated with the hydrophobic block portion of the polymer described above to be located in the hydrophobic core of the nanoparticles formed in the aqueous solution, wherein the particle size of the rapamycin-containing polymer nanoparticles is Preferably it is in the range of 10 to 150 nm.
- an injectable composition having a rapamycin concentration of at least 0.1 mg / ml, such as from 0.1 to 25 mg / ml, more specifically from 0.2 to 10 mg / ml. You can get it. If the rapamycin concentration is lower than 0.1 mg / ml, the desired level of rapamycin dosage effect cannot be obtained. If the rapamycin concentration is higher than 25 mg / ml, the viscosity of the aqueous solution is difficult to be injected at a temperature lower than room temperature. In one embodiment, an injectable composition is provided wherein the concentration of rapamycin is 0.1-25 mg / ml.
- the rapamycin-containing polymer micelle injectable composition of the present invention may further contain pharmaceutical supplements and other therapeutically useful substances such as preservatives, stabilizers, hydrates or emulsifiers, salts and / or buffers for controlling osmotic pressure. It may contain.
- injectable compositions of the invention may be administered rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, and the like.
- the composition in the lyophilized form may be administered in the form of vascular injection by reconstitution in an aqueous medium such as distilled water for injection, 5% glucose and physiological saline.
- AB type diblock copolymer composed of hydrophilic block (A) and hydrophobic block (B), (ii) polylactic acid comprising at least one carboxyl group at the end or Alkali metal salts of derivatives and (iii) solubilizing rapamycin as an active ingredient in an organic solvent; (b) removing the organic solvent from the result of step (a); And (c) adding an aqueous medium to the resultant of step (b), a method for producing a rapamycin-containing polymer nanoparticle composition.
- the organic solvent in step (a) is dichloromethane, ethanol, methanol, propanol, acetone, acetonitrile, 1,2-propylene glycol, N-methylpyrrolidone, N, N-diacetamide, polyethylene glycol or its One or more selected from the group consisting of derivatives (molecular weight 300 to 600 daltons) and glycerin are preferably used.
- Removal of the organic solvent in step (b) may be carried out by a conventional method, specifically, it may be evaporated using a vacuum evaporator.
- aqueous medium distilled water, water for injection, physiological saline or an aqueous solution of lyophilization aid may be used.
- a divalent or trivalent metal ion is added to the resultant to further fix the terminal group of polylactic acid or a derivative thereof (c It may further comprise step -1).
- a aqueous solution containing divalent or trivalent metal ions may be added to the aqueous polymer micelle solution obtained in step (c), and stirred at room temperature for 30 minutes or more.
- the divalent or trivalent metal ions may be added in the form of sulfate, hydrochloride, carbonate, phosphate and hydrate, specifically, calcium chloride, magnesium chloride, zinc chloride, aluminum chloride, iron chloride, calcium carbonate, magnesium carbonate, calcium phosphate
- Magnesium phosphate, aluminum phosphate, magnesium sulfate, calcium hydroxide, magnesium hydroxide, aluminum hydroxide or zinc hydroxide may be added.
- step (d) sterilizing the polymer nanoparticle composition obtained in the step (c) or (c-1); (E) filling a sterilized micelle aqueous solution in a predetermined amount in a container; And (f) lyophilizing the container filled in the step (e).
- step (f) one or more selected from the group consisting of mannitol, sorbitol, lactic acid, trehalose and sucrose may be used as a lyophilization aid. More specifically, mannitol can be used.
- the method may further include the step (g) of reconstitution with an aqueous solution such as distilled water, water for injection, saline, etc. to reconstitute the rapamycin-containing injection solution composition.
- an anticancer composition for use with radiation therapy utilizing the rapamycin-containing polymer nanoparticle composition of the present invention.
- the administration of rapamycin in the body is administered once at a dose of 30 mg / m 2 to 300 mg / m 2 , wherein the radiation is 5 times at 80 Gy daily Applicable
- the anticancer composition of the present invention it is possible to slowly instill intravenously or subcutaneously or intramuscularly.
