pH triggered site specific targeted controlled drug delivery system for the treatment of cancer

Abstract

The present invention relates to a novel pH triggered, targeted controlled release system. The controlled delivery system of the present invention is substantially a free-flowing powder formed of solid hydrophobic nanospheres comprising pharmaceutical active ingredients that are encapsulated in pH sensitive microspheres. The invention also relates to the processes for preparing the compositions and processes for using same. The controlled release system can be used to target and control the release of active ingredients for treating a cellular proliferation disease or tumors. The invention further pertains to pharmaceutical products comprising the controlled release system of the present invention.

What is claimed is:  
     
         1 . A controlled release composition comprising: 
 a plurality of solid nanospheres encapsulated in a microsphere formed of a pH sensitive or salt sensitive matrix material, and    a first active agent incorporated into at least one of: the nanospheres or the microsphere; wherein said first active agent is selected from the group consisting of a cytotoxic agent, a chemotherapeutic agent, an anti-oncology agent, a radionuclide, a nucleic acid, a protein, and a biopharmaceutical.    
     
     
         2 . The composition of  claim 1  wherein said first pharmaceutical active agent is incorporated into the nanospheres and a second pharmaceutical active agent is incorporated into the microsphere wherein said second active agent is selectively released upon contact with an aqueous solution having a predetermined pH or predetermined salt concentration.  
     
     
         3 . The composition according to  claim 1  wherein said microsphere degrades or dissolves in an aqueous solution having a pH within the range of about 3.5 to about 6.8.  
     
     
         4 . The composition according to  claim 1  wherein the microsphere degrades or dissolves in an aqueous solution at a pH lower than about 6.8.  
     
     
         5 . The composition according to  claim 1  wherein the microsphere degrades or dissolves in an aqueous solution at pH lower than about 6.5.  
     
     
         6 . The composition according to  claim 1  wherein the microsphere degrades or dissolves in an aqueous solution at a pH lower than about 6.  
     
     
         7 . The composition of  claim 1  wherein said pH sensitive matrix is relatively insoluble and impermeable at a normal physiological pH of about 7.4, and is more soluble and permeable at an ambient pH at or near cancerous tissue at a pH between about 3.5 and about 6.8.  
     
     
         8 . The composition of  claim 1  wherein said pH sensitive matrix material is selected from the group consisting of: acrylate polymers with amino substituents, acrylic acid esters, polyacrylamides, phthalate derivatives and mixtures thereof.  
     
     
         9 . The composition of  claim 1  wherein said pH sensitive matrix material is selected from the group consisting of: acid phthalate of carbohydrate, amylose acetate phthalate, cellulose acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, hydroxy propyl cellulose phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl acetate phthalate copolymer, styrene and maleic acid copolymer, gelatin, gluten, shellac, salol, keratin, keratin sandarac-tolu, ammoniated shellac, benzophenyl salicylate, cellulose acetate trimellitate, cellulose acetate blended with shellac, hydroxypropylmethyl cellulose acetate succinate, oxidized cellulose, polyacrylic acid derivative, acrylic acid and acrylic ester copolymers, methacrylic acid, methacrylic acid ester, vinyl acetate, crotonic acid copolymer and mixtures thereof.  
     
     
         10 . The composition according to  claim 1  wherein a first portion of said plurality of nanospheres are adhered to a second portion of said plurality of nanospheres with a pH sensitive matrix material.  
     
     
         11 . The composition according to  claim 1  further comprising a moisture sensitive material mixed with said pH sensitive or salt sensitive material of said microsphere.  
     
     
         12 . The composition according to  claim 11  wherein said moisture sensitive material is selected from the group consisting of polyvinyl pyrrolidone, water soluble cellulose, polyvinyl alcohol, ethylene maleic anhydride copolymer, methyl vinyl ether maleic anhydride copolymer, polyethylene oxides, polyamide, polyester, copolymers or homopolymers of acrylic acid, polyacrylic acid, polystyrene acrylic acid copolymer, starch derivatives, polyvinyl alcohol, acrylic acid copolymer, anionic polymer of methacrylic acid and methacrylate, cationic polymer having dimethyl-aminoethyl ammonium functional groups, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose, hydroxypropyl methyl carboxyethyl cellulose, hydroxypropyl carboxypropyl cellulose, hydroxybutyl carboxymethyl cellulose, polysaccharide, hydrocolloid, natural gum, protein, and mixtures thereof.  
     
