Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
  • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
  • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
  • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
  • A61K47/6933—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
  • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
  • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
  • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
  • A61K47/6939—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/32—Antioestrogens

Definitions

• the present invention is in the field of nanoparticles. More particularly, the invention relates to nano-dispersions of water-soluble and stable nano-sized particles consisting of inclusion complexes of active compounds such as pharmaceutical drugs or pesticides surrounded by and entrapped within suitable amphiphilic polymers, and methods of producing said nano-dispersions.
• Nanotechnology is not an entirely new field: colloidal sols and supported platinum catalysts are nanoparticles. Nevertheless, the recent interest in the nanoscale has produced, among numerous other things, materials used for and in drug delivery. Nanoparticles are generally considered to be solids whose diameter varies between 1-1000 nm.
• liposomes are microscopic spherical structures composed of phospholipids that were first discovered in the early 1960s. In aqueous media, phospholipid molecules, being amphiphilic, spontaneously organize themselves in self-closed bilayers as a result of hydrophilic and hydrophobic interactions.
• liposomes The resulting vesicles, referred to as liposomes, therefore encapsulate in the interior part of the aqueous medium in which they are suspended, a property that makes them potential carriers for biologically active hydrophilic molecules and drugs in vivo. Lipophilic agents may also be transported, embedded in the liposomal membrane. Liposomes resemble the bio-membranes and have been used for many years as a tool for solubilization of biological active molecules insoluble in water. They are non-toxic and biodegradable and can be used for specific target organs. Liposome technology allows for the preparation of smaller to larger vesicles, using unilamellar (ULV) and multilamellar (MLV) vesicles.
• UUV unilamellar
• MLV multilamellar
• MLVs are produced by mechanical agitation.
• Large ULVs are prepared from MLV by extrusion under pressure through membranes of known pore size. The sizes are usually 200 nm or less in diameter; however, liposomes can be custom designed for almost any need by varying lipid content, surface change and method of preparation.
• liposomes As drug carriers, liposomes have several potential advantages, including the ability to carry a significant amount of drug, relative ease of preparation, and low toxicity if natural lipids are used.
• common problems encountered with liposomes include: low stability, short shelf-life, poor tissue specificity, and toxicity with non-native lipids. Additionally, the uptake by phagocytic cells reduces circulation times.
• Cyclodextrins are crystalline, water-soluble, cyclic, non-reducing oligo- saccharides built from six, seven, or eight glucopyranose units, referred to as alpha, beta and gamma cyclodextrin, respectively, which have long been known as products that are capable of forming inclusion complexes.
• the cyclodextrin structure provides a molecule shaped like a segment of a hollow cone with an exterior hydrophilic surface and interior hydrophobic cavity.
• the hydrophilic surface generates good water solubility for the cyclodextrin and the hydrophobic cavity provides a favorable environment in which to enclose, envelope or entrap the drug molecule. This association isolates the drug from the aqueous solvent and may increase the drug's water solubility and stability.
• most cyclodextrins had been no more than scientific curiosities due to their limited availability and high price.
• cyclodextrins and their chemically modified derivatives are now available commercially, generating a new technology: packing on the molecular level. Cyclodextrins are, however, fraught with disadvantages. An ideal cyclodextrin would exhibit both oral and systemic safety.
• cyclodextrins It would have water solubility greater than the parent cyclodextrins yet retain or surpass their complexation characteristics.
• the disadvantages of the cyclodextrins include: limited space available for the active molecule to be entrapped inside the core, lack of pure stability of the complex, limited availability in the marketplace, and high price.
• Microencapsulation is a process by which tiny parcels of a gas, liquid, or solid active ingredient (also referred to herein and used interchangeably with "core material”) are packaged within a second material for the purpose of shielding the active ingredient from the surrounding environment. These capsules, which range in size from one micron (one-thousandth of a millimeter) to approximately seven millimeters, release their contents at a later time by means appropriate to the application.
• microcapsulation covers several technologies, where a certain material is coated to obtain a micro-package of the active compound. The coating is performed to stabilize the material, for taste masking, preparing free flowing material of otherwise clogging agents etc. and many other purposes. This technology has been successfully applied in the feed additive industry and to agriculture. The relatively high production cost needed for many of the formulations is, however, a significant disadvantage.
• nanoencapsulation and nanoparticles which are advantageously shaped as spheres and, hence, nanospheres
• two types of systems having different inner structures are possible: (i) a matrix-type system composed of an entanglement of oligomer or polymer units, defined as nanoparticles or nanospheres, and (ii) a reservoir-type system, consisting of an oily core surrounded by a polymer wall, defined as a nanocapsule.
• Dendrimers are a class of polymers distinguished by their highly branched, tree-like structures. They are synthesized in an iterative fashion from ABn monomers, with each iteration adding a layer or "generation" to the growing polymer. Dendrimers of up to ten generations have been synthesized with molecular weights in excess of 106 kDa. One important feature of dendrimeric polymers is their narrow molecular weight distributions. Indeed, depending on the synthetic strategy used, dendrimers with molecular weights in excess of 20 kDa can be made as single compounds. Dendrimers, like liposomes, display the property of encapsulation, and are able to sequester molecules within the interior spaces.
• Nano-sized particles can be used in pharmacology, in the production of food additives, cosmetics, and agriculture, as well as in pet foods and veterinary products, amongst other uses.
