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 The leading web portal for pharmacy resources, news, education and careers December 15, 2017
Pharmacy Choice - Pharmaceutical News - "Low Dose Pharmaceutical Composition" in Patent Application Approval Process (USPTO 20170312254) - December 15, 2017

Pharmacy News Article

 11/20/17 - "Low Dose Pharmaceutical Composition" in Patent Application Approval Process (USPTO 20170312254)

By a News Reporter-Staff News Editor at Pharma Business Week A patent application by the inventors MALHOTRA, Geena (Mumbai, IN); PURANDARE, Shrinivas Madhukar (Mumbai, IN), filed on July 14, 2017, was made available online on November 9, 2017, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also Patents).

This patent application has not been assigned to a company or institution.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Deferasirox has the chemical name 4-[3, 5-bis (2-hydroxyphenyl)-[1, 2, 4] triazol-1-yl] enzoic acid and is reported to have the following chemical structure.

"##STR00001##

"Deferasirox is an orally active iron chelator and has been approved for the treatment of iron overload in transfusion dependent anemias (transfusion hemosiderosis) in particular thalassemia major, thalassemia intermediate and in sickle cell disease to reduce iron-related morbidity and mortality in patients having an age of two years and older.

"Chronic iron overload is a result of regular blood transfusions used in the treatment of several conditions including .beta.-thalassemia, sickle cell disease and myelodysplastic syndromes.

"Each unit of blood contains iron and as the human body has no physiological mechanism to actively excrete excess iron, repeated blood transfusions result in excessive accumulation of iron. This excess of iron deposited in body tissues can cause severe damage to organs such as liver, heart, endocrine organs. This may lead to many complications including cardiomyopathy, liver cirrhosis, diabetes mellitus and reduced life expectancy.

"Deferasirox mobilizes tissue iron by forming soluble stable complexes that are then excreted in the feces. It is a tridentate iron chelator requiring two molecules of the drug to form a stable complex. Iron is chelated both from the reticuloendothelial cells (RE cells) as well as various parenchymal tissues. The chelated iron is cleared by the liver and excreted through the bile. It also has the ability to prevent the myocardial cell iron uptake by removing iron directly from myocardial cells.

"Deferasirox is highly water insoluble and is highly lipid-soluble and is also observed to possess good permeability. According to the Bio-pharmaceutics Classification System (BCS), it has been classified as a Class II drug, implying that it is a poorly soluble, and a highly permeable drug. Though deferasirox is highly water insoluble, whatever limited solubility it has, that too exhibits a high pH-dependent solubility. Though it is practically insoluble in lower pH, even at a pH of 6.8, it still remains insoluble, until the buffer strength is altered to get optimal dissolution profile.

"Deferasirox being practically insoluble in aqueous media generally exhibits a poor dissolution profile and consequently poor bioavailability.

"Several strategies and formulations have been employed to overcome these limitations of solubility and poor bioavailability. Although existing strategies such as complexing drugs with cyclodextrins, conjugation to dendrimers, salt formation of ionizable drugs and the use of co-solvents have been shown to improve drug solubility, solubilization methods that can improve the absorption of the drug are still highly desirable.

"Deferasirox is commercially available as dispersible tablet (EXJADE.RTM.) for oral administration. EXJADE is supplied as a dispersible tablet containing 125 mg, 250 mg and 500 mg of deferasirox per tablet. This tablet is dispersed in a glass of water or any other suitable drink, and this resulting suspension is then administered to the patient.

"Deferasirox is administered as a once daily oral iron chelator, which is prescribed as a dispersible tablet, i.e., a tablet which needs to be dispersed in an aqueous medium prior to administration.

"Deferasirox is typically administered at an initial dose of about 20 mg/kg body weight, and the dose is adjusted up to a maximum of 40 mg/kg body weight, which means that, the recommended dosage of deferasirox is on the higher side in order to have a clinical benefit.

"More specifically, in transfusional overload, the initial dose of deferasirox is 20 mg/kg, not exceeding 40 mg/kg once daily, which ultimately amounts to an intake of 3-6 tablets of EXJADE.RTM.

