Patent Description:
The present invention relates to composites comprising organic agent, e.g., a drug, entrapped within crystalline lattice of a metal carbonate salt, processes of preparing same, and uses thereof in, for example, medicine.

"Drug release" refers to the process in which drug solutes migrate from its position within the release modifying compound or compounds into the medium. Drug release is an important topic in the field of drug delivery for decades. With advancement in material design and engineering, novel materials with increasing complexity and more functions have been introduced into the development of drug delivery devices and systems.

In general, development of an effective drug delivery system requires understanding of the chemical and physical properties that affect i) the interaction between the drug and the micro- nano- particles (carriers), and ii) the interaction between the micro- nano- carries and the biological environment. Often, the structural characterization of the interaction between drug and carrier is missing. Dopant molecules can be either located between individual crystallites of polycrystalline materials or entrapped inside single crystals where they can mimic the stereochemical features of the host.

Molecules, macromolecules and polymers are vastly used to control drug release. Controlling drug release has direct impact on the bioefficacy, the clinical effect and often times on the quality of life of the target patient population.

There are various factors that influence drug release such as: solute diffusion, polymeric matrix swelling, and material degradation. Fick's law of diffusion provides the fundament for the description of solute transport from polymeric matrices. Fickian diffusion refers to the solute transport process in which the polymer relaxation time (tr) is much greater than the characteristic solvent diffusion time (td). When tr ≈ td, the macroscopic drug release becomes anomalous or non-Fickian.

Nano- and micro-particles hold great promise for controlled and targeted drug release and delivery. An ideal drug carrier should not exert harmful effects on normal cells. It should also satisfy requirements of stability, in vivo biocompatibility, and ability of targeted on-demand release. Inorganic nanomaterials may fulfill most of these requirements. Due to the simplicity of synthesis and modification, it is possible to control the particle size, shape and surface functionalization. Inorganic nanomaterials are usually made of durable and robust materials, which allow encapsulation and protection of sufficient amounts of cargos, preventing pre-leakage and damage to normal cells.

The purpose of mathematical modeling is to simplify the complex release process and to gain insight into the release mechanisms of a specific material system. However, the existing mathematical models may be insufficient in describing more complex material systems, e.g. delivery systems integrating multiple material components, or stimuli-triggered delivery systems in which the interaction with complex physiological condition is involved.

The present invention relates to composition-of-matter comprising at least one composite, said at least one composite comprises a metal carbonate salt and at least one organic agent included within a crystal lattice of said salt, wherein said at least one organic agent comprises a functional group wherein:.

In one embodiment, the metal carbonate is CaCO<NUM>.

In another embodiment, the functional group is selected from the group consisting of: positively charged functional group, a negatively charged functional group, an uncharged group or neutral functional group. In another embodiment, the drug is an anti-cancer and/or anti-inflammatory agent selected from the group consisting of: tetracycline, minocycline, doxorubicin, anthracycline, dichloroacetic acid, ibuprofen, phenacetin, aspirin, RNA, DNA, and tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL).

In another embodiment, the disclosed composition-of-matter is soluble within a pH range of below <NUM>.

In another embodiment, a concentration of the organic agent in the at least one composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration is about <NUM> to <NUM> % by weight.

In another embodiment, the disclosed composition-of-matter comprises a plurality of the composites. In another embodiment, an average diameter of the plurality of the composites is in the range of <NUM> to <NUM>. In another embodiment, at least <NUM>% of the composites have a diameter that varies within a range of less than <NUM>%.

In another embodiment, the disclosed composition-of-matter is characterized by an X-Ray Powder Diffraction which is devoid of peaks at positions that correspond to the organic agent. In another embodiment, the disclosed composition-of-matter is characterized by an X-Ray Powder Diffraction exhibiting at least one peak at a position and/or width that is different from a position and/or width of a corresponding peak in an X-Ray Powder Diffraction of the metal carbonate salt. In another embodiment, the position of the at least one peak is different from the position of the corresponding peak in the X-Ray Powder Diffraction of the metal carbonate salt by at least <NUM>°.

According to the invention, the disclosed composition-of-matter is characterized by a crystal lattice exhibiting at least one cell parameter that is different from a corresponding cell parameter of a pristine crystal lattice of the metal carbonate salt. In another embodiment, the cell parameter is different from a corresponding cell parameter of a pristine crystal lattice of the metal carbonate salt by at least <NUM>Å. According to the invention, a crystal lattice is characterized by a strain of at least <NUM>×<NUM>-<NUM> in one or more axis thereof.

In another embodiment, the disclosed composition-of-matter is prepared by dissolving a least one organic agent in a precursor of the metal carbonate salt, thereby forming a solution, and subjecting the solution to vapors of CO<NUM> and NH<NUM>.

In a further embodiment, the invention provides a pharmaceutical or cosmeceutical product, comprising: (<NUM>) at least one composite, wherein the at least one composite comprises a metal carbonate salt and at least one organic agent included within a crystal lattice of said salt, wherein said at least one organic agent comprises a functional group wherein: said organic agent is a drug;said organic agent is doped within the crystal lattice;said crystal lattice is a single crystal;said composition-of-matter is characterized by an X-Ray Powder Diffraction (XRD) which is devoid of peaks at positions that correspond to said at least one organic agent; and wherein said composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of at least 3xl0-<NUM>;said composition is characterized by an XRD exhibiting at least one peak having a different width compared to a width of a corresponding peak in an XRD of the non-doped metal carbonate salt; and wherein said different width corresponds to a broadening of the at least one peak by <NUM>% to <NUM>% as measured by a full width at half maximum (FWHM); and (<NUM>) a carrier. In another embodiment, the product is a pharmaceutically acceptable injectable matrix. In another embodiment, the disclosed composition-of-matter is for use in monitoring or treating a medical condition.

In a further aspect, the disclosure provides a method for treating a medical condition, comprising administering to a subject in a need thereof the disclosed composition-of-matter comprising at least one composite, wherein the at least one composite comprises a metal carbonate salt and at least one organic agent included within a crystal lattice of the salt, wherein the at least one organic agent comprises a functional group. Any references to methods of treatment by therapy or surgery or in vivo diagnosis methods of this description is to be interpreted as a reference to compounds, pharmaceutical compositions and medicaments of the present invention for use in those methods.

In another embodiment, the medical condition is selected from the group consisting of: cancer, inflammatory disease, and diabetes.

In a further embodiment, the invention provides a method for extending the release period in a physiological environment of at least one organic agent comprising a functional group, the method comprising incorporating at least one organic agent in a crystal lattice of a metal carbonate salt.

