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.

Description

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10/315,801, filed Dec. 9, 2002, entitled pH Triggered Targeted Controlled Release Systems For The Delivery Of Pharmaceutical Active Ingredients, the entirety of which is hereby incorporated by reference into this application.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to a novel targeted controlled drug delivery system for the treatment of patients afflicted with oncological disorders, such as cancer tumors. More specifically, the present invention relates to a site specific targeted controlled drug delivery composition that comprises solid hydrophobic nanospheres encapsulated in a pH sensitive microsphere for treating cancer tumors.

[0004] 2. Description of the Related Art

[0005] Systemic chemotherapy is one of the most successful treatments for cancer out of the current available treatment strategies, including surgical resection and external beam radiation therapy and has been successful in treating colon-rectum, esophagus, liver, pancreas, kidney, and melanoma cancers. However, efficacious systemic chemotherapeutic agents at the doses that control tumor growth have high systemic toxicity and adverse side effects such as vomiting, myelosuppression, cardiac toxicity, pulmonary fibrosis, hepatobiliary toxicity, and others. These toxic side effects are the limiting factor in determining the concentration of the drug that can be prescribed to the patient and as a result the doses that are administered may be insufficient to completely kill the tumor cells and prevent their spreading and regrowth. Poor solubility and low bioavailability of some of the chemotherapeutic agents were also observed to reduce treatment efficacy. For example, paclitaxel (taxol), a high molecular weight, lipophilic deterpenoid isolated from the western yew, Taxus brevifolia, is insoluble in water and needs to be administered intravenously by dilution into saline of the drug dissolved or suspended in polyoxyethylated castor oil.

[0006] Targeted controlled delivery of the chemotherapeutic agent to the tumor site and the ability to maintain efficacious levels of these agents at the target site over the duration of treatment has long been the goal of the pharmaceutical industry. The aim in this form of treatment is to deliver higher and more effective doses of the chemotherapeutic agent to the tumor tissue without affecting the surrounding healthy tissue. If successful, targeted delivery provides a significant reduction in systemic toxicity, reduction of the chemotherapeutic agent dose, and increased treatment efficacy.

[0007] Liposomes have been widely used as delivery vehicles for anti-cancer drugs. U.S. Pat. No. 6,426,086 discloses a serum of liposomes that are pH-sensitive for controlled drug delivery. The liposomes are complexed with a molecule comprising a thermally-sensitive polymer showing lower critical solution temperature behavior in aqueous solutions. The thermally-sensitive polymer bears a hydrophobic substituent and a pH sensitive substituent, wherein the hydrophobic substituent is less than 10 kD and which pH sensitive substituent remains ionizable following the covalent bonding to the thermally-sensitive polymer, and whose pH sensitive does not depend on cleavage of the covalent bond to the thermally-sensitive polymer. The limited stability of liposomes both in terms of shelf life and after administration, their ability to encapsulate only certain types of molecules, as well as their rapid clearance from the blood have hampered the use of liposomes as effective controlled drug delivery systems.

[0008] U.S. Pat. No. 6,602,524 discloses methods for treating tumors comprising the administration of a drug loaded in pH-sensitive microspheres wherein said pH-sensitive microspheres comprise a cross-linked polymer gel comprising ethyl methacrylate, diethyl aminoethyl methacrylate, and divinyl benzene. The pH-sensitive microspheres have a swelling transition with the pH range found in or near tumor tissue. When the microspheres swell, the loaded drug is released into the microenvironment of the tumor tissue. The microspheres are capable of effectively releasing a loaded substance at a pre-determined pH. The major drawback of the pH sensitive microspheres disclosed in U.S. Pat. No. 6,602,524 is that the matrix structure created by the cross-linking of ethyl methacrylate, diethyl aminoethyl methacrylate, and divinyl benzene is most likely to facilitate the diffusion and premature release of the chemotherapeutic agents, that are relatively small molecules, before these microspheres reach the target site of the tumor. Further protection of these molecules is needed to ensure that they are sustained by microspheres until they reach the tumor site. Also, at a pre-determined pH these microspheres quickly release the drug and cannot provide prolonged release of these active agents over an extended period of time.

[0009] The prior art of which applicant is aware does not set forth a controlled release system for the effective treatment of patients afflicted with oncological disorders, such as cancer tumors, that effectively deliver and localize the therapeutic effect of chemotherapeutic agents to the target site or the tumor tissue and maintains efficacious levels of these agents at the target site for the duration of treatment. Therefore, there remains a need for a system and method of cancer treatment that overcomes the drawbacks of the systems disclosed in the prior art and that effectively deliver effective concentrations of chemotherapeutic agent targeting only the tumor tissue while reducing the damage to surrounding healthy tissue, and maintain efficacious levels of these agents at the target site for the duration of treatment.

SUMMARY OF THE INVENTION

[0010] The present invention relates to an improved carrier system for site-specific targeted controlled delivery of pharmaceutical active ingredients onto cancer tumors and maintains efficacious levels of these agents at the target site for the duration of treatment. More particularly, the invention relates to a controlled release system that comprises solid hydrophobic nanospheres encapsulated in a pH sensitive microsphere for the treatment of patients afflicted with oncological disorders, such as cancer tumors. Pharmaceutical active ingredients can be incorporated in the solid hydrophobic nanospheres, in the pH sensitive microsphere, or in both the micro and nanospheres. The active ingredients and the nanospheres are released from the microsphere at the pH range typically found in the surrounding of tumor tissues. At the pH range typically found in the surrounding of tumor tissues the microsphere pH sensitive matrix materials dissolve or swell. The dissolution or swelling of the matrix disrupts the microsphere structure and facilitates the release of the nanospheres and the active ingredients. The deposition of the nanospheres onto the tumor tissue is improved by optimizing particle size to ensure entrainment of the nanospheres within the target tissue and by modifying the surface properties of the nanospheres to enhance their affinity for a particular residue expressed on a cell surface or enhance their affinity for a cell surface protein or receptor to maximize interaction between the nanospheres and the tumor tissue.

[0011] The present invention also pertains to solid hydrophobic nanospheres encapsulated in a pH sensitive microsphere that can be loaded with a pharmaceutical active ingredient useful in treating cancerous cells. The microspheres are capable of effectively releasing a pre-determined pH pharmaceutical active ingredients and the nanospheres loaded with pharmaceutical active ingredients. The nanospheres can be designed to release their incorporated pharmaceutical active ingredients over an extended period of time at a pH that is typically found in or near cancerous tissue.

[0012] The present invention also provides a method of treating cancer tumors comprising administering an effective amount of microspheres that are capable of enhancing the bioavailability of the pharmaceutical active ingredient encapsulated in the solid hydrophobic nanospheres and releasing the pharmaceutical active ingredient over an extended period of time at a specified pH.

[0013] In one embodiment, the pH-sensitive microspheres of the present invention swell and release the pharmaceutical active ingredients and the solid hydrophobic nanospheres within a pH range typically found in tumor tissue. The compositions and methods of the present invention provide a novel treatment of cancer, which specifically targets tumor tissue and reduces damage to surrounding healthy tissue.

[0014] The pharmaceutical active ingredient encapsulated in the controlled release system of the present invention include, but are not limited to, cytotoxic agents, chemotherapeutic agents, radionuclides, gene based drugs or gene based treatment modalities, including the use of sense, antisense nucleotide sequences, antigens, antibodies, ribozymes, as well as chimeric oligonucleotides constructs for gene correction. The pharmaceutical active ingredient may also include DNA or RNA fragments, which code functionally active or inactive or conditionally inactivatable proteins.

[0015] The invention further provides a method to effectively deliver and localize the therapeutic effect of chemotherapeutic agents to the target site or tumor tissue and maintain efficacious levels of these agents at the target site for the duration of treatment, that reduces the amount of adverse side effects such as vomiting, myelosuppression, cardiac toxicity, pulmonary fibrosis, hepatobiliary toxicity, and pericholangitis commonly associated with other current non-invasive treatments.

[0016] A preferred embodiment of the present invention pertains to a method of treating a tumor with the solid hydrophobic nanospheres encapsulated in a pH sensitive microsphere which contain a selected anti-tumor substance and injecting the microspheres in a blood vessel suitable for carrying the microspheres to the tumor.

