A win-win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability.

Recently, we have revealed a trade-off between solubility increase and permeability decrease when solubility-enabling oral formulations are employed. We have shown this trade-off phenomenon to be ubiquitous, and to exist whenever the aqueous solubility is increased via solubilizing excipients, regardless if the mechanism involves decreased free fraction (cyclodextrins complexation, surfactant micellization) or simple cosolvent solubilization. Discovering a way to increase drug solubility without concomitant decreased permeability represents a major advancement in oral delivery of lipophilic drugs and is the goal of this work. For this purpose, we sought to elucidate the solubility-permeability interplay when increased apparent solubility is obtained via supersaturation from an amorphous solid dispersion (ASD) formulation. A spray-dried ASD of the lipophilic drug progesterone was prepared in the hydrophilic polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which enabled supersaturation up to 4× the crystalline drug's aqueous solubility (8 µg/mL). The apparent permeability of progesterone from the ASD in HPMC-AS was then measured as a function of increasing apparent solubility (supersaturation) in the PAMPA and rat intestinal perfusion models. In contrast to previous cases in which apparent solubility increases via cyclodextrins, surfactants, and cosolvents resulted in decreased apparent permeability, supersaturation via ASD resulted in no decrease in apparent permeability with increasing apparent solubility. As a result, overall flux increased markedly with increasing apparent solubility via ASD as compared to the other formulation approaches. This work demonstrates that supersaturation via ASDs has a subtle yet powerful advantage over other solubility-enabling formulation approaches. That is, increased apparent solubility may be achieved without the expense of apparent intestinal membrane permeability. Thus, supersaturation via ASDs presents a markedly increased opportunity to maximize overall oral drug absorption.

The value of serum biomarkers in prediction models of outcome after mild traumatic brain injury.

BACKGROUND: To determine, using a civilian model of mild traumatic brain injury (TBI), the added value of biomarker sampling upon prognostication of outcome at 1 week and 6 weeks postinjury. METHODS: The Galveston Orientation and Amnesia test was administered, and blood samples for serum protein S100B and neuron-specific enolase (NSE) were collected from 141 emergency department patients within 4 hours of a suspected mild TBI (mTBI). The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) was administered via telephone 3 days postinjury. Patients were assessed by a physician at 1 week (n = 113; 80%) and 6 weeks (n = 95; 67%) postinjury. Neurocognitive and postural stability measures were also administered at these follow-ups. RESULTS: Levels of S100B and NSE were found to be abnormally elevated in 49% and 65% of patients with TBI, respectively. Sixty-eight percent and 38% of the patients were considered impaired at 1 week and 6 weeks postinjury, respectively. Stepwise logistic regression modeling identified admission Galveston Orientation and Amnesia test score, S100B level, and RPQ score at day 3 postinjury to be predictive of poor outcome at 1 week postinjury (c-statistic 0.877); female gender, loss of consciousness, NSE level, and RPQ score at day 3 postinjury were predictive of poor outcome at 6 weeks postinjury (c-statistic 0.895). The discriminative power of the biomarkers alone was limited. CONCLUSIONS: Biomarkers, in conjunction with other readily available determinants of outcome assessed in the acute period after injury, add value in the early prognostication of patients with mTBI. Our findings are consistent with the notion that S100B and NSE point to biological mechanisms underlying poor outcome after mTBI.

A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: application to physiologically based pharmacokinetic modeling.

Physiologically based pharmacokinetic (PBPK) modeling tools have become an integral part of the modern drug discovery-development process. However, accurate PK prediction of enabling formulations of poorly soluble compounds by applying PBPK modeling has been very limited. This is because current PBPK models rely only on thermodynamic drug solubility inputs (e.g., pH-solubility profile) and give little consideration to the dynamic changes in apparent drug solubility (e.g., supersaturation) that occur during gastrointestinal (GI) transit of an enabling formulation of a water insoluble drug. Moreover, biorepresentative and predictive in vitro tools to measure formulation dependent solubility changes during GI transit remain underdeveloped. In this work, we have developed an in vitro dual pH-dilution method based on rat physiology to estimate the apparent drug concentration in solution along the GI tract during release from solubility enabling formulations. This simple dual pH-dilution method was evaluated using various solubility enabling formulations (i.e., cosolvent solution, amorphous solid dispersions) made using a model early development drug candidate with poor aqueous solubility. The in vitro drug concentration-time profiles from the enabling formulations were used as solubility inputs for PBPK modeling using GastroPlus software. This resulted in excellent predictions of the in vivo oral plasma concentration-time profiles, as compared to using the traditional inputs of thermodynamic pH-solubility profiles. In summary, this work describes a novel in vitro method for facile estimation of formulation dependent GI drug concentration-time profiles and demonstrates the utility of PBPK modeling for oral PK prediction of enabling formulations of poorly soluble drugs.

The impact of rural residence on medically serious medicinal self-poisonings.

