Quality by design development of brivanib alaninate tablets: degradant and moisture control strategy.

A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent compound, BMS-540215. The shelf-life of the tablets is determined by the rate of the hydrolysis reaction. Hydrolysis kinetics in the tablets was studied to understand its dependence on temperature and humidity. The BMS-540215 amount versus time profile was simulated using a kinetic model for the formation of BMS-540215 as function of relative humidity in the environment and a sorption-desorptiom moisture transfer model for the relative humidity inside the package. The combined model was used to study the effect of initial tablet water content on the rate of degradation and to identify a limit for initial tablet water content that results in acceptable level of the degradant at the end of shelf-life. A strategy was established for the moisture and degradant control in the tablet based on the understanding of its stability behavior and mathematical models. The control strategy includes a specification limit on the tablet water content and manufacturing process controls that achieve this limit at the time of tablet release testing.

Update on tamper-resistant drug formulations.

An expert panel convened in 2005 by the College on Problems of Drug Dependence (CPDD) to consider strategies to reduce the risk of prescription medication abuse concluded that drug formulation plays a significant role in determining risk of abuse. Efforts on the part of the pharmaceutical industry to develop drugs that deter abuse have focused primarily on opioid formulations resistant to common forms of tampering, most notably crushing or dissolving the tablet to accelerate release. Several opioid formulations developed to be tamper resistant have been approved, but the US Food and Drug Administration has not approved explicit label claims of abuse deterrence and has stated that any such claim will require substantial postmarketing data. Drug development efforts in this area raise questions about the relative impact of abuse-deterrent formulations, not only on individuals who might abuse a medication, but also on patients who are compliant with therapy. This review discusses progress since the 2005 CPDD meeting with an emphasis on opioids. Articles cited in the review were identified via a PubMed search covering the period between January 1, 2000, and October 5, 2011. Scientific work presented by the authors and their colleagues at meetings held through May 2012 also was included. Published literature suggests that development of abuse-deterrent products will require broad public health support and continued encouragement from regulatory authorities so that such products will become the expected standard of care for certain drug classes.

Current approaches in tamper-resistant and abuse-deterrent formulations.

CONTEXT: The escalating abuse of prescription drugs has recently spawned the development of novel drug formulations resistant to various methods of tampering and misuse. OBJECTIVE: The intent of this paper is to provide an overview and classification system of formulation approaches, developed to produce what most refer to as abuse-deterrent or tamper-resistant dosage forms. METHODS: A comprehensive literature search was conducted within Embase™ and Medline using key words "abuse deterrentâ and "tamper resistantâ to identify relevant technologies. Only issued patents were examined using the phrase "abuse deterrent compositionâ searched through PatFT from the United States Patent and Trademark Office. Current information from press releases and product innovator websites was obtained for additional data. RESULTS: Identified formulation approaches were organized into two categories, physical approaches and chemical approaches. Physical approaches were subcategorized into solids, gels or non-intentionals, while chemical approaches were further broken down into agonists/antagonists, aversives, or metabolics. Among issued patents specifying an abuse-deterrent method, nine diverse approaches were found. Most formulations under development combined approaches, and utilized proprietary technologies from pharmaceutical manufacturers. CONCLUSIONS: Prodrug and agonist/antagonist formulations are popular in marketed products, while solid and gel approaches are more recent additions. However, the inclusion of aversive agents or enzyme inhibitors in a product is proving to be more difficult to develop. Overall, detailed formulation and manufacturing methods still remain rather elusive to protect public health. Moreover, these innovative formulations are mostly untried in the general population and their abuse deterring effects has yet to be proven.

A PAMPA assay as fast predictive model of passive human skin permeability of new synthesized corticosteroid C-21 esters.