• the present invention provides nano-dispersions of nano-particles and methods for the production of soluble nano-particles and, in particular, inclusion complexes of water-insoluble lipophilic and water-soluble hydrophilic organic materials.
• An inclusion complex is a complex in which one component, designated “the host”, forms a cavity in which molecular entities of a second chemical species, designated "the guest”, are located.
• the solu-nanoparticles comprise inclusion complexes in which the host is the amphiphilic polymer or group of polymers and the guest is the active compound molecules wrapped and fixated or secured within the cavity or space formed by said polymer host.
• the inclusion complexes contain the active compound molecules, which interact with the polymer by non-valent interactions and form a polymer-active compound as a distinct molecular entity.
• the particles comprising the inclusion complexes are nano-level in size, and no change occurs in the drug molecule itself when it is enveloped, or advantageously wrapped, by the polymer.
• the outer surface of the inclusion complexes is comprised of a polymer that carries the active compound, when it is a drug molecule, to the target destination.
• the drugs and pharmaceuticals within the complex are able to reach specific areas of the body readily and quickly.
• the polymer and active compound selected will also provide nano-particles capable of multi-level, multi-stage and/or controlled release of the drug or pharmaceutical vvithin the body.
• the present invention provides nano-dispersions of water- soluble and stable nano-sized particles comprising hydrophilic inclusion complexes consisting essentially of an active compound surrounded by and entrapped within an amphiphilic polymer, wherein said active compound is in a non-crystalline state and said inclusion complex is stabilized by non-valent interactions between the active compound and the surrounding amphiphilic polymer, and wherein said inclusion complex is selected from the group consisting of: (i) an inclusion complex wherein the active compound is clarithromycin and the amphiphilic polymer is alginate or chitosan or the active compound is azithromycin and the amphiphilic polymer is a polysaccharide or polyvinyl alcohol; (i) an inclusion complex wherein the active compound is donepezil hydrochloride and the amphiphilic polymer is a polysaccharide; (i)
• Fig. 1 illustrates the size distribution of nano-particles comprising clarithromycin-chitosan inclusion complexes (#10-134, Table 3) having a size of approximately 838 nm, as measured by light diffraction (ALV).
• Fig. 2 illustrates the in vitro release via a dialysis membrane of commercial clarithromycin (Clari) in comparison with particles comprising clarithromycin inclusion complexes with PVA (S-Clari#-34, Table 3) or nano-particles comprising clarithromycin inclusion complexes with chitosan (S-Clari#135, Table 3).
• Fig. 1 illustrates the size distribution of nano-particles comprising clarithromycin-chitosan inclusion complexes (#10-134, Table 3) having a size of approximately 838 nm, as measured by light diffraction (ALV).
• Fig. 2 illustrates the in vitro release via a dialysis membrane of commercial clarithromycin (Clari)
• FIG. 3 illustrates the size distribution of nano-particles comprising azithromycm-chitosan inclusion complexes (#10-148/2, Table 4) having a size of approximately 362 nm, as measured by light diffraction (ALV).
• Fig. 4 illustrates X-ray spectra of 10-month old azithromycin-chitosan inclusion complex sample (bottom trace) compared to the commercially available azithromycin (upper trace).
• FIG. 5 illustrates the size distribution of nano-particles comprising itraconazole-modified starch inclusion complexes (#23-120, Table 5) having a size of approximately 414 nm, as measured by light diffraction (ALV).
• FIG. 6A-6B illustrates differential scanning calorimetry (DSC) analysis of commercial crystalline itraconazole (12A) and of nano-particles comprising itraconazole-polyacrylic acid inclusion complexes (#IT-56, Table 5).
• Fig. 7 illustrates the size distribution of nano-particles comprising paclitaxel- gelatin inclusion complexes (# 25-85, Table 6) having a size of approximately 179 nm, as measured by light diffraction (ALV).
• FIG. 8 illustrates the size distribution of nano-particles comprising donepezil- modified starch inclusion complexes (#LG-7-51, Table 7) having a size of approximately 600 nm, as measured by light diffraction (ALV).
• Fig. 7 illustrates the size distribution of nano-particles comprising paclitaxel- gelatin inclusion complexes (# 25-85, Table 6) having a size of approximately 179 nm, as measured by light diffraction (ALV
• the nanoparticles of the present invention comprise the insoluble or soluble active compound or core, wrapped within a water-soluble amphiphilic polymer.
• a variety of different polymers can be used according to the present invention for any ofthe selected active compound, that can be lipophilic or hydrophilic.
• the polymer, or groups of polymers is selected according to an algorithm that takes into account various physical properties of both the active lipophilic or hydrophilic compound and the interaction of this compound within the resulting active compound /polymer nano-particle. This technology is fully described in the above-referenced US 2003/0129239.
• One important parameter in the choice of the polymer or polymers is the
• HLB i.e., the measure of the molecular balance of the hydrophilic and lipophilic portions of the compound.
• lipophilic molecules have a HLB of less than 6, and hydrophilic molecules have a HLB of more than 6.
• the HLB of the polymer is selected in such a way that, after combining to it the active compound, the total resulting HLB value of the complex will be greater than 8, rendering the complex water-soluble.