[0017] In one embodiment, the nanospheres of the present invention are bioadhesive. Bioadhesive nanosphere can be created by incorporating a bioadhesive material into the solid hydrophobic matrix of the nanospheres, by incorporating a bioadhesive material in the pH-sensitive microsphere matrix, or by using a bioadhesive material in the nanosphere matrix in conjunction with a bioadhesive material in the microsphere matrix.

[0018] The carrier system of the present invention is a free-flowing powder formed of solid hydrophobic nanospheres comprising various active ingredients that are encapsulated in a pH sensitive microspheres, having the advantages of:

[0019] (i) protection of the pharmaceutical active ingredients, during storage, or until they reach the target site;

[0020] (ii) pH triggered controlled release of a first pharmaceutical active ingredient from the microspheres and of a second pharmaceutical active ingredient from the nanospheres at the pH range typically found in the surrounding of tumor tissues, and,

[0021] (iii) site specific targeted delivery and enhanced deposition of the nanospheres comprising pharmaceutical active ingredients, onto the target tumor site;

[0022] (iv) enhanced bioavailability and efficacy of pharmaceutical active ingredients encapsulated in the nanospheres; and

[0023] (v) prolonged release of pharmaceutical active ingredients encapsulated in the nanospheres over an extended period of time.

[0024] The invention also provides a method for producing the multi component controlled release system of the present invention including active ingredients that comprises the steps of:

[0025] (i) incorporating the pharmaceutical active ingredients into solid hydrophobic nanospheres;

[0026] (ii) forming an aqueous mixture comprising of one or more pharmaceutical active agents, the nanospheres, and pH sensitive materials; and

[0027] (iii) spray drying the mixture to form a dry powder composition.

[0028] The invention further provides a process for producing the multi component controlled release system of the present invention including the pharmaceutical active ingredients that comprises the steps of:

[0029] (i) heating hydrophobic materials to a temperature above the melting point of the materials to form a melt;

[0030] (ii) dissolving or dispersing a first pharmaceutical active agent into the melt;

[0031] (iii) dissolving or dispersing a second pharmaceutical active agent, pH sensitive material, and a targeting material, in the aqueous phase;

[0032] (iv) heating the composition to above the melting temperature of the hydrophobic materials;

[0033] (v) mixing the hot melt with the aqueous phase to form a dispersion;

[0034] (vi) high shear homogenization of the dispersion at a temperature above the melting temperature until a homogeneous fine dispersion is obtained having a sphere size of from about 1 micron to about 2 microns;

[0035] (vii) cooling the dispersion to ambient temperature; and

[0036] (viii) spray drying the emulsified mixed suspension to form a dry powder composition.

[0037] The invention also provides pharmaceutical products comprising the multi component controlled release system of the present invention.

[0038] The invention will be more fully described by reference to the following drawings:

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG. 1 is a schematic diagram of the pH sensitive microspheres of the present invention

[0040] FIG. 2 is a schematic diagram of the release profile of active ingredients from the controlled release system of the present invention.

[0041] FIG. 3 is a schematic diagram of the nanospheres encapsulated in the pH sensitive microsphere of the present invention. The surface properties of the nanospheres (shown as squiggly lines) can be altered to be bioadhesive, negatively charged, or positively charged, depending on the intended target site.

DETAILED DESCRIPTION

[0042] pH levels in human tumors are substantially and consistently lower than that in normal tissue (Gerweck L. E. et al., “Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer”, Cancer Research 56, issue 6, pp. 1194-1198, 1996). Deborah M. P. et al. (“The Relationship between Intracellular and Extracellular pH in Spontaneous Canine Tumors”, Clinical Cancer Research Vol. 6, pp. 2501-2505, 2000) have also reported that the cellular uptake of chemotherapeutic drugs may be dependent on the pH gradient between the intracellular and extracellular compartments. Hence, pH-sensitive delivery systems can be a useful route for tumor targeting. The pH difference provides an exploitable avenue for targeting the chemotherapeutic agent to the tumor site. Also, weakly acidic drug delivery systems, which are relatively lipid soluble in their nonionized state have been found to diffuse freely across the cell membrane and, upon entering a relatively basic intracellular compartment, become trapped and accumulate within a cell, leading to substantial differences in the intracellular/extracellular drug distribution between tumor and normal tissue for drugs exhibiting appropriate pKas.

[0043] The present invention provides an improved pH triggered, site-specific targeted controlled delivery system for the treatment of patients afflicted with conditions associated with or mediated by cell proliferation, e.g., oncological disorders, such as cancer and tumors. The controlled delivery system of the present invention comprises solid hydrophobic nanospheres encapsulated in a pH sensitive microsphere, as shown in FIG. 1. Pharmaceutical active ingredients useful in treating cancerous cells can be incorporated in the solid hydrophobic nanospheres, in the pH sensitive microsphere, or in both the microspheres and nanospheres. A first pharmaceutical active ingredient can be incorporated in the nanosphere and a second pharmaceutical active ingredient, which can be the same or different from the first pharmaceutical active ingredient, can be incorporated into the microsphere.

[0044] The compositions and methods of the present invention provide a novel treatment of cell proliferation and the control of cancer, specifically targeting tumor tissue thereby reducing damage to surrounding tissue. The pH-sensitive microspheres of the present invention swell or dissolve within a pH range typically found in tumor tissue and effectively release the pharmaceutical active ingredients from the microspheres and the solid hydrophobic nanospheres comprising the same or different pharmaceutical active ingredients onto the tumor site, as shown in FIG. 2. The nanospheres can be designed to release their pharmaceutical active ingredient over an extended period of time at a pH that is typically found in or near cancerous tissue and maintain efficacious levels of these agents at the target site for the duration of treatment.

[0045] The deposition of the nanospheres onto the tumor tissue is improved by optimizing particle size to ensure entrainment of the nanospheres within the target tissue and by modifying the surface properties of the nanospheres to enhance their affinity for a particular residue expressed on a cell surface or enhance their affinity for a cell surface protein or receptor to maximize interaction between the nanospheres and the tumor tissue, as shown in FIG. 3. With respect to the interaction between the nanospheres and the target surface, various chemical groups and bioadhesive materials can be incorporated in the nanospheres structure, for improving interaction with the target surface. A cationic surface active agent creates positively charged nanospheres; an anionic surface active agent creates negatively charged nanospheres; a nonionic surface active creates neutral charged nanospheres; and a zwitterionic surface active agent creates variable charged nanospheres.

[0046] In one embodiment, the nanospheres of the present invention are bioadhesive. Bioadhesive nanosphere can be created by incorporating a bioadhesive material into the solid hydrophobic matrix of the nanospheres, by incorporating a bioadhesive material in the pH sensitive microsphere matrix, or by using a bioadhesive material in the nanosphere matrix in conjunction with bioadhesive material in the microsphere matrix.

[0047] The term “spheres” is intended to describe solid, substantially spherical particulates. It will be appreciated that the term “sphere” includes other particle shapes that can be formed in accordance with the teachings of the present invention.

[0048] The term “pH triggered release” is intended to mean that the rate of release is dependent of or regulated by the pH of the system surrounding media or environment.

[0049] The present invention also provides a method of treating cancer tumors comprising administering an effective amount of microspheres that are capable of enhancing the bioavailability of the pharmaceutical active ingredient encapsulated in solid hydrophobic nanospheres and release them over an extended period of time at a specified pH. The term extended period of time at a specified pH is intended to mean an extended release a selected pH suitable for treating a cellular proliferation disease characterized by the abnormal proliferation of cells, such as cancer.

[0050] Frequent cancer tumor sites are the lung, colon, rectum, breast, prostate, testicles, bladder, uterus, liver, pancreas, ovary, head and neck and the like. Prevalent types of cancer include leukemia, central nervous system cancers, brain cancer, melanoma, lymphoma, erythro leukemia, uterine cancer, bone cancer and head and neck cancer.

