US20120276169A1 - Polymer nanoparticle injection formulation composition containing rapamycin with improved water solubility, preparation method thereof, and anticancer composition for combined use with radiotherapy - Google Patents

Polymer nanoparticle injection formulation composition containing rapamycin with improved water solubility, preparation method thereof, and anticancer composition for combined use with radiotherapy Download PDF

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US20120276169A1
US20120276169A1 US13/519,914 US201013519914A US2012276169A1 US 20120276169 A1 US20120276169 A1 US 20120276169A1 US 201013519914 A US201013519914 A US 201013519914A US 2012276169 A1 US2012276169 A1 US 2012276169A1
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rapamycin
composition
polylactic acid
polymeric nanoparticles
group
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Hye Won Kang
Min Hyo Seo
Sa Won Lee
Bong Oh Kim
Eun kyung Choi
Seong Yun Jeong
Ha Na Woo
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Samyang Biopharmaceuticals Corp
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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 an injectable composition comprising polymeric nanoparticles containing rapamycin with an improved water solubility, more specifically, to an injectable composition containing rapamycin wherein the poorly water-soluble rapamycin is solubilized with polymeric nanoparticles and its water solubility is improved thereby, and a method for preparing the same, and an anticancer composition comprising the same for a combination therapy with radiation.
  • Rapamycin (molecular formula: C 51 H 79 NO 13 , molecular weight: 914.2), also known as sirolimus, is a macrolide lactone-based compound. It has an immunosuppressive activity and so has been commercialized as a transplant rejection inhibitor (Rapamune) for organ transplant patients. As well as for inhibiting the organ transplant rejection, rapamycin can be used for treating pulmonary inflammation, systemic lupus erythematosis, immunoinflammatory skin disorders including psoriasis, immunoinflammatory bowel disorders, ocular inflammation, restenosis, rheumatoid arthritis, etc.
  • rapamycin has the function of an anticancer agent which acts as an inhibitor of mammalian target of rapamycin (mTOR) to induce apoptosis and destroy cancer cells thereby.
  • mTOR mammalian target of rapamycin
  • rapamycin has a very low solubility in water (1 to 2 ⁇ g/ml), it shows a very low absorption rate upon oral administration and has a great variance in bioavailability between individuals.
  • Rapamune tablet has been introduced as a formulation containing rapamycin.
  • This tablet comprises excipients including sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, povidone, poloxamer 188, glyceryl monooleate, etc.
  • Rapamune oral solution comprises Phosal 50 PG (phosphatidyl choline, propylene glycol, mono-glyceride, di-glyceride, ethanol, soy bean fatty acid, ascorbyl palmitate) and polysorbate 80, with 1.5 to 2.5% of ethanol content.
  • Phosal 50 PG phosphatidyl choline, propylene glycol, mono-glyceride, di-glyceride, ethanol, soy bean fatty acid, ascorbyl palmitate
  • Rapamune oral solution When Rapamune oral solution is orally administered to human patients, the absolute bioavailability is about 14%.
  • Rapamune tablet is orally administered, the absolute bioavailability is relatively higher by about 25% as compared with the oral administration Rapamune oral solution.
  • both formulations show low absolute bioavailability below 20% and this is due to the low solubility of rapamycin in water.
  • U.S. Pat. No. 5,559,121 discloses a capsule formulation composition containing a solution of rapamycin wherein rapamycin is dissolved in a mixed solution comprising polysorbate 80 surfactant, N,N-dimethylacetamide, and either lecithin or phospholipid.
  • U.S. Pat. No. 5,616,588 discloses an injectable aqueous solution of rapamycin wherein rapamycin is dissolved in an aqueous solution of propylene glycol at a concentration of 0.1 to 4 mg/ml, without containing non-ionic surfactant.
  • the known injectable aqueous solutions of rapamycin have a poor stability as an aqueous solution and thus should be administered within a short period of time. No injectable formulations are commercially available at present.
  • Korean Patent No. 0160957 discloses a composition for inhibiting organ or tissue transplant rejection, which comprises rapamycin in an effective amount for inhibiting mammalian organ or tissue transplant rejection.
  • rapamycin is used together with oils such as olive oil, alcohols, propylene glycols, and polyethylene glycols and surfactants such as Cremophor EL and polysorbate 80.
  • U.S. Pat. Nos. 6,322,805 and 6,616,941 disclose a polymeric micelle using an amphiphilic block copolymer in which a hydrophilic polyethylene glycol (A) block and a hydrophobic polylactide (B) block are combined in the form of an A-B type diblock.