"In non-transfusion-dependent thalassemia (NTDT), the initial dose of deferasirox is 10 mg/kg, not exceeding 20 mg/kg once daily, which ultimately amounts to an intake of 2-3 tablets of EXJADE.RTM.

"Premarketing studies have demonstrated elevations in liver transaminases in almost 1/3 of patients. While these initial reports documented only non-sustained elevations, in September 2007, the FDA updated post market safety findings of this agent, previously documenting incidents of renal failure, to include adverse hepatic events, including drug-induced hepatitis and liver failure.

"There have been a few post marketing notifications of hepatic failure some with a fatal outcome to the FDA. Most of these events have occurred in patients greater than 55 years of age with significant co-morbidities including liver cirrhosis and multiorgan failure.

"Mitochondrial injury is one of the possible mechanisms of deferasirox-induced liver injury. Hallmark of this type of injury is microvesicular fat in hepatocytes that can revolve into macrovesicular lesions, focal necrosis, fibrosis, and cholestasis consistent with this patient's liver biopsy. Furthermore, patients often experience nonspecific symptoms of insidious onset, such as nausea, vomiting, fatigue, and weight loss, while jaundice is a late finding. Hence, extreme caution should be taken in using deferasirox in patients who have underlying liver disease.

"Renal toxicity is a relatively frequent adverse event in patients receiving deferasirox treatment, with proximal tubular dysfunction and a decreased Glomerular Filtration Rate. Clinicians have to regularly assess their patients to prevent chronic renal injury that may result from a prolonged tubular injury. Long-term follow-up is therefore needed.

"Further, Fanconi Syndrome is associated with the use of deferasirox. Fanconi Syndrome is a generalized disturbance of proximal tubular function leading to renal losses of glucose, phosphate, calcium, uric acid, amino acids, bicarbonates, and other organic compounds.

"Acute interstitial nephritis was also observed in a patient treated with deferasirox for myelodysplastic syndrome.

"As side effects are not uncommon with the use of deferasirox, optimal therapy is always required to achieve the best clinical outcomes while minimizing these side effects.

"Further, deferasirox is recommended to be taken daily on an empty stomach at least 30 minutes before food, preferably at the same time each day.

"That means the pharmacokinetic properties of deferasirox are affected by the prandial status of a patient receiving the treatment, i.e. it exhibits a 'food effect'.

"Accordingly, the patients receive specific instructions to administer deferasirox on an empty stomach. Hence, deferasirox is administered in a fasting state in an attempt to minimize the food effect. Administration of a deferasirox composition with food may change its bioavailability by affecting either the drug substance or the composition in which the drug substance is formulated.

"This situation is unsatisfactory and inconvenient to the thalassemia patients undergoing treatment with deferasirox since their medication usually consists of multiple tablets.

"The general therapy regimen and its administration limitation such as food effect are unavoidable. Also, to achieve the maximal effect of the administered medications it would be necessary to consider the bioavailability of the administered drugs to achieve the desired effect failing which such therapies and drug regimens would be futile and would also be taxing to the morbid state of the patients.

"Accordingly, there have been no prior art disclosures of compositions of deferasirox that are free of the food effect and which thereby facilitate patient compliance and superior bioavailability. The currently commercialized dosage form and the recommended dose still do not address the unsolved tribulations of the deferasirox therapy.

"WO 2004035026 discloses a dispersible tablet of deferasirox wherein the active ingredient is present in an amount of from 5% to 40% by weight based on total weight of the tablet.

"WO 2005097062 discloses a dispersible tablet of deferasirox wherein the active ingredient is present in an amount of from 42% to 65% by weight based on total weight of the tablet.

"WO 2007045445 discloses a dispersible tablet of deferasirox or a pharmaceutically acceptable salt thereof present in an amount of from 42% to 65% by weight based on total weight of the tablet and at least one pharmaceutically acceptable excipient suitable for the preparation of dispersible tablets and to process for making said dispersible tablet.