• non-crystalline refers to materials both in amorphous or disordered crystalline state. In preferred embodiments, the material is amorphous.
• the amorphous state is preferred for drug delivery as it may indeed enhance bioavailability.
• water-soluble nano-particles aqueous solution of nano-particles
• nano-dispersion aqueous solution of nano-particles
• stable nano-dispersion and “nano-dispersion of water-soluble and stable nano-sized particles” are used interchangeably and both intend to refer to the same thing, namely, to a stable fine dispersion of the nanoparticles.
• the nano-particles and of the inclusion complexes has more than one meaning.
• the nano-particles should be stable as part of a nanocomplex over time, while remaining in the dispersion media.
• the nano-dispersions are stable over time without separation of phases. Furthermore, the amorphous state should be also retained over time. It is worth noting that in the process used in the present invention, the components of the system do not result in micelles nor do they form classical dispersion systems.
• the technology of the present invention causes the following: (i) after forming the inclusion complex, the poorly soluble or insoluble (or even non-wettable) active compound becomes pseudo-soluble.
• the material becomes soluble and visually transparent, rather than opaque; (ii) after dispersion of the active compound to nano-size and fixation by the polymers to form an inclusion complex, enhanced solubility in physiological fluids, in vivo, improved absorption, and improved biological activity, as well as transmission to a stable non-crystalline, preferably amorphous, state, are achieved ; (iii) a crystalline biologically-active compound becomes amorphous and thus exhibits improved biological activity.
• not less than 80% of the nano-particles in the nano-dispersion are within the size range, when the size deviation is not greater than 20%, and the particle size is within the nano range, namely less than 1000 nm.
• the polymer molecule in the polymer solution "wraps" the active compound via non-valent interactions.
• non-valent is intended to refer to non- covalent, non-ionic and non-semi-polaric bonds and/or interactions, and includes, for example, electrostatic forces, Van der Waals forces, and hydrogen-bonds between the polymer and the active compound in the inclusion complex such that the non-valent interactions fixate the active compound within the polymer which thus reduces the molecular flexibility of the active compound and polymer.
• electrostatic forces Van der Waals forces
• hydrogen-bonds between the polymer and the active compound in the inclusion complex such that the non-valent interactions fixate the active compound within the polymer which thus reduces the molecular flexibility of the active compound and polymer.
• the formation of any valent bonds could change the characteristics or properties of the active compound.
• the formation of non-valent bonds preserves the structure and properties of the lipophilic compound, which is particularly important when the active compound is a pharmaceutical.
• the present invention provides a nano-dispersion of water-soluble and stable nano-sized particles comprising hydrophilic inclusion complexes consisting essentially of an active compound surrounded by and entrapped within an amphiphilic polymer, wherein said active compound is in a non-crystalline state and said inclusion complex is stabilized by non-valent interactions between the active compound and the surrounding amphiphilic polymer, and wherein said inclusion complex is selected from the group consisting of: (i) an inclusion complex wherein the active compound is a macrolide antibiotic selected from clarithromycin and azithromycin, and when the active compound is clarithromycin then the amphiphilic polymer is alginate or chitosan, and when the active compound is azithromycin then the amphiphilic polymer is a polysaccharide or polyvinyl alcohol; (ii) an inclusion complex wherein the active compound is donepezil hydrochloride and the amphiphilic polymer is a polysaccharide; (iii) an inclusion complex wherein the active compound is an azo
• the nano-particles of the invention comprise inclusion complexes in which the active compound is the macrolide antibiotic clarithromycin or the first azalide antibiotic, azithromycin.
• the active compound is the macrolide antibiotic clarithromycin or the first azalide antibiotic, azithromycin.
• macrolides are large, lipophilic molecules, broad-spectrum antibiotics active against a wide variety of bacteria and can be used both in human and veterinary medicine.
• Macrolide antibiotics are particularly useful in treating respiratory infections.
• Polymers suitable for the preparation of inclusion complexes with the macrolide antibiotics are polysaccharides, in natural form or modified. In one embodiment, the polysaccharide is starch that should preferably have a large proportion of linear chains, i.e.
• starch with high contents of amylose the constituent of starch in which anhydroglucose units are linked by (-D-1,4 glucosidic bonds to form linear chains, and low contents of amylopectin, a constituent of starch having a polymeric, branched structure.
• the levels of amylose and amylopectin and their molecular weight vary between different starch types.
• starch e.g. corn or potato starch, can be modified, for example by increasing its hydrophilicity by acid hydrolysis, e.g., with citric acid, and/or by reaction with an agent, e.g. polyethylene glycol (PEG) and/or hydrogen peroxide.
• PEG polyethylene glycol
• starch can be subjected to thermal treatment, for example at 160-180°C, for about 30-60 min, to reduce the amount of branching, optionally after treatment with PEG and/or hydrogen peroxide (hereinafter designated "thermodestructed starch")
• the nano-particles of the invention comprise inclusion complexes in which the active compound is clarithromycin and the amphiphilic polysaccharide is selected from the group consisting of starch, chitosan and alginate, e.g. sodium alginate.
• the starch may be hydrolyzed starch, starch modified by different amounts of PEG, preferably PEG-400, and or by H 2 0 2 , and thermodestructed starch.
• the nano-particles of the invention comprise inclusion complexes in which the active compound is azithromycin and the amphiphilic polysaccharide is chitosan or an alginate derivative such as propylene glycol alginate (Manucol ester B).
