FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
(See section 10 and rule 13)
BIOCOMPATIBLE METAL BASED NANOSTRUCTURES FOR DRUG DELIVERY
PANACEA BIOTEC LIMITED
A COMPANY INCORPORATED UNDER THE LAWS OF INDIA HAVING THEIR
OFFICE AT 104, SAMARPAN COMPLEX, NEW-LINK ROAD, CHAKALA, ANDHERI
(E), MUMBAI 400099, MAHARASHTRA, INDIA
The following specification describes the invention
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FIELD OF THE INVENTION
The present invention is directed to the field of drug delivery. It relates to agents for the delivery of active ingredients in mammalian systems. More specifically, the present invention relates to biocompatible metal based nanostructures for the delivery of active ingredients in mammalian systems.
BACKGROUND OF THE INVENTION
Modern drug delivery technologies have led to sophisticated systems which allow targeting and controlled release of active ingredients in mammalian systems. Delivery systems which are in nano-scale dimensions provide an efficient, less risky solution to many drug delivery challenges. They can be used for targeting to highly specific sites of action, and due to their small dimensions, can be used for delivery to tissues which are inaccessible to the more conventional delivery agents. Polymer based nanoparticles are known for such systems. However, they utilize costly raw materials, are often expensive to manufacture and are not very scale-up friendly.
In recent years, inorganic metal based systems have been developed by sol gel technique. This technique refers to a low-temperature method using chemical precursors which can produce diverse types of ceramics and glasses. It enables researchers to design and fabricate a wide variety of different materials with unique chemical and physical properties. The sol-gel materials are based on silica, alumina, titania and other compounds. The technology allows to fabricate: monolithic and porous glasses, fibers, powders, thin films, nanocrystallites, photonic crystals etc.
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Recently, biological applications, where biomolecules (such as proteins, enzymes, antibodies etc.) are incorporated into the sol-gel matrix, have been studied. Applications include biosensors in diagnostic applications, environmental testing, biochemical process monitoring and food processing. In 1983, Unger and coworkers used sol-gel derived silica gel for drug delivery applications. (Unger, et. al 1983, The use of porous and surface modified silica as drug delivery and stabilizing agents. Drug Dev. Ind. Pharm., 9, 69-91.) Since then, the use of silica based materials, especially the silica based xerogels and mesoporous structures as carrier systems for controlled delivery of drugs, has been explored.
Application of metal based systems for delivery of active ingredients is one of the current research interests, and there is a need to develop novel carriers in this field which can be used for the controlled delivery of active ingredients to human and animal tissues. Especially, there is a need for carrier systems which are easier to produce, biocompatible and easily and predictably biodegraded.
Metal elements such as Titanium, Magnesium, Calcium, Aluminum and others are present at least in trace amounts in human bodies and have been used in various biocompatible products. They are also easily available.
Zinc oxide is an inorganic metal oxide used for diverse purposes, such as, a white pigment, as a catalyst, as an antibacterial in ointments etc. Nanoparticulate Zinc oxide, having particle sizes below 30 nm, has been used as a UV absorber in sun protection creams. The present invention is directed towards the use of such inorganic biocompatible metals to form structures for encapsulation and controlled delivery of active ingredients to human and animal tissues.
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United States Patent No. 6,710,091 discloses a process for preparing nanoparticulate redispersible Zinc oxide gels. The process leads to Zinc oxide particles having an average primary particle diameter of less than 15 nm. The application discloses use of Zinc oxide particles as UV absorbers, in plastics, paints, coatings and for the protection of UV-sensitive organic pigments. It does not disclose Zinc oxide structures for encapsulation of any species, nor does it disclose the application of Zinc oxide particles in drug delivery.
United States Application No. 2005/0226805 describes a process for producing micro-mesoporous metal oxide having average pore size of not more than 2 nm and not less than 1 nm, by sol-gel synthesis, using non-ionic surfactant as a template. The mesoporous metal oxides of the invention are expected to be useful in catalysts, sensors or semiconductors. The application does not disclose any use in drug delivery or encapsulation of any active species.
United States Application No. 2005/0003014 describes synthetic inorganic nanoparticles as carriers for ophthalmic and otic drugs. The carriers of the invention are mainly water swellable clays, although other materials, such as zeolites, silica, aluminum oxide, titanium oxide, cerium oxide and zinc oxide, are also included. The materials are finely dispersed in a vehicle to form clear low viscosity gels. The nanoparticles of the invention function as chemically inert carriers for the drugs, possibly only by association. Encapsulation of active ingredients in nanostructures for their controlled release is not disclosed. Also, the nanoparticles may not be biodegradable.
