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. A two-compartment pharmacokinetic model featuring a parallel-competitive absorption pathway and a presystemic metabolism pathway was employed. A training data set comprised 19 monoclonal antibodies (geometric mean bioavailability of 68%), with previously reported human pharmacokinetic parameters, while a validation set included data compiled from 5 commercial drug products (geometric mean bioavailability of 69%). A single fitted absorption rate constant, paired with compound-specific estimates of presystemic metabolism rate proportional to compound-specific systemic clearance parameters, resulted in calculations of human subcutaneous bioavailability closely mimicking clinical data in the training data set with a root-mean-square error of 5.5%. Application of the same approach to the validation data set resulted in predictions characterized by 12.6% root-mean-square error. Factors that may have impacted the prediction accuracy include a limited number of validation data set compounds and an uncertainty in the absorption rate, which were subsequently discussed. The predictive method described herein provides an initial estimate of the subcutaneous bioavailability based exclusively on pharmacokinetic parameters available from intravenous dosing.

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. The objective of this study was to develop a drug product using the MN technology that has similar bioperformance when compared to subcutaneous route of delivery and can provide improved stability under storage. Therapeutic peptide (Peptide A, Merck & Co., Inc., Kenilworth, NJ, USA) is being developed as a subcutaneous injection for chronic dosing with a submilligram estimated therapeutic dose. Peptide A has chemical and physical stability challenges in solution and this led to exploration of a viable drug product which could provide therapeutic dosages while overcoming the stability issues seen with the compound. This work focused on developing a coated solid microstructure transdermal system (sMTS) for Peptide A followed by detailed in vitro and preclinical evaluation for two different coating formulations. Based on initial assessment, ~250 µg of Peptide A could be coated with precision on a 1.27cm2 patch which contained 316 MN's. The delivery from these systems was achieved with absolute bioavailability being similar to the subcutaneous delivery (88% and 74% for coated sMTS 1 & 2 and 75% for subcutaneous delivery). Stability of Peptide A was also found to be significantly improved when coated on the sMTS system with minimal degradation recorded at room temperature storage as compared to the subcutaneous liquid formulation. Additionally, skin irritation (on pig skin) was also measured in this study and it was found to be minimal and self-resolving. This evaluation provided a viable option for developing a drug product with improved stability and successful delivery of the investigated molecule. Graphical abstractSchematic showing uncoated sMTS, resulting product with coated peptide, successful skin penetration with high delivery efficiency and bioavailability.

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. This study was conducted to support Merck for Mothers, Merck's 10-year global initiative to end preventable maternal deaths. METHODS: A partial-crossover pharmacokinetic (PK) study in cynomolgus monkeys (n = 6) was utilized to compare in vivo absorption of dry-powder IN oxytocin at three dose levels against an IM injection of an aqueous oxytocin formulation. Particle size distribution, delivered dose and chemical assay were monitored over a 12 month stability study. RESULTS: IN administration of oxytocin resulted in short (5 min) Tmax and good dose linearity in AUC and Cmax over the dose range tested (10-80 IU per animal). The relative bioavailability (BA) of IN oxytocin to IM injection was approximately 12%. The 80 IU formulation exhibited good physical stability and consistent dosing. After 12 months at 30°C/65%RH, pouched samples retained 86.0% of their original assay value. CONCLUSIONS: The PK and stability data suggests that IN administration of oxytocin formulated in the µco™ carrier may represent a viable option for rapid systemic absorption in humans and a product compatible with resource-scarce regions.

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

A small library of amino acid ester prodrugs of 6-ß-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 5.0) to move forward to studies in 50% human plasma. The lead compound (6 e) exhibited the most rapid bioconversion to NTXOL in human plasma (t1/2 = 2.2 ± 0.1h).

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. The profile demonstrates a rapid achievement of maximum naltrexone hydrochloride plasma concentration followed by a relatively abrupt concentration decline. No steady state was achieved in vivo. In an attempt to correlate the present in vivo findings with formerly published in vitro steady-state permeation data, a diffusion-compartmental mathematical model was developed. The model incorporates two parallel permeation pathways, barrier-thickness-dependent diffusional resistance, microchannel closure kinetics, and a pharmacokinetic module. The regression analysis of the pharmacokinetic data demonstrated good agreement with an independently calculated microchannel closure rate and in vitro permeation data. Interestingly, full-thickness rather than split-thickness skin employed in in vitro diffusion experiments provided the best correlation with the in vivo data. Data analysis carried out with the model presented herein provides new mechanistic insight and permits predictions with respect to pharmacokinetics coupled with altered microchannel closure rates.