[0051] The pharmaceutical active ingredient encapsulated in the controlled release system of the present invention include, but are not limited to, cytotoxic agents, chemotherapeutic agents, radionuclides, nucleic acids, hormones, proteins, secreted proteins, and biopharmaceiticals including but not limited to antibodies or antibody-engineered therapeutic entities, ligands, receptors and mimetics thereof. Nucleic acids as used herein also includes gene based drugs or gene based treatment modalities, including the use of sense, and antisense nucleic acids, ribozymes, as well as chimeric oligonucleotides constructs for gene correction. Antigens, including protein antigens, are agents for use in compositions of the present invention. Nucleic acids include DNA or RNA fragments, which encode functionally active or inactive or conditionally inactivatable proteins.

[0052] The invention further provides a method to effectively deliver and localize the therapeutic effect of chemotherapeutic agents to the target site or tumor tissue and maintain efficacious levels of these agents at the target site for the duration of treatment, that reduces the amount of adverse side effects such as vomiting, myelosuppression, cardiac toxicity, pulmonary fibrosis, hepatobiliary toxicity, and pericholangitis commonly associated with other current non-invasive treatments.

[0053] A preferred embodiment of the present invention pertains to a method of treating a tumor with the solid hydrophobic nanospheres encapsulated in a pH sensitive microsphere which contain a selected anti-tumor substance and injecting the microspheres in a blood vessel suitable for carrying the microspheres to the tumor.

[0054] The multi-component controlled release system of the present invention can comprise from about 1% to about 50% by weight hydrophobic matrix, from about 1% to about 50% by weight pH sensitive matrix, from about 0% to about 10% by weight targeting materials, from about 0% to about 20% by weight surface active agents, and from about 0.01% to about 50% by pharmaceutical weight active ingredients. The hydrophobic matrix enhances bioavailability and sustains the diffusion rate of the pharmaceutical active ingredients, through the nanospheres and enables them to be released onto the target site over an extended period of time. The microsphere has an average sphere size in the range from about 0.1 micron to about 50 microns. The nanosphere has an average sphere size in the range from about 0.001 micron to about 1 micron and has a melting point in the range from about 30° C. to about 90° C. This linear dimension for any individual sphere represents the length of the longest straight line joining two points on the surface of the sphere.

[0055] Additional components can be added to the carrier system or can be incorporated into the nanospheres, the microspheres, or both the nano and micro spheres matrices. The controlled release system of the present invention can readily include other pharmaceutical active agents, including but are not limited to: anti-oxidants; free radical scavengers; anti-microbial agents; antibacterial agents; allergy inhibitors; anti-aging agents; antiseptics; analgesics; anti-inflammatory agents; healing agents; inflammation inhibitors; vasoconstrictors; vasodilators; wound healing promoters; peptides, polypeptides and proteins; anti-fungal; depilating agents; counterirritants; vitamins; amino acids and their derivatives; herbal extracts; flavoids; chelating agents; cell turnover enhancers; and nourishing agents. The additional components are usually present in an amount from about 1% to about 20% by weight of the spheres.

[0056] The controlled release compositions of the present invention can be easily processed into articles of predetermined generic dimensions. Examples of articles include pharmaceutical doses, diagnostics materials, implants including depots, imaging entities, medical devices, and the like.

[0057] I. Matrix Materials for Forming the Nanospheres

[0058] Considerations in the selection of the matrix material include good barrier properties to the active ingredients, low toxicity and irritancy, stability, integrity, and high loading capacity for the active agents of interest. Suitable wax materials for the compositions and devices of the present invention are inert nontoxic materials with a melting point range between about 25° C. and about 150° C. and penetration point of about 1 to about 10. Examples of wax materials include natural waxes, synthetic waxes and mixtures thereof. Suitable waxes also include natural, regenerated, or synthetic food approved waxes including animal waxes such as beeswax, vegetable waxes such as carnauba, candelilla, sugar cane, rice bran, and bayberry wax, mineral waxes such as petroleum waxes including paraffin and microcrystalline wax, and mixtures thereof.

[0059] Other wax materials that are known to those skilled in the art and suitable materials as described in “Industrial Waxes” Vol. I and II, by Bennett F.A.I.C., published by Chemical Publishing Company Inc., 1975 and Martindale, “The Extra Pharmacopoeia”, The Pharmaceutical Press, 28th Edition pp. 1063-1072, 1982 can be used in the present invention.

[0060] Suitable fat materials and/or glyceride materials which can be used as matrix materials for forming the nanospheres of the present invention include, but are not limited to, the following classes of lipids: mono-, di and triglycerides, phospholipids, sphingolipids, cholesterol and steroid derivatives, terpenes and vitamins.

[0061] The fat material of the present invention can be a glyceride selected from monoglycerides, diglycerides, glyceryl monostearate, glyceryl tristearate and mixtures thereof. Other fat materials which can be used are hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, partially hydrogenated soybean oil, partially hydrogenated cottonseed oil, and mixtures thereof.

[0062] Examples of solid fat materials, which can be used in the present invention, include solid hydrogenated castor and vegetable oils, hard fats, and mixtures thereof. Other fat materials which can be used, include triglycerides of food grade purity, which can be produced by synthesis or by isolation from natural sources. Natural sources can include animal fat or vegetable oil, such as soy oil, as a source of long chain triglycerides (LCT). Other triglycerides suitable for use in the present invention are composed of a majority of medium length fatty acids (C10-C18), denoted medium chain triglycerides (MCT). The fatty acid moieties of such triglycerides can be unsaturated or polyunsaturated and mixtures of triglycerides having various fatty acid material.

[0063] Phospholipids which can be used include, but are not limited to, phosphatidic acids, phosphatidyl cholines with both saturated and unsaturated lipids, phosphatidyl ethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, lysophosphatidyl derivatives, cardiolipin, and beta-acyl-y-alkyl phospholipids. Examples of phospholipids include, but are not limited to, phosphatidylcholines such as dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLPC); and phosphatidylethanolamines such as dioleoylphosphatidylethanolamine or 1-hexadecyl-2-palmitoylglycerophosphoethanolamine. Synthetic phospholipids with asymmetric acyl chains (e.g., with one acyl chain of 6 carbons and another acyl chain of 12 carbons) can also be used.

[0064] Steroids which can be used include as fat materials, but are not limited to, 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 and cholesteryl)4′-trimethyl 35 ammonio)butanoate. Additional lipid compounds as fat material which can be used include tocopherol and derivatives, and oils and derivatized oils such as stearlyamine.

[0065] The fat material can be fatty acids and derivatives thereof which can include, but are not limited to, saturated and unsaturated fatty acids, odd and even number fatty acids, cis and trans isomers, and fatty acid derivatives including alcohols, esters, anhydrides, hydroxy fatty acids and prostaglandins. Saturated and unsaturated fatty acids that can be used include, but are not limited to, molecules that have between 12 carbon atoms and 22 carbon atoms in either linear or branched form. Examples of saturated fatty acids that can be used include, but are not limited to, lauric, myristic, palmitic, and stearic acids. Examples of unsaturated fatty acids that can be used include, but are not limited to, lauric, physeteric, myristoleic, palmitoleic, petroselinic, and oleic acids. Examples of branched fatty acids that can be used include, but are not limited to, isolauric, isomyristic, isopalmitic, and isostearic acids and isoprenoids. Fatty acid derivatives include 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 and palmitoyl-homocysteine; and/or combinations thereof. Mono, di and triglycerides or derivatives thereof that can be used include, but are not limited to, molecules that have fatty acids or mixtures of fatty acids between 6 and 24 carbon atoms, digalactosyldiglyceride, 1,2-dioleoyl-sn-glycerol; 1,2-cdipalmitoyl-sn-3 succinylglycerol; and 1,3-dipalmitoyl-2-succinylglycerol.

[0066] The nanospheres of the present invention can have a melting point in the range from about 30° C. to about 90° C., preferably from about 40° C. to about 90° C. The melting point of the spheres is typically a function of the carrier matrix employed. Accordingly, preferred matrix materials have a melting point in the range of about 50° C. to about 80° C., preferably from about 60° C. to about 70° C. It should be understood that it is the melting point of the sphere rather than the melting point of the carrier matrix that is important for use of the carrier system of the present invention.

