Predicting Human Subcutaneous Bioavailability of Therapeutic Monoclonal Antibodies from Systemic Clearance and Volume of Distribution.

Subcutaneous delivery of monoclonal antibody therapeutics is often preferred to intravenous delivery due to better patient compliance and overall lower cost to the healthcare system. However, the systemic absorption of biologics dosed subcutaneously is often incomplete. The aim of this work was to describe a human bioavailability prediction method for monoclonal antibodies delivered subcutaneously that utilizes intravenous pharmacokinetic parameters as input.

Development of a thermostable oxytocin microneedle patch.

Oxytocin is a nonapeptide hormone used in labor to initiate uterine contractions and to prevent and treat postpartum hemorrhage. Oxytocin is currently administered by injection and requires refrigerated transport and storage, which limits access, especially during home birth in developing countries. Here, we propose a thermostable, simple-to-administer microneedle (MN) patch for rapid delivery of oxytocin suitable for use by healthcare workers with limited training, like traditional birth attendants.

Modeling Drug Absorption from the Dermis after an Injection.

A dermal absorption model for small and macromolecules was previously proposed by Ibrahim et al. This model estimated absorption of therapeutics from the dermal tissue based on their molecular size and protein binding through blood and lymphatics. Blood absorption followed a two-pore theory and the lymphatic absorption was limited by the constant lymphatic flow rate.

Coated microneedles for transdermal delivery of a potent pharmaceutical peptide.

Minimally invasive delivery of peptide and protein molecules represents a significant opportunity for product differentiation and value creation versus standard injectable routes of administration. One such technology utilizes microneedle (MN) patches and it has made considerable clinical advances in systemic delivery of potent macromolecules and vaccines. A sub-class of this technology has focused on preparation of solid dense MN arrays followed by precision formulation coating on the tips of the MN.

Stabilization and Transdermal Delivery of an Investigational Peptide Using MicroCor® Solid-State Dissolving Microstructure Arrays.

The formulation of biotherapeutics presents unique challenges especially with regard to physical and chemical stability and often requires refrigerated storage conditions of final drug products. Peptide A is an example of a developmental compound which showed significant stability challenges when prepared as a liquid formulation for a subcutaneous injection. The aim of the present study was to evaluate whether Peptide A can be successfully formulated in MicroCor® microstructure arrays (MSAs) as an alternative delivery option.

Rapid Absorption of Dry-Powder Intranasal Oxytocin.

Purpose: To probe the suitability of a dry-powder oxytocin formulation containing a carrier (μco™; SNBL, Ltd.) for intranasal (IN) administration to treat post-partum hemorrhage in the developing world. Specifically, to investigate (1) whether IN administration can achieve rapid systemic absorption in cynomolgus monkeys, and (2) whether the formulation exhibits sufficient physical and chemical stability.

Clarifications: Dermal Clearance Model for Epidermal Bioavailability Calculations.

Delivery through the skin, either through topical application for therapeutic or cosmetic benefits or intradermal delivery through emerging technologies such as microneedles, has been studied extensively in past decades. In a previous report in this journal one of the authors proposed an extensive model for predicting dermal clearance under pseudo steady-state conditions from the physiochemical properties of the compound (Ibrahim et al. 2012 J Pharm Sci, 101:2094-2108).

In vitro/in vivo correlations in transdermal product development.

As per the US FDA's guidance for industry entitled 'Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations', in vitro-in vivo correlations (IVIVC) can be used to establish a dissolution test as a surrogate for human bioequivalence studies and certain scale-up and postapproval changes. However, at the present time, establishment of a transdermal IVIVC is not used to support biowaiver claims in late phases of clinical development or postapproval changes (major formulation changes, i.e.

Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem.

Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate).

Analysis of the absorption kinetics of macromolecules following intradermal and subcutaneous administration.

Recent years have witnessed rapid growth in the area of microneedle-assisted intradermal drug delivery. Several publications involving in vivo studies in humans and minipigs have demonstrated distinct change in pharmacokinetics of peptides and proteins following intradermal (ID) administration as compared to subcutaneous (SC) injections. Specifically, ID administration produced a "left-shift" in pharmacokinetic profiles i.