The permeation properties of twenty newly synthesized α-alkoxyalkanoyl and α-aryloxyalkanoyl C-21 esters of standard corticosteroids: Fluocinolone acetonide, dexamethasone, triamcinolone acetonide and hydrocortisone were established using a PAMPA assay (70% silicone oil and 30% isopropyl myristate). The data were compared with parent corticosteroids with addition of mometasone furoate and hydrocortisone acetate. All newly synthesized corticosteroid C-21 esters have effective permeability coefficients higher then -6, mostly followed with high values of retention factors and low permeation. The examined compounds were grouped through relationship between obtained retention factors and permeation parameters (groups I-III). The classification confirmed group I (membrane retentions as well as permeation lower then 30%) for all corticosteroid standards except mometasone furoate, a potent topical corticosteroid which, with high membrane retention (81%) and low permeation (7.7%) fits into group III. The largest number of new synthesized corticosteroids C-21 esters, among them all fluocinolone acetonide C-21 esters, have high membrane retentions (32.4%-86.5%) and low permeations (1.3%-27.1%), fitting in group III. The classification was related to previously obtained anti-inflammatory activity data for the fluocinolone acetonide C-21 esters series. According to the PAMPA results the new synthesized esters could be considered as potential new prodrugs with useful benefit/risk ratio.

Synthesis and characterization of novel dextran-conjugated macromolecules of aceclofenac

The study involves the condensation of acylimidazole derivatives of acaclofenac (AC) with dextran 10,000 and 20,000 to obtain aceclofenac-dextran prodrugs AC10 and AC20 respectively with an aim to improve aqueous solubility, increase therapeutic efficiency and reduce the gastrointestinal side effects. The structure of synthesized prodrugs was confirmed by IR and NMR spectroscopy. The molecular weight was determined by Mark-Howink Sakurada equation and the degree of substitution was obtained as 13.3 and 16 % for the prodrugs. In vitro hydrolysis carried out in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and simulated colonic fluid (SCF) showed faster hydrolysis in SIF and SCF. The percentage anti-inflammatory activity of AC was found as 49.56 whereas an improved value of 56.44 and 61.82 % were obtained for AC10 and AC20 respectively. The prodrugs showed improved analgesia and reduced ulcerogenicity than aceclofenac, thereby proving to be better in action than the parent drug(AU)

El estudio se centra en la condensación de acilimidazoles derivados de aceclofenaco (AC) con dextrano 10.000 y 20.000 para obtener los profármacos de aceclofenaco-dextrano AC10 y AC20, respectivamente, con el objetivo de mejorar la hidrosolubilidad, aumentar la eficacia terapéutica y reducir los efectos secundarios gastrointestinales. La estructura de los profármacos sintetizados se ha confirmado a través de espectroscopia IR y RMN. El peso molecular ha sido determinado a través de la ecuación de Mark-Houwink-Sakurada y se ha obtenido un grado de sustitución de 13,3 y 16% para los profármacos. La hidrólisis in vitro llevada a cabo en fluido gástrico simulado (FGS), fluido intestinal simulado (FIS) y fluido colónico simulado (FCS) ha mostrado una hidrólisis más rápida en FIS y FCS. De ello ha resultado un porcentaje de actividad antiinflamatoria de AC de 49,56, mientras que para AC10 y AC20 se ha obtenido un valor aumentado de 56,44 y 61,82% respectivamente. Los profármacos han mostrado una mejor analgesia y una menor ulcerogenicidad que el aceclofenaco, por lo que se demuestra que su acción es mejor que la del fármaco base(AU)

Toxicity testing: the search for an in vitro alternative to animal testing.

Prior to introduction to the clinic, pharmaceuticals must undergo rigorous toxicity testing to ensure their safety. Traditionally, this has been achieved using in vivo animal models. However, besides ethical reasons, there is a continual drive to reduce the number of animals used for this purpose due to concerns such as the lack of concordance seen between animal models and toxic effects in humans. Adequate testing to ensure any toxic metabolites are detected can be further complicated if the agent is administered in a prodrug form, requiring a source of cytochrome P450 enzymes for metabolism. A number of sources of metabolic enzymes have been utilised in in vitro models, including cell lines, primary human tissue and liver extracts such as S9. This review examines current and new in vitro models for toxicity testing, including a new model developed within the authors' laboratory utilising HepG2 liver spheroids within a co-culture system to examine the effects of chemotherapeutic agents on other cell types.

Preformulation studies of a prodrug of Delta9-tetrahydrocannabinol.