• the nano-particles of the invention comprise inclusion complexes in which the active compound is azithromycin and the amphiphilic polymer is polyvinyl alcohol (PVA).
• the nano-particles of the invention comprise inclusion complexes in which the active compound is donepezil hydrochloride and the amphiphilic polymer is a polysaccharide.
• Donepezil, l-benzyl-4-((5,6-dimethoxy- l-indanon)-2-yl)methylpiperidine, and analogues were described in US 4,895,841 as acetylcholinesterase inhibitors and useful for treatment of various kinds of dementia including Alzheimer senile dementia, Huntington's chorea, Pick's disease, and ataxia.
• Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonirrile and practically insoluble in ethyl acetate and in n-hexane.
• Donepezil hydrochloride is available for oral administration in film-coated tablets containing 5 or 10 mg of donepezil hydrochloride for treatment of mild to moderate dementia of the Alzheimer's type.
• Amorphous donepezil hydrochloride is mentioned in the patents US 5,985,864 and US 6, 140,321.
• US 6,734, 195 disclosed that wet granulation of donepezil hydrochloride yields, after drying and milling, a stable granulate that uniformly contains donepezil hydrochloride amorphous.
• water-soluble nano-particles are provided comprising inclusion complexes in which the donepezil hydrocloride in a non-crystalline state, e.g.
• the amorphous state is wrapped by an amphiphilic polysaccharide and is fixated/stabilized by non-valent interactions with the surrounding amphiphilic polysaccharide.
• the polysaccharide is alginate.
• the polysaccharide is sodium starch glycolate.
• the polysaccharide is pregelatinized modified starch.
• the nano-particles of the invention comprise inclusion complexes in which the active compound is an azole compound and the amphiphilic polymer is selected from the group consisting of a polysaccharide, polyacrylic acid, a copolymer of polyacrylic acid, polymethacrylic acid and a copolymer of polymethacrylic acid.
• Azole compounds play a key role as antifungals in agriculture and in human mycoses and as nonsteroidal antiestrogens in the treatment of estrogen-responsive breast tumors in postmenopausal women.
• This broad use of azoles is based on their inhibition of certain pathways of steroidogenesis by high-affinity binding to the enzymes sterol 14-demethylase and aromatase.
• Azole fungicides show a broad antifungal activity and are used either to prevent fungal infections or to cure an infection. Therefore, they are important tools in integrated agricultural production. According to their chemical structure, azole compounds are classified into triazoles and imidazoles; however, their antifungal activity is due to the same molecular mechanism.
• Azole fungicides are broadly used in agriculture and in human and veterinary antimycotic therapies.
• an "azole compound" refers to irnidazole and triazole compounds for human or veterinary application or for use in the agriculture.
• the azole compound is selected from azole fungicides used in many different antimycotic formulations including, but not limited to the triazoles terconazole, itraconazole, and fluconazole, and the imidazoles clotrimazole, miconazole, econazole, ketoconazole, tioconazole, isoconazole, oxiconazole, and fenticonazole.
• the azole compound is selected from azoles that act as nonsteroidal antiestrogens and can be used in the treatment of estrogen- responsive breast tumors in postmenopausal women, including, but not limited to letrozole, anastrozole, vorozole, and fadrozole.
• the azole compound is an azole fungicide useful in the agriculture including, but not limited to, the triazoles bitertanol, cyproconazole, difenoconazole, epoxiconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, metconazole, myclobutanil, penconazole, propiconazole, tebuconazole, triadimefon, triadimenol, and triticonazole, and the imidazoles imazalil, prochloraz, and triflumizole.
• the azole compound is a nonfungicidal azole for use in the agriculture such as the triazoles azocyclotin used as an acaricide, paclobutrazole as a growth regulator, carfentrazone as a herbicide, and isazophos as an insecticide, and the imidazole metazachlor used as herbicide.
• the azole compound is itraconazole, an azole medicine used to treat fungal infections.
• Itraconazole is available as 100 mg capsules under the trademark SporanoxTM (Janssen-Cilag). It is a white to slightly yellowish powder. It is lipophilic, insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. Sporanox contains 100 mg of itraconazole coated on sugar spheres.
• the amphiphilic polymer used to wrap the azole compound is a polysaccharide, more preferably chitosan or hydrolyzed or thermodestructed starch, both optionally modified by PEG, H 2 0 or both. Alginate can also be used with certain concentrations of the azole compound (see Table 5 hereinbelow).
• the amphiphilic polymer used to wrap the azole compound is selected from the group consisting of polyacrylic acid, a copolymer of polyacrylic acid, polymethacrylic acid and a copolymer of polymethacrylic acid.
• the copolymers of poly(meth)acrylic acid may be copolymers of (meth)acrylic acid with another (meth)acrylic derivative, e.g. alkyl (meth)acrylate.
• the amphiphilic polymer is polyacrylic acid.
• the amphiphilic polymer is a copolymer of acrylic acid with butyl acrylate in different proportions (see Table 5).
• the nano-particles of the invention comprise inclusion complexes in which the active compound is a taxane and the amphiphilic polymer is gelatin.
• taxane refers to compounds containing the twenty carbon taxane core framework represented by the structural formula shown, for example, in US 6,201, 140, herein incorporated by reference in its entirety as if fully disclosed herein.