[0067] II. Materials for Forming a Microsphere Matrix

[0068] The microsphere can be composed of purely pH sensitive materials or be comprised of a mixture of pH sensitive materials, salt sensitive, water sensitive or bioadhesive materials.

[0069] pH Sensitive Materials

[0070] The pH-sensitive materials that are utilized to form the microspheres of the present invention comprises any material or structure that has the ability to maintain the integrity of the microsphere at normal physiological pH, of about 7.4, until the microspheres reach the pH found in or near cancerous tissue that is more acidic than the surrounding normal tissues typically, between about 3.5 and about 6.8. Suitable pH sensitive materials for targeting the controlled delivery system of the present invention to the tumor sites are materials that have a threshold pH of about 6.8 or less, alternatively those with threshold pH of about 6.5 or less, and alternatively have threshold pH of about 6 or less.

[0071] The trigger pH is the threshold pH value or range of values at which either above or below the trigger pH the pH-sensitive material degrades, and/or dissolves. The microsphere can be formed to be stable in solutions and then as the pH increases above the trigger pH the microspheres are activated to swell or dissolve. Likewise, microspheres can be formed to be stable in solutions and as the pH drops below the trigger pH the microspheres are activated to swell or dissolve. Once activated, the active ingredients and the nanospheres are released.

[0072] In one embodiment a pH-sensitive trigger means is used such that the microsphere is capable of becoming more permeable to water and/or losing physical strength following triggering by a solution of the desired pH, either above or below the trigger pH. In another embodiment a pH-sensitive trigger means is used to hold together two nanosphere portions. The trigger means is capable of losing its adhesive quality or strength, such as to degrade or dissolve, following triggering by a solution of the desired pH, either above or below the trigger pH. The reduction in adhesion strength allows the hydrostatic pressure inside the microsphere core to push apart the nanospheres portions held together by the adhesive trigger means, thereby releasing the contents of the nanospheres.

[0073] The pH-sensitive materials can be insoluble solids in acidic or basic aqueous solutions, which dissolve, or degrade and dissolve, as the pH of the solution is neutral. The pH-sensitive materials can be insoluble solids in acidic or basic aqueous solutions which dissolve, or degrade and dissolve, as the pH of the solution rises above or drops below a trigger pH value.

[0074] Exemplary pH-sensitive materials include copolymers of acrylate polymers with amino substituents, acrylic acid esters, polyacrylamides, phthalate derivatives (i.e., compounds with covalently attached phthalate moleties) such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, 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 copolymers, formalized 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 derivatives such as acrylic acid and acrylic ester copolymers, methacrylic acid and esters thereof, vinyl acetate and crotonic acid copolymers.

[0075] Examples of suitable pH sensitive polymers for use are the Eudragit® polymers series from Rohm America Inc., a wholly-owned subsidiary of Degussa-Huls Corporation, headquartered in Piscataway, N.J., and an affiliate of Rohm GmbH of Darmstadt, Germany. EUDRAGIT® L 30 D-55 and EUDRAGIT® L 100-55, pH dependent anionic polymer that is soluble at pH above 5.5 and insoluble blow pH 5. These polymers can be utilized for targeted drug delivery in the duodenum. EUDRAGIT® L 100 pH dependent anionic polymer that is soluble at pH above 6.0 for targeted drug delivery in the jejunum. EUDRAGIT® S 100 pH dependent anionic polymer that is soluble at pH above 7.0 for targeted drug delivery in the ileum. EUDRAGIT® E 100 and EUDRAGIT® EPO, pH dependent cationic polymer, soluble up to pH 5.0 and insoluble above pH 5.0 dependent cationic polymer, soluble up to pH 5.0 and insoluble above pH 5.0. Accordingly, suitable pH sensitive materials degrade or dissolve when said pH sensitive microsphere contacts a solution having a pH greater than about 5.

[0076] Additional pH-sensitive materials include poly functional polymers containing multiple groups that become ionized as the pH drops below their pKa. A sufficient quantity of these ionizable groups must be incorporated in the polymer such that in aqueous solutions having a pH below the pKa of the ionizable groups, the polymer dissolves. These ionizable groups can be incorporated into polymers as block copolymers, or can be pendent groups attached to a polymer backbone, or can be a portion of a material used to crosslink or connect polymer chains. Examples of such ionizable groups include polyphosphene, vinyl pyridine, vinyl aniline, polylysine, polyornithine, other proteins, and polymers with substituents containing amino moieties.

[0077] pH-sensitive polymers which are relatively insoluble and impermeable at the pH of the stomach, but which are more soluble and permeable at the pH of the small intestine and colon include polyacrylamides, phthalate derivatives such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid copolymers.

[0078] Other pH-sensitive polymers include shellac; phthalate derivatives, particularly cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulose phthalate; polyacrylic acid derivatives, particularly polymethyl methacrylate blended with acrylic acid and acrylic ester copolymers; and vinyl acetate and crotonic acid copolymers.

[0079] Anionic acrylic copolymers of methacrylic acid and methylmethacrylate are also particularly useful coating materials for delaying the release of compositions and devices until the compositions and devices have moved to a position in the small intestine which is distal to the duodenum. Copolymers of this type are available from RohmPharma Corp, under the trade names Eudragit-L.R™ and Eudragit-S.R™, are anionic copolymers of methacrylic acid and methylmethacrylate. The ratio of free carboxyl groups to the esters is approximately 1:1 in Eudragit-L.R™ and approximately 1:2 in Eudragit-S.RT™. Mixtures of Eudragit-L.R™ and Eudragit-S.R™ can also be used.

[0080] The pH-sensitive and salt sensitive materials can be blended with an inert water sensitive material. By inert is meant a material that is not substantially affected by a change in pH or salt concentration in the triggering range. By altering the proportion of a pH-sensitive material to inert material the time lag subsequent to triggering and prior to release can be tailored.

[0081] In an embodiment of the present invention, the micro sphere is formed of a pH sensitive material which is substantially insoluble and impermeable at the pH of the stomach, and is more soluble and permeable at the pH of the small intestine. Preferably, the micro spheres are substantially insoluble and impermeable at pH less than about 5.0, and water-soluble at pH greater than about 5.0. pH-sensitive polymers which are relatively insoluble and impermeable at the pH of the stomach, but which are more soluble and permeable at the pH of the small intestine and colon include polyacrylamides, phthalate derivatives such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid copolymers.

[0082] Suitable pH-sensitive polymers include shellac; phthalate derivatives, particularly cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulose phthalate; polyacrylic acid derivatives, particularly polymethyl methacrylate blended with acrylic acid and acrylic ester copolymers; vinyl acetate; crotonic acid copolymers and Eudragit® polymers series from Rohm America Inc.

[0083] Water Sensitive Materials

[0084] Water-sensitive materials can be mixed with the pH or salt sensitive materials to form the microspheres of the present invention. Suitable water sensitive materials comprise polyvinyl pyrrolidone, water soluble celluloses, polyvinyl alcohol, ethylene maleic anhydride copolymer, methyl vinyl ether maleic anhydride copolymer, polyethylene oxides, water soluble polyamide or polyester copolymers or homopolymers of acrylic acid such as polyacrylic acid, polystyrene acrylic acid copolymers or starch derivatives, polyvinyl alcohol, polysaccharides, hydrocolloids, natural gums, proteins, and mixtures thereof. Examples of synthetic water sensitive polymers which are useful for the invention include polyvinyl pyrrolidone, water soluble celluloses, polyvinyl alcohol, ethylene maleic anhydride copolymer, methylvinyl ether maleic anhydride copolymer, acrylic acid copolymers, anionic polymers of methacrylic acid and methacrylate, cationic polymers with dimethyl-aminoethyl ammonium functional groups, polyethylene oxides, water soluble polyamide or polyester.

[0085] Examples of water soluble hydroxyalkyl and carboxyalkyl celluloses include hydroxyethyl and carboxymethyl cellulose, hydroxyethyl and carboxyethyl cellulose, hydroxymethyl and carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose, hydroxypropyl methyl carboxyethyl cellulose, hydroxypropyl carboxypropyl cellulose, hydroxybutyl carboxymethyl cellulose, and the like. Also useful are alkali metal salts of these carboxyalkyl celluloses, particularly and preferably the sodium and potassium derivatives.

