Polylactide nanoparticles

Abstract

A drug targeting system for administering a pharmacologically active substance to the central nervous system of a mammal across the animal's blood brain barrier. The drug targeting system comprises nanoparticles made of poly(DL-lactide) and/or poly(DL-lactide-co-glycolide), a pharmacologically active substance which is absorbed to, adsorbed to, and/or incorporated into the nanoparticles, and either contains TPGS or comprises a pluronic 188 surfactant coating deposited on the drug-loaded nanoparticles.

1 . A method of preparing a drug targeting system for administering a pharmacologically active substance to the central nervous system of a mammal across the blood brain barrier of the mammal, the method comprising the steps of:
 solubilizing poly(DL-lactide) and/or poly(DL-lactide-co-glycolide) in an organic solvent to obtain an organic phase;   dissolving at least one pharmacologically active substance in an aqueous solution;   pouring the aqueous solution into the organic phase;   emulsifying the mixture to obtain a primary emulsion;   pouring the primary emulsion into an aqueous solution of TPGS to form a mixture of primary emulsion and aqueous solution of TPGS;   homogenizing the mixture of primary emulsion and aqueous solution of TPGS;   removing the organic solvent from the mixture of primary emulsion and aqueous solution of a stabilizing agent selected from the group consisting of at least one polyvinyl alcohol, serum albumin, TPGS, and γ-cyclodextrin to form a nanosuspension comprising drug-loaded nanoparticles; and   filtering the resulting nanosuspension comprising drug-loaded nanoparticles.   
     
     
         2 . The method of preparing a drug targeting system for administering a pharmacologically active substance to the central nervous system of a mammal across the blood brain barrier of the mammal according to  claim 1 , said method further comprising the step of coating the nanoparticles with poloxamer 188. 
     
     
         3 . The method according to  claim 1 , wherein the polyvinyl alcohol has a molecular weight of 30-70 kDa. 
     
     
         4 . The method according to  claim 1 , wherein the serum albumin is human serum albumin. 
     
     
         5 . The method according to  claim 1 , wherein the pharmacologically active substance is selected from the group consisting of a therapeutic agent and a diagnostic agent. 
     
     
         6 . The method according to  claim 5 , wherein the therapeutic agent is selected from the group consisting of drugs acting at synaptic and neuroeffector junctional sites; general and local analgesics and anesthetics; hypnotics and sedatives; drugs for the treatment of psychiatric disorders; drugs for the treatment of depression; drugs for the treatment of schizophrenia; anti-epileptics and anticonvulsants; drugs for treating Huntington's disease, aging and Alzheimer's disease; excitatory amino acid antagonists and neurotropic factors and neuroregenerative agents; trophic factors; drugs aimed at the treatment of CNS trauma or stroke; drugs for the treatment of addiction and drug abuse; autacoids and anti-inflammatory drugs; chemotherapeutic agents for parasitic infections and microbial diseases; immunosuppressive agents and anti-cancer drugs; hormones and hormone antagonists; heavy metals and heavy metal antagonists; antagonists for nonmetallic toxic agents; cytostatic agents for the treatment of cancer; diagnostic substances for use in nuclear medicine; immunoactive and immunoreactive agents; transmitters and their respective receptor agonists and receptor antagonists, their respective precursors or metabolites; antibiotics, antispasmodics, antihistamines, antinauseants, relaxants, stimulants, “sense” and “anti-sense” oligonucleotides, cerebral dilators, psychotropics, anti-manics, vascular dilators and constrictors, anti-hypertensives, agents for migraine treatment, hypnotics, hyper- or hypo-glycemic agents, mineral or nutritional agents, anti-obesity drugs, anabolics and anti-asthmatics, and mixtures thereof. 
     
     
         7 . The method according to  claim 5 , wherein the diagnostic agent is useful in the diagnosis for nuclear medicine and/or radiation therapy. 
     