- the anticancer composition of the present invention may be administered before or after irradiation at intervals of several minutes to several weeks.
- Radiation that can be used in combination with the anticancer composition of the present invention includes, for example, ⁇ -rays, X-rays (external beams) and the like.
- the amount of radiation may be irradiated in the range of about 1 to about 100 Gy, specifically about 5 to about 80, more specifically 10 to 50 Gy, but the dose range for radioisotopes is equivalent It depends on the half-life of the element and the intensity and type of radiation emitted.
- the anticancer composition for use in combination with radiation therapy, utilizing the rapamycin-containing polymer nanoparticle composition of the present invention may be administered 1 minute to 7 days before irradiation.
- the anticancer composition for use in combination with radiation therapy utilizing the rapamycin-containing polymer nanoparticle composition of the present invention is used for chemotherapy and radiotherapy by its administration over 4 to 12 weeks. It can be used in combination therapy that is carried out once to five times a week (for example, once a week, twice a week, three times a week, five times a week).
- the rapamycin-containing polymer nanoparticle injection composition of the present invention is administered to the cancer cells of the mammal at the time of irradiation, before or after irradiation It can enhance the sensitivity to radiation treatment of cancer cells in mammals.
- the polylactic acid alkali metal salt of the present invention was prepared according to a known method such as Korean Patent Application No. 2002-63955. That is, 1,000 g of D, L-lactic acid was put into a 2 L three-necked round bottom flask and a stirrer was installed. Then, the mixture was reacted for 1 hour while heating at 80 ° C. in an oil bath and depressurizing to 25 mmHg with a reduced pressure aspirator to remove excess water. The reaction temperature was raised to 160 ° C., and the reaction was terminated after the reaction was carried out for 7 hours under the reduced pressure of 5 to 10 mmHg.
- A is the peak area of the methylene protons of D, L-polylactic acid
- B is the peak area of the methylene proton of the polymer terminal D, L-lactic acid,
- C is the peak area of the methylene protons of the dicarboxylic acid
- N is the number of methylene protons of the dicarboxylic acid.
- the resulting polymer was dissolved in methylene chloride and added to diethyl ether to precipitate the polymer.
- the obtained polymer was dried in a vacuum oven for 48 hours.
- the number average molecular weight of mPEG-PLA obtained through the above process was 2,000-1,750 Daltons, and it was confirmed to be AB type by 1 H-NMR of FIG. 2.
- Rapamycin content of the prepared composition and the size measurement results of the polymer nanoparticles are as follows.
- Example 1 the in vivo kinetics of the rapamycin-embedded nanoparticle composition was evaluated.
- male Sprague-Dawley rats weighing 210-250 g were used, 5 mg / kg doses based on rapamycin at 5, 15, 30 minutes and 1, 2, 4, 8 after intravenous and subcutaneous injection. Every 24 hours, 0.3 ml of whole blood was collected into the tail artery. Collected whole blood was treated with protein precipitation (PPT, Progress in Pharmaceutical and Biomedical Analysis, Volume 5, 2003, Pages 199-254), followed by centrifugation to obtain 0.15 ml of clear supernatant, followed by LC / MS / MS method. The blood rapamycin concentration was analyzed.
- PPT protein precipitation
- the in vivo kinetic profile of rapamycin is shown in FIG. 3 and the in vivo kinetic parameters are shown in Table 1.
- the C max of intravenous and subcutaneous administration was about 7 times higher than that of subcutaneous administration, and the half-life (t 1/2 ) in disappearance was about 3 hours, but the blood concentration at 24 hours was subcutaneous.
- Cigars were about two times higher than intravenous administration. When the intravenous administration was 100, the bioavailability (F%) of subcutaneous administration was about 74%.