[0086] The polyvinyl alcohol useful in the practice of the invention is partially and fully hydrolyzed polyvinyl acetate, termed “polyvinyl alcohol” with polyvinyl acetate as hydrolyzed to an extent, also termed degree of hydrolysis, of from about 75% up to about 99%. Such materials are prepared by means of any of Examples I-XIV of U.S. Pat. No. 5,051,222 issued on Sep. 24, 1991, the specification for which is incorporated by reference herein.

[0087] Polyvinyl alcohol useful for practice of the present invention is Mowiol® 3-83, having a molecular weight of about 14,000 Da and degree of hydrolysis of about 83%, Mowiol® 3-98 and a fully hydrolyzed (98%) polyvinyl alcohol having a molecular weight of 16,000 Da commercially available from Gehring-Montgomery, Inc. of Warminister Pa. Other suitable polyvinyl alcohols are: AIRVOL® 205, having a molecular weight of about 15,000-27,000 Da and degree of hydrolysis of about 88%, and VINEX® 1025, having molecular weight of 15,000-27,000 Da degree of hydrolysis of about 99% and commercially available from Air Products & Chemicals, Inc. of Allentown, Pa.; ELVANOL® 51-05, having a molecular weight of about 22,000-26,000 Da and degree of hydrolysis of about 89% and commercially available from the Du Pont Company, Polymer Products Department, Wilmington, Del.; ALCOTEX® 78 having a degree of hydrolysis of about 76% to about 79%, ALCOTEX®D F88/4 having a degree of hydrolysis of about 86% to about 88% and commercially available from the Harlow Chemical Co. Ltd. of Templefields, Harlow, Essex, England CM20 2BH; and GOHSENOL® GL-03 and GOHSENOL® KA-20 commercially available from Nippon Gohsei K.K., The Nippon Synthetic Chemical Industry Co., Ltd., of No. 9-6, Nozaki Cho,Kita-Ku, Osaka, 530 Japan.

[0088] Suitable polysaccharides are polysaccharides of the non-sweet, coloidally-soluble types, such as natural gums, for example, gum arabic, starch derivates, dextrinized and hydrolyzed starches, and the like. A suitable polysaccharide is a water dispersible, modified starch commercially available as Capule®, N-Lok®, Hi-Cap™ 100 or Hi-Cap™ 200 commercially available from the National Starch and Chemical Company of Bridgewater, N.J.; Pure-Cote™, commercially available from the Grain Processing Corporation of Muscatine, Iowa. In the preferred embodiment the natural gum is a gum arabic, commercially available from TIC Gums Inc. Belcamp, Midland. Suitable hydrocolloids are xanthan, maltodextrin, galactomanan or tragacanth, preferably maltodextrins such as Maltrin™ M100, and Maltrin™ M150, commercially available from the Grain Processing Corporation of Muscatine, Iowa.

[0089] Bioadhesive Polymers

[0090] An orally ingested drug delivery system can adhere to either the epithelial surface or the mucus. For the delivery of bioactive active ingredients, it is advantageous to have the system adhere to the epithelium rather than solely to the mucous layer, although mucoadhesion can also substantially improve bioavailability. For some types of imaging purposes, adhesion to both the epithelium and mucus is desirable whereas in pathological states, such as in the case of gastric ulcers or ulcerative colitis, adhesion to cells below the mucous layer may occur. Duchene, et al., Drug Dev. Ind. Pharm. 14(2&3), 283-318 (1988), reviews the pharmaceutical and medical aspects of bioadhesive systems for drug delivery. “Bioadhesion” is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Bioadhesion is a solution to the problem of inadequate residence time resulting from the stomach emptying and intestinal peristalsis, and from displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate contact is needed between the bioadhesive and the receptor tissue, the bioadhesive must penetrate into the crevice of the tissue surface and/or mucus, and mechanical, electrostatic, or chemical bonds form. Bioadhesive properties of the polymers are affected by both the nature of the polymer and by the nature of the surrounding media. Incorporating bioadhesive polymers in the microsphere of the present invention can be utilized to control or increase the absorption of the nanosphere through the mucosal lining, or to further delay transit of the nanosphere through the gastrointestinal passages. A bioadhesive polymer as used in the disclosure is one that binds to mucosal epithelium under normal physiological conditions. Bioadhesion in the gastrointestinal tract proceeds in two stages: (1) viscoelastic deformation at the point of contact of the synthetic material into the mucus substrate, and (2) formation of bonds between the adhesive synthetic material and the mucus or the epithelial cells. In general, adhesion of polymers to tissues can be achieved by (i) physical or mechanical bonds, (ii) primary or covalent chemical bonds, and/or (iii) secondary chemical bonds such as ionic. Physical or mechanical bonds can result from deposition and inclusion of the bioadhesive material in the crevices of the mucus or the folds of the mucosa. Secondary chemical bonds, contributing to bioadhesive properties, can comprise dispersive interactions such as Van der Waals interactions and stronger specific interactions, such as hydrogen bonds. Hydrophilic functional groups primarily responsible for forming hydrogen bonds include hydroxyl and the carboxylic groups. Suitable bioadhesive polymers for use in the present invention include bioerodible hydrogels as described by H. S. Sawhney, C. P. Pathak and J. A. Hubell in Macromolecules. 1993, 26:581-587, the teachings of which are incorporated herein, 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), and poly(octadecl acrylate) and poly(fumaric-co-sebacic)acid.

[0091] Polymers with enhanced bioadhesive properties can be provided wherein anhydride monomers or oligomers are incorporated into the polymer. The oligomer excipients can be blended or incorporated into a wide range of hydrophilic and hydrophobic polymers including proteins, polysaccharides and synthetic biocompatible polymers. Anhydride oligomers can be combined with metal oxide particles to improve bioadhesion in addition to the use of organic additives alone. Organic dyes because of their electronic charge and hydrophobicity/hydrophilicity can either increase or decrease the bioadhesive properties of polymers when incorporated into the polymers. The incorporation of oligomer compounds into a wide range of different polymers which are not normally bioadhesive can be used to increase the adherence of the polymer to tissue surfaces such as mucosal membranes.

[0092] III. Targeting Mechanism

[0093] The nanospheres can be targeted specifically or non-specifically through the selection of the pH of the material forming the microsphere, the size of the nanosphere, and/or incorporation or attachment of a ligand to the nanospheres. For example, biologically active molecules, or molecules affecting the charge, lipophilicity or hydrophilicity of the nanospheres, can be attached to the surface of the nanospheres. Additionally, molecules can be attached to the nanospheres which minimize tissue adhesion, or which facilitate specific targeting of the nanosphere in vivo. Representative targeting molecules include antibodies, ligands, lectins, and other molecules which are specifically bound by receptors on the surfaces of cells of a particular type.

[0094] The term “cell recognition component”, as used herein, refers to a molecule capable of recognizing a component on a surface of a targeted cell. Cell recognition components may include an antibody to a cell surface antigen, a ligand for a cell surface receptor, such as cell surface receptors involved in receptor-mediated endocytosis, peptide hormones, and the like.

[0095] In one embodiment of the present invention, the nanospheres are modified with lectins attached to the nanosphere surface and targeted to mucosal epithelium of the small intestine and are absorbed into the systemic circulation and lymphatic circulation. In an embodiment of the present invention, carbohydrates or lectins are used to target the nanospheres of the present invention to M cells and Peyer's Patch cells of the small intestine. In another embodiment of the present invention lectins which bind to fucosyl sugars are used to modify the nanospheres. Lectins are a heterogenous group of proteins or glycoproteins that recognize carbohydrate residues on cell surface glycoconjugates with a high degree of specificity. Examples of lectins that can be used to modify the nanospheres of the present invention, include but are not limited to, lectins specific for binding to fucosyl glycoconjugates, such as Ulex Europeas Agglutinin I (UEA); lectins specific for binding to galactose/N-acetylgalactoseamine, such as Phaseolus vulgaris haemagglutinin (PHA), tomato lectin (Lycopersicon esculentum) (TL), wheat germ agglutinin (WGA); lectins specific for binding to mannose, such as, Galanthus nivalis agglutinin (GNA); lectins specific for mannose and/or glucose, such as, con A/concavalan A. (See e.g., Lehr et al., 1995, in Lectins Biomedical Perspectives, pp. 117-140, incorporated by reference into this application). The targeting molecules can be derivatized if desired. See e.g., Chen et al., 1995, Proceed. Internat. Symp. Control. Rel. Bioact. Mater. 22 and Cohen WO 9503035, incorporated by reference into this application.

