Influence of Drug Property and Product Design on In Vitro–In Vivo Correlation of Complex Modified-Release Dosage Forms

The present study examines how drug's inherent properties and product design influence the evaluation and applications of in vitro–in vivo correlation (IVIVC) for modified-release (MR) dosage forms consisting of extended-release (ER) and immediate-release (IR) components with bimodal drug release. Three analgesic drugs were used as model compounds, and simulations of in vivo pharmacokinetic profiles were conducted using different release rates of the ER component and various IR percentages. Plasma concentration–time profiles exhibiting a wide range of t_max and maximum observed plasma concentration (C_max) were obtained from superposition of the simulated IR and ER profiles based on a linear IVIVC. It was found that depending on the drug and dosage form design, direct use of the superposed IR and ER data for IVIVC modeling and prediction may (1) be acceptable within errors, (2) become unreliable and less meaningful because of the confounding effect from the non-negligible IR contribution to C_max, or (3) be meaningless because of the insensitivity of C_max to release rate change of the ER component. Therefore, understanding the drug, design and drug release characteristics of the product is essential for assessing the validity, accuracy, and reliability of IVIVC of complex MR products obtained via directly modeling of in vivo data.     

Molecular Simulation Analyses of Polymorphism Control Factors by the Example of Carbamazepine Forms I-IV: A Blueprint for Industrial Drug Formulation?

We outline comparably simple molecular simulation techniques to elucidate the interactions that determine the polymorphism of carbamazepine. Starting from the established GAFF molecular mechanics model, only a small series of tailor-made improvements is needed to tackle the subtle differences in the interaction energies of polymorphs I - IV. On this basis, molecular dynamics simulations provide melting enthalpies at < 1 kcal/mol accuracy (0.2 kcal/mol for forms I-III) as compared to the experiment. Yet, the predicted stability ranking of III > I > II > IV only partially reproduces the experimentally observed III > I > IV > II series. Despite this limitation, we demonstrate how insights from molecular simulation offer the elucidation of possible factors for polymorph control. Apart from characterizing bulk crystals, we outline the evaluation of size-dependent profiles of crystallite formation energy. Contrasting the contributions of bulk, surface and edge terms to the formation energy of nano-scale precipitates, we suggest a multi-step nucleation mechanism leading from amorphous aggregates to crystallites. We argue that carbamazepine aggregates of less than ～100 molecules adopt a spherical shape to minimize edge/surface energy – overcompensating the loss in bulk energy inherent to non-crystalline ordering in the inner core. In turn, for large crystallites polymorph form III is preferred, whilst suitable spatial confinement to crystallites of 100–500 carbamazepine molecules appears to promote form II.     

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

We developed a simulation method to describe in vitro drug concentration?time profiles under supersaturated conditions. In a nonsink dissolution test of carbamazepine polymorphic form III (CBZ_III), a model supersaturable solid, the concentration of carbamazepine reached a supersaturated state against its dihydrate form (CBZ_DH). After a certain period, de-supersaturation due to the precipitation of CBZ_DH was observed. In the simulation of this typical dissolution?precipitation profile, the precipitation process of CBZ_DH was simulated by a population balance model in which the rates of primary/secondary nucleation and growth of CBZ_DH were considered. Six rate constants in the precipitation model were determined from de-supersaturation profiles in unseeded isothermal crystallization experiments of CBZ_DH. The dissolution process of CBZ_III was modeled on the basis of its dissolution profile under a sink condition. The simulated concentration versus time curves satisfactorily reproduced the characteristics of dissolution, supersaturation, and precipitation behavior of the model drug. The presented method will enable rational design of formulations and accurate prediction of the oral absorbability of drugs in supersaturable solid forms.     

Does the Number of Irradiated Cells Influence the Spatial Distribution of Bystander Effects?

There is growing evidence that the radiation effects at low doses are not adequately described by a simple linear extrapolation from high doses, due, among others, to bystander effects. Though several studies have been published on this topic, the explanation of the mechanisms describing the bystander effects remains unclear. This study aims at understanding how the bystander signals are or can be propagated in the cell culture, namely if the number of irradiated cells influences the bystander response. An A549 cell line was exposed to several doses of α-particles, being the bystander response quantified in two non-irradiated areas. The radius of irradiated areas differs by a factor of 2, and the non-irradiated areas were optimally designed to have the same number of cells. Our results show evidence for bystander effects occurring in cells far away from the irradiated ones, meaning that bystander signals can easily spread throughout the cell culture. Additionally, our study highlights that the damage caused by radiation on the surrounding of irradiated areas could be different according to the number of irradiated cells, i.e., for the same dose value; the overall cellular damage could be different.     