  • A polyethylene glycol
  • B hydrophobic polylactide
  • the present invention is to solve the problems involved in the prior arts as stated above.
  • the technical purpose of the present invention is to provide an injectable composition comprising polymeric nanoparticles containing rapamycin—the composition containing no organic solvent, having good biocompatibility, using a biodegradable polymeric material only and injectable via intravenous or subcutaneous/intramuscular route—and a method for preparing the same, and an anticancer composition comprising the same for a combination therapy with radiation.
  • the present invention provides an injectable composition comprising polymeric nanoparticles containing rapamycin, the composition comprising: (i) an A-B type diblock copolymer having a hydrophilic block (A) and a hydrophobic block (B), (ii) an alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end, and (iii) rapamycin as an active ingredient, wherein rapamycin is entrapped within the micelle formed from the A-B type diblock copolymer and the alkali metal salt of polylactic acid or its derivative.
  • the present invention provides a method for preparing an injectable composition comprising polymeric nanoparticles containing rapamycin, comprising the steps of: (a) solubilizing, in an organic solvent (i) an A-B type diblock copolymer having a hydrophilic block (A) and a hydrophobic block (B), (ii) an alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end, and (iii) rapamycin as an active ingredient; (b) removing the organic solvent from the product of step (a); and (c) adding an aqueous medium to the product of step (b).
  • the present invention provides an anticancer composition for a combination therapy with radiation, comprising (i) an A-B type diblock copolymer having a hydrophilic block (A) and a hydrophobic block (B), (ii) an alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end, and
  • rapamycin as an active ingredient, wherein rapamycin is entrapped within the micelle formed from the A-B type diblock copolymer and the alkali metal salt of polylactic acid or its derivative.
  • the injectable composition according to the present invention after drying and when reconstituted in the aqueous solution, can provide an injectable solution having a solubility of rapamycin of 0.1 mg/ml or more.
  • an injectable composition of rapamycin the composition capable of providing a solubility of rapamycin of 0.1 mg/ml or more, containing no organic solvent, having good biocompatibility, using a biodegradable polymeric material only and injectable via intravenous or subcutaneous/intramuscular route—can be obtained.
  • the composition of the present invention is administered in combination with radiotherapy, the effect of remarkably increasing the anti-cancer efficacy can be expected.
  • the present injectable composition containing rapamycin can maximize the effect of irradiation through synergistic action, it can reduce the radiotherapy-induced toxicity. Furthermore, rapamycin is a drug having potent pharmacological effects including immunosuppressive activity as well as radiation sensitizing activity, but also has serious side effects. In addition, since rapamycin is not dissolved in water, it should be formulated by using a solubilizing agent.
  • the solubilizing agents currently used in the injection formulation are surfactants which mostly have toxicities such as hypersensitivity. However, the present injectable composition containing rapamycin causes no such toxicity of solubilizing agents and can exhibit the maximum radiation sensitizing effect while minimizing the dose of rapamycin and reducing the side effects.
  • FIG. 1 is a NMR spectrum of D,L-PLA-COONa according to Preparation Example 1.
  • FIG. 2 is a NMR spectrum of mPEG-PLA according to Preparation Example 2.
  • FIG. 3 is a graph obtained from Experiment 1, showing the results of in vivo pharmacokinetic test for the polymeric nanoparticles containing rapamycin.
  • FIG. 4 is a graph obtained from Experiment 2, showing the results of radiation sensitizing effect test for the polymeric nanoparticles containing rapamycin.
  • FIG. 5 is a graph obtained from Experiment 3, showing the results of in vitro anti-cancer activity test for the polymeric nanoparticles containing rapamycin.
  • FIG. 6 is a graph obtained from Experiment 4, showing the results of in vivo pharmacokinetic test for the polymeric nanoparticles containing rapamycin.
  • FIG. 7 is a graph obtained from Experiment 5, showing the results of anti-cancer efficacy test in animal model for the polymeric nanoparticles containing rapamycin.
  • FIG. 8 is a graph obtained from Experiment 6, showing the results of radiation sensitizing effect test in animal model for the polymeric nanoparticles containing rapamycin.
  • rapamycin as used herein includes all of rapamycin, its derivatives or analogs, and the pharmaceutically acceptable salts thereof. Rapamycin derivatives or analogs concretely include benzoyl rapamycin, everolimus, temsirolimus, pimetrolimus, violimus and the like, but not limited thereto.