[0096] In another embodiment of the invention, the nanospheres of the present invention can be modified with viral proteins or bacterial proteins that have an affinity for a particular residue expressed on a cell surface or that have an affinity for a cell surface protein or receptor. Examples of such proteins include, but are not limited to, cholera toxin B subunit, and bacterial adhesotopes.

[0097] In yet another embodiment of the present invention, the nanospheres of the present invention can be modified with monoclonal antibodies or fragments of antibodies which target the nanospheres to a particular cell type. The nanospheres of the present invention can be modified with ligands for specific mucosal cell surface receptors and proteins. As used herein, the term “ligand” refers to a ligand attached to a nanosphere which adheres to the mucosa in the intestine or can be used to target the nanospheres to a specific cell type in the G-I tract or following absorption of the nanospheres onto the mucosa in the intestine. Suitable ligands can include ligands for specific cell surface proteins and antibodies or antibody fragments immunoreactive with specific surface molecules. Suitable ligands can also include less specific targeting ligands such as coatings of materials which are bioadhesive, for example alginate and polyacrylate.

[0098] IV. Active Ingredients

[0099] The pharmaceutical active ingredient encapsulated in the controlled release system of the present invention include, but are not limited to, cytotoxic agents, chemotherapeutic agents, radionuclides, gene based drugs or gene based treatment modalities, including the use of sense, antisense nucleotide sequences, antigens, antibodies, ribozymes, as well as chimeric oligonucleotides constructs for gene correction. These actives may also include DNA or RNA fragments, which code functionally active or inactive or conditionally inactivatable proteins. Examples of chemotherapeutic agents include inhibitors of purine synthesis (e.g., pentostatin, 6-mercaptopurine, 6thioguanine, methotrexate) or pyrimidine synthesis (e.g. Pala, azarbine), the conversion of ribonucleotides to deoxyribonucleotides (e.g. hydroxyurea), inhibitors of dTMP synthesis (5-fluorouracil), DNA damaging agents (e.g. radiation, bleomycines, etoposide, teniposide, dactinomycine, daunorubicin, doxorubicin, mitoxantrone, alkylating agents, mitomycin, cisplatin, procarbazine) as well as inhibitors of microtubule function (e.g. vinca alkaloids and colchicine).

[0100] Although all taxanes are contemplated for formulation in compositions of the present invention an example suitable pharmaceutical active ingredient is, Paclitaxel, (also referred to as TAXOL®), first identified in 1971 by Wani and collaborators (Wani MC et al., J. Am. Chem. Soc., 93: pp. 2325-2327, 1971) following a screening program of plant extracts of the National Cancer Institute. This complex diterpene shows cytotoxic activity against several types of tumors and is presently used in the treatment of some cancers such as ovarian and breast cancers. Clinical studies suggest that Paclitaxel could eventually be used in the treatment of over 70% of human cancers. Paclitaxel differs from other cytotoxic drugs by its unique mechanism of action. It interferes with cell division by manipulating the molecular regulation of the cell cycle. Paclitaxel binds to tubulin, the major structural component of microtubules that are present in all eukaryotic cells. Unlike other antimitotic agents such as vinca alkaloids and colcichine, which inhibit the polymerization of tubulin, paclitaxel promotes this assembly of tubulin and stabilizes the resulting microtubules. This event leads to the interruption of cell division, and ultimately to cell death. Various derivatives of paclitaxel may be used in accordance with the invention, such as taxotere or other related taxanes. Cisplatin, another of the cytotoxic chemical compounds, which may be used in accordance with the invention, also is known as cis-Diamminedichloroplatinum. Well known analogues of cisplatin such as carboplatin and iproplatin (also known as CHIP[cis-dichloro-trans-dihydroxo-bis[isopropylamine]platinum IV) can also be used in the present invention. It will be appreciated those of ordinary skill in the art would be familiar with other specific cytotoxic agents that could be used in the present invention.

[0101] Other pharmaceutical compounds that are particularly well-suited for encapsulation according to the present invention, include: Tamoxifen, Dacarbazine, Ifosfamide, Streptozocin, Thiotepa, Nandrolone decanoate, Fentanyl citrate, Testosterone, Albendazole, Esmolol, Mytomycin, Bleomycin sulfate, Dactinomycin, Amikacin sulfate, Gentamicin, Netilmicin, Streptomycin, Tobramycin, Doxorubicin, Epirubicin, Idarubicin, Valrubicin, Bacitracin, Colistimethate, Oxybutinin, Antithrombin III Human, Heparin, Lepirudin, Adenosine phosphate, Amphotericin B, Enalaprilat, Cladribine, Cytarabine, Fludarabine phosphate, Gemcitabine, Pentostatin, Docetaxel, Paclitaxel, Vinblastine, Vincristihe, Vinorelbine, Batimastat, Rituximab, Trastazumab, Abciximab, Eptifibatide, Tirofiban, Droperidol, Aurothioglucose, Capreomycin disulfide, Acyclovir, Cidofovir, Pentafuside, Saquinavir, Ganciclovir, Cromolyn, Aldesleukin, Denileukin, Edrophonium, Infliximab, Doxapram, SN-38 (Irinotecan), Topotecan, Hemin, Daunorubicin, Teniposide, Trimetrexate, Octreotride, Ganirelix acetate, Histrelin acetate, Somatropin, Epoetin, Filgrastim, Oprelvekin, Leuprolide, Basiliximab, Daclizumab, Glatiramer acetate, Interferons, Muromonab-CD3, Clyclosporin A, Milrinone lactate, Buprenorphine, Nalbuphine, Urofollitropin, Desmopressin, Carboplatin, Cisplatin, Mitoxantrone, Estradiol, Hydroxyprogesterone, L-Thyroxine, Etanercept, Neostigmine, Epoprostenol, Methoxamine, Versed, Bupivacaine, Heparin, Insulin, Antisense compounds, Ibuprofen, Fluorouracil, Mechlor, Fluorouridine, Tiazofurin Ketoprofen, Thanive, Etoposide, Docetaxel, Alendronate, Etidronate, Zoledronate, Ibandronate, Risedronate, and Pamidronate. These compounds represent the following classes of drug: Alkylating agent, Anabolic steroid, Analgesic, Androgen, Anthelmintic, Antiadrenergic, Antibiotic, Antibiotic, aminoglycoside, Antibiotic, antineoplastic, Antibiotic, polypeptide, Anticholinergic, Anticoagulant, Anticonvulsant, Antifungal, Antihypertensive, Antimetabolite, Antimitotic, Antineoplastic, Antiplatelet, Antipsychotic, Anesthetic, Antirheumatic, Antituberculosal, Antiviral, Antiviral (HIV), Asthma anti-inflammatory, Biological response modifier, Cholinergic muscle stimulant, CNS stimulant, DNA topoisomerase inhibitor, Enzyme inhibitor, Epipodophyllotoxin, Folate antagonist, Gastric antisecretory, Gene therapy agents, Gonadotropin-releasing, Growth hormone, Hematopoietic, Hormone, Immunologic agent, Immunosuppressant, Inotropic agent, Local anesthetic, Narcotic agonist/antagonist, Ovulation stimulant, Pituitary hormone, Platinum complex, Sex hormone, Thyroid hormone, TNF inhibitor (arthritis), Urinary cholinergic, Vasodilator, and Vasopressor. Other suitable active agents are described in U.S. Pat. No. 6,656,955 hereby incorporated by reference into this application. The present invention is very well suited for the incorporation of functional excipients, such as gum benzoin or essential oils that improve absorption of poorly-absorbed drugs, in some cases by inhibiting drug efflux proteins. As discussed in more detail elsewhere herein, there are a number of sites within, and at the surface of the particles, where actives, excipients, and functional excipients can be localized within the context of this invention.