In a further embodiment, the invention provides a process for preparing a composition-of-matter comprising at least one composite, the at least one composite comprising a metal carbonate salt, and at least one organic agent included within a crystal lattice of the salt. In another embodiment, the process comprises the steps of: (a) dissolving a least one organic agent in a precursor of the carbonate salt, thereby forming a solution; (b) subjecting the solution to vapors of CO<NUM> and NH<NUM>. In another embodiment, the process further comprises a step of annealing the composition-of-matter. In another embodiment, the precursor of the metal carbonate salt is CaCl<NUM>. In another embodiment, the vapors of CO<NUM> and NH<NUM> is produced by using a solution of (NH<NUM>)<NUM>CO<NUM> in a crystallization chamber.

The present invention provides, in one embodiment, a composition-of-matter comprising at least one composite, wherein the at least one composite comprises a metal carbonate salt and at least one organic agent included within a crystal lattice of said salt, wherein said at least one organic agent comprises a functional group wherein: said organic agent is a drug;said organic agent is doped within the crystal lattice;said crystal lattice is a single crystal;said composition-of-matter is characterized by an X-Ray Powder Diffraction (XRD) which is devoid of peaks at positions that correspond to said at least one organic agent; and wherein said composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of at least 3xl0-<NUM>;said composition is characterized by an XRD exhibiting at least one peak having a different width compared to a width of a corresponding peak in an XRD of the non- doped metal carbonate salt; and wherein said different width corresponds to a broadening of the at least one peak by <NUM>% to <NUM>% as measured by a full width at half maximum (FWHM). As used herein, the unit cell is the smallest component of the crystal lattice and describes the 3D arrangement of atoms in a crystal. The unit cell is represented in terms of its lattice parameters which are the lengths of the cell edges (a, b and c) and the angles between them (alpha, beta and gamma), while the positions of the atoms inside the unit cell are described by the set of atomic positions (xi, yi, zi) measured from a lattice point. X-ray Powder Diffraction (XRD) is typically used to determine the crystal arrangement of a crystal lattice.

In another embodiment, "included within" is engulfed by. In another embodiment, "included within" is entrapped. In another embodiment, "included within" is being chemically adsorbed within the crystal lattice. The inclusion of such organic agent in the crystal lattice of the metal carbonate is also referred to herein and in the art as "doping", with the organic agent being referred to as "dopant". In another embodiment, the organic agent is doped within the crystal lattice.

In another embodiment, metal carbonate is Lithium (Li) carbonate. In another embodiment, metal carbonate is Sodium (Na) carbonate. In another embodiment, metal carbonate is Potassium (K) carbonate. In another embodiment, metal carbonate is Rubidium (RB) carbonate. In another embodiment, metal carbonate is Cesium (Cs) carbonate. In another embodiment, metal carbonate is Beryllium (Be) carbonate. In another embodiment, metal carbonate is Strontium (Sr) carbonate. In another embodiment, metal carbonate is Magnesium (Mg) carbonate. In another embodiment, metal carbonate is Manganese (Mn) carbonate. In another embodiment, metal carbonate is Iron (Fe) carbonate. In another embodiment, metal carbonate is zinc (Zn) carbonate. In another embodiment, metal carbonate is Cobalt (Co) carbonate. In another embodiment, metal carbonate is nickel (Ni) carbonate. In another embodiment, metal carbonate is Copper (Cu) carbonate. In another embodiment, metal carbonate is Silver (Ag) carbonate. In another embodiment, metal carbonate is Francium (Fr) carbonate. In another embodiment, metal carbonate is CaCO<NUM>.

In another embodiment, a functional group is or comprises any one of a charged functional group, a positively charged functional group, a negatively charged functional group, an uncharged group or neutral functional group. In another embodiment, a functional group is or comprises an amino acid. In another embodiment, a functional group is or comprises a carboxylic acid.

In another embodiment, at least one organic agent is doxorubicin (DOX). In another embodiment, a crystal nanoparticle (e.g., of calcium carbonate) is used as a host for DOX. In another embodiment, DOX is incorporated inside metal carbonate (e.g., CaCO<NUM>) single crystals.

In another embodiment, a crystal is characterized by the presence of a rounded cavity at the center of one of the (<NUM>) faces. In another embodiment, the wall of the cavity is stepped, with each step formed by a flat (<NUM>) face and some unspecific rough riser. In another embodiment, moving toward the centre of the crystal, the thickness of the steps decreases from <NUM> to <NUM> to less than <NUM>. In another embodiment, the surface of the (hk. l) face shows the presence of packed spheroid nanoparticles, of <NUM> to <NUM>.

In another embodiment, the composition-of-matter and/or the composite is characterized by an X-Ray Powder Diffraction (XRD) which is devoid of peaks at positions that correspond to a pristine metal carbonate of the metallic element. In another embodiment, the composition-of-matter and/or the composite (or a plurality of composites) is characterized by an X-Ray Powder Diffraction exhibiting at least one peak at a position and/or width that is different from a position and/or width of a corresponding peak in an X-Ray Powder Diffraction of a pristine crystal lattice of the metal carbonate. In another embodiment, the composition-of-matter and/or the composite (or a plurality of composites) is characterized by a crystal lattice exhibiting at least one cell parameter that is different from a corresponding cell parameter of a pristine crystal lattice of the metal carbonate. Hereinthroughout, "peak position" refers to the reflection peaks along the 2θ refractive angle axis in an XRD spectrum, and refers to the peak position at any peak intensity. The peak position is denoted by the <NUM> theta angle. By "devoid of peaks at positions that correspond to a pristine metal carbonate of the metallic element" it is meant that an XRD pattern of the composition-of-matter or of the composites (e.g., nanosized composite) comprised therein do not include peaks in intensity higher than <NUM> counts, or higher than <NUM> counts, which correspond to e.g., international standard values of XRD pattern of a metal carbonate of the metallic element. In another embodiment, by "devoid of" it is meant no more than <NUM> % of the metal carbonate of organic agent, by weight. In another embodiment, by "devoid of" it is meant no more than <NUM> % of the metal carbonate of organic agent, by weight. In another embodiment, by "devoid of" it is meant no more than <NUM> % of the metal carbonate of the organic agent, by weight.

In one embodiment, the term "composite" include composites. In one embodiment, the term "composite" means the inclusion of an organic agent in the crystal lattice of the metal carbonate. In one embodiment, the term "composite" refers to "doping" (the state of the lattice and the organic agent) wherein the organic agent is the dopant. In one embodiment, the term "composite" refers to an organic agent doped within the crystal lattice.