  • nanoparticle denotes the general concept referring to particles having a diameter of nanometer level, and includes micelle, mixed micelle, nanocapsule, nanosphere and the like, and the size thereof can be, for example, of 1 to 500 nm but not limited thereto.
  • amphiphilic diblock copolymer (i) is an A-B type diblock copolymer having a hydrophilic block (A) and a hydrophobic block (B) wherein the hydrophilic block (A) can be polyethylene glycol and the hydrophobic block (B) can be polylactic acid or its derivative.
  • Polyethylene glycol for the hydrophilic block (A) can be polyethylene glycol, methoxy polyethylene glycol, etc. and concretely methoxy polyethylene glycol, but not limited thereto.
  • 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, and even more preferably 1,000 to 5,000 daltons. If the number average molecular weight of the hydrophilic block (A) is less than 500 daltons, the hydrophilic portion becomes smaller than the hydrophobic portion and thus the present composition may not be dissolved in water. If the number average molecular weight is greater than 20,000 daltons, the hydrophilic portion becomes too large and thus the micelle formation may be difficult.
  • the content of the hydrophilic block (A) in the amphiphilic diblock copolymer is preferably 40 to 70 wt %, more preferably 50 to 65 wt %, on the basis of total 100 wt % of the diblock copolymer, in view of stable maintenance of the micelle of the amphiphilic diblock copolymer.
  • Polylactic acid or its derivative for the hydrophobic block (B) can be, for example, one or more selected from the group consisting of polylactic acid, polylactide, polyglycolide, polymandelic acid, polycaprolactone, polydioxan-2-one, polyamino acid, polyortho ester, polyanhydride and copolymers thereof, and more specifically polylactic acid, polylactide, polyglycolide, polymandelic acid, polycaprolactone or polydioxan-2-one.
  • polylactic acid or its derivative for the hydrophobic block (B) can be one or more selected from the group consisting of polylactic acid, polylactide, polycaprolactone, copolymer of lactic acid and mandelic acid, copolymer of lactic acid and glycolic acid, copolymer of lactic acid and caprolactone, and copolymer of lactic acid and 1,4-dioxan-2-one.
  • the number average molecular weight of the hydrophobic block (B) is preferably 500 to 10,000 daltons, and more preferably 500 to 5,000 daltons.
  • the content of the hydrophobic block (B) in the amphiphilic diblock copolymer is preferably 30 to 60 wt %, more preferably 35 to 50 wt %, on the basis of total 100 wt % of the diblock copolymer, in view of stable maintenance of the micelle of the amphiphilic diblock copolymer.
  • the alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end makes the inside of the drug-containing core of the micelle hard, and thus improves the inclusion efficiency of drug.
  • polylactic acid or its derivative having at least one carboxyl group on its end one or more selected from the group consisting of polylactic acid, polylactide, polyglycolide, polymandelic acid, polycaprolactone, polyanhydride and copolymers thereof can be used. More specifically, the polylactic acid or its derivative can be polylactide, polyglycolide, polycaprolactone or copolymer thereof. According to a preferable embodiment of the present invention, polylactic acid or its derivative can be one or more selected from the group consisting of polylactic acid, copolymer of lactic acid and mandelic acid, copolymer of lactic acid and glycolic acid, and copolymer of lactic acid and caprolactone.
  • the alkali metal salt of polylactic acid or its derivative has a form wherein the terminal carboxylic acid anion of polylactic acid or its derivative is combined with the alkali metal ion via ionic binding.
  • the alkali metal is one or more monovalent metals preferably selected from the group consisting of sodium, potassium and lithium, and is more preferably sodium.
  • the alkali metal salt of polylactic acid having at least one carboxyl group on its end according to the present invention can be represented by the following chemical formula 1.
  • R is hydrogen, acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group or ethyl group,
  • Z and Y are independently hydrogen, methyl group or phenyl group
  • M is sodium, potassium or lithium
  • n is an integer of 1 to 30, and
  • n is an integer of 0 to 20.
  • salt of polylactic acid or its derivative can be represented by the following chemical formula 2.
  • R is hydrogen, acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group or ethyl group,
  • X is methyl group
  • Y′ is hydrogen or methyl group
  • Z is hydrogen, methyl group or phenyl group
  • M is sodium, potassium or lithium
  • p is an integer of 0 to 25, and
  • q is an integer of 0 to 25,
  • p+q is an integer of 5 to 25.
