News Column

Patent Issued for Oral Formulations for Tetrapyrrole Derivatives

September 10, 2014

By a News Reporter-Staff News Editor at Biotech Week -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Grafe, Susanna (Jena, DE); Nifantiev, Nikolay (Moscow, RU); Volker, Albrecht (Bergholz Rehbrucke, DE); Neuberger, Wolfgang (Dubai, AE); Wieland, Gerhard (Jena, DE); Scheglmann, Dietrich (Jena, DE); Fahr, Alfred (Colbe, DE); Wiehe, Arno (Berlin, DE), filed on April 27, 2010, was published online on August 26, 2014 (see also Biolitec Pharma Marketing Ltd).

The assignee for this patent, patent number 8815931, is Biolitec Pharma Marketing Ltd (F.T. Labuou, MY).

Reporters obtained the following quote from the background information supplied by the inventors: "Photosensitizers are compounds which can be photoactivated by irradiation of specific wavelength matching the absorption spectrum of the photosensitizer. Photosensitizers are used in Photodynamic Therapy (PDT) treatment, a novel method used initial in treating cancer and now found to be effective in treating other medical problems also. PDT method is used to treat different kinds of cancers including proliferating and non-proliferating types, Benign Prostate Hyperplasia (BPH), other Inflammatory conditions, cosmetic applications and others. Generally photosensitizers are administered to patient systemically and topically, which both have their own merits and demerits.

"In general, photosensitizers are now delivered topically or intravenously. Especially, the intravenous delivery poses problems for the medical treatment as many photosensitizers are hydrophobic or amphiphilic substances which are non-soluble in water. Sometimes the photosensitizers are administered in alcoholic solution (ethanol, propylene glycol) as e.g. the photosensitizer temoporfin. However, the alcohol content can induce pain during administration and alcohol as a solubilizing agent in general is not feasible for certain groups of patients. Therefore, there have been efforts to formulate hydrophobic photosensitizers in a way that renders them water-soluble. These approaches include many different carrier systems such as liposomes, nanoparticles, quantum dots, or carrier systems based on inorganic materials. Of special interest in this respect are carrier systems based on highly biocompatible materials such as lipids, proteins or biocompatible polymers. There are a number of such carrier systems known in the art (F. L. Primo, P. P. Macaroff, Z. G. M. Lacava, R. B. Azevedo, P. C. Marais, A. C. Tedesco, Binding and photophysical studies of biocompatible magnetic fluid in biological medium and development of magnetic nanoemulsion: A new candidate for cancer treatment. J. Magnetism Magn. Mater., 2007, 310, 2838-2840; patent application WO 06133271A2; A. J. Gomes, C. N. Lunardi, A. C. Tedesco, Characterization of biodegradable poly(D,L-lactide-co-glycolide) nanoparticles loaded with bacteriochlorophyll-a for photodynamic therapy, Photomed. Laser Surg., 2007, 25, 428-435; E. Ricci-Junior, J. M. Marchetti, Preparation, characterization, photocytotoxicity assay of PLGA nanoparticles containing zinc(II) phthalocyanine for photodynamic therapy use, J. Microencapsul., 2006, 23, 523-538; E. Ricci-Junior, J. M. Marchetti, Zinc(II) phthalocyanine loaded PLGA nanoparticles for photodynamic therapy use, Int. J. Pharm., 2006, 310, 187-195; V. Saxena, M. Sadoqi, J. Shao, Polymeric nanoparticulate delivery system for indocyanine green: Biodistribution in healthy mice, Int. J. Pharm., 2006, 308, 200-204; A. Vargas, B. Pegaz, E. Debefve, Y. Konan-Kouakou, N. Lange, J.-P. Ballini, H. van den Bergh, R. Gurny, F. Delie, Improved photodynamic activity of porphyrin loaded into nanoparticles: an in vivo evaluation using chick embryos, Int. J. Pharm., 2004, 286, 131-145; Y. N. Konan, M. Berton, R. Gurny, E. Allemann, Enhanced photodynamic activity of meso-tetra(4-hydroxyphenyl)porphyrin by incorporation into sub-200 nm nanoparticles, Eur. J. Pharm. Sci., 2003, 18, 241-249; Y. N. Konan, R. Cerny, J. Favet, M. Berton, R. Gurny, E. Allemann, Preparation and characterization of sterile sub-200 nm meso-tetra(4-hydroxyphenyl)porphyrin loaded nanoparticles for photodynamic therapy, Eur. J. Pharm. Biopharm., 2003, 55, 115-124; A. Vargas, M. Eid, M. Fanchaouy, R. Gurny, F. Delie, In vivo photodynamic activity of photosensitizer-loaded nanoparticles: Formulation properties, administration parameters and biological issues involved in PDT outcome, Eur. J. Pharm. Biopharm., 2008, 69, 43-53; B. Pegaz, E. Debefve, F. Borle, J.-P. Ballini, H. Van den Bergh, Y. N. Kouakou-Konan, Encapsulation of porphyrins and chlorins in biodegradable nanoparticles: The effect of dye lipophilicity on the extravasation and the photothrombic activity. A comparative study, J. Photochem. Photobiol. B: Biology, 2005, 80, 19-27; patent application WO 97010811A1 and patent application WO 03097096A1). However, these water-soluble carrier systems were developed for intravenous administration. They have not yet been evaluated for their potential for oral administration.