OBJECTIVE: Suicide rates are often high in rural areas. Despite the strong association between deliberate self-harm (DSH) and suicide, few have studied rural residence and DSH. Self-poisonings dominate DSH hospital presentations. We investigate a previously reported association between rural residence and medical severity (defined as a subsequent medical/surgical inpatient stay) among emergency department presentations for medicinal self-poisoning (SP) to determine whether differences in agents taken, mental health service use or hospital-level resources explain the relationship. METHOD: A cohort of n=16,294 12-64-year olds presenting with SP to hospital emergency departments in Ontario, Canada, in 2001/2002 was linked to their service records over time. RESULTS: The rural-medical severity association was best explained by differences in hospital resources; presenting to hospitals providing inpatient psychiatric services appeared to reduce medical/surgical inpatient stays in favor of psychiatric ones. Among those with a recent psychiatric admission, more intensive ambulatory psychiatric contact may be protective of a psychiatric inpatient stay subsequent to the SP presentation. Compared to nonrural residents, deliberate intent was identified less often in rural residents, particularly males. CONCLUSIONS: The rural-medical severity association was best explained by disparities in the delivery systems serving rural and nonrural residents, important to rural suicide prevention efforts.

Age-sex differences in medicinal self-poisonings: a population-based study of deliberate intent and medical severity.

BACKGROUND: Deliberate self-harm (DSH) is related to suicide and DSH repetition is common. DSH hospital presentations are often self-poisonings with medicinal agents. While older age and male sex are known risk factors for suicide, it is unclear how these factors are related to the nature and severity of medicinal self-poisoning (SP). Such knowledge can guide prevention strategies emphasizing detecting and treating mental illness and controlling access to means. METHODS: Medicinal SP presentations by 18,383 residents of Ontario, Canada, aged 12 years and older, who presented to a hospital emergency department in that province between April 1, 2001-March 31, 2002 were characterized by the agents taken, identification of deliberate intent and medical severity. RESULTS: We found distinct age-sex differences in the nature and severity of medicinal SP. In youths, aged 12-17, about 40% of presentations involved analgesics, typically not prescribed and most often the acetaminophen agent-group. Females aged 12-64 were identified as deliberate more often than their male counterparts and this pattern occurred in most agent-groups, even among those who took antidepressants. The acetaminophen agent-group was most consistently associated with medical severity and this effect was strongest among female youths. Although medicinal SP was less frequent in the elderly, these presentations tended to be more medically serious and less often identified deliberate. CONCLUSIONS: The high proportion of medicinal SP in youths involving agents typically not prescribed and the medical severity of the acetaminophen agent-group underscore how prevention strategies must extend beyond controlling access to antidepressants. Despite a higher risk for suicide, males and the elderly may not have their deliberate intent detected and therefore, may not receive appropriate treatment. The emergency department can serve as important link to mental health care and usage patterns can provide feedback about the need for system-level enhancements and DSH surveillance.

The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia.

Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types. To further elucidate the enzymatic role of G9a in cancer, we describe herein the biological activities of a novel peptide-competitive histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1), but not other histone methyltransferases. A-366 has significantly less cytotoxic effects on the growth of tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite equivalent cellular activity on methylation of H3K9me2. Additionally, the selectivity profile of A-366 has aided in the discovery of a potentially important role for G9a/GLP in maintenance of leukemia. Treatment of various leukemia cell lines in vitro resulted in marked differentiation and morphological changes of these tumor cell lines. Furthermore, treatment of a flank xenograft leukemia model with A-366 resulted in growth inhibition in vivo consistent with the profile of H3K9me2 reduction observed. In summary, A-366 is a novel and highly selective inhibitor of G9a/GLP that has enabled the discovery of a role for G9a/GLP enzymatic activity in the growth and differentiation status of leukemia cells.

Rational design of a topical androgen receptor antagonist for the suppression of sebum production with properties suitable for follicular delivery.

A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.

Comparison of artificial sebum with human and hamster sebum samples.

To understand drug delivery to the sebum filled hair and sebaceous follicles, it is essential to use an artificial sebum as a surrogate of the human sebum for the investigation of drug transport properties. Artificial sebum L was developed in-house based on the chemical similarity to human sebum. The partition and diffusion of model compounds (ethyl 4-hydroxybenzoate, butyl 4-hydroxybenzoate, and hexyl 4-hydroxybenzoate) were measured in human sebum, hamster ear and body sebum (a commonly used animal model), and four representative artificial sebum samples (N, S, F, and L) in which artificial sebums, N, S and F were selected based on the available literature. DSC and NMR studies were also conducted on all sebums to compare their melting properties and chemical compositions. In vitro studies show that the partition coefficients of the three model compounds in artificial sebum L were similar to that of human sebum, whereas the hamster ear and body sebum, and other three artificial sebum samples were different from that of human sebum. Additionally, the in vitro sebum flux (microg/(cm(2)min) of three model compounds through artificial sebum L was closer to that of human sebum when compared with the other three artificial sebum (N, S and F), hamster body and hamster ear sebum. The results of this study indicate that the artificial sebum L could be used as an alternative to human sebum, as the physicochemical properties of this artificial sebum is relatively similar to human sebum.

Increased dissolution rate and bioavailability through comicronization with microcrystalline cellulose.

Micronization is a commonly used enabling technology to improve the bioavailability of compounds where absorption is dissolution rate limited. However, decreasing particle size often results in increased Van der Waals' interactions and electrostatic attraction between particles. This causes agglomeration of particles, thereby compromising the increase in surface area gained by micronization. Comicronization with excipients has been reported to offer significant advantages over neat micronization. The present work describes the comicronization of a model compound CI-1040 at a high drug load that shows an increase in the dissolution rate and bioavailability in male Wistar rats. Physicochemical characterization of the comicronized and neat micronized material is presented to help explain the in-vitro and in-vivo data.