• the term taxane includes the chemotherapy agents Taxol (generic name: paclitaxel; chemical name: 5 ⁇ , 20-epoxy-l,2a,4,7 ⁇ , 10 ⁇ , 13a-hexahydroxytax- l l-en-9-one, 4, 10-diacetate 2-benzoate 13-ester with (2R, 3S)-N-benzoyl-3- phenylisoserine) and Taxotere (generic name: docetaxel) and semy-synthetic derivatives of taxanes having, for example, an ester or ether substituent at C(7), a hydroxy substituent at C(10), and a range of C(2), C(9), C(14), and side chain substituents, as described for example in the patent
• Taxol an anticancer drug that now has the generic name "paclitaxel”, and the registered tradename “Taxol®” (Bristol-Myers Squibb Company), is a complex polyoxygenated diterpene originally isolated from the bark of the Pacific yew tree (Taxus brevifolia). It has been approved by the FDA to treat breast, ovarian, and lung cancers as well as AIDS-related Kaposi's sarcoma.
• Docetaxel (Taxotere-R), a substance that is similar to paclitaxel and also comes from the needles of the yew tree, has been approved by the FDA to treat advanced breast and non-small cell lung cancers that have not responded to other anticancer drugs. Paclitaxel and docetaxel are administered intravenously. Both paclitaxel and docetaxel have side effects that can be serious. Paclitaxel is a white to off-white crystalline powder. This natural compound is highly hydrophobic, insoluble in water.
• water-soluble nano-particles comprising inclusion complexes in which paclitaxel in a non-crystalline state, e.g. amorphous state, is wrapped by gelatin and is fixated/stabilized by non- valent interactions with the surrounding gelatin.
• vitamin B 12 and/or polystyrene sulfonic acid are added to the gelatin to increase solubility of paclitaxel.
• the aqueous nano-dispersions of the invention can be lyophilized and then mixed with pharmaceutically acceptable carriers to provide stable pharmaceutical composition.
• the pharmaceutically acceptable carriers or excipients are adapted to the type of active compound and the type of formulation and can be chosen from standard excipients as well-known in the art, for example, as described in Remington: The Science and Practice of Pharmacy (Formerly Remington's Pharmaceutical Sciences) 19th ed., 1995.
• the present invention provides stable pharmaceutical compositions comprising pharmaceutically acceptable carriers and a nano- dispersion of the invention.
• the compositions are intended for oral administration, intravenous administration, mucosal administration and pulmonary administration.
• the compositions are for oral administration, and may be in liquid or solid form.
• tablets are provided, as exemplified herein for azithromycin.
• the invention relates to stable pharmaceutical compositions for treatment of bacterial infections comprising a nano-dispersion of water-soluble nano-particles comprising an inclusion complex wherein the active compound is a macrolide antibiotic selected from the group consisting of erythromycin, clarithromycin and azithromycin and the amphiphilic polymer is a polysaccharide.
• a macrolide antibiotic selected from the group consisting of erythromycin, clarithromycin and azithromycin
• the amphiphilic polymer is a polysaccharide.
• the invention relates to stable pharmaceutical compositions for treatment of dementia and Alzheimer's disease comprising a nano-dispersion of water-soluble nano-particles comprising an inclusion complex wherein the active compound is donepezil hydrochloride and the amphiphilic polymer is a polysaccharide.
• the invention relates to stable pharmaceutical composition for treatment of fungal infections comprising a nano- dispersion of water-soluble nano-particles comprising an inclusion complex wherein the active compound is an azole fungicide and the amphiphilic polymer is selected from the group consisting of a polysaccharide, polyacrylic acid, a copolymer of polyacrylic acid, polymethacrylic acid and a copolymer of polymethacrylic acid.
• the azole fungicide is itraconazole and the amphiphilic polymer is selected from the group consisting of polyacrylic acid, a copolymer of acrylic acid with butyl acrylate, chitosan, and starch that has been modified by one or more of the following treatments: acid hydrolysis, reaction with polyethylene glycol or hydrogen peroxide, or thermal treatment.
• the invention relates to stable pharmaceutical compositions for treatment of estrogen-responsive breast tumors comprising a nano-dispersion of water-soluble nano-particles comprising an inclusion complex wherein the active compound is a nonsteroidal antiestrogen azole selected from the group consisting of letrozole, anastrozole, vorozole and fadrozole.
• the invention relates to stable pharmaceutical compositions for treatment of cancer comprising a nano-dispersion of water-soluble nano-particles comprising an inclusion complex wherein the active compound is a taxane, most preferably paclitaxel, and the amphiphilic polymer is gelatin.
• a polymer is added to an aqueous solvent, preferably water, to form a polymer solution in a first vessel of a chemical reactor.
• ingredients may be added to adjust the pH and ionic force level of this solution as needed based on the parameters determined via the algorithm used to select the active compound and polymer.
• the active compound which may be a water-insoluble (lipophilic) or a water-soluble (hydrophilic) compound, is placed in a second vessel of the chemical reactor.
• a solution of the active lipophilic or hydrophilic compound in a non- aqueous solvent (or mixture of solvents) is referred to as the "carrier".
• the velocity of pouring or adding the carrier to the polymer solution is regulated by one or more regulating taps, which ensure that the organic solution being added to the polymer solution has a concentration below 3%.