In another embodiment, XRD measurements of a composition-of-mater, a composite, or of a plurality of composites as described herein exhibits a shift at a peak position of at least one peak with respect to the corresponding peak position(s) of a pristine (non-doped) metal carbonate. In another embodiment, a shift is observed in at <NUM> to <NUM> peak position(s) with respect to the corresponding peak position(s) of pristine metal carbonate. In another embodiment, a shift is observed in at <NUM> to <NUM> peak position(s) with respect to the corresponding peak position(s) of pristine metal carbonate. In another embodiment, a shift is observed in at <NUM> to <NUM> peak position(s) with respect to the corresponding peak position(s) of pristine metal carbonate. In another embodiment, a shift is observed in at <NUM> to <NUM> peak position(s) with respect to the corresponding peak position(s) of pristine metal carbonate. In another embodiment, a shift is observed in at <NUM> to <NUM> peak position(s) with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a shift is observed in at <NUM> to <NUM> peak position(s) with respect to the corresponding peak position(s) of pristine metal carbonate. In another embodiment, a shift is observed in at least one peak position with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a shift is observed in at least <NUM> peak positions with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a shift is observed in at least <NUM> peak positions with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a shift is observed in at least <NUM> peak positions with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a shift is observed in at least <NUM> peak positions with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a shift is observed in all peak positions with respect to the corresponding peak positions of pristine metal carbonate.

In another embodiment, a shift in the one or more peak positions is of <NUM>° to <NUM>°. In another embodiment, a shift in the one or more peak positions is of <NUM>° to <NUM>°. In another embodiment, a shift in the one or more peak positions is of <NUM>° to <NUM>°. In another embodiment, a shift in the one or more peak positions is of <NUM>° to <NUM>°. In another embodiment, a shift in the one or more peak positions is of <NUM>° to <NUM>°.

In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°. In another embodiment, a shift in the one or more peak positions is of at least <NUM>°.

In another embodiment, a shift can be the same or different in size and/or direction, for each peak position which is shifted.

In another embodiment, an XRD measurement of a composition-of-mater or of a plurality of composites or of a composite as described herein exhibits a different peak width of at least one peak with respect to the width of corresponding peaks at corresponding positions of a pristine (non-doped) metal carbonate. In another embodiment, a different peak width is observed in at least one peak position, with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a different peak width is observed in at least <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a different peak width is observed in at least <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a different peak width is observed in at least <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a different peak width is observed in at least <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate.

In another embodiment, a different peak width is observed in <NUM> to <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a different peak width is observed in <NUM> to <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a different peak width is observed in <NUM> to <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a different peak width is observed in <NUM> to <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate. In another embodiment, a different peak width is observed in <NUM> to <NUM> peak positions, with respect to the corresponding peak positions of pristine metal carbonate.

In another embodiment, a change in peak width is measured by a change in the full width at half maximum (FWHM) of the peak with respect to corresponding peaks of a pristine metal carbonate. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by <NUM>% to <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by <NUM>% to <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by <NUM>% to <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by <NUM>% to <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by <NUM>% to <NUM>%.

In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%. In another embodiment, the FWHM of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal carbonate by at least <NUM>%.

In another embodiment, both shift in peak position and broadening of peak width are observed in one or more peaks, with respect to the corresponding peaks of a pristine metal carbonate. In another embodiment, both shift in peak position and broadening of peak width are observed in one or all of the peaks, with respect to the corresponding peaks of a pristine metal carbonate.

In another embodiment, a difference in the cell parameter can be a difference of any one or all of the parameters a, b and c of a cell unit, as measured by XRD measurements.

In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by at least <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by at least <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by at least <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by at least <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by at least <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by at least <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by at least <NUM>.

In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by <NUM> to <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by <NUM> to <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by <NUM> to <NUM>. In another embodiment, one or all of the cell parameters of the composite is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal carbonate by <NUM> to <NUM>.

In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of at least <NUM>×<NUM>-<NUM>, such as 3x <NUM>-<NUM> to <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of <NUM>×<NUM>-<NUM> to <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and in the a-axis.

In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of approximately <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of approximately <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of approximately <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of approximately <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of approximately <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of approximately <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of approximately <NUM>×<NUM>-<NUM>. In another embodiment, the composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of approximately <NUM>×<NUM>-<NUM>.

In some embodiments, the composite is characterized by a crystallite size of about <NUM>. In some embodiments, the composite is characterized by a crystallite size of about <NUM>. In some embodiments, the composite is characterized by a crystallite size of about <NUM>. In some embodiments, the composite is characterized by a crystallite size of about <NUM>. In some embodiments, the composite is characterized by a crystallite size of about <NUM>. In some embodiments, the composite is characterized by a crystallite size of about <NUM>. In some embodiments, the composite is characterized by a crystallite size of about <NUM>. In another embodiment, the term "about" means ±<NUM>% of the recited value. In another embodiment, the term "about" means ±<NUM>% of the recited value.

In some embodiments, the composite is characterized by a crystallite size of <NUM> to <NUM>. In some embodiments, the composite is characterized by a crystallite size of <NUM> to <NUM>. In some embodiments, the composite is characterized by a crystallite size of <NUM> to <NUM>. In some embodiments, the composite is characterized by a crystallite size of <NUM> to <NUM>.

In some embodiments, the composite is annealed. In some embodiments, the annealed composite is characterized by a crystallite size of <NUM> to <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of <NUM> to <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of <NUM> to <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>. In some embodiments, the annealed composite is characterized by a crystallite size of about <NUM>.

In aspect of the disclosure, the organic agent comprises or is a substance such as therapeutic agent. In another embodiment, the organic agent comprises or is a tumor-targeting- ligand or moiety. In another embodiment, the organic agent comprises or is a cell proliferation inhibitor. In another embodiment, the organic agent comprises or is a drug. In another embodiment, the organic agent comprises or is a monoclonal antibody. In another embodiment, the organic agent comprises or is a SiRNA. In another embodiment, the organic agent comprises or is an RNA. In another embodiment, the organic agent comprises or is a microRNA. In another embodiment, the organic agent comprises or is a DNA or a plasmid. In another embodiment, the organic agent comprises or is a peptide or a protein. In another embodiment, the organic agent comprises or is an anti-inflammatory agent. In another embodiment, the organic agent comprises or is an antibiotic agent. In another embodiment, the organic agent comprises or is a cardiovascular drug. In another embodiment, the organic agent comprises or is an anti-diabetic agent. In another embodiment, the organic agent comprises or is insulin. In another embodiment, the organic agent comprises or is an anti-cancer drug.

In some embodiments, the term anti-cancer drug, as used herein, refers to a drug used to treat malignancies or cancerous growths that may be used alone or in combination with other treatments. Examples of anti-cancer drugs include but are not limited to: dichloroacetic acid (DCA), doxorubicin, and retinoic acid (RA).