- Cells were harvested from stored in liquid nitrogen and established in vitro cell culture. After harvesting the cells, the cells were washed with sterile discrete saturated saline (PBS) and the number of viable cells was measured. The cells were resuspended in sterile PBS at a concentration of 7 ⁇ 10 7 cells / ml.
- PBS sterile discrete saturated saline
- non-thymus mice (20-25 g, 8-week old) were injected subcutaneously with 0.1 ml of cell suspension containing 7 ⁇ 10 5 human lung cancer cells (A549).
- A549 is a well known cancer that is resistant to chemotherapy, including radiation and some anticancer agents. After the cancer reached a certain size, three xenografts were transplanted three times to form a xenograft of 3 to 4 mm. Xenograft fragments were injected subcutaneously with 12 gauge trocane in the right flank of healthy nude (nu / nu) non-thymus mice (20-25 g, 8 weeks old).
- the drug was administered and this time point was recorded as 1 day.
- the mice were divided into 5 groups and the composition of Example 1 was administered at a 5 mg / kg dose of rapamycin through the tail vein daily for 5 days and the radioactivity of 2 Gy was examined after 3 hours.
- the major and minor axis of the tumor was measured over time, from which the tumor volume was calculated by Equation 1 below.
- the relative tumor volume was calculated as in Equation 2 below to evaluate the therapeutic effect.
- Tumor volume (TV) 0.5 x L x W 2 (L: long axis, W: short axis)
- Relative Tumor Volume (RTV) (Vt / Vo) x 100% (Vt: TV on t day, Vo: TV on day 0)
- mice per treatment and 4 or more tumors per group were used.
- the minimum tumor diameter was 4 or 30 mm 3 volumes. Animals that die within two weeks after the last drug administration were considered toxic killing and were excluded from the evaluation. Treatment groups that did not fully recover after more than 1 toxic killing per 3 animals or reduced average body weight by more than 15% were considered to be non-tumor efficacy.
- the experimental results are shown in FIG. 4.
- the anticancer efficacy of the composition alone group (PNP-Si) and the radiation alone group (IR) of Example 1 was better than that of the non-treated group (CONT) and the polymer nanoparticle carrier group (PNP). Cancer growth inhibition.
- the combination of the composition of Example 1 and radiation treatment (IR + PNP-Si) compared to the CONT and PNP groups as well as the PNP-Si and IR groups, the anti-cancer effect was significantly increased, and the growth of cancer was almost suppressed. Appeared to stop.
- rapamycin 25 mg of rapamycin, 1650 mg of mPEG-PLA of Preparation Example 2 and 825 mg of D, L-PLACOONa of Preparation Example 1 were completely dissolved in dichloromethane, and then the organic solvent was volatilized using a rotary depressurizer. Rapamycin concentration was added to the dry matter to 1.0 mg / ml to form a micelle. 100 mg / mL calcium chloride solution was further added to 67.5 mg of calcium chloride, followed by stirring. The solution was sterilized by 0.2 ⁇ m membrane filter paper and lyophilized into a vial. Rapamycin content of the prepared composition and the size measurement results of the polymer nanoparticles are as follows.
- Example 2 Using the rapamycin-containing polymer nanoparticle composition of Example 2, the following experiment was performed to evaluate whether the inhibitory effect of cancer cells is maintained even after rapamycin is encapsulated in the polymer nanoparticles.
- Lung cancer cells A549, NCI-H460 cell lines and breast cancer cells MDA-MB-231, MCF7 were cultured in DMEM (A549, MCF7), RPMI1640 (NCI-H460, MDA-MB-231) cell culture, respectively.
- DMEM A549, MCF7
- RPMI1640 NCI-H460, MDA-MB-231) cell culture
- 50 cells serum experimental group, rapamycin free polymer nanoparticle composition
- 100 cells rapamycin containing polymer nanoparticle composition, rapamycin
- Cell culture was obtained by culturing for 14 days in the incubator. After fixing and staining the cells with 0.5% crystal violet solution, the number of generated colonies was counted. The plating efficiency was calculated using the number of cell colonies obtained from Saline experimental group (Equation 3).