  • the alkali metal salt of polylactic acid or its derivative shows preferably the water solubility of 20 mg/ml or more and, when dissolved in an aqueous medium, it participates in the micelle formation by achieving the balance between the hydrophilic portion of carboxylic acid anion and the hydrophobic portion of polylactic acid present in the molecule. Therefore, if the molecular weight thereof is too large, the hydrophobic portion becomes large such that the association between terminal carboxylic acid anions contributing to the hydrophilicity is difficult, by which the micelle may not be formed well. To the contrary, if the molecular weight thereof is too small, the alkali metal salt of polylactic acid or its derivative becomes completely dissolved in water and thus the micelle formation itself is to be difficult.
  • the number average molecular weight of the alkali metal salt of polylactic acid or its derivative is 500 to 2,500 daltons, and particularly 1,000 to 2,000 daltons. If the molecular weight is less than 500 daltons, the alkali metal salt of polylactic acid or its derivative becomes completely dissolved in water and thus the micelle formation itself is to be difficult. If the molecular weight is greater than 2,500 daltons, the hydrophobicity is too great and the dissolution in an aqueous solution becomes difficult, and thus the micelle may not be formed.
  • the weight ratio of the A-B type diblock copolymer and the alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end is 9:1 to 3:7, and more concretely 5:1 to 1:2.
  • a divalent or trivalent metal ion can be further added in order to further improve the stability of nanoparticles.
  • the divalent or trivalent metal ion is substituted for the terminal monovalent alkali metal cation of the alkali metal salt of polylactic acid or its derivative in the polymeric nanoparticle to form a stronger ionic bond with carboxyl group on the terminal of polylactic acid or its derivative.
  • an embodiment of the present invention provides an injectable composition comprising polymeric nanoparticles containing rapamycin, comprising (i) the A-B type diblock copolymer having the hydrophilic block (A) and the hydrophobic block (B), (ii) the polylactic acid or its derivative comprising at least one carboxyl group on its end, the carboxyl group being fixed with the divalent or trivalent metal ion, and (iii) rapamycin as an active ingredient, wherein rapamycin is entrapped within the nanoparticle formed from the A-B type diblock copolymer and the polylactic acid or its derivative.
  • polylactic acid or its derivative comprising at least one carboxyl group on its end
  • those described above can be used.
  • the ionic bond with the divalent or trivalent metal ion acts to further improve the stability of polymeric nanoparticles through strong binding force.
  • the divalent or trivalent metal ion is preferably a divalent or trivalent metal ion selected from the group consisting of calcium, magnesium, barium, chrome, iron, manganese, nickel, copper, zinc and aluminum, and more preferably a divalent cation of calcium or magnesium.
  • the equivalent of the divalent or trivalent metal ion can be adjusted, according to the release rate of the drug entrapped within polymeric nanoparticles. Concretely, if the divalent or trivalent metal ion is contained in the polymeric nanoparticle composition in an amount of less than 1 equivalent with respect to the equivalent of carboxyl group of the alkali metal salt of polylactic acid, the number of metal ion to be combined with carboxyl terminal group of polylactic acid salt is small and thus the release rate of drug increases. If the divalent or trivalent metal ion is contained in an amount of greater than 1 equivalent, the number of metal ion to be combined with carboxyl terminal group of polylactic acid salt is large and thus the release rate of drug decreases.
  • the composition of the present invention comprises preferably 0.1 to 10 wt %, more preferably 0.2 to 5 wt % of rapamycin; 40 to 90 wt %, more preferably 45 to 74 wt % of the amphiphilic block copolymer; and 10 to 50 wt %, more preferably 25 to 45 wt % of polylactic acid or its derivative having at least one carboxyl group on its end, on the basis of total weight of the composition, and further comprises 0.01 to 10 equivalent, more preferably 1 to 2 equivalent of the divalent or trivalent metal ion with respect to the equivalent of the terminal carboxyl group of polylactic acid or its derivative.
  • the composition would have the properties of micelle, rather than the properties of polymeric nanoparticles and thus it may have a problem in stability when it is diluted. If the relative proportion of the metal salt of polylactic acid or its derivative is too large, the divalent or trivalent metal salt of polylactic acid or its derivative may be precipitated when the divalent or trivalent metal ion is added and thus uniformly dispersed nanoparticle solution may not be obtained.
  • the use of the divalent or trivalent metal ion can result in obtaining the composition in which the drug is entrapped within the nanoparticle comprising the amphiphilic block copolymer and polylactic acid or its derivative wherein carboxyl terminal group is fixed with the divalent or trivalent metal ion.