In another embodiment, the organic agent comprises or is doxorubicin. In another embodiment, the organic agent comprises or is dichloroacetic acid (DCA). In another embodiment, the organic agent comprises or is doxorubicin retinoic acid (RA). In another embodiment, the organic agent comprises or is anthracycline. In another embodiment, the organic agent comprises or is ibuprofen (IBU). In another embodiment, the organic agent comprises or is phenacetin (PHE). In another embodiment, the organic agent comprises or is aspirin (ASP). In another embodiment, the organic agent comprises or is a tumor necrosis factor (TNF). In another embodiment, the organic agent comprises or is tumor necrosis factor related apoptosis inducing ligand (TRAIL).

In another embodiment, the organic agent comprises or is drug-delivery system e.g., aimed to deliver active molecules to the site of action.

Non-limiting exemplary drug-delivery system comprises or is liposome.

In some embodiments, the term "liposome" refers to fully closed carrier molecules comprising a spherical lipid membrane which itself is in a liquid crystalline phase or a liquid gel phase, in which an entrapped liquid volume is contained. A variety of therapeutic agents can be entrapped in lipid vesicles, including water-soluble agents that can be stably encapsulated in the aqueous compartment of the liposome, lipophilic compounds that stably partition in the lipid phase of the vesicles, or agents that can be stably or transiently attached, conjugated, adsorbed or expressed on to the outer or inner surfaces of the liposomes, e.g., by electrostatic, covalent or hydrophobic interactions.

Delivering can be for diagnostic reasons (e.g., the liposome includes a diagnostic agent) or for treating (i.e., as a drug delivery tool, delivering a therapeutic agent).

In another embodiment, the organic agent comprises or is attached to a labeled compound. In certain embodiments, the labeled compound comprises a radioisotopic moiety. In another embodiment, the substance is carried by or via the circulatory system to the brain. In another embodiment, the substance to be carried by or via the circulatory system to the brain is a marker or a probe. In another embodiment, the substance to be carried by or via the circulatory system to the brain is a substance that can be precisely identified by radiological methods. In another embodiment, the substance is a labeled compound. In another embodiment, a marker or a probe is an agent useful in carrying out in vivo diagnostic procedures. In another embodiment, a "labeled compound" a "marker" or a "probe", are used interchangeably.

In another embodiment, the amount of labeled compound to be included in the compositions and formulations thereof, as described herein, can be readily determined by the skilled artisan in view of the state of the art and teaching herein provided and depending on the labeled compound selected and the use intended for the composition or formulation, taking into account factors specific to both the labeled compound and the individual to be diagnosed.

In another embodiment, the labeled compound is an isotope. In another embodiment, the labeled compound is a radiolabeled compound. Exemplary labeled compounds include, for example, materials comprising radioisotopes (e.g., <NUM>H, <NUM>C, <NUM>Ga, <NUM>In, <NUM>I, <NUM>I, <NUM>Xe, etc.), material comprising fluorescent moieties (e.g., fluorescein, fluorescein isothiocyanate, etc.), material comprising enzyme (e.g., peroxidase, alkaline phosohatase, etc.), as well as additional labeled compounds known to those of skill in the art. In another embodiment, the labeled compound is an imaging agent for all imaging modalities. In another embodiment, the labeled compound is a contrast agent. In another embodiment, the labeled compound comprises a radionuclide or a paramagnetic metal.

In another embodiment, the selection of the labeled compound and methods used in diagnosis will depend upon the tissue (e.g., malignant or non-malignant or tissue type to be investigated. In another embodiment, the tissue is a brain tissue. In another embodiment, compositions of the invention incorporating <NUM>I are particularly useful for identifying the presence and determining the severity (e.g., initially, during a course of treatment, after treatment) of cancer by gamma-counter.

In another aspect of the disclosure, the organic agent is or comprises unstable molecules. In another embodiment unstable molecules refer to photosensitive molecules (e.g., minocycline). As used herein "photosensitive molecule" refers to a molecule that becomes more reactive when exposed to light (photons).

In another embodiment, the composition-of-matter is being water soluble within a pH of below <NUM>. In another embodiment, the composition-of-matter is being water soluble within a pH range of below <NUM>. In another embodiment, the composition-of-matter is being water soluble within a pH range of <NUM> to <NUM>.

In another embodiment, the composition-of-matter is being not soluble in water within a pH <NUM>. By "not soluble in water" it is meant, in one embodiment, that the Ksp of the composition-of-matter in water is below <NUM>-<NUM>, or in another embodiment below <NUM>-<NUM>, or in another embodiment below <NUM>-<NUM>, below <NUM>-<NUM>, or in another embodiment below <NUM>-<NUM>, or in another embodiment below <NUM>-<NUM>, or in another embodiment below <NUM>-<NUM>, or in another embodiment below <NUM>-<NUM>, or in another embodiment below <NUM>-<NUM>, or in another embodiment below <NUM>-<NUM>.

In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight. In another embodiment, the concentration of the organic agent within the composite ranges from <NUM> % to <NUM>%, by weight.

In another embodiment, a composition of the invention comprises a plurality of composites. In another embodiment, a composition of the invention comprises a plurality of composites or composite and a carrier as described hereinbelow. In another embodiment, a composition of the invention comprises a plurality of composites or composite and a stabilizer as described hereinbelow. In another embodiment, a composition of the invention comprises a plurality of composites or composite and a buffer solution. In another embodiment, a composition of the invention comprises a plurality of composites or composite dissolved within the composition. In another embodiment, a composition of the invention comprises a plurality of composites or composite and has a pH of below <NUM>. In another embodiment, a composition of the invention comprises a plurality of composites or composite undissolved within the composition. In another embodiment, a composition of the invention comprises a plurality of composites or composite and has a pH of above <NUM>. In another embodiment, a composition of the invention comprises a plurality of composites or composite and has a pH value of between <NUM> to <NUM>. In another embodiment, a composition of the invention comprises a plurality of composites or composite and has a pH value of between <NUM> to <NUM>.

In another embodiment, a composite diameter is in the range of <NUM> to <NUM>. In another embodiment, a composite diameter is in the range of <NUM> to <NUM>. In another embodiment, a composite diameter is in the range of <NUM> to <NUM>. In another embodiment, a composite diameter is in the range of <NUM> to <NUM>. In another embodiment, a composite diameter is in the range of <NUM> to <NUM>. In another embodiment, the average diameter of the plurality of the composites within a composition as described herein is in the range of <NUM> to <NUM>. In another embodiment, the average diameter of the plurality of the composites within a composition as described herein is in the range of <NUM> to <NUM>. In another embodiment, the average diameter of the plurality of the composites within a composition as described herein is in the range of <NUM> to <NUM>. In another embodiment, the average diameter of the plurality of the composites within a composition as described herein is in the range of <NUM> to <NUM>. In another embodiment, the average diameter of the plurality of the composites within a composition as described herein is in the range of <NUM> to <NUM>.

