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Patent Issued for Water-Dispersible Oral, Parenteral, and Topical Formulations for Poorly Water Soluble Drugs Using Smart Polymeric Nanoparticles

May 23, 2014

By a News Reporter-Staff News Editor at Drug Week -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Maitra, Anirban (Baltimore, MD); Feldmann, Georg (Bonn, DE); Bisht, Savita (Bonn, DE), filed on October 12, 2012, was published online on May 6, 2014 (see also The Johns Hopkins University).

The assignee for this patent, patent number 8715741, is The Johns Hopkins University (Baltimore, MD).

Reporters obtained the following quote from the background information supplied by the inventors: "During the last two decades numerous drug delivery systems have been developed for hydrophobic and poorly water soluble medicines. These systems are focused on overcoming the poor availability of the drug and the subsequent ineffective therapy inherent to these types of molecules.

"To solve the above mentioned problem associated with the solubilization of poorly water-soluble medicines, U.S. Pat. Nos. 5,645,856 and 6,096,338 disclose methods for preparing carriers for hydrophobic drugs, and pharmaceutical compositions based thereon, in which the carrier is comprised of biocompatible oil and a pharmaceutically acceptable surfactant component for dispersing the oil in vivo upon administration of the carrier. The amphiphilic surfactant component utilized does not substantially inhibit the in vivo lipolysis of the oil. These types of formulations can be utilized as a carrier system for many hydrophobic drugs resulting sometimes in enhanced bioavailability as compared with existing formulations of such drugs. However, these formulations are not stable in vivo and there is the possibility of drug leakage from the emulsion leading to unnecessary side effects in the body. Moreover, the surfactants used may disrupt the biological membranes causing cytotoxicity. In addition, targeting of a drug using such emulsion systems is not possible.

"Other drug carriers have been used such as amphiphilic block copolymers which form polymeric micelles or supramolecular assemblies wherein the hydrophobic part forms the core and the hydrophilic part the shell. The U.S. Pat. No. 5,510,103 describes block copolymers having the hydrophilic and hydrophobic segments forming micelles and entrapping the hydrophobic drugs by physical methods. The hydrophilic segment is preferably poly(ethylene oxide) and the hydrophobic segment is preferably poly(epsilon-benzyl-L-aspartate), while the preferred drug is Adriamycin.

"Recently, polymeric micelles have been widely used as drug delivery carriers for parenteral administration. Micellar drug delivery carriers have several advantages including biocompatibility, solubilization of hydrophobic drugs in the core, nanometric size ranges which facilitate extravasation of the drug carrier at the site of inflammation, site-specific delivery, etc. For example, U.S. Pat. No. 5,955,509 describes the use of poly(vinyl-N-heterocycle)-b-poly(alkylene oxide) copolymers in micelles containing pharmaceutical formulations. These copolymers respond to pH changes in the environment and can be used to deliver therapeutic compounds at lower pH values. These polymeric micelles remain intact at physiological pH, while they will release their content when exposed to a lower pH environment such as in tumor tissue.

"A number of amphiphilic copolymers, having non-ionic and/or charged hydrophobic and hydrophilic segments, that form micelles are reported in the literature. For example, U.S. Pat. No. 6,322,817 discloses the injectable formulation of cross-linked polymeric micelles constituted by acrylic monomers--N-isopropylacrylamide, N-vinylpyrrolidone and PEGylated monoesters of maleic acid. These polymeric nanoparticles are reported to have dissolved paclitaxel and delivered the drug to the tumor tissue through parenteral administration. However, these particles are only reported to be suitable for delivery via the intravenous route. Moreover, the reported use of alkylcyanoacrylate as one of the components in the copolymeric micelles may render the formulations toxic and unsuitable for in vivo applications.

"One patent, U.S. Pat. No. 6,555,139 has disclosed a process of microfluidization or wet-micronization of hydrophobic drugs in combination with dextrins such as .beta.-cyclodextrin. The patent indicated that the process of microfluidization facilitates the reduction of mean particle size of slightly soluble but highly permeable drugs, and creates a smooth, latex-like micro-suspension. A blend of expandable polymer and insoluble, hydrophilic excipients granulated with the micro-suspension create a matrix that after compaction erodes uniformly over a 24-hour period. However, the problems associated with these microfluidization systems are that for every molecule of drug, one molecule of .beta.-cyclodextrin is required leading to large amounts of this compound to be administered inside the body along with drug. Moreover, drug leakage from .beta.-cyclodextrin as well as poor bioavailability of .beta.-cyclodextrin-drug complex has the potential to cause side effects. Finally, the particle size of up to 500 nm diameter may be responsible for limited utility for drug delivery purposes.

"Another patent, U.S. Pat. No. 6,579,519 has disclosed the formulation of non-PEGylated pH sensitive and temperature sensitive cross-linked polymeric micelles constituted of N-isopropylacrylamide, acrylic acid and N-vinylpyrrolidone. These particles have extremely limited applications and can be used only for the specific purpose of topical delivery on the ocular surface. This is because of the fact that the LCST (lower critical solution temperature) of the particles is below ambient body temperature, and the particles are aggregated to a hydrophobic mass in vivo. Therefore, these particles are not suitable for systemic circulation and targeting, including oral delivery. Other similar patents are U.S. Pat. No. 6,746,635 and U.S. Pat. No. 6,824,791.