  • the composition of the present invention can be in a dry form prepared by lyophilization or spray drying. That is, the polymeric nanoparticle composition can be obtained in solid state by producing the micelle in an aqueous solution containing the above-mentioned components, and then drying the micelle by lyophilization, spray drying, etc.
  • the lyophilized composition it can further comprise polysaccharides, mannitol, sorbitol, lactose, etc. as a protective agent for lyophilization.
  • the protective agent for lyophilization preferably one or more selected from the group consisting of mannitol, sorbitol, lactose, trehalose and sucrose, and more preferably mannitol and lactose, can be used.
  • rapamycin is physically associated with the hydrophobic block portion of the polymer as explained above, and is located in the hydrophobic core of nanoparticles formed from the polymer in an aqueous solution, wherein the particle size of the rapamycin-containing polymeric nanoparticle is preferably in the range of 10 to 150 nm.
  • an injection formulation composition having the rapamycin concentration of 0.1 mg/ml or more, for example, 0.1 to 25 mg/ml and more concretely 0.2-10 mg/ml can be obtained. If the rapamybin concentration is less than 0.1 mg/ml, the desired pharmacological effect of rapamycin cannot be attained. If the concentration is greater than 25 mg/ml, the viscosity of the aqueous solution at a temperature below room temperature becomes so high and thus its injection becomes difficult. In an embodiment, the injection formulation composition having the rapamycin concentration of 0.1 to 25 mg/ml is provided.
  • the polymeric micelle injection formulation composition containing rapamycin according to the present invention can further contain one or more pharmaceutical additives such as preservative, stabilizing agent, wetting agent or emulsifying agent, salts and/or buffers for controlling osmotic pressure, etc., and other therapeutically useful materials.
  • the injection formulation composition of the present invention can be administered via rectal, topical, percutaneous, intravenous, intramuscular, intraperitoneal, subcutaneous route, and the like.
  • the composition in a lyophilized form can be reconstituted with an aqueous medium such as water for injection, 5% glucose and physiological saline, and administered by intravenous injection.
  • Another aspect of the present invention provides a method for preparing an injectable composition comprising polymeric nanoparticles containing rapamycin, comprising the steps of: (a) solubilizing, in an organic solvent (i) an A-B type diblock copolymer having a hydrophilic block (A) and a hydrophobic block (B), (ii) an alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end, and (iii) rapamycin as an active ingredient; (b) removing the organic solvent from the product of step (a); and (c) adding an aqueous medium to the product of step (b).
  • the organic solvent can be preferably one or more selected from the group consisting of dichloromethane, ethanol, methanol, propanol, acetone, acetonitrile, 1,2-propylene glycol, N-methylpyrrolidone, N,N-diacetamide, polyethylene glycol or its derivative (molecular weight of 300 to 600 daltons), and glycerin.
  • the removal of the organic solvent can be carried out by a conventional method. Concretely, it can be evaporated by using a vacuum evaporator.
  • the aqueous medium can be distilled water, water for injection, physiological saline or aqueous solution of protective agent for lyophilization.
  • the method for preparing the polymeric nanoparticle composition containing rapamycin according to the present invention can further comprise, after step (c), the step of (c-1) adding divalent or trivalent metal ion to the product of step (c) in order to fix the terminal group of polylactic acid or its derivative further.
  • an aqueous solution comprising the divalent or trivalent metal ion can be added to the aqueous solution of the polymer micelle obtained in step (c), and then the mixture can be stirred for 30 minutes or more at room temperature.
  • the divalent or trivalent metal ion can be added in the form of sulfate salt, hydrochloride salt, carbonate salt, phosphate salt and hydrate.
  • calcium chloride, magnesium chloride, zinc chloride, aluminum chloride, ferric chloride, calcium carbonate, magnesium carbonate, calcium phosphate, magnesium phosphate, aluminum phosphate, magnesium sulfate, calcium hydroxide, magnesium hydroxide, aluminum hydroxide or zinc hydroxide can be added.
  • the method for preparing the polymeric nanoparticle composition containing rapamycin according to the present invention can further comprise the steps of: (d) sterilizing the polymeric nanoparticle composition obtained in step (c) or (c-1); (e) filling the sterilized aqueous solution of micelle in a suitable container in a constant amount; and (f) lyophilizing the filled container obtained in step (e).