In another embodiment, a composition of the invention or a composite is characterized by an X-Ray Powder Diffraction which is devoid of peaks at positions that correspond to the organic agent. In another embodiment, a composition of the invention or a composite is characterized by an X-Ray Powder Diffraction exhibiting at least one peak at a position and/or width that is different from a position and/or width of a corresponding peak in an X-Ray Powder Diffraction of the metal carbonate salt. In another embodiment, the position of the at least one peak is different from the position of the corresponding peak in the X-Ray Powder Diffraction of the metal carbonate salt by at least <NUM>°.

In another embodiment, a composition of the invention is characterized by a crystal lattice exhibiting at least one cell parameter that is different from a corresponding cell parameter of a pristine crystal lattice of the metal carbonate salt. In another embodiment, the cell parameter is different from a corresponding cell parameter of a pristine crystal lattice of the metal carbonate salt by at least <NUM>Å.

In another embodiment, the invention further provides processes and methods for preparing a composition and/or a composite as described herein. In another embodiment, a composition and/or a composite is prepared by dissolving at least one organic agent in a precursor of a metal carbonate salt, thereby forming a solution, and subjecting the solution to vapors of CO<NUM> and NH<NUM>. In another embodiment, the process or method further includes a step of annealing the composition-of-matter or the composite. In another embodiment, the metal carbonate salt is CaCO<NUM>. In another embodiment, the precursor of the metal carbonate salt is CaCl<NUM>. In another embodiment, vapors of CO<NUM> and NH<NUM> are produced by using a solution of (NH<NUM>)<NUM>CO<NUM> in a crystallization chamber. The term "crystallization chamber" is known in the art and refers to a chamber adapted to crystallization of materials, typically comprising a sealed space to liquids and/or gases, and volatile solvents.

In another embodiment, a pharmaceutical or cosmeceutical (also referred to as "cosmeceutic") product comprises the composition-of-matter and/or composite as described herein. In another embodiment, a pharmaceutical or a cosmeceutical product further comprises a stabilizer. In another embodiment, a pharmaceutical or a cosmeceutical product further comprises a diluent. In another embodiment, a pharmaceutical or a cosmeceutical product further comprises a thickener. In another embodiment, a pharmaceutical or a cosmeceutical product further comprises a preservative.

In another aspect of the disclosure, there is provided herein a method for treating a subject by a administering the composition-of-matter the invention. In another embodiment, the subject is afflicted with e.g., inflammation, cancer, diabetes, metabolic disease, infection, cardiovascular disease, renal disease, an endocrine pathology, a viral infection, a liver disease, or any combination thereof.

In another aspect of the disclosure, there are provided methods of diagnosis comprising the steps of a) administering a composition as described herein to an individual in need thereof in an amount effective for detection, wherein the targeted composite comprises a labeled compound; and b) detecting the labeled compound. In another embodiment, the methods further comprise a step (c) comparing a level of labeled compound detected with a reference amount of the labeled compound detected at health or disease. In another embodiment, the reference amount is a threshold amount indicative of a disease.

In another embodiment, a composition comprising a composite as described herein is utilized in photo-dynamic therapy. In another embodiment, a composition comprising a composite as described herein is utilized as a drug carrier, an enhancer or both. In another embodiment, a composition comprising a composite as described herein is utilized for controlled release of drugs including a photosensitizing agent in tumors.

In another embodiment, a composition as described herein is utilized for extending the release of an organic agent as described herein. In another embodiment, a composition as described herein is utilized for extending the release of an organic agent for a total of up to one week. In another embodiment, a composition as described herein is utilized for extending the release of an organic agent for a total of up to <NUM> hours. In another embodiment, a composition as described herein is utilized for extending the release of an organic agent for a total of up to <NUM> hours. In another embodiment, a composition as described herein is utilized for extending the release of an organic agent for a total of up to <NUM> hours. In another embodiment, a composition as described herein is utilized for extending the release of an organic agent for a total of up to <NUM> hours.

In another aspect of the disclosure, a method as described includes doping an organic agent within a metal carbonate lattice as described herein. In another embodiment, provided herein a method for extending the t<NUM>/<NUM> (half-life elimination time) of an organic agent (compared to a non-extended formulation or other known extended release formulations). In another embodiment, there is provided herein a method for minimizing elevated blood peaks and possible side-effects of an organic agent. In another embodiment, there is provided herein a method for decreasing the effective dose of an organic agent. In another embodiment, there is provided herein a method for increasing dosing interval of an organic agent. In another embodiment, there is provided herein a method for increasing tmax of an organic agent. In another embodiment, there is provided herein a method for decreasing Cmax of an organic agent. In another embodiment, there is provided herein a method for extending elimination half-life of an organic agent. The terms Cmax, Tmax, and the half-life elimination time (t<NUM>/<NUM>), are known in the kinetic art.

In another embodiment, there is provided herein a method for extending the release period in a physiological environment of at least one organic agent comprising a functional group, the method comprising incorporating at least one organic agent in a crystal lattice of a metal carbonate salt. In another embodiment, there is provided herein a method for extending the release period in a bodily fluid of at least one organic agent comprising a functional group, the method comprising incorporating (e.g., doping) at least one organic agent in a crystal lattice of a metal carbonate salt. In another embodiment, there is provided herein a method for extending the release period in fat of at least one organic agent comprising a functional group, the method comprising incorporating at least one organic agent in a crystal lattice of a metal carbonate salt. In another embodiment, there is provided herein a method for extending the release period in the blood of at least one organic agent comprising a functional group, the method comprising incorporating at least one organic agent in a crystal lattice of a metal carbonate salt.

In another embodiment, a composition of the invention comprises a solution. In another embodiment, a composition of the invention further comprises one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, or preservatives.

In one embodiment, a composition as described herein comprises a "physiologically acceptable carrier" and "pharmaceutically acceptable carrier". In another embodiment, the phrases "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An adjuvant is included under these phrases.

In one embodiment, a composition as described herein comprises an "excipient" which refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. In one embodiment, excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and/or polyethylene glycols.

Techniques for formulation and administration of drugs are found in "<NPL>on.

In one embodiment, suitable routes of administration, for example, include oral, rectal, transmucosal, transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.

In one embodiment, the disclosed composition (also referred to as "preparation") is administered in a local rather than systemic manner, for example, via injection of the preparation directly into a specific region of a patient's body.

In another embodiment, the composition as described herein is administered via parenteral administration. In another embodiment, parenteral administration is via injection or intravenous infusion.

Oral administration of a composition of the invention, in one embodiment, comprises a unit dosage form comprising tablets, capsules, lozenges, chewable tablets, suspensions, emulsions and the like. Such unit dosage forms comprise a safe and effective amount of the desired compound, or compounds, each of which is in one embodiment, from about <NUM> or <NUM> to about <NUM>/<NUM>, or in another embodiment, about <NUM> or <NUM> to about <NUM>/<NUM>. The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration are well-known in the art. In some embodiments, tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. In one embodiment, glidants such as silicon dioxide can be used to improve flow characteristics of the powder-mixture. In one embodiment, coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. In some embodiments, the selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which may not be critical for the purposes of this invention, and can be readily made by a person skilled in the art.