"WO 2009067557 discloses a process of preparing deferasirox formulations having sufficiently high dissolution rate and good bioavailability wherein said process comprises co-milling deferasirox with at least two pharmaceutically acceptable excipients in the absence of any solvent.

"WO 2010035282 discloses oral pharmaceutical composition comprising deferasirox in the form of a dispersible tablet wherein the active ingredient has a mean particle size less than about 100 .mu.m and is present in an amount greater than 66% by weight based on total weight of the tablet.

"WO 2012/042224 discloses a pharmaceutical composition comprising deferasirox in the form of particles wherein the particles have an average particle size of less than or equal to about 2000 nm.

"Deferasirox Induced Liver Injury in Haemochromatosis, Journal of the College of Physicians and Surgeons Pakistan 2010, Vol. 20 (8): 551-553, Naeem Aslam, Parveen Mettu, Luis S. Marsano-Obando and Anthony Martin explains that drug-induced liver injury is a common side-effect of many medicines and is particularly problematic when the original condition under treatment is already causing liver damage. In particular, this article describes the hepatotoxicity induced by deferasirox in a patient with haemochromatosis with a discussion of possible pathogenetic mechanism.

"Acute interstitial nephritis due to deferasirox: a case report, Nephrol. Dial. Transplant (2008) 23 (10): 3356-3358, Godela Brosnahan, Neriman Gokden and Sundararaman Swaminathan describes the case of a 62 year-old man with myelodysplastic syndrome who developed a progressive decline in renal function after starting deferasirox. A kidney biopsy showed acute interstitial nephritis with increased eosinophils, suggesting drug hypersensitivity. Deferasirox was discontinued and renal function returned to baseline.

"Deferasirox-induced renal impairment in children: an increasing concern for pediatricians. Pediatric Nephrology, 2012 Nov; 27(11):2115-22, Dubourg L, Laurain C, Ranchin B, PondarreC, Hadj-AIssa A, Sigaudo-Roussel D, Cochat P evaluated tubular and glomerular function before and after the initiation of deferasirox therapy in a pediatric patient population and found that renal toxicity was a frequent adverse event. The article advised that routine renal assessment was required to prevent chronic kidney disease that could result from prolonged tubular injury.

"Acute renal failure and Fanconi syndrome due to deferasirox, Nephrol. Dial. Transplant (2010) 25 (7): 2376-2378, Steven Grange, Dominique M. Bertrand, Dominique Guerrot, Florence Eas, Michel Godin explains that recent data from large studies have confirmed the renal toxicity of deferasirox. This article reports a case of Fanconi syndrome associated with acute renal failure in a patient receiving deferasirox.

"Combined chelation of lead (II) by deferasirox and deferiprone in rats as biological model, Biometals (2014), 27:89-95, F. Dahooee Balooch et al investigated the capability of deferasirox and deferiprone in removing lead from the body. Rats were dosed with lead for 45 days then received chelation therapy with deferasirox and deferiprone for 10 days to reduce the lead levels. Combined chelation therapy showed higher efficacy and lower toxicity than single therapies.

"Various formulations that are disclosed and that are available in the market contain a dose of 20 mg/kg body weight and a maximum of 40 mg/kg body weight.

"Although deferasirox is the drug of choice for the treatment of thalassemia, administration of deferasirox for a longer duration and in higher doses to achieve the desired clinical effects may result in serious side effects. Accordingly, patients need to be regularly monitored for vital organs such as heart, endocrine organs (thyroid, testes, ovaries, and pancreas) and the liver but additional attention needs to be given to regular monitoring of renal function in patients who are at an increased risk of complications or on chelator therapy.

"The possible strategies for optimizing deferasirox therapy and ultimately reducing the side effects may include applying alternate day treatment or allowing a washout period or using deferasirox in combination with other iron chelators. However, large and detailed clinical studies would be required to verify these strategies.

"Considering the existing variety, deferasirox compositions with low dose could be the best available option. However, no composition is yet available which includes low dose deferasirox, wherein the total daily dose of deferasirox is less than the conventionally administered daily dose, and which is equally effective for the treatment of chronic iron overload.