"Oral administration is one of the easiest routes for drug administration and is particularity useful for patient compliance. The main hurdles faced in oral administration of drugs include biological barriers which makes it difficult for poorly water soluble drug molecules to be administered orally. Commonly the drug size, its bioavailability, the solubility and stability makes it difficult to pass through the biological barriers like the intestinal mucosa and gut epithelium. To overcome these biological barriers drug development and manufacturing units have found novel methods of formulation using more efficient delivery systems. Newer drug delivery systems are formulated to avoid the drug being accumulated in non-targeted site such as spleen and liver thus increasing dramatically the drug half life in the circulatory system. This is difficult in some cases, as well as undesirable if it is the liver for example which contains cancerous tissue.

"Oral drug delivery system development has been fostered by the need to deliver medications to patients more efficiently and with fewer side effects. The oral route is found to be the most convenient route of drug administration. The oral and other therapeutic systems in human use have been validated as concepts for controlled continuous drug release which can minimize the daily dose or the number of doses of a drug required to maintain the required therapeutic effect, while minimizing unwanted pharmacological effects. Oral drug delivery systems in particular have required innovation in material science to provide biocompatible materials during prolonged contact with body tissues, bioengineering methods to develop drug delivery modules, and clinical pharmacology studies for elucidation of drug pharmacokinetics under conditions of continuous controlled drug administration.

"Oral drug delivery systems/methods provide the possibility to maintain therapeutically optimum drug concentrations in plasma and target organs; and therefor eliminate the need for frequent single dose administration. Many pharmaceutical active agents used as medicines and supplements need to be stabilized and protected against degradation or oxidation activity using suitable carrier systems. The effectiveness of such agents may be improved by increasing their solubility in body fluids or by masking their unwanted properties (such as toxicity, odor, taste and other characteristics) before reaching the target organ using drug delivery systems.

"Oral administration of unstable, insoluble and bad tasting active agents would require a delivery system which can stabilize the drug, avoid precipitation, and prevent early degradation. It also calls for a system which can improve the solubility. A system to mask the bad taste, reduce toxicity and side effects. Drug formulation units use different means to achieve these characteristics by using carrier system like nano-capsule, microspheres, liposomes, and pegylation. These carrier systems are made of biocompatible polymers, lipids or even natural/synthetic proteins. Natural stable proteins/lipids have been used because of their less immunogenic properties, and additionally can be used for specific targeting.

"Drug delivery systems have been widely used to administer drugs with high molecular weight, having low solubility and permeability and having high susceptibility to enzymatic action in the GIT. Examples of macromolecules include peptides, proteins, nucleotides, sugars, etc. In prior art we see many such examples of using drug delivery systems for oral administration.

"In U.S. Pat. No. 7,432,369 by Williams et al., discloses pyridyl-substituted Porphyrin compounds and their effective amount used in treating various disorders. They also discuss the method of administrating the drug which include oral route along with other well established methods. Composition for oral administration of their invention include tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. The method of formulating the oral formulation is not discussed.

"Prasad, et al., in their U.S. Pat. No. 7,364,754 disclose a certain ceramic based nanoparticle agents for encapsulating hydrophobic photosensitizers used in PDT methods. Such nanoparticles entrapping drug/dyes can be administrated orally, parenterally or topically. The specific photosensitizer used here is 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide.

"Robinson in his U.S. Pat. No. 6,376,483 discloses use of bacteriochlorins and bacteriopurpurins and their production methods. In his disclosure he describes the oral administration of this active agents using inert diluent or with assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or compressed into tablets or incorporated directly in food. This patent basically describes new routes for synthesis of bacteriochlorins and bacteriopurpurins from symmetrical and asymmetrical mesodiacrylate porphyrins and their uses in PDT treatment.

"In U.S. Patent Application No. 2007/0237827 by Sung et al., disclose a oral formulation consisting of biodegradable nanoparticles encapsulating therapeutically active agents like HMG-CoA reductase inhibitors, erythropoietin etc., to be orally delivered showing effective paracellular permeability. This patent does not discuss photosensitizer, but relates to nanoparticles as carrier for hydrophilic protein having high molecular weight which cannot easily be absorbed in the gut and also to prevent the proteases activity on the enclosed proteineous drug.