In one embodiment, the oral dosage form of the present invention comprises a slow release tablets, capsules, lozenges or chewable tablets. In one embodiment, the oral dosage form of the present invention comprises an immediate release tablets, capsules, lozenges or chewable tablets. In one embodiment, the oral dosage form is formulated according to the desired release profile of the pharmaceutical active ingredient as known to one skilled in the art.

Peroral compositions, in some embodiments, comprise liquid solutions, emulsions, suspensions, and the like. In some embodiments, pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. In some embodiments, liquid oral compositions comprise from about <NUM>% to about <NUM>% of the desired compound or compounds, or in another embodiment, from about <NUM>% to about <NUM>%.

In some embodiments, compositions for use in the methods of this invention comprise solutions or emulsions, which in some embodiments are aqueous solutions or emulsions comprising a safe and effective amount of the compounds of the present invention and optionally, other compounds, intended for topical intranasal administration. In some embodiments, the disclosed compositions comprise from about <NUM>% to about <NUM>% w/v of a subject compound, more preferably from about <NUM>% to about <NUM>, which is used for systemic delivery of the compounds by the intranasal route.

In another embodiment, the pharmaceutical compositions are administered by intravenous, intra-arterial, or intramuscular injection of a liquid preparation. In some embodiments, liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment, the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration. In another embodiment, the pharmaceutical compositions are administered intra-arterially, and are thus formulated in a form suitable for intra-arterial administration. In another embodiment, the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration.

Further, in another embodiment, the pharmaceutical compositions are administered topically to body surfaces, and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administration, the compounds of the present invention are combined with an additional appropriate therapeutic agent or agents, prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

In one embodiment, injectables, of the invention are formulated in aqueous solutions. In one embodiment, injectables, of the invention are formulated in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer. In some embodiments, for transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

In one embodiment, the preparations described herein are formulated for parenteral administration, e.g., by bolus injection or continuous infusion. In some embodiments, formulations for injection are presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative. In some embodiments, compositions are suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

The compositions also comprise, in some embodiments, preservatives, such as benzalkonium chloride and thimerosal and the like; chelating agents, such as edetate sodium and others; buffers such as phosphate, citrate and acetate; tonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcystine, sodium metabisulfote and others; aromatic agents; viscosity adjustors, such as polymers, including cellulose and derivatives thereof; and polyvinyl alcohol and acid and bases to adjust the pH of these aqueous compositions as needed. The compositions also comprise, in some embodiments, local anesthetics or other actives. The compositions can be used as sprays, mists, drops, and the like.

In addition, the compositions of the invention may further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCI. , acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween <NUM>, Tween <NUM>, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents (e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.

Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, cellulose (e.g. Avicel™, RC-<NUM>), tragacanth and sodium alginate; typical wetting agents include lecithin and polyethylene oxide sorbitan (e.g. polysorbate <NUM>). Typical preservatives include methyl paraben and sodium benzoate. In another embodiment, peroral liquid compositions also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

In one embodiment, toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. In one embodiment, the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. In one embodiment, the dosages vary depending upon the dosage form employed and the route of administration utilized. In one embodiment, the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. [See e.g., <NPL>].

In one embodiment, depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.

In another embodiment, the amount of a composition to be administered may be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc..

In another embodiment, compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier are also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

In another embodiment, compositions of the present invention are presented in a pack or dispenser device, such as an FDA approved kit, which contain one or more unit dosage forms containing the active ingredient. In one embodiment, the pack, for example, comprise metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, in one embodiment, is labeling approved by the U. Food and Drug Administration (FDA) for prescription drugs or of an approved product insert.

In one embodiment, it will be appreciated that the composite or composites of the present invention can be provided to the individual with additional active agents to achieve an improved therapeutic effect as compared to treatment with each agent by itself. In another embodiment, measures (e.g., dosing and selection of the complementary agent) are taken to adverse side effects which are associated with combination therapies.

As used herein the term "about", unless stated otherwise, refers to ± <NUM>%.

The term "consisting of means "including and limited to".

In those instances where a convention analogous to "at least one of A, B, and C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to "at least one of A, B, or C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B".

Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

In exemplary procedures, a 30x30x50 cm<NUM> crystallization chamber was used. Two <NUM> beakers half-full of (NH<NUM>)<NUM>CO<NUM> (Carlo Erba) and two Petri dishes (d = <NUM>) full of anhydrous CaCl<NUM> (Fluka) were placed inside the chamber. Microplates for cellular culture (Microplate <NUM> well with Lid, IWAKI) containing a round glass cover slip in each well were used. Into each well, <NUM>µL of <NUM> CaCl<NUM> solutions were poured.

In the experiment with DOX, the required amount of DOX (from LC Laboratories) was dissolved in the <NUM> CaCl<NUM> solution. The micro-plate was covered with aluminum foil and a hole was made over every well. After <NUM> days the crystals were washed three times with milli-Q water (resistivity <NUM> MΩ cm at <NUM>; filtered through a <NUM> membrane) and then analyzed. All the experiments were conducted at room temperature. The crystallization trials of CaCO<NUM> in the different conditions were replicated three times.

The optical microscope observations of CaCO<NUM> precipitates were made with a Leica microscope equipped with a digital camera. The SEM observations were conducted in a scansion electronic microscope using a Phenom™ microscope (FEI) for uncoated samples and a Hitachi FEG <NUM> microscope for samples after coating with gold.

Atomic absorption measurements of calcium and magnesium were carried out with Perkin Elmer AAnalyst <NUM> flame and graphite furnace (HGA <NUM>) spectrometer equipped with a Zeeman effect background corrector, and an automatic data processor. A <NUM>-µl volume sample solution obtained by precipitated dissolution in <NUM> HNO<NUM>, was injected by an auto sampler. A multi element hollow cathode lamp of analytes was used as radiation source. Three measurements were carried out for each sample.

X-ray diffraction analysis was performed utilizing high resolution synchrotron powder diffraction instrument: <NUM>-BM beamline at Argonne's Advanced Photon Source (Argonne National Laboratory, Argonne, USA). Collection temperature <NUM>, calibrated wavelength <NUM>Å. Powders were packed and sealed into polyimide tubes and placed in the beam. Data collected from <NUM> crystal two-axis analyzer detector.

Confocal laser scanning microscopy analysis was carried out on cells cultured onto glass coverslips, fixed with <NUM>% paraformaldehyde (Sigma) in PBS and mounted with an antifade glycerol-based medium. Samples were observed with a LEICA TCS SP2 confocal laser scanning microscope (Leica Instruments) without any further modification, the fluorescence of DOX molecule was used to obtain the fluorescence images.