"Another U.S. Pat. No. 7,094,810 describes a formulation which is composed of a hydrophilic segment made of poly(ethylene oxide) and a hydrophobic segment composed of vinyl monomers containing at least one pendant carboxyl group. More particularly, the vinyl monomers included in the polymer are acrylic acid or methacrylic acid having pendant carboxyl groups and butyl(alkyl)acrylate where the butyl segment can be a linear or branched chain. Thus, the hydrophobic segment is a mixture of non-ionizable butyl(alkyl)acrylate and ionizable(alkyl)acrylic acid which controls the hydrophobicity of the polymer. The ionizable carboxylic group of the polymer extended towards the surface of the particle is reported to be responsible for pH sensitivity.

"Though the majority of these polymers can be used for injectable or topical delivery of bioactive agents, what are presently lacking are multifunctional amphiphilic polymers capable of oral delivery applications, by means of their nanoparticulate size and mucoadhesivity. The surface reactive functional groups of such 'smart' nanoparticles would be capable of optional modification through PEGylation, ligand attachment, or fluorophore tagging for the purposes of systemic targeting, thus being useful for concurrent biological applications in diagnostics, therapeutics, and in imaging. Herein, we describe such an orally bioavailable smart polymeric nanoparticle system."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "The invention relates to cross-linked polymeric nanoparticles, which may contain one or more bioactive agents such as poorly water-soluble medicines, and that are particularly suitable for oral delivery, but are also amenable to other applications, including injectable or topical formulations.

"A further object of this invention is to provide a process for the preparation of polymeric nanoparticles that can entrap poorly water-soluble drugs, alone or in combination with other bioactive agents, to the maximum extent possible. The polymeric nanoparticles preferably entrap one or more types of medicament. Preferably the polymeric nanoparticles have an average diameter of less than or equal to 50-100 nm, and less than 5% are in excess of 200 nm in diameter.

"Another object of this invention is to provide a process for the preparation of nanoparticles having inter-crosslinked polymeric chains so that the release of the entrapped medicine(s) encapsulated in these nanoparticles can be controlled.

"Yet another object of this invention is to provide a process for the preparation of nanoparticles incorporating single or combinations of medicines, with the option of chemically conjugating polyethylene glycol (PEG) chains of varying chain length (50-8000 D) at the outer surface of the nanoparticles to reactive moieties on the surface of formed nanoparticles. The PEG chains help the particles to circulate in the blood for a relatively long time, following systemic administration.

"Yet another object of this invention is to enable the delivery of otherwise water soluble drugs, but for which oral delivery is currently not an option, by chemically conjugating the drug, or combinations thereof, on the surface of the nanoparticles, which then act as a vehicle for absorption via the oral route so as to enhance the bioavailability of the drug.

"Another objective of this invention is to use carboxylic acid, amine or aldehyde derivatives of acrylic compounds or similar vinyl derivatives alone or in combination as monomers during polymerization for rendering multifunctional characteristics of the nanoparticles so as to make `smart` nanoparticles.

"Still another object of this invention is to provide a process for the preparation of polymeric nanoparticles incorporating poorly soluble medicines or combinations of medicines dispersed in aqueous solution which are free from unwanted and toxic materials, such as non-reacted monomers.

"Another object of this invention is to provide a process for the preparation of polymeric nanoparticles incorporating poorly water-soluble medicine or combinations of medicines which can be used for in vivo experiments for the purpose of targeting maximum amounts of medicine to a diseased site and only negligible amounts to other tissues, which obviates the disadvantages associated with the prior art. For example, the polymerized micelle complexes contemplated herein can be functionalized with a targeting moiety such as a fluorophore, a dye, a contrasting agent, an antigen, an antibody, an amino acid, or a sugar like glucosamine or related carbohydrate derivatives, through chemical conjugation with the PEG chains associated with the polymeric micelles, such that the complexes could be used, in addition to stated oral formulations, in medical therapeutics, diagnostics and imaging applications requiring targeted delivery to specific cell or tissue types.

"A still further object of this invention is to mask the native taste of certain medicaments incorporated in the polymeric micelles by chemically conjugating taste modifying agents to the surface of the micelles so that the formulation is rendered more palatable during oral uptake.

"A still further object of this invention is to provide a method for using polymeric nanoparticles incorporating poorly water-soluble medicine or combinations of medicines prepared according to the process of this invention for the treatment of conditions arising out of undesirable pathogenic and anatomic conditions.

"According to the invention, medicinal compositions are prepared which comprise polymeric nanoparticles preferably of a size on average of less than 100 nm diameter entrapping at least one poorly water-soluble hydrophobic medicine alone or in combination with one or more additional medicines. These amphiphilic nanoparticles can be made of cross-linked polymers which are mainly composed of the following three constituents added as monomers at specific molar ratios: (1) N-isopropylacrylamide (NIPAAM), plus (2) either a water-soluble vinyl compound like vinyl acetate (VA) or vinyl pyrrolidone (VP), so as to make the particle shell more hydrophilic, or a water-insoluble vinyl derivative such as styrene (ST) or methylmethacrylate (MMA), so as to make the particle core more hydrophobic, plus (3) acrylic acid (AA), which provides surface reactive functional groups. The surface of the nanoparticles can be optionally functionalized using the reactive functional groups provided by AA, including by PEGylation for long circulation in blood, or by addition of other surface reactive groups which can be used for targeting to tissues in vivo for therapeutic, diagnostic, and imaging applications."

For more information, see this patent: Maitra, Anirban; Feldmann, Georg; Bisht, Savita. Water-Dispersible Oral, Parenteral, and Topical Formulations for Poorly Water Soluble Drugs Using Smart Polymeric Nanoparticles. U.S. Patent Number 8715741, filed October 12, 2012, and published online on May 6, 2014. Patent URL:

Keywords for this news article include: Therapy, Legal Issues, Nanoparticle, Nanotechnology, Drug Delivery Systems, Emerging Technologies, The Johns Hopkins University.

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Source: Drug Week

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