"Harel in his U.S. patent Application No. 2008/044481 discloses use of microparticles for oral administration of bioactive agents like drug, protein, vitamins, probiotic organism etc. The encapsulation material can be made of oil, polysaccharides, proteins, synthetic polymers or combination of these.

"In publication WO 2007/122613, by Yoav D. Livney et al., the inventors describe a method of encapsulating hydrophobic compounds including nutrients, therapeutic and cosmetic compounds and their administration via food and beverages. Especially used milk protein casein for the encapsulation.

"Generally photosensitizers in the prior art are administrated systemically or topically, depending on the place of treatment and drug properties. The solubility, molecular size and stability are certain factors used to decide the mode of administration. The present invention provides a oral formulation which can be easily administered to the patient through the oral route without any complication such as pain due to needle pricks, or staining of skin due to local application etc. Present invention aims to provide a formulation which can be easily absorbed by the gastrointestinal tract."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "It is an objective of the present invention to provide a suitable formulation of photosensitizer for oral administration, which can deliver the therapeutic drug dosage required for photodynamic therapy and antimicrobial photodynamic therapy treatment to the target organ or body region.

"It is also an objective of the present invention to provide a suitable oral formulation using a carrier system encapsulating photosensitizer which is stable in the gastrointestinal tract.

"It is yet another objective, to provide a suitable oral formulation which increases the bioavailability of the drug to ensure sufficient accumulation at the target site.

"It is the still another objective, of the present invention to provide oral formulation of photosensitizer which can be administered in the form of a tablet; a capsule; a liquid fill; a powder; a paste; a syrup etc.

"It is also another objective of the present invention to provide oral formulation using carrier system comprising of lipids, conventional liposomes, pegylated liposomes, thermodynamically stable nano-emulsions, Alpha-feto Protein (AFP), BSA (Bovine Serum Albumin), Hydrosoles, Self-Micro-Emulsifying-Drug-Delivery-Systems (SMEDDS), fat emulsion system, nanoparticles and other known suitable carriers.

"It is further objective of the present invention to provide oral formulation, which can be easily adhered on the gastrointestinal tract mucosa, where the drug subsequently will be absorbed.

"Briefly stated, present invention discloses a method of formulating photosensitive agents for oral administration during photodynamic therapy (PDT) and Antimicrobial photodynamic therapy (APDT) treatment. The oral formulated photosensitizers show increased solubility and permeability, thus improving the bioavailability of photosensitizers at the treatment site. An orally administrated photosensitizer is suitable formulated for mucosal adhesion and absorption via gastrointestinal mucosal membranes. Present invention of oral formulation uses lipids and known proteins as carriers for photosensitizer by oral route. Carriers known for encapsulating photosensitizer include conventional liposome, pegylated liposome, nanoemulsion, nanocrystrals, nanoparticles, fatty emulsions, lipidic formulation, hydrosols, SMEDDS, Alpha-Feto protein (AFP), and Bovine-Serum-Albumin (BSA), fatty emulsions and nanoparticles. The oral formulation in case of a hydrophobic photosensitizer in the present invention is stabilized using suitable surfactant/solubilizers thus preventing aggregation of the drug in the stomach and until it is absorbed in the duodenum and the small intestine. This formulation can be administered in the form of liquid, capsules, tablets, powder, paste or gel. Thus formulated drug can be administered orally as one single dose or in multiple doses before administering PDT. It is one of the embodiments of this invention to use Temoporfin (m-THPC) as a photosensitizer in the oral formulations. This compound is especially suitable to be administered orally because there is no known enzyme system in the mammalian body which can metabolize Temoporfin. So, Temoporfin can reach the blood system unchanged and fully active after absorption of the formulation in the gastrointestinal tract.

"The above, and other objects, features and advantages of the present invention will become apparent from the following description to be read in conjunction with the accompanying drawings."

For more information, see this patent: Grafe, Susanna; Nifantiev, Nikolay; Volker, Albrecht; Neuberger, Wolfgang; Wieland, Gerhard; Scheglmann, Dietrich; Fahr, Alfred; Wiehe, Arno. Oral Formulations for Tetrapyrrole Derivatives. U.S. Patent Number 8815931, filed April 27, 2010, and published online on August 26, 2014. Patent URL:

Keywords for this news article include: Advertising, Biocompatible Materials, Biolitec Pharma Marketing Ltd, Biological Pigments, Biomedical and Dental Materials, Clinical Trials and Studies, Drug Administration Routes, Drug Delivery Systems, Emerging Technologies, Gastroenterology, Liposomes, Marketing, Nanoparticle, Nanotechnology, Oral Administration, Pharmaceuticals, Porphyrins, Therapeutics, Therapy.

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Source: Biotech Week

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