The kinetic of the drug (e.g. DOX) release was studied by UV-Vis spectroscopy (Perkin-Elmer Lambda <NUM>). The crystals dissolution was conducted in a <NUM> citrate buffer solution at pH <NUM> following the absorption intensity of the drug molecules at <NUM>.

MCF10A cells (ATCC: crl-<NUM>) were cultured in (<NUM>:<NUM>) Dulbecco's Modified Eagle's Medium (DMEM) / Nutrient Mixture F-<NUM> Ham (Gibco-Life Technologies Corporation) supplemented with <NUM>% horse serum, <NUM> ng/ml epidermal growth factor (EGF), <NUM> ng/ml cholera toxin, <NUM> ng/ml hydrocortisone and <NUM>/ml insulin (Gibco-Life Technologies Corporation). Cells were infected using a puromycin-resistant retroviral construct containing an oncogenic form of Ras (pBabe-RasV12) or using the empty vector (pBabe). Forty-eight hours post infection cells were selected using <NUM> puromycin for <NUM> days.

In the present example, doxorubicin (DOX), an anthracycline drug widely used in chemotherapy, was used as a model molecule to study the entrapment in calcite crystals and its release.

In exemplary procedures, calcium carbonate/DOX hybrid crystal precipitation was conducted at room temperature by controlled diffusion of CO<NUM> and NH<NUM> vapors into <NUM> calcium chloride solutions containing different concentrations of DOX. The precipitation process was stopped after <NUM> days.

In the absence of DOX, only rhombohedral single crystals of calcite are precipitated. In these crystals, characterized by an average size of <NUM>, only the typical (<NUM>) faces are observable. The presence of DOX influenced the crystallization process as a function of its initial concentration in solution. At low concentrations, <NUM>·<NUM>-<NUM> mM and <NUM>·<NUM>-<NUM> mM, DOX did not affect the precipitation of calcite. At a concentration of <NUM>·<NUM>-<NUM> mM the crystals became hoppered, showing holes on the {<NUM>} rhombohedral faces. Increasing the concentration of DOX to <NUM>·<NUM>-<NUM> mM and <NUM> results both in the observation of the co-presence of spherulites with aggregated rhombohedral crystals and in the strong inhibition of the precipitation that is usually associated with the deposition of few aggregates and submicron sized particles. Calcite was the only crystalline phase detected by X-ray powder diffraction in the control experiments and in the experiments where <NUM>·<NUM>-<NUM> mM, <NUM>·<NUM>-<NUM> mM or <NUM>·<NUM>-<NUM> mM DOX was used. When a higher concentration of DOX was used (<NUM>·<NUM>-<NUM> mM and <NUM>), small amounts of vaterite co-precipitated with calcite (<FIG>). The optimal initial concentration of DOX was <NUM>·<NUM>-<NUM> mM.

The textural features of the DOX/calcite hybrid crystals were further investigated by scanning electron microscopy, as illustrated in <FIG>. Each crystal was characterized by the presence of a rounded cavity at the center of one of the {<NUM>} faces. The diameter of this cavity increased from inside to outside and changed among crystals. The wall of the cavity was stepped, with each step formed by a flat (<NUM>) face and some unspecific rough riser. Moving toward the centre of the crystal, the thickness of the steps decreases from about <NUM> to less than <NUM>. The surface of the (hk. l) face showed the presence of packed spheroid nanoparticles, of about <NUM>, on which particles of few nanometers were observed. The formation of hoppers was explained by limited diffusion of constituent ions towards the growing crystal face. In this case, formation of additional crystalline faces on the hole walls supports a mechanism of thermodynamic control of growth spiraling due to the screw dislocations induced by the DOX - calcite interaction. This aspect was further investigated by X-ray diffraction analysis.

To examine the influence of DOX on the crystal structure of the hybrid crystals formed in the presence of the optimal concentration <NUM>·<NUM>-<NUM> mM of DOX, high-resolution synchrotron powder diffraction (HRXRD) measurements were carried out on the <NUM>-BM beamline (Argonne National Laboratory, Argonne, USA). These measurements allowed, by determination of lattice distortion parameters, to ascertain whether DOX indeed is incorporated into the calcite lattice. It was already demonstrated that when organic molecules are incorporated into an inorganic crystalline host they induce lattice distortions and lead to unique microstructures. This has been shown both in biogenic crystals as well as in bio-inspired calcite and ZnO. The procedure of the measurements has been described extensively elsewhere. In short, Rietveld analysis and line profile analysis were applied on the full diffraction patterns.

The measurements were performed on the control calcite sample, DOX/calcite hybrid sample and on the DOX/calcite hybrid sample after a mild thermal annealing at <NUM>° C for <NUM>. Analysis of the diffraction patterns indicates a single calcite phase in all measured samples (see <FIG> as an example).

The (<NUM>) diffraction peak of DOX/calcite hybrid crystals shifts towards a smaller Bragg angle, which indicates lattice expansion compared to the control sample (see <FIG>). This lattice distortion is due to the incorporation of DOX inside the calcite crystal. In <FIG> the (<NUM>) diffraction peak of the hybrid crystal is split. The splitting is due to the fact that the majority of the crystals well incorporate DOX, while some of them do not. After the mild annealing treatment the diffraction peak shifts back to that of the control sample. The lattice distortion relaxes as the organics are burnt out. The post-annealing peak becomes considerably wider, the FWHM doubles (from <NUM>° to <NUM>°) and is symmetrical. This phenomenon was also observed in previous cases such as those of biogenic crystals and for crystals that contained amino acids incorporation. The cause of the broadening after annealing has been discussed previously, but in short, it stems from the formation of new interfaces as the organics are burnt out.

Rietveld structure refinement analysis was applied to all diffraction spectra utilizing the GSAS software and the EXPGUI interface. This analysis determined the lattice distortion, see Table <NUM> presenting quantitative data of lattice parameters, lattice distortions, unit cell volume and goodness of fit parameters for the Rietveld refinement fit (χ2). The strain along the a and c axes are almost equivalent (~<NUM>·<NUM>-<NUM>) and of positive sign (i.e., expansion) (see <FIG>). The volume change due to the incorporation is <NUM> %, which may imply that the level of DOX incorporation is about <NUM>% in volume.

Line profile analysis was further performed on the diffraction spectra. This allowed extraction of microstructural parameters (coherence length and micro-strain fluctuations). Single diffraction peaks were fitted to a Voigt function, which enabled independent evaluation of the contributions of the Lorentzian and Gaussian types, which correlate to the coherence length (crystalline size) and micro-strain fluctuations respectively. The profile fitting was performed using the Gnuplot <NUM> interface on the most intense calcite (<NUM>) peak (<FIG>). The results revealed noticeable reduction in crystallite size (threefold) upon annealing, which were accompanied by an increase in the averaged micro-strain fluctuations, similar to biogenic and other biomimetic crystals in which intra-crystalline organic molecules exist.