Preformulation studies were performed on a hemiglutarate ester prodrug of Delta(9)-tetrahydrocannabinol (THC-HG), to facilitate the development of stable formulations by hot-melt methods. The various studies performed included solid-state thermal characterization, pKa, logP, aqueous and pH dependent solubility, pH stability and effect of moisture, temperature and oxygen on solid-state stability. A hot-melt method was utilized to fabricate THC-HG incorporated poly (ethylene oxide) (PEO) matrices and the bioadhesive properties, release profiles and post-processing stability of these matrices were assessed as a function of the polymer molecular weight. The prodrug exhibited a T (g) close to 0 degrees C, indicating its amorphous nature. Thermogravimetric analysis revealed a rapid weight loss after 170 degrees C. The prodrug exhibited a seven-fold higher aqueous solubility as compared to the parent drug (THC). Also, the solubility of the compound increased with increasing pH, being maximum at pH 8. The prodrug exhibited a v-shaped pH-rate profile, with the degradation rate minimum between pH 3 and 4. The moisture uptake and drug degradation increased with an increase in relative humidity. Solid-state stability indicated that the prodrug was stable at -18 degrees C but demonstrated higher degradation at 4 degrees C, 25 degrees C and 40 degrees C (51.6%, 74.5% and 90.1%, respectively) at the end of 3-months. THC-HG was found to be sensitive to the presence of oxygen. The release of the active from the polymeric matrices decreased, while bioadhesion increased, with an increase in molecular weight of PEO.

Strategies to improve oral drug bioavailability.

Efforts to improve oral drug bioavailability have grown in parallel with the pharmaceutical industry. As the number and chemical diversity of drugs has increased, new strategies have been required to develop orally active therapeutics. The past two decades have been characterised by an increased understanding of the causes of low bioavailability and a great deal of innovation in oral drug delivery technologies, marked by an unprecedented growth of the drug delivery industry. The advent of biotechnology and consequent proliferation of biopharmaceuticals have brought new challenges to the drug delivery field. In spite of the difficulties associated with developing oral forms of this type of therapeutics, significant progress has been made in the past few years, with some oral proteins, peptides and other macromolecules currently advancing through clinical trials. This article reviews the approaches that have been successfully applied to improve oral drug bioavailability, primarily, prodrug strategies, lead optimisation through medicinal chemistry and formulation design. Specific strategies to improve the oral bioavailability of biopharmaceuticals are also discussed.

The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine.

To identify an orally available fluoropyrimidine having efficacy and safety profiles greatly improved over those of parenteral 5-fluorouracil (5-FU: 1), we designed a 5-FU prodrug that would pass intact through the intestinal mucisa and be sequentially converted to 5-FU by enzymes that are highly expressed in the human liver and then in tumors. Among various N4-substituted 5'-deoxy-5-fluorocytidine derivatives, a series of N4-alkoxycarbonyl derivatives were hydrolyzed to 5'-deoxy-5-fluorocytidine (5'-DFCR: 8) specifically by carboxylesterase, which exists preferentially in the liver in humans and monkeys. Particularly, derivatives having an N4-alkoxylcarbonyl moiety with a C4-C6 alkyl chain were the most susceptible to the human carboxylesterase. Those were then converted to 5'-deoxy-5-fluorouridine (5'-DFUR: 4) by cytidine deaminase highly expressed in the liver and solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumors. When administered orally to monkeys, a derivative having the N4-alkoxylcarbonyl moiety with a C5 alkyl chain (capecitabine: 6) The highest AUC and Cmax for plasma 5'-DFUR. In tests with various human cancer xenograft models, capecitabine was more efficacious at wider dose ranges than either 5-FU or 5'-DFUR and was significantly less toxic to the intestinal tract than the others in monkeys.

Possible mechanisms of gastroduodenal mucosal damage in volunteers treated with nonsteroidal antiinflammatory drugs--the usefulness of prodrugs.

A controlled double blind study on the incidence of nonsteroidal antiinflammatory drug (NSAID) gastropathy was performed in 29 healthy volunteers administered diclofenac Na (10 subjects) or a prodrug (loxoprofen Na in 10 subjects and proglumetacin maleate in 9 subjects). The incidence of NSAID gastropathy was significantly lower in the subjects administered the prodrugs than in those administered diclofenac Na (p less than 0.05), which suggested the clinical usefulness of the prodrugs.