United States Application No. 2006/0171990 describes drug delivery materials which include active compounds encapsulated within a polymeric shell; the encapsulated compounds are then incorporated in a matrix prepared by sol-gel technology. The matrices thus prepared are
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used for porous or non-porous film coatings for implants such as stents, bone grafts, prostheses etc. The invention thus discloses a two step process, where first the active compound is encapsulated into a conventional polymeric shell, before dispersing the encapsulated particles into a matrix prepared by sol-gel process. The application does not disclose biocompatible metal based nanostructures which themselves encapsulate the active ingredients and modulate their release.
DESCRIPTION OF THE INVENTION
The present invention relates to biocompatible metal based nanostructures for the delivery of active ingredients to human and animal tissues.
The present invention relates to biocompatible metal based nanostructures, prepared by sol-gel synthesis, for the delivery of active ingredients to human and animal tissues.
The present invention relates to biocompatible metal based hybrid nanostructures, such as organic-inorganic hybrids, prepared by sol-gel synthesis, for the delivery of active ingredients to human and animal tissues.
Nanostructures of the invention are structures that have at least one dimension in the nano-scale.
The nanostructures of the invention may be produced by conventional sol-gel synthesis or any of its modifications known in the art. Such nanostructures will be bioerodible, produced at low temperatures and easily amenable to large scale production.
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The nanostructures of the present invention may be produced by sol-gel processes generally comprising of the following steps: preparation of a solution or suspension, of a precursor formed by a compound of the element (M) forming the oxide or alkoxide; hydrolysis (acid or base catalyzed), of the precursor, to form M-OH groups. The so obtained mixture, i.e. a solution or a colloidal suspension, is named sol; polycondensation of the M—OH or M-OR groups according to the reactions M-OH+M-OH—>M--0-M+H20 and M-OR+M--OH—>M--0--M+ROH characterized by an increase of the liquid viscosity (gelation) and by the contemporaneous formation of a matrix called gel.
The gel may be dried to a porous monolithic body or dried by a controlled solvent evaporation, to produce xerogels, or by a solvent supercritical extraction to produce aerogels.
Alternatively, the process may involve the use of 'template' molecules during the sol-gel conversion, leading to the formation of ordered structures with well defined pore morphology. Examples of such structures are the mesoporous structures, micro-mesporous structures etc. The template molecules may be inorganic or organic metal salts, small organic molecules, such as polyethylene glycol, long chain surfactant molecules, liquid crystal templates, room temperature ionic liquids etc.
Alternatively, the process may involve non-hydrolytic sol-gel processing in the absence of water carried out by reacting alkylated metals or metal alkoxides with anhydrous organic acids, acid anhydrides or acid esters, or the like.
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According to an embodiment of the invention, the sol-gel forming components may comprise alkoxides, oxides, acetates, or nitrates of various metals such as Zinc, Titanium, Magnesium, Calcium, and Aluminum, as well as combinations thereof.
In an embodiment, the sol-gel forming component comprises alkoxides or oxides of metals, preferably Zinc.
According to another embodiment of the invention, the nanostructures are hybrid materials, where organic precursors are used during the sol-gel processing, leading to organic-inorganic composites, exhibiting new morphologies and unique properties. The extent of phase mixing can vary, but domain sizes are typically on the nanometer scale. The hybrids may be produced by various methods such as using low molecular weight organoalkoxymetal derivatives as precursors; or co-condensation of functionalized organic species with metal alkoxides and establishing covalent bonding; or infiltration of preformed oxide gels with polymerizable organic monomers/polymers; or forming interpenetrating networks by simultaneous formation of organic and inorganic phases. Alternatively, the metal nanostructures may be coated or encapsulated within the polymers, which may help in modulating the release of active ingredients.
Various organic groups may be used for forming the hybrids; examples include, but are not limited to celluloses, vinyl pyrrolidone polymers, alkylene oxide homopolymers, superdisintegrant polymers, acrylic acid polymers etc.
In an embodiment of the invention, Zinc oxide based nanostructures are prepared and combined with acrylate polymers, such as polymethacrylates or polycyanoacrylates, to form
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'organo-zinc' nanostructures. The organic portion of the nanostructures helps in controlling the release of active ingredients as well as affects the biodegradation and biodistribution of the system.
Incorporation of active ingredients into the sol-gel derived nanostructures may be done by any of the means known in the art. The incorporation may be done at any suitable stage during sol-gel synthesis, such as by co-condensation, if the ingredient can withstand the subsequent steps in the synthesis. The systems can be prepared by molecular imprinting or impregnation of the active ingredients within the nanostructures. Alternatively the incorporation may be done by loading after the basic metal or organo-metal hybrid structure has been prepared.
The nanostructures of the invention may be processed to form nanoparticles, nanospheres, nanorods, nanotubes, monolithic systems, indented systems, aggregates or combinations thereof. They may also be processed to form ordered materials such as mesoporous, microporous or macroporous structures. The nanostructures may degrade and release the active ingredients by surface erosion or biodegradation in presence of physiological fluid. The nanostructures can be used for dermal, mucosal, injectable, oral, pulmonary or any other form of suitable drug delivery. The nanostructures can alternatively be formulated as implants for prolonged active ingredient release.