- the rapamycin-free polymer nanoparticle carrier has little effect on the cell proliferation ability, and the rapamycin-containing polymer nanoparticle composition (PNP-sirolimus) has a rapamycin itself.
- the proliferation ability of cancer cells was significantly decreased. This is a result that can be seen that the drug is maintained even if the rapamycin is encapsulated in the polymer nanoparticles.
- Example 2 The in vivo kinetics of the rapamycin-enclosed composition in Example 2 was evaluated in the same manner as in Experimental Example 1. However, a 10 mg / kg dose based on rapamycin was orally, intravenous or subcutaneous injection, and 15 ml of blood every 15, 30 minutes and 1, 2, 4, 8, 24, 48 hours were collected into the tail artery.
- the AUC of the composition of Example 2 was higher than that of the AUC of rapamycin itself (Free sirolimus) by more than three times, indicating that the polymer nanoparticle composition of the present invention had blood retention.
- the fact that the particulate drug carrier has blood retention is meant to have cancer tissue accumulation by EPR (Enhanced Permeability and Retention) effect, which means that the same effect can be obtained even at a low dose.
- the bioavailability (BA%) was 100%, AUC level was 33% than intravenous administration, but the blood concentration was about 2 times or more at 24 and 48 hours. It was continuously maintained above the effective concentration.
- the bioavailability was about 30%, indicating that the composition of the present invention exhibited higher bioavailability than conventional oral formulations (less than 20%).
- the anticancer efficacy in the animal model of the rapamycin-containing polymer nanoparticle composition of Example 2 was evaluated as follows.
- A549 cells a lung cancer cell line, were cultured in DMEM medium. The cells were harvested, washed with sterile discrete complete saline (PBS) and counted. The right thigh of healthy nude (nu / nu) non-thymus mice (20-25 g, 6 weeks old) was injected subcutaneously with 0.1 ml suspension containing 1 ⁇ 10 6 A549 cells. After three weeks the size of the carcinoma reached about 70 mm 3 , mice were divided into five groups and this time point was recorded as 1 day. From this point, a rapamycin-containing, non-containing polymer micelle composition was administered to each experimental group via tail vein injection at a dose of 20 mg / kg. From the day 1, measuring the long axis and shortening of the tumor twice a week from which the volume of the tumor was calculated by the equation (5). The weight of the mice was measured at the same time as the tumor volume.
- PBS sterile discrete complete saline
- Tumor volume 0.5 x length of major axis x length of minor axis 2
- the rapamycin-containing polymer nanoparticle composition showed a significant growth retardation effect of A549 carcinoma compared to the control group and the vehicle-administered group, and administered three times a week for 4 weeks (q3d x 3 days x 4 weeks).
- the anticancer efficacy was slightly better than that of the group administered once weekly for 4 weeks (qw x 4 weeks), but there was no significant difference. From this, it is judged that the formulation according to the present invention can exert efficacy even at a low dose in consideration of the toxic expression of the drug when the drug is administered in excess.
- the weight change of the mice according to the drug administration tended to recover after completion of less than 10%, the group administered three times a week for four weeks was slower than the group administered once a week for four weeks.
- the anticancer activity of the composition of Example 2 in combination with radiation therapy was evaluated in the same manner as in Experiment 2 and the experimental results are shown in FIG.
- the dose was administered only 5 mg / kg daily for 5 days and then compared with the irradiated group (2Gy treatment) and the untreated group.
- Example 2 Example 2
- IR radiation alone treatment
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Abstract
Description
Claims (16)
- (i) 친수성 블록(A)과 소수성 블록(B)으로 구성된 A-B형 이중블록 공중합체,(ii) 말단에 적어도 하나의 카르복시기를 포함하는 폴리락트산 또는 그 유도체의 알칼리 금속염, 및(iii) 활성성분으로서 라파마이신을 포함하며,여기에서 상기 A-B형 이중블록 공중합체와 폴리락트산 또는 그 유도체의 알칼리 금속염이 형성하는 미셀의 내부에 라파마이신이 봉입되는 것을 특징으로 하는, 라파마이신 함유 고분자 나노입자 주사제형 조성물.