     
         13 . The composition of  claim 1  wherein said solid nanospheres are formed of a wax material having a melting point in the range of between about 25° C. and about 150° C.  
     
     
         14 . The composition of  claim 13  wherein said wax material has a penetration point of about 1 to about 10.  
     
     
         15 . The composition of  claim 13  wherein said wax material is selected from the group consisting of: natural wax, synthetic wax, regenerated wax, vegetable wax, animal wax, mineral wax, petroleum wax, microcrystalline wax and mixtures thereof.  
     
     
         16 . The composition of  claim 13  wherein said wax comprises one or more of carnauba wax, candelilla wax and beeswax.  
     
     
         17 . The composition of  claim 1  wherein said solid nanospheres are formed of a fat material selected from the group consisting of: hydrogenated castor oil, hydrogenated vegetable oil, hard fat, glyceride, fatty acids, fatty acid derivative, lipid, steroid and mixtures thereof.  
     
     
         18 . The composition of  claim 17  wherein said glyceride is selected from the group consisting of: triglyceride, monoglyceride, diglyceride, glyceryl monostearate, glycerol tristearate and mixtures thereof.  
     
     
         19 . The composition of  claim 17  wherein said fatty acid derivative is selected from the group consisting of: alcohol, ester, anhydride, hydroxy fatty acid and prostaglandin.  
     
     
         20 . The composition of  claim 17  wherein said fat material is selected from the group consisting of: lauric acid, physeteric acid, myristoleic acid, palmitoleic acid, petroselinic acid, oleic acid, isolauric acid, isomyristic acid, isopalmitic acid, isostearic acid, isoprenoid, 12-(((7′-diethylaminocoumarin-3yl)carbonyl)methylamino)-octadecanoic acid, N-[12-(((7′-diethylaminocoumarin-3-yl)carbonyl)methyl-amino)octadecanoyl]-2-aminopalmitic acid, N succinyl-dioleoylphosphatidylethanol amine, palmitoyl-homocysteine, digalactosyldiglyceride, 1,2-dioleoyl-sn-glycerol; 1,2-cdipalmitoyl-sn-3 succinylglycerol; 1,3-dipalmitoyl-2-succinylglycerol and mixtures thereof.  
     
     
         21 . The composition of  claim 17  wherein said fat material is selected from the group consisting of: phospholipid, sphingolipid, cholesterol, steroid derivative, terpene, tocopherol, stearlyamine, vitamin and mixtures thereof.  
     
     
         22 . The composition of  claim 21  wherein said phospholipid is selected fom the group consisting essentially of phosphatidic acid, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, lysophosphatidyl derivative, cardiolipin, beta-acyl-y-alkyl phospholipid, phosphatidylcholines, dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLPC), phosphatidylethanolamine, dioleoylphosphatidylethanolamine, 1-hexadecyl-2-palmitoylglycerophosphoethanolamine, synthetic phospholipids and mixtures thereof.  
     
     
         23 . The composition of  claim 21  wherein said steroid derivative is selected from the group consisting of: cholesterol, cholesterol sulfate, cholesterol hemisuccinate, 6-(5-cholesterol 3 beta-yloxy) hexyl6-amino-6-deoxy-1-thio-alpha-D-galactopyranoside, 6-(5-cholesten-3 beta-tloxy)hexyl-6-amino-6-deoxyl-1-thio-alpha-D mannopyranoside, cholesteryl(4′-trimethyl 35 ammonio)butanoate and mixtures thereof.  
     