[0102] V. Processing Method

[0103] Va. Nanospheres

[0104] The encapsulated active agent in the nanospheres of the present invention can be prepared by the steps of (1) heating hydrophobic materials to a temperature above the melting point to form a melt, (2) dissolving or dispersing the active agent in the melt, (3) emulsifying the melt in the aqueous phase; and (4) cooling the dispersion to ambient temperature to form a fine suspension.

[0105] The active ingredients can be incorporated into hydrophobic solid nanospheres, the pH sensitive microsphere, or in both the nano and micro spheres.

[0106] Vb. Microspheres

[0107] The controlled release system of the present invention can be prepared by the steps of (a) incorporating the selected active agents into the hydrophobic interior of the nanospheres, (b) forming an aqueous mixture comprising one or more active agents, the nanospheres, and a pH sensitive material, and (c) spray drying the mixture of the present invention to form a dry powder composition. Accordingly, the nanospheres can be encapsulated into the microsphere structure. One or more of the active agents, which can be the same or different than the active agents incorporated in the nanosphere, can be incorporated into the microsphere structure.

[0108] A process for producing the multi component controlled release system includes the following steps:

[0109] (i) heating a hydrophobic material to a temperature above the melting point to form a melt;

[0110] (ii) dissolving or dispersing the selected first active agent into the melt;

[0111] (iii) dissolving or dispersing a second active agent, and the pH sensitive materials, in the aqueous phase and heating it to above the melting temperature of the hydrophobic material;

[0112] (iv) mixing the hot melt with the aqueous phase to form a dispersion;

[0113] (v) high shear homogenization of the dispersion at a temperature above the melting temperature until a homogeneous fine dispersion is obtained having a sphere size of from about 1 microns to about 2 microns;

[0114] (vi) cooling the dispersion to ambient temperature; and

[0115] (vii) spray drying the emulsified mixed suspension to form a dry powder composition.

[0116] Homogenization can be accomplished in any suitable fashion with a variety of mixers known in the art such as simple paddle or ribbon mixers although other mixers, such as ribbon or plow blenders, drum agglomerators, and high shear mixers may be used. Suitable equipment for this process include a model Rannie 100 lab homogenizer available from APV Gaulin Inc. Everett, Mass., a rotor stator high shear mixer available from Silverson Machines, of East Long Meadow, Mass., or Scott Processing Equipment Corp. of Sparta, N.J., and other high sear mixers.

[0117] The suspension is spray dried to remove the excess water. Spray drying is well known in the art and been used commercially in many applications, including foods where the core material is a flavoring oil and cosmetics where the core material is a fragrance oil. Cf. Balassa, “Microencapsulation in the Food Industry”, CRC Critical Review Journal in Food Technology, July 1971, pp 245-265; Barreto, “Spray Dried Perfumes for Specialties, Soap and Chemical Specialties”, December 1966; Maleeny, Spray Dried Perfumes, Soap and San Chem, January 1958, pp. 135 et seq.; Flinn and Nack, “Advances in Microencapsulation Techniques”, Batelle Technical Review, Vo. 16, No. 2, pp. 2-8 (1967); U.S. Pat. Nos. 5,525,367; and 5,417,153 which are incorporated herein as references.

[0118] The use of pH activated microspheres which provide varying rates of diffusion are contemplated. For example, the active ingredients encapsulated in the pH activated microspheres may diffuse at any of the rates of the following:

[0119] at steady-state or zero-order release rate in which there is a substantially continuous release per unit of time;

[0120] a first-order release rate in which the rate of release declines towards zero with time; and

[0121] a delayed release in which the initial rate is slow, but then increases with time.

[0122] Nanospheres formed of a hydrophobic material provide a controlled release system in order to release the active agent over an extended period of time by molecular diffusion. Active agents in the hydrophobic matrix of the nanospheres can be released by transient diffusion. The theoretical early and late time approximation of the release rate of the active ingredients dissolved in the hydrophobic matrix of the nanospheres can be calculated from the following equations:

[0123] Early time approximation

(mt/msec)<0.4 1 M t M ∞ = 4 ⁢ ( D p ⁢ t Π ⁢   ⁢ r 2 ) 1 / 2 - D p ⁢ t r 2 ( 1 ) ⅆ M t / M ∞ ⅆ t = 2 ⁢ ( D p Π ⁢   ⁢ r 2 ⁢ t ) 1 / 2 - D p r 2 ( 2 )

[0124] Late time approximation

(mt/m∞)>0.6 2 M t M ∞ = 1 - 4 ( 2.405 ) 2 ⁢ exp ⁡ ( - ( 2.405 ) 2 ⁢ D p ⁢ t r 2 ) ( 3 ) ⅆ M t / M ∞ ⅆ t = 1 - 4 ⁢ D p r 2 ⁢ exp ⁡ ( - ( 2.405 ) 2 ⁢ D p ⁢ t r 2 ) ( 4 )

[0125] wherein:

[0126] r is the radius of the cylinder,

[0127] m∞ is the amount of active agent released from the controlled release system after infinite time;

[0128] mt is the amount of active agent released from the controlled release system after time t; and

[0129] Dp is the diffusion coefficient of the active agent in the matrix.

[0130] The release rate for releasing the active agents from the hydrophobic nanospheres is typically slower than the release rate for releasing active agent from the pH sensitive matrix. The active agents can be selected to be incorporated into either the hydrophobic nanospheres or the pH sensitive matrix depending on the desired time for release of the active agents. For example, a predetermined first active agent can be incorporated in the pH or salt sensitive matrix to be released first and a predetermined second active agent can be incorporated in the hydrophobic nanospheres for release over an extended period of time during or after the first agent has been released. For example, the pH sensitive matrix formed in accordance with the present invention can release the first active agent at a predetermined pH to provide a “burst” with continued release of the first active agent and nanospheres formed in accordance with the present invention can release the active agent depending on the release rate from an initial time such as a day or within few days, up to a period of few weeks.

[0131] In the preferred embodiment, the active agent is present at a level from about 0.01% to about 60%, preferably from about 1% to about 50% by weight of the microsphere. In the preferred embodiment, the nanospheres are generally present in the pH sensitive matrix at a level from about 1% to about 80%, preferably from about 1% to about 60% by weight of the matrix material with the balance being the active agents, and the pH sensitive materials. In the preferred embodiment, the pH sensitive matrix is generally present at a level from about 1% to about 80%, preferably from about 1% to about 60% by weight of the matrix material with the balance being the active agents, and the hydrophobic materials.

[0132] The subject methods may be used to treat a wide variety of hosts, including mammalian hosts, such as domestic animals, e.g. pets and livestock, rare or exotic animals, and humans. Cellular proliferative diseases amenable to treatment with the subject formulations are diseases characterized by the abnormal proliferation of cells. Diseases characterized by the abnormal proliferation of cells include neoplasia, psoriasis, hyperplasia and the like.

[0133] Neoplastic diseases amenable to treatment according to the subject methods include neoplastic dieases characterized by the development of solid tumors or lesions, including solid malignant tumors of the lung, breast, colon, rectum, ovaries, stomach, pancreas, uterus, testicles, brain, liver, head and neck.

[0134] Particular neoplastic cellular proliferative diseases that may be treated with the subject methods include carcinomas, sarcomas and melanomas, such as basal cell carcinoma, squamous cell carcinoma, melanoma, soft tissue sarcoma, solar keratoses, Kaposi's sarcoma, cutaneous malignant lymphoma, Bowen's disease, Wilm's tumor, hepatomas, colorectal cancer, brain tumors, mycosis fungoides, Hodgkins lymphoma, polycythemia ver, lymphomas, oat cell sarcoma, superficial and invasive bladder tumors, ovarian cancer, etc.