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. The use of all three can be justified on the theoretical basis of their influence on the solute aqueous solubility and the partitioning into the stratum corneum lipid domain. The model explains 81% of the variability in the permeation data set composed of 208 entries and can be used to obtain a quick estimate of maximum transdermal flux when experimental data is not readily available.

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. The objective of the present study is to evaluate the influence of formulation on MN-enhanced transdermal transport of naltrexone hydrochloride (NTX HCl). METHODS: A series of in vitro experiments employing binary mixtures of propylene glycol (PG) and water as vehicle were used with either MN-treated or untreated skin. A simple model taking into account two parallel flux values through intact skin and microchannels was used to analyze data. RESULTS: Transdermal permeation of NTX HCl from different donor solutions indicated that PG-rich formulations greatly limited MN-enhanced transport but had a much smaller effect on transport through intact skin. CONCLUSIONS: Diffusion through the microchannel pathway seems to be donor viscosity-related and follows the relationship predicted by the Stokes-Einstein equation as shown by linear dependence of flux on diffusivity of NTX in donor solutions.

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. Oxytocin (10 IU, 16.8 µg) coated onto stainless steel MN arrays was released into skin within 1-5 min after manual insertion. Among tested excipients, polyacrylic acid was best at stabilizing oxytocin stored at 75% relative humidity, with no significant loss for up to 2 months at 40 °C. Under desiccated conditions, MNs coated with formulations containing trehalose in a mixture of citrate buffer and ethanol retained 75% oxytocin potency at 40 °C for 12 months; the commercial oxytocin product Pitocin® was reduced to 35% potency under these conditions. These findings support development of MN patches for oxytocin administration with improved ease of use, extended thermostability and simplified logistics to enable greater access to this life-saving medicine.

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. Current work builds on this steady-state concept by modeling the absorption from the dermis immediately after an injection is given (unsteady state). An injection in the dermis creates a localized pressure gradient which resolves itself over time. This phenomenon is captured in the model to estimate the impact of injection volume on the absorption rate constant. Blood absorption follows the two-pore theory but is time-dependent and the lymphatic absorption is determined based on valve opening and pressure driven convective flow, returning to steady-state as the molecule is absorbed. A direct comparison of the steady-state analysis, experimental data and the current model is made. The results indicate that accounting for the localized time-varying pressure can better predict the experimental absorption rate constants. This work significantly improves the existing understanding of macromolecule uptake from the interstitial fluid following intradermal injection.

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. Viscosity effects were postulated to be responsible for the observed non-linearity in the flux-concentration profile of these prodrugs.

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. MSAs contain a high density of dissolving microstructures allowing for transdermal delivery. In the present work, a 5600-needle MSA (~200 µm long microstructures, 2 cm2 array) was prepared with a therapeutically-relevant dose of Peptide A. The array was shown to be stable under room-temperature storage conditions for 3 months. On in vivo application to Yucatan minipigs, Peptide-A-loaded MSAs demonstrated only mild and transient skin irritation and a very high efficiency of peptide transfer from dissolving microstructures into the skin resulting in absolute bioavailability of 74%. This transdermal bioavailability was very similar to the 73% bioavailability obtained from a subcutaneous injection. This technical feasibility study demonstrated that MicroCor® technology represents a viable option for delivery of Peptide A with significant improvements in peptide stability.

Building a better particle: Leveraging physicochemical understanding of amorphous solid dispersions and a hierarchical particle approach for improved delivery at high drug loadings.