  • step (f) one or more selected from the group consisting of mannitol, sorbitol, lactic acid, trehalose and sucrose can be used as a protective agent for lyophilization. More concretely, mannitol can be used.
  • the method can further comprise the step of (g) reconstituting the product with an aqueous medium such as distilled water, water for injection, physiological saline, etc. to obtain the injectable solution composition containing rapamycin.
  • an aqueous medium such as distilled water, water for injection, physiological saline, etc.
  • Another aspect of the present invention provides an anticancer composition for a combination therapy with radiation, utilizing the polymeric nanoparticle composition containing rapamycin according to the present invention.
  • rapamycin can be administered once at a dose of 30 mg/m 2 to 300 mg/m 2 , and the radiation can be applied 5 times at a daily dosage of 80 Gy.
  • the anticancer composition of the present invention it can be administered either by slow intravenous infusion or by subcutaneous or intramuscular injection.
  • the use of the polymeric nanoparticle composition according to the present invention in combination with radiation remarkably improves the effectiveness of the composition.
  • the anticancer composition of the present invention can be administered at an interval of from minutes to weeks before or after the irradiation.
  • the radiation useful in combination with the anticancer composition of the present invention includes, for example, ⁇ -ray, X-ray (external beam), etc.
  • the quantity of radiation to be irradiated can be in a range of from about 1 to about 100 Gy, concretely from about 5 to about 80 Gy, and more concretely from 10 to 50 Gy.
  • the dose range for radioisotope can be determined according to the half-life of isotope and the intensity and kind of radiation as emitted.
  • the anticancer composition for a combination therapy with radiation which utilizes the polymeric nanoparticle composition containing rapamycin according to the present invention, can be administered at a timing of 1 minute to 7 days before irradiation.
  • the anticancer composition for a combination therapy with radiation which utilizes the polymeric nanoparticle composition containing rapamycin according to the present invention, can be used for the combination therapy wherein chemotherapy in combination with radiotherapy is practiced 1 to 5 times per week (for example, 1, 2, 3, 5 times per week) over a period of 4 to 12 weeks.
  • Another embodiment of the present invention provides a method for treating mammalian cancer cell with radiotherapy, wherein the injectable composition comprising polymeric nanoparticles containing rapamycin according to the present invention is administered at the time of, before or after irradiation to mammalian cancer cell, by which a sensitivity of mammalian cancer cell to radiotherapy can be increased.
  • the alkali metal salt of polylactic acid was prepared according to the known methods including those disclosed in Korean Patent Application No. 2002-0063955, etc. That is, 1,000 g of D,L-lactic acid was introduced into a 2L three-neck round bottom flask equipped with a stirrer. Then the mixture was reacted for one hour in an oil bath at 80° C. under heating and pressure reduction to 25 mmHg with a vacuum aspirator to remove the excessively existing water. The reaction temperature was raised to 160° C. and the reaction was conducted for 7 hours under the condition of pressure reduction to 5 to 10 mmHg, and then the reaction was terminated. As a result, 646 g of unpurified polylactic acid was obtained.
  • the result of measurement by the following NMR analysis showed that the number average molecular weight of the prepared polylactic acid was 1,200 daltons.
  • 750 mL of acetonitrile was added to 500 g of the prepared polylactic acid to dissolve it.
  • 750 mL of aqueous solution of sodium hydrogen carbonate (0.1 g/mL) was slowly added thereto.
  • the resulting mixture was stirred for 2 hours at room temperature to neutralize the polymer.
  • 75 g of sodium chloride was added to the neutralized polymer solution for phase separation.
  • the separated organic solvent layer was collected, and then the organic solvent was removed by fractional distillation to prepare sodium salt of polylactic acid.
  • NMR spectrum of the prepared sodium salt of polylactic acid is shown in FIG. 1 .
  • A denotes the peak area of methylene proton of D,L-polylactic acid
  • B denotes the peak area of methylene proton of terminal D,L-lactic acid of the polymer
  • C denotes the peak area of methylene proton of dicarboxylic acid
  • N denotes the number of methylene protons in dicarboxylic acid.
  • the in vivo pharmacokinetic behavior of the rapamycin-entrapping nanoparticle composition of Example 1 was evaluated.
  • male Sprague-Dawley rats weighing 210 to 250 g were used, and 0.3 ml of whole blood was taken from caudal vein every 5, 15 and 30 minutes, and 1, 2, 4, 8 and 24 hours after intravenous and subcutaneous injection of the dose of 5 mg/kg, on the basis of rapamycin.