[0135] The compounds can be administered orally, rectally, parenterally, or by injection, alone or in combination with other therapeutic agents including antibiotics, steroids, etc., to a mammal in need of treatment. Oral dosage forms include tablets, capsules, dragees, and similar shaped, compressed pharmaceutical forms. Isotonic saline solutions containing 20-100 milligrams/milliliter can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes of administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter.

[0136] Dosage regimens must be titrated to the particular indication, the age, weight, and general physical condition of the patient, and the response desired but generally doses will be from about 1 to about 1000 milligrams/day as needed in single or multiple daily administration.

[0137] The compositions preferably are formulated in unit dosage form, meaning physically discrete units suitable as a unitary dosage, or a predetermined fraction of a unitary dose to be administered in a single or multiple dosage regimen to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0138] Pharmaceutical compositions thus comprise one or more compounds of the present invention associated with at least one pharmaceutically acceptable carrier, diluent or excipient. In preparing such compositions, the active ingredients are usually mixed with or diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule or sachet. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient. Thus the compositions can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidinone, cellulose, water, syrup, and methyl cellulose, the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents.

[0139] The carrier system of the present invention can be incorporated in pharmaceutical and health care products.

[0140] The invention can be further illustrated by the following examples thereof, although it will be understood that these examples are included merely for purposes of illustration and are not intended to limit the scope of the invention unless otherwise specifically indicated. All percentages, ratios, and parts herein, in the Specification, Examples, and claims, are by weight and are approximations unless otherwise stated.

Preparation of a pH Sensitive Drug Delivery Systems

EXAMPLE 1

[0141] The following procedure is used for the preparation of multi component controlled release system with the chemotherapeutic drug paclitaxel (taxol), a high molecular weight, lipophilic deterpenoid isolated from the western yew, as the active agent encapsulated in the solid hydrophobic nanosphere matrix. The nanosphere hydrophobic matrix is candelilla wax, commercially available from Strahl & Pitsch Inc. of West Babylon, N.Y. The microsphere pH sensitive matrix is a pH dependent anionic polymer stable at pH 7.4 and solubilizing at pH 6 and lower.

[0142] 40 grams of candelilla wax is placed in an oven at 80° C. and allowed to melt. 500 grams of deionized water are placed into Igallon vessel, fitted with an all-purpose silicon rubber heater (Cole-Palmer Instrument Company). 50 grams of the pH sensitive polymer were added to the water and the aqueous solution is heated to 90° C. while mixing it with a propeller mixer. The candelilla wax is removed from the oven. 10 grams of paclitaxel are dispersed into the melt by hand with a glass rod. The drug/wax mixture is poured into the aqueous solution and the dispersion is homogenized at 25,000 psi using a Rannie 100 lab homogenizer available from APV Gaulin Inc. The dispersion is cooled to ambient temperature by passing it through a tube-in-tube heat exchanger (Model 00413, Exergy Inc. Hanson Mass.) to form a suspension. The resulting suspension is spray dried with a Bowen Lab Model Drier (at Spray-Tek of Middlesex, N.J.) utilizing 250 c.f.m of air with an inlet temperature of 380° F., and outlet temperature of 225° F. and a wheel speed of 45,000 r.p.m to produce a free flowing, dry powder, consisting of 10% paclitaxel.

EXAMPLE 2

[0143] The following procedure is used for the preparation of multi component controlled release system with the chemotherapeutic drug doxorubicin (hydroxydaunomycin hydrochloride) (commercially available from Sigma) as the drug encapsulated in the solid hydrophobic nanosphere matrix. Doxorubicin (hydroxydaunomycin hydrochloride) is commercially available as the hydrochloride salt. It is an antineoplastic antibiotic but it is too cytotoxic to be used as an anti-infective agent. The exact mechanism of its anticancer activity is not well understood but some evidence suggests that the drug forms a complex with DNA which inhibits both DNA synthesis and DNA-dependent RNA synthesis by the resulting template disordering. Cells that are the most sensitive to doxorubicin are from rapidly proliferating tissues such as those of normal bone marrow, gastrointestinal mucosa, and hair follicles (Budavari, et al., 1989). Doxorubicin is administered intravenously and commonly used in the treatment of solid tumors including bladder carcinoma, breast carcinoma, ovarian carcinoma, gastric carcinoma, malignant lymphomas, and acute lymphoblastic and myeloblastic leukemias. Doxorubicin is rapidly metabolized in a first pass effect through the liver by an aldo-keto reductase enzyme which forms doxorubicinol, the metabolite with the major antineoplastic activity. A common adult dose of doxorubicin would be a 60 to 75 mg/m2 (skin area), intravenous injection once every 21 days, but other schedules require smaller injections (20-30 mg/m2) either once weekly or for 3 to 4 successive days every few weeks (Trissel, L. A., Handbook on Injectable Drugs, (8th ed.), American Society of Hospital Pharmacists, Inc., 1994). The nanosphere hydrophobic matrix is candelilla wax, commercially available from Strahl & Pitsch Inc. of West Babylon, N.Y. The microsphere pH sensitive matrix is a pH dependent anionic polymer stable at pH 7.4 and solubilizing at pH 6 and lower.

[0144] 40 grams of candelilla wax is placed in an oven at 80° C. and allowed to melt. 500 grams of deionized water are placed into 1 gallon vessel, fitted with an all-purpose silicon rubber heater (Cole-Palmer Instrument Company). 50 grams of the pH sensitive polymer were added to the water and the aqueous solution is heated to 90° C. while mixing it with a propeller mixer. The candelilla wax is removed from the oven. 10 grams of doxorubicin are dispersed into the melt by hand with a glass rod. The drug/wax mixture is poured into the aqueous solution and the dispersion is homogenized at 25,000 psi using a Rannie 100 lab homogenizer available from APV Gaulin Inc. The dispersion is cooled to ambient temperature by passing it through a tube-in-tube heat exchanger (Model 00413, Exergy Inc. Hanson Mass.) to form a suspension. The resulting suspension is spray dried with a Bowen Lab Model Drier (at Spray-Tek of Middlesex, N.J.) utilizing 250 c.f.m of air with an inlet temperature of 380° F., and outlet temperature of 225° F. and a wheel speed of 45,000 r.p.m to produce a free flowing, dry powder, consisting of 10% doxorubicin.

EXAMPLE 3

[0145] The following procedure is used for the preparation of multi component controlled release system with the chemotherapeutic drug fluorodeoxyuridine (FUDR) (commercoially available Sigma) as the active agent encapsulated in the hydrophobic nanosphere matrix. The nanosphere hydrophobic matrix is beeswax wax, commercially available from Strahl & Pitsch Inc. of West Babylon, New-York. The microsphere pH sensitive matrix is a pH dependent anionic polymer stable at pH 7.4 and solubilizing at pH 6 and lower. 40 grams of beeswax wax is placed in an oven at 80° C. and allowed to melt. 500 grams of deionized water are placed into 1 gallon vessel, fitted with an all-purpose silicon rubber heater (Cole-Palmer Instrument Company). 50 grams of the pH sensitive polymer were added to the water and the aqueous solution is heated to 90° C. while mixing it with a propeller mixer. The beeswax is removed from the oven, 10 grams of fluorodeoxyuridine are mixed into the melt by hand with a glass rod. The drug/wax mixture is poured into the aqueous solution and the dispersion is homogenized at 25,000 psi using a Rannie 100 lab homogenizer available from APV Gaulin Inc. The dispersion is cooled to ambient temperature by passing it through a tube-in-tube heat exchanger (Model 00413, Exergy Inc. Hanson Mass.) to form a suspension. The resulting suspension is spray dried with a Bowen Lab Model Drier (at Spray-Tek of Middlesex, N.J.) utilizing 250 c.f.m of air with an inlet temperature of 380° F., and outlet temperature of 225° F. and a wheel speed of 45,000 r.p.m to produce a free flowing, dry powder, consisting of 10% fluorodeoxyuridine.

[0146] It is to be understood that the above-described embodiments are illustrative of only a few of the many possible specific embodiments which can represent applications of the principles of the invention. Numerous and varied other arrangements can be readily devised in accordance with these principles by those skilled in the art without departing from the spirit and scope of the invention.

Claims

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.