Amorphous solid dispersions are a promising option for managing compounds with poor aqueous solubility. However, for compounds with high melting points, thermal stability limitations, or poor solubility in volatile solvents, conventional routes of hot melt extrusion or spray drying may not be viable. Co-precipitated amorphous dispersions (cPAD) can provide a solution. For the material studied in this paper, the cPAD material that was seemingly identical to spray dried material in terms of being single phase amorphous (as measured by DSC and XRD ) but showed slower dissolution behavior. It was identified that physical properties of the cPAD material could be improved to enhance wettability and improve dissolution performance. This was achieved by incorporating the cPAD material into a matrix of water soluble excipients generated via evaporative isolation routes. Importantly, this approach appears to offer another route to further increase the drug load in final dosage units and is significant as increased drug loading generally results in slower or incomplete release. Results showed successful proof of concept via in vitro biorelevant dissolution and confirmatory canine pharmacokinetic studies yielding comparable exposure for capsules comprised of conventional spray dried material as well as capsules with elevated drug load comprised of cPAD hierarchical particles.

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). This note provides some clarifications regarding this model, highlighting critical points that must be considered when using the model. The points are discussed in the order of relevance and complement the understanding of how molecules delivered intradermally clear from the dermis into the systemic circulation. In brief, solute binding to protein is reconsidered, limitations in using empirical models to determine physiochemical properties of a molecule are highlighted, and readers are informed about critical details regarding the calculations.

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., >10% changes in inactive ingredients) to the best of the authors' knowledge. The value of developing an IVIVC for percutaneous drugs lies mainly in facilitating permeation testing of transdermal drug candidates and formulation performance optimization at much lower cost as compared with carrying out multiple in vivo studies. The present article will introduce the concept of transdermal IVIVC, outlining certain limitations to its applicability, in vitro and in vivo methods, regulatory product development requirements and the most common approaches to establish an IVIVC for a transdermal drug. Additionally, this article will also summarize some challenges and recent advancements in this field, along with selected academic examples of transdermal IVIVCs.

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.e. shorter time to achieve maximum plasma concentrations (shorter Tmax), and often higher maximum plasma concentrations (higher Cmax), as compared to the SC route. In the present work differences in the kinetics of drug absorption after ID and SC administration were explored for eight peptides and proteins with the focus on obtaining quantitative information about the absorption process and identifying similarities and differences in the absorption behavior across compounds. We confirmed that systemic uptake, as judged by apparent absorption rate constants, was 2- to 20-fold higher from the dermis as compared to the subcutis. Additionally, shapes of time-resolved absorption rate profiles demonstrated notable differences in absorption kinetics between ID and SC routes. For both administration routes evaluated herein there was a general trend of small macromolecules absorbing at higher rates as compared to the large macromolecules.

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). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C max, T max, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F a_IO). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R (2) > 0.9). The predicted deviations (%) for C max, AUC0-inf, AUC0-20 min, and T max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F a_IO was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f ut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD pH = 7.4). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations.

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. The purpose of this study was to identify a NTX salt that would (1) provide elevated in vitro percutaneous drug transport across MN-treated skin as compared with that of the NTX hydrochloride and (2) prove nonirritating to the skin in vivo. The pH-solubility profiles of NTX salts were investigated with three drug salts showing improved solubility at physiologically relevant skin surface pH of 5.0. The skin-irritation potential of NTX glycolate and lactate gels was not greater than that of placebo gel in the guinea pig model. Additionally, in vitro diffusion studies indicated that NTX glycolate provides around 50% enhancement in the flux through MN-treated skin at the cost of doubling the drug concentration in the donor solution. Overall, a new NTX glycolate salt appears to be a promising candidate for MN-assisted transdermal drug delivery system.

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. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance-time curve (AUC) was calculated. AUC was significantly higher at MN+diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions.

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. Other factors, including drug formulation and rate of micropore closure, are also important for optimizing delivery by this route. AREAS COVERED IN THIS REVIEW: This review aims to highlight work that has been done in these areas, with an emphasis on drug formulation parameters that affect transdermal flux. WHAT THE READER WILL GAIN: This review creates an appreciation for the many factors affecting microneedle-enhanced delivery. Most results clearly indicate that microneedle skin pretreatment by itself may have different effects on drug transport depending on the formulation used, and formulation characteristics have different effects on the transport through untreated skin and microneedle-treated skin. Several formulation approaches are reported to optimize microneedle-enhanced drug delivery, including co-solvent use, vesicular, nanoparticulate and gel systems. TAKE HOME MESSAGE: In addition to well-established factors that affect microneedle-assisted delivery (geometry, type of microneedle, etc.), formulation and pore viability are also critical factors that must be considered.