Continuous Release of rh-Interferon α-2a from Triglyceride Implants: Storage Stability of the Dosage Forms

Tristearin implants containing polyethylene glycol 6000 (PEG) were shown to be a promising platform for the delivery of pharmaceutical proteins for periods up to 1 month. The objective of this study was to investigate the storage stability of the lipid devices, as long-term storage stability ensuring acceptable shelf-life can be considered the most important parameter for commercially viable sustained-release dosage forms. Rh-Interferon α-2a was stabilized by a lyophilization process using either trehalose or hydroxypropyl-β-cyclodextrin as stabilizer. Tristearin implants containing the lyophilized protein material and 10% PEG were stored over 3 months and 6 months, both at 4°C and room temperature, before release studies were initiated. Data from stored implants demonstrated trehalose not to be effective to provide full protein stabilization during long-term storage of the lipid matrices, this was apparent from both the reduced total drug level liberated and the release of aggregated specimen compared to the situation immediately after implant manufacture. In contrast, hydroxypropyl-β-cyclodextrin (HP-β-CD) exhibited a high potential for protein stabilization within the matrices during both storage and release. Generally, 95% of the incorporated protein was delivered continuously within 1 month in monomeric form, even after 6 months' storage of the implants at room temperature.     

Drug discovery for heart failure: a new era or the end of the pipeline?

Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of beta-blockers and antagonists of the renin-angiotensin system, there is still a major unmet need for better therapies for many patients with heart failure. However, disappointment related to late-stage clinical failures of a number of novel agents, including endothelin antagonists and tumour-necrosis factor blockers, has reduced the impetus of drug development in this field. Here, we review possible targets for heart failure therapy that have emerged from recent progress in our understanding of the underlying disease mechanisms, and highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.     

Lengthening of Insect Development on Bt Zone Results in Adult Emergence Asynchrony: Does It Influence the Effectiveness of the High Dose/Refuge Zone Strategy?

The “High Dose/Refuge” strategy (HD/R) is the currently recommended Insect Resistance Management strategy (IRM) to limit resistance development to Bacillus thuringiensis (Bt) plants. This strategy requires planting a “refuge zone” composed of non-Bt plants suitable for the target insect and in close proximity to a “Bt zone” expressing a high toxin concentration. One of the main assumptions is that enough susceptible adults mate with resistant insects. However, previous studies have suggested that the high toxin concentration produced by Bt plants induces slower insect development, creating an asynchrony in emergence between the refuge and the Bt zone and leading to assortative mating between adults inside each zone. Here, we develop a deterministic model to estimate the impact of toxin concentration, emergence asynchrony and refuge zone size on the effectiveness of the HD/R strategy. We conclude that emergence asynchrony only affects resistance when toxin concentration is high and resistance is recessive. Resistance develops more rapidly and survival of susceptible insects is higher at lower toxin concentration, but in such situations, resistance is insensitive to emergence asynchrony.     

Evaluation of the in Vivo Disintegration of Solid Dosage Forms of a Bile Acid Sequestrant in Dogs Using γ-Scintigraphy and Correlation to in Vitro Disintegration

Purpose. To evaluate the in vivo disintegration behavior of tablets and capsules of a bile acid sequestrant, DMP 504, in beagle dogs and to assess the significance of the in vitro disintegration of the dosage forms on subsequent in vivo behavior in order to draw possible in vitro-in vivo correlations. Methods. Tablet and capsule formulations of a bile acid sequestrant, DMP 504, were formulated with samarium oxide and neutron activated to produce radioactive ¹⁵³Sm to noninvasively evaluate their in vivo behavior in beagle dogs by -scintigraphy. A four-way crossover design was completed (n = 4) in which (a) tablets from two different batches were administered under the fasted condition and manufactured using different lots of drug substance where one batch exhibited relatively faster in vitro disintegration time (30 min) than the other tablet batch, which resulted in slower disintegration (45 min), (b) a capsule formulation was administered to fasted beagles, and (c) the tablet having slower in vitro disintegration was also administered in the fed state, and its in vivo disintegration was compared to that observed in the fasted state. Results. Tablets manufactured using a lot of DMP 504 having relatively fast in vitro disintegration (30 min) resulted in relatively rapid in vivo disintegration time (15 min) in the fasted condition. This in vivo disintegration time was comparable to the in vivo disintegration of the capsules (17 min) even though the in vitro capsule disintegration time was considerably faster (2 min). Tablets prepared using a drug substance that provided a longer in vitro disintegration time (45 min) resulted in a slower in vivo disintegration (63 min). There was no difference observed in the in vivo disintegration behavior in fasted and fed dogs for the tablets that provided slower in vitro disintegration. Conclusion. In vivo disintegration of tablets of the bile acid sequestrant DMP 504 correlated with in vitro disintegration times. -Scintigraphy continues to be a good tool to use during early stages of product development to investigate in vivo performance of dosage forms. The results of this study provided evidence that the physical chemical specifications of the drug substance may not always be indicative of in vitro or in vivo performance of tablet dosage form, even when formulation and process are not changed.     