  • the collected whole blood was treated with the Protein Precipitation (PPT, Progress in Pharmaceutical and Biomedical Analysis, Volume 5, 2003, Pages 199-254) and then centrifuged to obtain 0.15 ml of clear supernatant which was analyzed to check the rapamycin concentration in blood by LC/MS/MS method.
  • PPT Protein Precipitation
  • the pharmacokinetic profile of rapamycin is shown in FIG. 3 , and the parameters of pharmacokinetic behavior thereof are shown in Table 1.
  • the C max value was as high as about 7 times that of subcutaneous administration, and the half life (t 1/2 ) at the disappearance phase was about 3 hours, which was substantially similar to that of subcutaneous administration, but the concentration in blood at 24 hours after subcutaneous administration is as high as about 2 times that of intravenous administration.
  • the bioavailability (F %) in the intravenous administration was about 74%.
  • the anticancer activity of the composition of Example 1 was examined when the composition was used in combination with radiotherapy.
  • Cells were taken from those stored in liquid nitrogen, and then established for in vitro cell culture. Cells were harvested, washed with sterile phosphate buffered solution (PBS), and then the number of viable cells was counted. Cells were re-suspended in sterile PBS to the level of 7 ⁇ 10 7 cells/ml.
  • PBS sterile phosphate buffered solution
  • 0.1 ml of the cell suspension containing 7 ⁇ 10 5 human lung cancer cells was subcutaneously injected into the right flank of healthy nude (nu/nu) athymic mouse (20 to 25 g, 8 weeks old).
  • A549 has been well known as a cancer which is resistant to radiotherapy and chemotherapy including some anticancer agents. After the cancer reached a certain size, heterologous graft was conducted three times to form xenografts of 3 to 4 mm. The xenograft fragments were subcutaneously injected by means of 12 gauge trocar needle into the right flank of healthy nude (nu/nu) athymic mouse (20 to 25 g, 8 weeks old).
  • mice were divided into 5 groups, into which the composition of Example 1 was daily administered through caudal vein in a dose corresponding to 5 mg/kg of rapamycin for 5 days, and after 3 hours the radiation of 2 Gy was irradiated.
  • the long axis and short axis of tumor were measured with the passage of time, and the tumor volume was calculated therefrom by means of the following math equation 1.
  • the relative tumor volume was calculated according to the following math equation 2.
  • mice or more per treatment and 4 tumors or more per group were used.
  • the minimum diameter of tumor corresponded to the volume of 4 or 30 mm 3 .
  • Animals died within 2 weeks after the last drug administration were considered as being the cytotoxic death, and thus excluded from the evaluation.
  • the experimental result is shown in FIG. 4 .
  • the anticancer efficacy in the group to which the composition of Example 1 was solely administered (PNP-Si) and the group to which radiotherapy was solely provided (IR) showed better inhibition of cancer growth as compared with the no-treatment group (CONT) and the group to which the vehicles for polymeric nanoparticles were administered (PNP).
  • CONT no-treatment group
  • PNP vehicles for polymeric nanoparticles were administered
  • IR+PNP-Si greater anticancer efficacy than that in CONT and PNP groups, and even than that in PNP-Si group and IR group, were exhibited as nearly stopping the growth of cancer.
  • Lung cancer A549 and NCI-H460 cell lines, and breast cancer MDA-MB-231 and MCF7 cell lines were respectively incubated in DMEM (A549, MCF7) and RPMI1640 (NCI-H460, MDA-MB-231) culture solutions.
  • DMEM A549, MCF7
  • RPMI1640 NCI-H460, MDA-MB-231 culture solutions.
  • 50 cells serum experiment group, rapamycin-free polymeric nanoparticle composition
  • 100 cells rapamycin-containing polymeric nanoparticle composition, rapamycin
  • the culture solution was removed, and the samples were diluted, respectively, to 10, 100, and 500 nM in 2 ml of fresh culture medium to treat the cells.
  • the cells were cultured for 14 days in the incubator to obtain the cell colonies.
  • the cells were fixed and stained with 0.5% crystal violet solution, and then the number of generated colonies was counted.
  • the plating efficiency was calculated using the number of colonies obtained from the saline experiment group (Math equation 3).