• the active compound solution is formed when the polymer solution is heated and steam from the heated polymer solution condenses and dissolves the active compound, present in the second vessel.
• the active compound solution (in carrier) is then mixed with the polymer solution to form a dispersed phase in emulsion or suspension.
• the emulsion is fed into an area of turbulence caused by a disperser (more precisely a nano-disperser) that causes the formation of nano-sized active compound molecules within the emulsion or suspension.
• the area of turbulence is referred to as the "action zone” or the “zone of interaction”.
• the emulsion or suspension being fed into the area of turbulence has a Reynolds number of Re >10,000.
• the emulsion thus becomes a "nano-emulsion” or “nano-suspension” having particles in the range of approximately 1 to approximately 1000 nm.
• the particle production can also be extended to include small micron-sized particles and these particles may be suitable for several uses and are also encompassed by the present invention.
• a dispersion medium comprised of the polymer solution, and a dispersed phase comprising the solution of the active compound in the carrier.
• This two-phased nano-emulsion or nano-suspension is, however, unstable. Evaporating the carrier leaves particles of the dispersed phase in sizes ranging from approximately 1 to approximately 1000 nanometers.
• the polymer molecule in the polymer solution then surrounds or envelopes, and more appropriately wraps, the active compounds that had remained in the particles of the dispersed phase after evaporation of the carrier, thus forming a homogeneous nano-sized dispersion of water-insoluble lipophilic compound wrapped by a hydrophilic polymer in an inclusion complex.
• the remaining carrier is then evacuated by vacuum evaporation or other appropriate drying techniques (e.g., lyophilization, vacuum distillation).
• vacuum evaporation or other appropriate drying techniques (e.g., lyophilization, vacuum distillation).
• the stable inclusion complex is comprised of amorphous and or partially crystalline or crystalline active entities.
• starch for use in the invention, it is desirable to use starch with a large proportion of linear chains, i.e. starch with high contents of amylose, the constituent of starch in which anhydroglucose units are linked by a-D-1,4 glucosidic bonds to form linear chains, and low contents of amylopectin, a constituent of starch having a polymeric, branched structure.
• the levels of amylose and amylopectin and their molecular weight vary between different starch types.
• starch e.g. corn or potato starch, can be modified, for example by increasing its hydrophilicity by acid hydrolysis and/or by reaction with an agent, e.g.
• starch can be subjected to thermal treatment, for example at 160-180°C, for about 30-60 min, to reduce the amount of branching (hereinafter designated "thermodestructed starch”).
• thermal treatment for example at 160-180°C, for about 30-60 min, to reduce the amount of branching (hereinafter designated "thermodestructed starch”).
• the obtained suspension was heated from room temperature to 70- 95°C, for approximately 10-20 minutes with continuous mixing until a homogeneous opaque mass was obtained (hydrolyzed starch).
• the obtained mass was exposed to 160-180°C in an autoclave for time X3 (min). Under these conditions, the network structures of starch are partially or completely transformed to linear weakly branched macromolecules which dissolve in water. The mass was cooled below 100°C (thermodestructed starch). To some of the samples, PEG-400 was added (amount X4, % in relation to starch, Table 1), the obtained mixture was heated at 160-180°C in an autoclave for time X5 (Table 1), and thereafter cooled below 100°C (PEG-modified thermodestructed starch). Turbidity (in FTU, Formazin Turbidity Unit) and viscosity (molecular weight, MW) of the solution were measured. The results are shown in Table 1.
• the solution appropriate for further use should be transparent or opalescent, and should have preferably a turbidity within the range 20-40 FTU.
• MW molecular weight
• Acceptable MW (as reflected by the intrinsic viscosity) values are up to approximately 100,000 and depend on the active compound to be complexed.
• a solution of clarithromycin in methyl acetate or dichloromethane was prepared.
• the aqueous solution of the modified starch was put in a reaction vessel and heated up to 60°C while mixing with a homogenizer at speed of 10,000 and up rev/min. After the temperature of the starch solution reached 60°C, the clarithromycin solution was added thereto at a rate of about 1 ml/sec. The homogenizer speed was also at least 10,000 rev/min. Clarithromycin interacted with the modified starch to create nano-particles, and the organic solvent was evaporated and condensed in a direct condenser.
• Stable Turbidity stable nano-dispersion.
• Example 4 Physical characteristics of further clarithromycin-polymer inclusion complexes Further inclusion complexes of clarithromycin hydrophilic inclusion complexes were prepared according to the method described in Example 1, in which clarithromycin was dissolved in methyl acetate or dichloromethane and the polymers were hydrolyzed potato starch, alginate, chitosan or polyvinyl alcohol (PVA). Table 3 below shows the properties of various such complexes. Shown in
• Table 3 are complex designation (Exp., first column), polymer name and concentration (%), drug concentration, pH, and physico-chemical analysis of the various complexes nano-particles including ALV-size and size distribution (nm), HPLC (concentration and thus solubility) and, in some cases, powder X-ray analyses for the determination of crystalline phase. Size measurements of the complexes performed using ALV technique and powder X-ray analyses were carried out as described in Example 6 above.
• Fig. 1 illustrateates the size distribution of of nano-particles comprising the clarithromycin hydrophilic inclusion complex within 1% chitosan (# 10-134 in Table 3) having a size of approximately 838 nm.