Does Drug Use Inhibit Crime Deceleration or Does Crime Inhibit Drug Use Deceleration? A Test of the Reciprocal Risk Postulate of the Worst of Both Worlds Hypothesis

Background: Prior research has shown that ongoing drug use inhibits the commonly reported maturing out of crime process and that ongoing crime inhibits the commonly reported maturing out of drug use process. Objectives: To test the predictive efficacy of drug use for crime deceleration and of crime for drug deceleration using a prospective analysis of data on a group of 524 male California Youth Authority parolees to see if both effects exist simultaneously. Method: A two-equation regression analysis of Year 3 arrests and illicit drug use was performed, controlling for age, race, marital status, employment status, and number of months free in the community. Results: It was determined that illicit drug use at Year 2 predicted an increase in arrests between the first and third years of the analysis and arrests at Year 2 predicted an increase in illicit drug use over this same time period. Alcohol use, on the other hand, failed to predict a change in arrests and arrests failed to predict a change in alcohol use. Conclusions: The results of this study suggest that illicit drug use may inhibit the natural maturing out of crime process observed in emerging adults whereas involvement in crime may inhibit the natural maturing out of illicit drug use process. These findings not only support the reciprocal risk postulate from the Worst of Both Worlds hypothesis but also have implications for risk prediction, risk management, and treatment.     

Identification of a nicotinic acid receptor: is this the molecular target for the oldest lipid-lowering drug?

Nicotinic acid has been used clinically for over 40 years in the treatment of dyslipidemia, producing a desirable normalization of a range of cardiovascular risk factors. The precise mechanism of action of nicotinic acid is unknown, although it is believed that activation of a Gi-type G protein-coupled receptor, resulting in the inhibition of adipocyte lipolysis, may contribute. This review describes the identification of this elusive receptor, and outlines the evidence suggesting that this may be the molecular target for the clinical effects of nicotinic acid.     

Does the New Formulation of OxyContin® Deter Misuse? A Qualitative Analysis

The purpose of this qualitative study is to understand changing illicit drug use patterns in rural Appalachia since a new formulation of OxyContin® was released with the goal of deterring diversion and misuse. Participants (n = 25) from a longitudinal study of rural drug users (N = 192) were approached to participate in semistructured qualitative interviews between April and June 2011. The primary finding is that the majority of participants switched from using the original formulation OxyContin to immediate-release oxycodone. We discuss the implications and limitations of these findings.     

Drug delivery’s quest for polymers: Where are the frontiers?

Since the legendary 1964 article of Folkman and Long entitled “The use of silicone rubber as a carrier for prolonged drug therapy” the role of polymers in controlled drug delivery has come a long way. Today it is evident that polymers play a crucial if not the prime role in this field. The latest boost owes to the interest in drug delivery for the purpose of tissue engineering in regenerative medicine. The focus of this commentary is on a selection of general and personal observations that are characteristic for the current state of polymer therapeutics and carriers. It briefly highlights selected examples for the long march of synthetic polymer–drug conjugates from bench to bedside, comments on the ambivalence of selected polymers as inert excipients versus biological response modifiers, and on the yet unsolved dilemma of cationic polymers for the delivery of nucleic acid therapeutics. Further subjects are the complex design of multifunctional polymeric carriers including recent concepts towards functional supramolecular polymers, as well as observations on stimuli-sensitive polymers and the currently ongoing trend towards natural and naturally-derived biopolymers. The final topic is the discovery and early development of a novel type of biodegradable polyesters for parenteral use. Altogether, it is not the basic and applied research in polymer therapeutics and carriers, but the translational process that is the key hurdle to proceed towards an authoritative approval of new polymer therapeutics and carriers.     

Drug Release from Ammonio–Methacrylate-Coated Diltiazem Particles: Influence of the Reservoir on Membrane Behavior

Drug-layered sugar spheres 15, 45, and 64% potent were made such that each had the same particle size distribution. The particles were coated to the same coat thickness with an ammonio polymethacrylate formulation, and drug release was measured in two media. The products exhibited a sigmoidal release pattern, where a lag time was followed by relatively rapid drug release. Lag time depended on the applied polymer amount, the media used, and the sugar content, where an increase in sugar content caused greater expansion before drug release. Lag times were related to expansion. Expansion of coated sugar spheres was measured.     

The co-dependency concept: Does it offer a solution for the spouses of alcoholics?

The popularity of the co-dependency concept has grown rapidly in the alcoholism treatment field. At the same time, empirical findings gained through scientific research have raised questions concerning the validity of the concept. This paper discusses some of the problems that are created by the disease model of co-dependency and highlights some alternatives views that may be more appropriate. It is argued that the field's understanding of the alcoholic/spouse relationship and its ability to help the spouse are limited unless other conceptualizations are seriously considered.