An evaluation of the total amount of DOX adsorbed in the calcite crystal was carried out by combining UV-vis spectroscopy, for the determination of DOX, and flame atomic absorption spectroscopy, for the determination of Ca<NUM>+. A loading of <NUM> ± <NUM> wt% was determined.

The spatial distribution of DOX in calcite crystals was also evaluated by assessing the DOX fluorescence by confocal laser scanning microscopy. <FIG> show the fluorescence images obtained by a z-stacking of DOX containing crystals. All longitudinal sections of the crystal display a homogeneous fluorescence intensity indicating that DOX was uniformly embedded in the crystal and that the drug is not simply adsorbed on the crystal surface. No luminescence could be detected from the reference crystal grown in the absence of DOX.

As expected, the drug carrier was pH-sensitive (<FIG>). The DOX release kinetics from DOX/calcite crystals was measured by UV-Vis spectrophotometry in a citrate buffer at a pH of <NUM>. The release of DOX was active for <NUM> hrs. The same measurements performed at a pH of <NUM> in PBS (phosphate buffered saline) did not show any detectable release of DOX. The drug release from the hybrid crystals is controlled by the dissolution rate of the CaCO<NUM> host crystals. In PBS no significant calcite crystals dissolution was observed (see <FIG>) and as a consequence no UV signal at <NUM>.

The pharmacological activity of DOX/calcite hybrid crystals was tested in vitro on cell cultures. The in vitro cancer model used is based on the activation of the Ras oncogenic pathway. Human non-tumorigenic breast epithelial cells (MCF10A) were subjected to retroviral (pBabe vector) infection to express the oncogenic form of Ras.

The transformed MCF10A cells were cultured in the medium in the presence of DOX/calcite hybrid crystals or calcite crystals as control. Cell growth was followed by cell counting. The contrast phase optical microscopy images at <NUM> and <NUM> from plating are presented in <FIG>.

Pure calcite crystals revealed no toxic effect on MCF10A transformed cells. MCF10A cells in the presence of these crystals followed the same cell growth curve of the control cells. In contrast the DOX/calcite hybrid crystals demonstrated heavy toxic effects for the cells (<FIG>) and after <NUM> hours the mortality reached <NUM>%. This result suggests that the activity of DOX is retained in the crystal and that the DOX/calcite hybrid crystals are able to release the drug in proper concentrations. The MCF10A transformed cells induce specifically a drug release as a consequence of the cell metabolism, which decreases the local pH as a result of the increased lactate production (see <FIG>).

The DOX uptake by MCF10A RasV12 cells from the DOX/calcite hybrid crystals was assessed by following DOX fluorescence signal, using confocal laser fluorescence microscopy (<FIG>). After <NUM> hrs of cell culturing in the presence of the crystals, the RasV12 MCF10A cell fluorescence images clearly indicated that the DOX molecules were inside the cells. Confocal measurements on the cells growth on pure calcite did not show the typical fluorescence of DOX. The DOX signal was clear on the dissolving surfaces of the DOX/calcite crystals (see arrows in <FIG>).

In conclusion, a complete structural and biological characterization of DOX/CaCO<NUM> crystals as a system to specifically target drugs to particular cells or tissues is provided. This pH sensitive CaCO<NUM> solubility can release entrapped molecules only when the dissolution of the crystals occurs and allows zero-leakage of drugs at the physiological pH. The main results can be summarized in the following points: i) calcite is able to host DOX molecules efficiently; ii) the entrapment occurs along specific crystallographic directions; iii) the release of DOX is controlled by pH and occurs preferentially in proximity of the surface of cancer cells; iv) the released drug molecules are uptaken by the cancer cells, killing them.

Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

In the present example, other molecules were incorporated in calcite crystals, and were tested in respects to their entrapment in calcite crystals.

The tested drug molecule were anti-inflammatory drugs: ibuprofen (IBU), phenacetin (PHE), aspirin (ASP), and minocycline (MIN); anticancer drugs: dichloroacetic acid (DCA), and retinoic acid (RA).

In additional example, the tested molecule was liposome which may be a promising new drug-delivery system aimed to deliver active molecules to the site of action.

In exemplary procedures, a 30x30x50 cm<NUM> crystallization chamber was used. Two <NUM> beakers half-full of (NH<NUM>)<NUM>CO<NUM> (Carlo Erba) and two Petri dishes (d = <NUM>) full of anhydrous CaCl<NUM> (Fluka) were placed inside the chamber. Microplates for cellular culture (Microplate <NUM> well with Lid, IWAKI) containing a round glass cover slip in each well were used. Into each well, <NUM>µL of <NUM> CaCl<NUM> solutions were poured. In the experiment with drugs, different amount of various drugs was dissolved in the <NUM> CaCl<NUM> solution. The micro-plate was covered with aluminum foil and a hole was made over every well. After <NUM> days the crystals were washed three times with milli-Q water (resistivity <NUM> MΩ cm at <NUM>; filtered through a <NUM> membrane) and then analyzed. All the experiments were conducted at room temperature.

Rietveld structure refinement analysis was applied to all diffraction spectra utilizing the GSAS software and the EXPGUI interface. The strain along the a and c axes are shown in <FIG>.

Table <NUM> below and <FIG> summarize the quantitative data of lattice distortions of calcite crystal following incorporation of IBU, PHE, ASP, or MIN.

Table <NUM> below and <FIG> summarize the quantitative data of lattice distortions of calcite crystal following incorporation of DCA, RA.

Table <NUM> below and <FIG> summarize the quantitative data of lattice distortions of calcite crystal following incorporation of liposome.

Claim 1:
A composition-of-matter comprising at least one composite, said at least one composite comprises a metal carbonate salt and at least one organic agent included within a crystal lattice of said salt, wherein said at least one organic agent comprises a functional group wherein:
said organic agent is a drug;
said organic agent is doped within the crystal lattice;
said crystal lattice is a single crystal;
said composition-of-matter is characterized by an X-Ray Powder Diffraction (XRD) which is devoid of peaks at positions that correspond to said at least one organic agent; and wherein said composite is characterized by a crystal lattice strain in the c-axis and/or in the a-axis of at least <NUM>×<NUM>-<NUM>;
said composition is characterized by an XRD exhibiting at least one peak having a different width compared to a width of a corresponding peak in an XRD of the non-doped metal carbonate salt; and wherein said different width corresponds to a broadening of the at least one peak by <NUM>% to <NUM>% as measured by a full width at half maximum (FWHM).