In an embodiment of the invention, the nanostructures are formulated for topical and mucosal delivery of active ingredients. Topical delivery may be dermal or ocular. Mucosal delivery includes buccal, vaginal, nasal and rectal delivery.
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Nanostructures of the invention may be useful for the delivery of any active ingredient known in the art. Examples include, but are not limited to, anti-infective such as antibiotics and antiviral agents, anti-fungals; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; Antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; tranquilizers; macromolecules such as proteins, polypeptides, polysaccharides, vaccines, antigens, antibodies. The nanostructures of the invention may also be used for cosmetic purposes, such as in the preparation of antiageing, sunblocking, antiwrinkle, moisturizing or any other cosmetic preparations.
In an embodiment of the invention, Zinc based nanostructures, preferably organo-Zinc based hybrid nanostructures, are prepared for the delivery of active ingredients into the dermal layer for the treatment of fungal infections. Fungal infections of the skin can be superficial which affect the outer layers of the skin (e.g. Dermatophytes, yeasts, moulds) or they can be subcutaneous which involve the deeper layers of the skin such as the dermis, subcutaneous tissue and even bone (eg. Mycetoma, chromoblastomycosis). Delivery systems which penetrate into the skin layers to release the drug at the site of infection will be advantageous.
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The nano-scale dimensions of the nanostructures of the invention help them to penetrate the upper layers of the skin and enter the intra-dermal layers. Here, they can be retained for a prolonged period of time, such as for example one week, exhibiting a long duration of action, even after the remnant vehicle on the skin surface has been washed off. Depending on their composition, the nanostructures are then biologically degraded and are disposed off by normal biological mechanisms. The duration and extent of active ingredient release as well as the depth of penetration may be modulated by the composition, morphology and process of preparation.
Suitable anti-fungal agents include allylamines (amrolfine, butenafine, naftifine, terbinafine), azoles (ketoconazole, fluconazole, elubiol, econazole, econaxole, itraconazole, isoconazole, imidazole, miconazole, sulconazole, clotrimazole, enilconazole, oxiconazole, tioconazole, terconazole, butoconazole, thiabendazole, voriconazole, saperconazole, sertaconazole, fenticonazole, posaconazole, bifonazole, flutrimazole), polyenes (nystatin, pimaricin, amphotericin B), pyrimidines (flucytosine), tetraenes (natamycin), thiocarbamates (tolnaftate), sulfonamides (mafenide, dapsone), glucan synthesis inhibitors (caspofungin), benzoic acid compounds, complexes and derivatives thereof (actofunicone) and other systemic or mucosal (griseofulvin, potassium iodide, Gentian Violet) and topical drugs (ciclopirox, ciclopirox olamine, haloprogin, undecylenate, silver sulfadiazine, undecylenic acid, undecylenic alkanolamide, Carbol-Fuchsin).
In an alternative embodiment, antibacterial or antiviral agents are incorporated into the Zinc based nanostructures. Suitable agents which may be used include, but are not limited to, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cuctinomycin, carubicin, carzinophilin, chromomycines, ductinomycin, daunorubicin, 6-diazo-5-oxn-l-norieucin,
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doxorubicin, epirubicin, mitomycins, mycophenolsaure, mogalumycin, olivomycin, peplomycin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, aminoglycosides or polyenes or macrolid-antibiotics, antivirals such as aciclovir, ganciclovir, famciclovir, foscamet, inosine-(dimepranol-4-acetamidobenzoate), valganciclovir, valaciclovir, cidofovir, brivudin; antiretroviral active ingredients (nucleoside analog reverse-transcriptase inhibitors and derivatives) such as lamivudine, zalcitabine, didanosine, zidovudin, tenofovir, stavudin, abacavir; non-nucleoside analog reverse-transcriptase inhibitors: amprenavir, indinavir, saquinavir, lopinavir, ritonavir, nelfinavir; amantadine, ribavirin, zanamivir, oseltamivir or lamivudine, as well as any combinations and mixtures thereof.
In an embodiment of the invention, the nanostructures are used for delivery of active ingredients through the oral route. The nanostructures may be targeted for delivery through the Peyer's patches, which are large aggregates of lymphoid tissue found in the small intestine as part of the lymphatic system. The transport of nanostructures may be done by the M cells which are present in the Peyer's patches and which are involved in transport of particles. The active ingredients delivered by such systems include macromolecules such as proteins, polypeptides, vaccines, antigens, antibodies etc.
Dated this 11th day of August 2006
FOR PANACEA BIOTEC LIMITED
(Dr. MAHALAXMIANDHERIA)
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