• Table 3 Properties of Clarithromycin Hydrophilic Inclusion Complexes
• nano-particles (size below 1000 nm) could be prepared using polymers such as hydrolyzed potato starch, alginate, and chitosan from different sources, but with PVA the particles had a size of 1600 nm and the particles were crystalline and not amorphous, indicating that apparently PVA is not useful for preparing macrolide-containing nano-particles.
• the results in Table 3 show that, when the macrolide antibiotic clarithromycin, which is a poorly soluble hydrophobic compound, is surrounded by an amphiphilic polymer, the resulting inclusion complex is hydrophilic.
• clarithromycin was rendered hydrophilic when surrounded by various polymers which meet the matching parameters; such as alginate, PVA and chitosan.
• the results show that 2% alginate combined with 10 mg/ml of clarithromycin at pH 5.5 resulted in nanoparticles with a ALV size distribution analysis of 530 nm; 2% PVA combined with clarithromycin at pH 6 resulted in nanoparticles with a ALV of 1600 nm; 1% chitosan (Fluka) combined with clarithromycin at pH 4-6 resulted in a ALV of 165 nm; 1% chitosan (Fluka) combined with clarithromycin at pH 4 resulted in an ALV of 321 nm; 1% chitosan (Fluka) combined with clarithromycin at pH 6 resulted in an ALV of 660 nm; and 1% chitosan (Sigma) combined with clarithro
• Example 5 Controlled release of clarithromycin from clarithromycin-polymer inclusion complexes via dialysis. This experiment was carried out as described in US 2003/0129239 (in
• Example 7 therein), using a cellulose dialysis membrane of molecular weight cutoff of 3500 D (SnakeSkinTM Dialysis Tubing, Pierce Chemical Co., Product #68035).
• Dialysis was performed for up to 6 hours under constant stirring at 23 ⁇ 2°C.
• Samples (1 ml) of external buffer were taken each hour during 5 hours of incubation for the analysis of drug release. Volume of exterior fluid was constantly 100 ml.
• the concentration of clarithromycin in external (out of sac) and internal (in the sac) fluids and tested samples were determined by HPLC. The results, depicted in Fig.
• Example 6 Physical Measurements and Characteristics of Various Azithromycin Hydrophilic Inclusion Complexes
• azithromycin was prepared according to the method described in Example 1, in which azithromycin was dissolved in methyl acetate or dichloromethane and the polymers were alginate, manucol ester B (an alginate derivative), chitosan or PVA.
• Table 4 shows the properties of various such complexes. Shown in Table 4 are complex designation (Exp., first column), polymer name and concentration (%), drug concentration, pH, and physico-chemical analysis of the various complexes nano-particles including ALV-size and size distribution (nm) and HPLC (concentration and thus solubility).
• Fig. 3 illustrates the size distribution of nano-particles comprising the azithromycin hydrophilic inclusion complex within 1% chitosan (# 10-148/2 in Table 4) having a size of approximately 362 nm. Furthermore, azithromycin in these particles was found to amorphous, as shown in the lower trace of Fig.
• Fig. 4 illustrates X- ray spectra of 10-month old azithromycin-chitosan inclusion complex sample (bottom trace) compared to the commercially available azithromycin (upper trace). Table 4. Properties of Azithromycin Hydrophilic Inclusion Complexes
• Example 7 Physical Measurements and Characteristics of Various Itraconazole Hydrophilic Inclusion Complexes
• Inclusion complexes of the azole fungicide itraconazole were prepared according to the method described in Example 1, in which itraconazole was dissolved in methyl acetate or dichloromethane and the polymers were hydrolyzed potato starch, thermodestructed potato starch, alginate, chitosan, polyacrylic acid and a copolymer acrylic acid-butyl acrylate.
• Table 5 shows the properties of various such itraconazole hydrophilic inclusion complexes. Fig.
• thermodestructed starch # 23-120 having a size of approximately 414 nm. Table 5. Properties of itraconazole hydrophilic inclusion complexes
• HPLC High Performance Liquid Chromatography assay
• ND not done
• Table 5 show that, when the anti-fungal agent itraconazole, which is an insoluble compound, is surrounded by an amphiphilic polymer, the resulting inclusion complex is hydrophilic.
• itraconazole is rendered hydrophilic when surrounded by various polymers which meet the matching parameters such as thermodestructed starch combined with H 2 0 2 and PEG modification, alginate, and chitosan.
• thermodestructed starch + 1.25% H 2 0 2 + 1.25% PEG combined with 5 mg/ml of iltraconazole resulted in an ALV of 382 nm
• 5% thermodestructed starch + 0.625% H 2 0 2 + 1.25% PEG combined with 5 mg/ml of itraconazole resulted in an ALV of 640 nm
• 5% thermodestructed starch + 1% H 2 0 2 + 1% PEG combined with 5 mg/ml of itraconazole resulted in an ALV of 793 nm
• 2% alginate combined with 20 mg/ml of itraconazole resulted in an ALV of 180 nm, and when combined with 10 mg/ml of itraconazole resulted ind in
• the insoluble anti-fungal agent itraconazole can be surrounded by various amphiphilic polymers (i.e. thermodestructed starch combined with H 2 0 2 and PEG, alginate, and chitosan) to render the resulting inclusion complex hydrophilic in water.