     
         8 . The method according to  claim 5 , further comprising the steps of adding a cryoprotecting agent to said nanosuspension; and freeze-drying the nanosuspension after the step of adding the cryoprotecting agent. 
     
     
         9 . The method according to  claim 8 , wherein the cryoprotecting agent is mannitol and wherein said cryoprotecting agent is added to the nanosuspension in an amount of 5% (w/v). 
     
     
         10 . A drug targeting system for administering a pharmacologically active substance to the central nervous system of a mammal across the blood brain barrier of the mammal, the targeting system comprising nanoparticles made of poly(DL-lactide) and/or poly(DL-lactide-co-glycolide), and at least one pharmacologically active substance being absorbed to, adsorbed to, and/or incorporated into the nanoparticles, wherein the system contains TPGS or comprises a pluronic 188 surfactant coating deposited on the drug-loaded nanoparticles, wherein the system has been prepared in accordance with a method of preparing a drug targeting system for administering a pharmacologically active substance to the central nervous system of a mammal across the blood brain barrier of the mammal, the method comprising the steps of:
 solubilizing poly(DL-lactide) and/or poly(DL-lactide-co-glycolide), at least one pharmacologically active substance, and a lipid compound selected from the group of lipid compounds consisting of cetyl phosphate, potassium cholesteryl sulphate and tocopheryl succinate, in an organic solvent to obtain an organic phase;   pouring the organic phase into an aqueous solution containing TPGS to form a mixture;   emulsifying the mixture to obtain a primary emulsion;   homogenizing the primary emulsion;   removing the organic solvent from the primary emulsion to form a nanosuspension comprising drug-loaded nanoparticles; and
 filtering the resulting nanosuspension comprising drug-loaded nanoparticles. 
   
     
     
         11 . The drug targeting system according to  claim 10 , wherein the nanoparticles comprise particles having a diameter between 150 and 600 nm. 
     
     
         12 . A drug targeting system for administering a pharmacologically active substance to the central nervous system of a mammal across the blood brain barrier of the mammal, the targeting system comprising nanoparticles made of poly(DL-lactide) and/or poly(DL-lactide-co-glycolide), and at least one pharmacologically active substance being absorbed to, adsorbed to, and/or incorporated into the nanoparticles, wherein the system contains TPGS or comprises a pluronic 188 surfactant coating deposited on the drug-loaded nanoparticles, wherein the system has been prepared in accordance with a method of preparing a drug targeting system for administering a pharmacologically active substance to the central nervous system of a mammal across the blood brain barrier of the mammal, the method comprising the steps of:
 solubilizing poly(DL-lactide) and/or poly(DL-lactide-co-glycolide) in an organic solvent to obtain an organic phase;   dissolving at least one pharmacologically active substance in an aqueous solution;   pouring the aqueous solution into the organic phase;   emulsifying the mixture to obtain a primary emulsion;   pouring the primary emulsion into an aqueous solution of TPGS to form a mixture of primary emulsion and aqueous solution of TPGS;   homogenizing the mixture of primary emulsion and aqueous solution of TPGS;   removing the organic solvent from the mixture of primary emulsion and aqueous solution of a stabilizing agent selected from the group consisting of at least one polyvinyl alcohol, serum albumin, TPGS, and γ-cyclodextrin to form a nanosuspension comprising drug-loaded nanoparticles; and   filtering the resulting nanosuspension comprising drug-loaded nanoparticles.   
     
     
         13 . The drug targeting system according to  claim 12 , wherein the nanoparticles comprise particles having a diameter between 150 and 600 nm. 
     
     
         14 . A method of treating a disease or disorder of the central nervous system of a mammal comprising the steps of:
 preparing drug-loaded nanoparticles made of poly(DL-lactide) and/or poly(DL-lactide-co-glycolide);   coating the drug loaded PLGA nanoparticles with poloxamer 188;   orally or intravenously administering the poloxamer 188-coated drug-loaded nanoparticles to the blood stream of a mammal; and   allowing the drug to achieve the particular pharmacological effect of the drug.