     
         24 . The composition of  claim 1 , wherein said microsphere further comprises a water sensitive material selected from the group consisting of: natural oligomer, synthetic oligomer, natural polymer, synthetic polymer and copolymer, starch, starch derivative, oligosaccharide, polysaccharide, hydrocolloid, natural gum, protein, cellulose, cellulose derivative and mixtures thereof.  
     
     
         25 . The composition of  claim 1  further comprising a bioadhesive material incorporated into said solid nanosphere or said microsphere or in both said nanosphere and said microsphere.  
     
     
         26 . The composition of  claim 25  wherein said bioadhesive material is a bioadhesive polymer.  
     
     
         27 . The composition of  claim 26  wherein said bioadhesive polymer is selected from the group consisting of polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly (butyl methacrylate), poly(isobutyl methacrylate), poly(hexl methacrylate), poly(isodecl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecl acrylate) and poly(fumaric-co-sebacic)acid.  
     
     
         28 . The composition of  claim 1  wherein said nanosphere further comprises a ligand.  
     
     
         29 . The composition of  claim 1  wherein said nanosphere further comprises a targeting material selected from the group comprising lectin viral protein, bacterial protein, monoclonal antibody and antibody fragment.  
     
     
         30 . The composition of  claim 1  wherein said first active agent is selected from the group consisting of: cisplatin, camptothecin, vinblastine, paclitaxel, fluorouracil, docetaxel, fluorourideine, tiazofurin, doxorubicin, mechlorethamine, etoposide, mitomycin, and bleomycin.  
     
     
         31 . The composition of  claim 1  wherein said nanospheres further comprise a cationic surface active agent, anionic surface active agent, a nonionic surface active agent or a zwitterionic surface active agent.  
     
     
         32 . The composition of  claim 1  wherein said microsphere has a size within the range of about 20 to about 100 microns.  
     
     
         33 . The composition according to  claim 1  wherein each of said nanospheres has an average size within the range of about 0.01 to about 5 microns.  
     
     
         34 . The composition according to  claim 1  wherein said first active agent is incorporated in said microsphere and said nanospheres, wherein said pH or salt sensitive material upon contact with an aqueous solution releases said first active agent to provide a burst and said first active agent is released continuously thereafter for an extended period of time.  
     
     
         35 . The composition according to  claim 34  wherein the extended period of time is within the range of about one day to about three weeks.  
     
     
         36 . The composition according to  claim 2  wherein upon contact with said solution said second pharmaceutical agent is released to provide a burst and said first pharmaceutical agent is released continuously thereafter for an extended period of time.  
     
     
         37 . The composition according to  claim 36  wherein the extended period of time is within the range of about one day to about three weeks.  
     
     
         38 . A pharmaceutical composition comprising a physiologically acceptable carrier, and a controlled release composition comprising: 
 a plurality of solid nanospheres encapsulated in a microsphere formed of a pH sensitive or salt sensitive matrix material, and    an effective amount of first active agent incorporated into at least one of: the nanospheres or the microsphere; wherein said first active agent is selected from the group consisting of a cytotoxic agent, a chemotherapeutic agent, an anti-oncology agent, a radionuclide, a nucleic acid, a protein, and a biopharmaceutical.    
     
     
         39 . The pharmaceutical composition according to  claim 38  in a dosage form selected from the group consisting of powder, tablets, capsules and injectable compositions.  
     
     
         40 . An article comprising the composition of  claim 1 .  
     
     
         41 . A method for selectively delivering an active substance to a preselected environment comprising aministering a controlled release composition to an environment, said composition comprising: 
 a plurality of solid nanospheres encapsulated in a microsphere formed of a pH sensitive or salt sensitive matrix material, and    a first active agent incorporated into at least one of: the nanospheres or the microsphere; wherein said first active agent is selected from the group consisting of a cytotoxic agent, a chemotherapeutic agent, an anti-oncology agent, a radionuclide, a nucleic acid, a protein, and a biopharmaceutical.    
     
     
         42 . The method of  claim 41  wherein said environment is a mammal and said preselected environment is a tumor.  
     