  • Plating efficiency Number of colonies in the saline treatment group/Number of cells dispended in the saline treatment group ⁇ 100 [Math Equation 3]
  • the rapamycin-free polymeric nanoparticle vehicles had substantially no effect on the proliferation ability of cells, and the rapamycin-containing polymeric nanoparticle composition (PNP-sirolimus) remarkably decreased the proliferation ability of cells as in the use of rapamycin itself. This result means that rapamycin can maintain its pharmacological effect even though it is entrapped within the polymeric nanoparticles.
  • the in vivo pharmacokinetic behavior of the rapamycin-entrapping nanoparticle composition of Example 2 was evaluated by means of the same method as in Experiment 1. However, the composition was administered via oral, intravenous or subcutaneous route in the dose of 10 mg/kg on the basis of rapamycin, and 0.3 ml of whole blood was taken from caudal vein every 15 and 30 minutes, and 1, 2, 4, 8, 24 and 48 hours after administration.
  • AUC of the composition of Example 2 as intravenously administered was as high as 3 times AUC of rapamycin itself, and therefore it can be seen that the polymeric nanoparticle composition of the present invention has a blood retention property.
  • the fact that a particulate drug delivery system has the blood retention property means that the system has the accumulative property in cancer tissue due to EPR (Enhanced Permeability and Retention) effect, and the same effect can be obtained even with a lower dose.
  • EPR Enhanced Permeability and Retention
  • the bioavailability (BA %) was 100%.
  • AUC was about 33% level of intravenous administration, but the blood levels at 24 and 48 hours were about 2 times or more. That is, the level was persistently maintained above the effective level for a long period.
  • the bioavailability was shown as about 30%, meaning that the composition of the present invention shows higher bioavailability as compared with the known oral formulations (less than 20%).
  • the anticancer efficacy of the rapamycin-containing polymeric nanoparticle composition of Example 2 in animal model was evaluated as follows.
  • A549 cells were cultured in DMEM medium. The cells were harvested, washed with sterile phosphate buffered solution (PBS), and then counted. 0.1 ml of the suspension containing 1 ⁇ 10 6 A549 cells was subcutaneously injected into right thigh of healthy nude (nu/nu) athymic mouse (20 to 25 g, 6 weeks old). After 3 weeks, when the tumor size reached about 70 mm 3 , mice were divided into five groups, and the day was recorded as Day 1. From this point of time, each of the rapamycin-containing polymer micelle composition and the rapamycin-free polymer micelle composition was intravenously administered into caudal vein of the respective experiment groups in a dose of 20 mg/kg. From Day 1, the long axis and short axis of tumor were measured two times per week, and the tumor volume was calculated therefrom by means of the following math equation 5. At the same time of measurement of the tumor volumes, the weights of mice were also measured.
  • PBS sterile phosphat
  • Tumor volume 0.5 ⁇ (Length of long axis) ⁇ (Length of short axis) 2 [Math Equation 5]
  • the rapamycin-containing polymeric nanoparticle composition showed a remarkable effect of delaying the growth of A549 cancer, as compared with the control group and the vehicle group.
  • the group to which the composition was administered three times per week for 4 weeks showed a slightly better anticancer efficacy as compared with the group to which the composition was administered once a week for 4 weeks (qw ⁇ 4 weeks), but there was no significant difference between the two groups. From this, in consideration of a possibility of expressing toxicity upon excessive administration of the drug, it is concluded that the formulation according to the present invention can exhibit the efficacy even at a lower dose.
  • the change in weight of mouse upon administration of the drug was less than 10%, showing a tendency of recovery after completion of the administration.
  • Such recovery was retarded in the group to which the drug was administered three times per week for 4 weeks, as compared with the group to which the drug was administered once a week for 4 weeks.
  • the anticancer activity of the composition of Example 2 was evaluated when the composition was used in combination with radiotherapy.
  • the experimental result is shown in FIG. 8 .
  • the present experiment daily administered the composition in a dose of 5 mg/kg only for 5 days, and then compared the irradiated group (2 Gy treatment) with the non-irradiated group.
  • Example 2 the group to which the composition of Example 2 was solely administered (Example 2) and the group to which radiotherapy was solely applied (IR) provided better anticancer efficacy as compared with the control group, and there was no significant difference between the Example 2 group and the IR group.

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Owner name: SAMYANG BIOPHARMACEUTICALS CORPORATION, KOREA, REP

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF ASSIGNEE PREVIOUSLY RECORDED AT REEL: 028477 FRAME: 0479. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT;ASSIGNORS:KANG, HYE WON;SEO, MIN HYO;LEE, SA WON;AND OTHERS;REEL/FRAME:036575/0691

Effective date: 20120524