"Hence, to achieve a promising result with the administration of deferasirox for the desired indications and with minimal side effects, there is a need to develop low dose compositions wherein the total daily dose of deferasirox is less than the conventionally administered daily dose and which is equally effective for the treatment of chronic iron overload.

"Further, to overcome the food effect, the inventors of the present invention have designed formulations comprising deferasirox which reduce or nullify the food effect to ensure better bioavailability. Such formulations of deferasirox are patient compliant, robust, and stable and also exhibit optimal dissolution properties.

"The above drawbacks and rationales have lead the inventors of the present invention to develop pharmaceutical compositions comprising a reduced dose or a low dose of deferasirox further exhibiting improved bioavailability, and exhibiting reduced or no food effect, without causing dose related side effects and which also can be prepared in an easy and cost-effective manner. These pharmaceutical compositions comprising a low dose of deferasirox further exhibit equally acceptable dissolution properties and absorption properties thus leading to better bioavailability."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent application: "According to one aspect of the present invention, there is provided a low dose pharmaceutical composition comprising deferasirox.

"According to one aspect of the present invention, there is provided a low dose pharmaceutical composition comprising deferasirox or a pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable excipients.

"According to one aspect of the present invention, there is provided a low dose pharmaceutical composition comprising deferasirox exhibiting reduced side effects.

"According to one aspect of the present invention, there is provided a low dose pharmaceutical composition comprising deferasirox exhibiting improved bioavailability.

"According to another aspect of the present invention, there is provided a low dose pharmaceutical composition comprising deferasirox exhibiting minimal or no food effect.

"According to another aspect of the present invention there is provided a process for preparing the low dose pharmaceutical composition comprising deferasirox.

"According to one aspect of the present invention there is provided a process for preparing the low dose pharmaceutical composition comprising

"dissolving or adsorbing or blending deferasirox and at least one excipient to produce a dispersion of deferasirox; and

"processing the dispersion to produce a desired dosage form.

"According to yet another aspect of the present invention there is provided a low dose pharmaceutical composition comprising deferasirox for use in the treatment of chronic iron overload.

"According to yet another aspect of the present invention there is provided a low dose pharmaceutical composition comprising deferasirox for use in the treatment of lead toxicity.

"According to another aspect of the present invention there is provided a low dose pharmaceutical composition comprising deferasirox and deferiprone for use in the treatment of lead toxicity.

"According to a further aspect of the present invention there is provided a method for the treatment of chronic iron overload which comprises administering a low dose pharmaceutical composition comprising deferasirox.

"According to a further aspect of the present invention there is provided a method for the treatment of lead toxicity which comprises administering a low dose pharmaceutical composition comprising deferasirox.

"According to another aspect of the present invention there is provided a method for the treatment of lead toxicity which comprises administering a low dose pharmaceutical composition comprising deferasirox and deferiprone.

"The present invention provides a pharmaceutical composition comprising deferasirox or a pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable excipients. Said pharmaceutical composition may comprise any of the features described below, including the quantity of deferasirox in a unit dose, the excipients present in the composition, the particle size of the deferasirox, its use in the treatment of chronic iron overload and its use in providing a specific daily dose of deferasirox."

URL and more information on this patent application, see: MALHOTRA, Geena; PURANDARE, Shrinivas Madhukar. Low Dose Pharmaceutical Composition. Filed July 14, 2017 and posted November 9, 2017. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220170312254%22.PGNR.&OS=DN/20170312254&RS=DN/20170312254

Keywords for this news article include: Patents, Hemolytic, Nephrology, Pediatrics, Deferasirox, Thalassemia, Fanconi Anemia, Renal Function, Kidney Function, Medical Devices, Chelating Agents, Fanconi Syndrome, Gastroenterology, Blood Transfusion, Congenital Anemia, Endocrine Research, Hemoglobinopathies, Drugs and Therapies, Risk and Prevention.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2017, NewsRx LLC



(c) 2017 NewsRx LLC

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