     
         43 . The method of  claim 42  wherein said pH sensitive matrix material degrades or dissolves when the microsphere contacts a solution having a pH in the range of about 3.5 to about 6.8.  
     
     
         44 . The method of  claim 43  wherein said pH sensitive material is selected from the group consisting of: acid phthalate of carbohydrate, amylose acetate phthalate, cellulose acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, hydroxy propyl cellulose phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl acetate phthalate copolymer, styrene and maleic acid copolymer, gelatin, gluten, shellac, salol, keratin, keratin sandarac-tolu, ammoniated shellac, benzophenyl salicylate, cellulose acetate trimellitate, cellulose acetate blended with shellac, hydroxypropylmethyl cellulose acetate succinate, oxidized cellulose, polyacrylic acid derivative, acrylic acid and acrylic ester copolymers, methacrylic acid, methacrylic acid ester, vinyl acetate, crotonic acid copolymer and mixtures thereof.  
     
     
         45 . The method of  claim 42  wherein a first portion of said plurality of nanospheres are adhered to a second portion of said plurality of nanospheres with a pH sensitive or salt sensitive matrix material.  
     
     
         46 . The method of  claim 42  further comprising a moisture sensitive material mixed with said pH sensitive or salt sensitive material of said microsphere.  
     
     
         47 . The method of  claim 42  wherein said active agent is selected from the group consisting of: cisplatin, camptothecin, vinblastine, paclitaxel, fluorouracil, docetaxel, fluorourideine, tiazofurin, doxorubicin, mechlorethamine, etoposide, mitomycin, and bleomycin.  
     
     
         48 . The method of  claim 42  further comprising a bioadhesive material incorporated into said solid nanosphere or said microsphere or in both said nanosphere and said microsphere.  
     
     
         49 . The method of  claim 48  wherein said bioadhesive material is a bioadhesive polymer.  
     
     
         50 . The method of  claim 42  wherein said nanosphere further comprises a ligand.  
     
     
         51 . The method of  claim 42  wherein said nanosphere comprises a targeting material selected from the group consisting essentially of lectin, viral protein, bacterial protein, monoclonal antibody and antibody fragment.  
     
     
         52 . A method for treating a host suffering from a cellular proliferation disease comprising: 
 administering to the host a composition comprising a controlled release composition comprising a plurality of solid nanospheres encapsulated in a microsphere formed of a pH sensitive or salt sensitive matrix material, and a first active agent incorporated into at least one of: the nanospheres or the microsphere; wherein said first active agent is selected from the group consisting of a cytotoxic agent, a chemotherapeutic agent, an anti-oncology agent, a radionuclide, a nucleic acid, a protein, and a biopharmaceutical.    
     
     
         53 . A method for treating a mammal according to  claim 52 , wherein the mammal has a solid tumor as a result of a cancer selected from the group consisting of melanoma, colon cancer, prostate cancer, lung cancer, pancreatic cancer, ovarioan cancer and breast cancer, comprising: 
 administering to the mammal an effective amount of a controlled release composition comprising a plurality of solid nanospheres encapsulated in a microsphere formed of a pH sensitive or salt sensitive matrix material, and a first active agent incorporated into at least one of: the nanospheres or the microsphere; wherein said first active agent is selected from the group consisting of a cytotoxic agent, a chemotherapeutic agent, an anti-oncology agent, a radionuclide, a nucleic acid, a protein, and a biopharmaceutical.    
     
     
         54 . A process for producing a controlled release composition comprising the steps of: 
 heating a hydrophobic material to a temperature above a melting point to form a hot melt;    dissolving or dispersing a first pharmaceutical active agent into the melt;    dissolving or dispersing a second active agent, and a pH sensitive matrix material, in an aqueous phase and heating it to above the melting temperature of the hydrophobic material;    mixing the hot melt with the aqueous phase to form a dispersion;    high shear homogenizing the dispersion at a temperature above the melting temperature until a homogeneous fine dispersion is obtained;    cooling the dispersion to ambient temperature; and    spray drying the emulsified mixed suspension to form a dry powder composition.