- 제1항에 있어서, 상기 이중블록 공중합체의 친수성 블록(A)의 수평균분자량이 500 내지 20,000 달톤이고, 소수성 블록(B)의 수평균분자량이 500 내지 10,000 달톤이며, 이중블록 공중합체 내의 친수성 블록(A)의 함량이 이중블록 공중합체 전체 100중량%를 기준으로 40 내지 70중량%인 것을 특징으로 하는, 라파마이신 함유 고분자 나노입자 주사제형 조성물.
- 제1항에 있어서, 상기 친수성 블록(A)이 폴리에틸렌 글리콜 또는 메톡시 폴리에틸렌 글리콜이고, 소수성 블록(B)가 폴리락트산, 폴리락타이드, 폴리글리콜라이드, 폴리만델릭산, 폴리카프로락톤, 폴리디옥산-2-온, 폴리아미노산, 폴리오르소에스터, 폴리언하이드라이드 및 그들의 공중합체로 이루어진 군에서 선택되는 하나 이상인 것을 특징으로 하는, 라파마이신 함유 고분자 나노입자 주사제형 조성물.
- 제1항에 있어서, 말단에 적어도 하나의 카르복시기를 포함하는 폴리락트산 또는 그 유도체가 폴리락트산, 폴리락타이드, 폴리글리콜라이드, 폴리만델릭산, 폴리카프로락톤, 폴리언하이드라이드 및 이들의 공중합체로 이루어진 군에서 선택되는 하나 이상이며, 그 수평균 분자량이 500 내지 2,500 달톤인 것을 특징으로 하는, 라파마이신 함유 고분자 나노입자 주사제형 조성물.
- 제1항에서, 상기 알칼리 금속이 나트륨, 칼륨 및 리튬으로 구성된 군으로부터 하나 이상 선택되는 일가 금속인 것을 특징으로 하는, 라파마이신 함유 고분자 나노입자 주사제형 조성물.
- 제1항에 있어서, 2가 또는 3가의 금속이온을 추가로 포함하는 것을 특징으로 하는 라파마이신 고분자 나노입자 주사제형 조성물.
- 제6항에 있어서, 2가 또는 3가의 금속이온이 칼슘, 마그네슘, 바륨, 크롬, 철, 망간, 니켈, 구리, 아연 및 알루미늄으로 이루어진 군으로부터 선택된 금속의 2가 또는 3가 양이온인 것을 특징으로 하는, 라파마이신 함유 고분자 나노입자 주사제형 조성물.
- 제1항에 있어서, A-B형 이중블록 공중합체와 말단에 적어도 하나의 카르복시기를 포함하는 폴리락트산 또는 그 유도체의 알칼리 금속염의 중량비가 9:1~3:7인 것을 특징으로 하는, 라파마이신 함유 고분자 나노입자 주사제형 조성물.
- 제1항에 있어서, 라파마이신의 농도가 0.1 ~ 25mg/ml로 재건하는 것을 특징으로 하는 라파마이신 함유 고분자 나노입자 주사제형 조성물.
- (a) (i) 친수성 블록(A)과 소수성 블록(B)으로 구성된 A-B형 이중블록 공중합체,(ii) 말단에 적어도 하나의 카르복시기를 포함하는 폴리락트산 또는 그 유도체의 알칼리 금속염 및 (iii) 활성성분으로서 라파마이신을 유기용매에 가용화시키는 단계;(b) 상기 (a)단계의 결과물로부터 유기용매를 제거하는 단계; 및 (c) 상기 (b)단계의 결과물에 수성 매질을 가하는 단계를 포함하는,라파마이신 함유 고분자 나노 입자 주사제형 조성물의 제조방법.