• various amphiphilic polymers i.e. thermodestructed starch combined with H 2 0 2 and PEG, alginate, and chitosan
• 6A-B provide illustrations of itraconazole crystals and the itraconazole complexes prepared in experiment IT-56 (see Table 5), respectively. While itraconazole crystals melt at the characteristic melting point, itraconazole complexes do not melt at the characteristic point.
• Example 8 Physical measurements and characteristics of various paclitaxel hydrophilic inclusion complexes Inclusion complexes of the anticancer paclitaxel were prepared according to the method described in Example 1, in which paclitaxel was dissolved in methyl acetate or dichloromethane and the polymer was gelatin of different molecular weights with or without the addition of vitamin B 12.
• Polyvinyl-pyrrolidone (PVP or povidone, e.g. Kollidon TM ) or polystyrene sulfonic acid can be added to increase solubilization of paclitaxel. Polystyrene sulfonic acid can also be used alone to solubilize paclitaxel.
• Fig. 7 illustrates the size distribution of nano-particles comprising paclitaxel hydrophilic inclusion complexes within gelatin (70-100 kD, lmg/ml vitamin B12) (# 25-85) having a size of approximately 179 nm.
• Example 9 Physical measurements and characteristics of various donepezil hydrophilic inclusion complexes Inclusion complexes of donepezil hydrochloride were prepared according to the method described in Example 1, in which donepezil hydrochloride was dissolved in methyl acetate or dichloromethane and the polymers were modified corn starch , alginate, and sodium starch glycolate. Table 7 below shows the properties of various such donepezil hydrochloride hydrophilic inclusion complexes.
• Fig. 8 illustrates the size distribution of nanoparticles comprising donepezil hydrochloride hydrophilic inclusion complexes within modified corn starch (#LG-7-51) having a size of approximately 600 nm. Table 7. Properties of donepezil hydrophilic inclusion complexes
• Example 10 Oral absorption of nano-sized, water-soluble particles of azithromycin and azithromycin compositions
• the oral absorption of water-soluble nano-sized particles comprising inclusion complexes of 1% azithromycin and 1% chitosan was studied in a preclinical model involving rats in comparison to a composition containing the commercially-available azithromycin (Azenil), in order to assess the contribution of the physical form for enabling absorption.
• Azithromycin 50 mg/kg is administered to male Sprague-Dawley rats (groups of 5), 250-280 g, by a feeding tube. At fixed times of administration (between 1-24 hours), blood samples are collected, and sera are prepared for analysis.
• the azithromycin concentration is quantified by comparison with a calibration curve in the range from 20 to 2000 ng/ml, that is prepared using blank rat serum spiked with azithromycin.
• a plot of the concentrations (not shown) is used to determine the timing of the maximal concentration (C max ) and to assess the total absorption of the drug (as reflected by the area under the curve (AUC).
• a summary of the main pharmacokinetic findings is presented in Table 8. These findings demonstrate that nano-sized, water-soluble particles having the same amount of azithromycin as Azenil, elevate the maximal concentration (C max ) obtained and the total amount of azithromycin absorbed (as reflected by the AUC).
• the concentration in the lung is particularly elevated, while the concentrations in other organs are increased to a less extent. Furthermore, there is no change in time at which the maximal concentration is reached.
• azithromycin particles following compression, and their compatibility with tablet excipients are assessed by comparing azithromycin absorption with that of the complexes prior to tablet preparation.
• Tablets are prepared following lyophilization of complexes and subsequent mixture with standard acceptable excipients. The tablets are formed by application of pressure up to 1 ton cm . Prior to administration to rats, the tablets are dissolved in water. Then, azithromycin (50 mg/kg) is administered to male Sprague-Dawley rats (groups of 5), 250-280 g, by a feeding tube. Pharmacokinetic studies involving oral administration are done as described above. Drug concentrations in rat serum are analyzed as described above. Plots of the serum concentrations are presented in Fig. 9.
• Azenil is a marketed commercial formulation of azithromycin
• lots 28-39 and 28-59 are solutions of nano-sized, water-soluble particles comprising 1% azithromycin complexes with 1% chitosan
• Tab28-59 is a tablet prepared from lot 28-59, dissolved in water immediately prior to administration.
• Example 11 Oral absorption of nano-sized, water-soluble particles of itraconazole
• the oral absorption of itiaconazole nano-sized, water-soluble particles comprising itraconazole inclusion complexes with copolymer of acrylic acid and butyl acrylate (#IT-50, Table 5) was studied in a preclinical model involving rats and compared with oral absorption of itraconazole in compositions comprising itraconazole mixed by vortex with polyacrylic acid, which do not form nanoparticles, in order to assess the contribution of the physical form for enabling absorption.
• Itraconazole 50 mg/kg is administered to male Sprague-Dawley rats (groups of 5), 250-280 g, by a feeding tube.
• the itraconazole concentration is quantified by comparison with a calibration curve in the range from 20 to 1000 ng/mL, that is prepared using blank rat serum spiked with itraconazole. .
• a plot of the concentrations (not shown) is used to deteirnine the timing of the maximal concentration (C max ) and to assess the total absorption of the drug (as reflected by the area under the curve (AUC).
• AUC area under the curve

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