Synthesis and in vitro stability of amino acid prodrugs of 6-β-naltrexol for microneedle-enhanced transdermal delivery.

A small library of amino acid ester prodrugs of 6-β-naltrexol (NTXOL, 1) was prepared in order to investigate the candidacy of these prodrugs for microneedle-enhanced transdermal delivery. Six amino acid ester prodrugs were synthesized (6a-f). 6b, 6d, and 6 e were stable enough at skin pH (pH 5.

Microneedle-assisted percutaneous delivery of naltrexone hydrochloride in yucatan minipig: in vitro-in vivo correlation.

Although microneedle-assisted transdermal drug delivery has been the subject of multiple scientific investigations, very few attempts have been made to quantitatively relate in vitro and in vivo permeation. The case of naltrexone hydrochloride is not an exception. In the present study, a pharmacokinetic profile obtained following a "poke and patch" microneedle application method in the Yucatan minipig is reported.

Diclofenac delays micropore closure following microneedle treatment in human subjects.

Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique.

Estimation of maximum transdermal flux of nonionized xenobiotics from basic physicochemical determinants.

An ability to estimate the maximum flux of a xenobiotic across skin is desirable from the perspective of both drug delivery and toxicology. While there is an abundance of mathematical models describing the estimation of drug permeability coefficients, there are relatively few that focus on the maximum flux. This article reports and evaluates a simple and easy-to-use predictive model for the estimation of maximum transdermal flux of xenobiotics based on three common molecular descriptors: logarithm of octanol-water partition coefficient, molecular weight and melting point.

Naltrexone salt selection for enhanced transdermal permeation through microneedle-treated skin.

The passive delivery rate of naltrexone (NTX) through intact skin is too slow to achieve therapeutic plasma levels in humans from a reasonably sized transdermal patch. A physical enhancement method--microneedles (MNs)--has been shown to afford a substantial increase in the percutaneous flux of NTX hydrochloride in vitro. However, for better therapeutic effect and decrease in the transdermal patch area, further enhancement is desired.

Challenges and opportunities in dermal/transdermal delivery.

Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limited to a narrow range of drugs.

In vitro permeation of a pegylated naltrexone prodrug across microneedle-treated skin.

Microneedles (MN) are a useful tool for increasing skin permeability to xenobiotics. Previous research showed marked improvement in the percutaneous flux of naltrexone (NTX) hydrochloride by the use of MN skin pretreatment alone; however, for better therapeutic effect, further enhancement is desired. The goal of this in vitro study was to combine microneedle skin pretreatment with the use of a highly water-soluble PEGylated naltrexone prodrug (polyethyleneglycol-NTX, PEG-NTX) to investigate its transdermal transport at varying concentrations.

Vehicle composition influence on the microneedle-enhanced transdermal flux of naltrexone hydrochloride.

Purpose: Transdermal delivery of drugs is often limited by formidable barrier properties of stratum corneum (SC). Microneedles (MN) enable creation of transient microchannels in the SC and bypass this barrier. Many reports have focused on the great effectiveness of MN in improving percutaneous flux values of a variety of drugs over a large molecular size spectrum.

Novel 3-O-pegylated carboxylate and 3-O-pegylated carbamate prodrugs of naltrexone for microneedle-enhanced transdermal delivery.

A small library of novel 3-O-pegylated carboxylate prodrugs (4a-4b) and 3-O-pegylated carbamate prodrugs (9a-9b) of naltrexone were synthesized. The goal behind the design of these prodrugs was to investigate their potential for microneedle-enhanced transdermal delivery. All the synthesized 3-O-pegylated carboxylate prodrugs (4a-4b) and 3-O-pegylated carbamate prodrugs (9a-9b) of naltrexone were found to have adequate stability in a transdermal formulation and improved apparent solubility compared to naltrexone.

Current aspects of formulation efforts and pore lifetime related to microneedle treatment of skin.

Importance Of The Field: The efficacy of microneedles in the area of transdermal drug delivery is well documented. Multiple studies have shown that enhancement of skin permeation by means of the creation of microscopic pores in the stratum corneum can greatly improve the delivery rates of drugs. However, skin pretreatment with microneedles is not the only factor affecting drug transport rates.