- 제10항에 있어서, 상기 (c) 단계 이후에, 그 결과물에 2가 또는 3가 금속이온을 첨가하는 (c-1)단계를 더 포함하는 것을 특징으로 하는, 라파마이신 함유 고분자 나노입자 주사제형 조성물의 제조방법.
- (i) 친수성 블록(A)과 소수성 블록(B)으로 구성된 A-B형 이중블록 공중합체,(ii) 말단에 적어도 하나의 카르복시기를 포함하는 폴리락트산 또는 그 유도체의 알칼리 금속염 및(iii) 활성성분으로서 라파마이신을 포함하며,여기에서 상기 A-B형 이중블록 공중합체과 상기 폴리락트산 또는 그 유도체의 알칼리 금속염이 형성하는 나노입자의 내부에 라파마이신이 봉입되는, 방사선 요법과 병용하기 위한 항암 조성물.
- 제12항에 있어서, 2가 또는 3가의 금속이온을 추가로 포함하는 것을 특징으로 하는, 방사선 요법과 병용하기 위한 항암 조성물.
- 제12항에 있어서, 방사선 조사 1분전 내지 7일전에 투여되는 것을 특징으로 하는, 방사선 요법과 병용하기 위한 항암 조성물.
- 제12항에 있어서, 화학요법과 방사선요법을 4주 내지 12주간에 걸쳐 주1회 내지 주5회 병행 실시하는 병용요법에 사용되는 것을 특징으로 하는, 방사선 요법과 병용하기 위한 항암 조성물.
- 포유동물의 암세포의 방사선 치료 방법에 있어서, 포유동물의 암세포에 방사선 조사시, 조사전 또는 조사후에 제1항 내지 제9항 중 어느 한 항의 라파마이신 함유 고분자 나노입자 주사제형 조성물을 투여하여 포유동물의 암세포의 방사선 치료에 대한 감수성을 증진시키는 것을 특징으로 하는 방법.
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JP2012547021A JP2013516407A (ja) | 2009-12-30 | 2010-12-29 | 改善された水溶解度を有するラパマイシン含有高分子ナノ粒子注射剤組成物及びその製造方法、並びに放射線療法と併用するための抗癌組成物 |
CN201080060367.2A CN102740834B (zh) | 2009-12-30 | 2010-12-29 | 具有提升的水溶解度的含雷帕霉素的高分子纳米粒子注射剂型组合物及其制备方法,以及用于与放射线疗法联用的抗癌组合物 |
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KR102584649B1 (ko) * | 2021-07-13 | 2023-10-04 | 충북대학교 산학협력단 | 펜벤다졸 및 라파마이신이 봉입된 폴리에틸렌 글리콜-폴리카프로락톤 공중합체 마이셀 및 이의 용도 |
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- 2010-12-29 JP JP2012547021A patent/JP2013516407A/ja active Pending
- 2010-12-29 US US13/519,914 patent/US20120276169A1/en not_active Abandoned
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- 2010-12-29 WO PCT/KR2010/009476 patent/WO2011081430A2/ko active Application Filing
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2014
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Also Published As
Publication number | Publication date |
---|---|
CN102740834A (zh) | 2012-10-17 |
WO2011081430A3 (ko) | 2011-11-10 |
JP2015078247A (ja) | 2015-04-23 |
US20140212462A1 (en) | 2014-07-31 |
EP2522338A4 (en) | 2013-09-18 |
JP2013516407A (ja) | 2013-05-13 |
KR101267813B1 (ko) | 2013-06-04 |
CN102740834B (zh) | 2017-04-05 |
US20120276169A1 (en) | 2012-11-01 |
EP2522338A2 (en) | 2012-11-14 |
KR20110079518A (ko) | 2011-07-07 |
US9173841B2 (en) | 2015-11-03 |
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