Flexibility in Drug Product Development: A Perspective.

The process of bringing a drug to market involves innumerable decisions to refine a concept into a final product. The final product goes through extensive research and development to meet the target product profile and to obtain a product that is manufacturable at scale. Historically, this process often feels inflexible and linear, as ideas and development paths are eliminated early on to allow focus on the workstream with the highest probability of success. Carrying multiple options early in development is both time-consuming and resource-intensive. Similarly, changing development pathways after significant investment carries a high "penalty of change" (PoC), which makes pivoting to a new concept late in development inhibitory. Can drug product (DP) development be made more flexible? The authors believe that combining a nonlinear DP development approach, leveraging state-of-the art data sciences, and using emerging process and measurement technologies will offer enhanced flexibility and should become the new normal. Through the use of iterative DP evaluation, "smart" clinical studies, artificial intelligence, novel characterization techniques, automation, and data collection/modeling/interpretation, it should be possible to significantly reduce the PoC during development. In this Perspective, a review of ideas/techniques along with supporting technologies that can be applied at each stage of DP development is shared. It is further discussed how these contribute to an improved and flexible DP development through the acceleration of the iterative build-measure-learn cycle in laboratories and clinical trials.

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.

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.

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.

3D printed capsules for quantitative regional absorption studies in the GI tract.

Drug development is a long process which requires careful evaluation of the drug substance (active pharmaceutical ingredient, API), drug product (tablet, capsule etc.) and the bioperformance (both pre-clinical and clinical) before testing the efficacy of the final dosage form. The earliest assessment of a new drug substance requires an understanding of the safety and clinical performance (Phase 1) wherein faster processes (like on-site formulation strategy) have been set in place for quick clinical read-outs. One key gap that exists in this early assessment is the ability to evaluate modified release drug products. Here, an additive manufacturing approach is used to prepare polyvinyl alcohol (PVA) capsule shells using 3D printing (3DP), where the shells can be filled with either a solid or a liquid vehicle containing the API. In this work we demonstrate how we can delay the release of the API from the printed capsules allowing us to evaluate regional absorption in pre-clinical studies. By using 3DP, a new method to provide a series of release profiles is demonstrated, where the induction time of a delayed burst release is controlled by the wall thicknesses of printed capsules. New hanging baskets were also designed and 3D printed for the dissolution tests to better understand the rupturing of these capsules in an USP 2 dissolution apparatus. By controlling the wall thickness of the capsule, the induction time of drug release can be controlled from 12 to 198 min. This wide range of induction times demonstrated with this 3DP strategy is not currently available in a commercially available oral drug product form. Varying the induction times to the drug release to interrogate different regions of the GI tract is exhibited in vivo (beagle dogs) and initial analysis suggested a good in vitro/in vivo relationship (IVIVR).

Pharmaceutical 3D printing: Design and qualification of a single step print and fill capsule.

Fused deposition modeling (FDM) 3D printing (3DP) has a potential to change how we envision manufacturing in the pharmaceutical industry. A more common utilization for FDM 3DP is to build upon existing hot melt extrusion (HME) technology where the drug is dispersed in the polymer matrix. However, reliable manufacturing of drug-containing filaments remains a challenge along with the limitation of active ingredients which can sustain the processing risks involved in the HME process. To circumvent this obstacle, a single step FDM 3DP process was developed to manufacture thin-walled drug-free capsules which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule 'shell' and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension '.gcode') were modified by creating discrete zones, so-called 'zoning process', with individual print parameters. Capsules printed without the zoning process resulted in macroscopic print defects and holes. X-ray computed tomography, finite element analysis and mechanical testing were used to guide the zoning process and printing parameters in order to manufacture consistent and robust capsule shell geometries. Additionally, dose consistencies of drug containing liquid formulations were investigated in this work.

Incorporation of drug particles for extended release of Cyclosporine A from poly-hydroxyethyl methacrylate hydrogels.

Cyclosporine A is prescribed for a number of ophthalmic applications such as dry eyes, uveitis in children and adolescents, vernal keratoconjunctivitis, and peripheral ulcerative keratitis. Extended release of cyclosporine from contact lenses has been explored due to the significant benefits of increased bioavailability in comparison with eye drops. Incorporation of drug loaded particles is considered to be a promising approach for increasing the drug release duration. Here we explore the feasibility of extended release of cyclosporine and possibly other hydrophobic drugs by dispersing particles that are 100% drug rather than drug loaded particles. The expected benefits are high drug loading and extended release. Specifically, we explore transport of cyclosporine in hydroxyethyl methacrylate gels for the case when the gel is loaded with high concentration of drug leading to in situ formation of particles. We explore whether we can increase the release duration from the gels by incorporation of the particles, without sacrificing light transmission which is a critical property for contact lenses. Hydrogels were prepared by free radical UV initiated polymerization with drug dissolved in the monomer solution at varying loadings. Drug release kinetics were measured from the particle loaded lenses and fitted to the Higuchi model to determine the diffusivity. The measured diffusivity is two orders of magnitude lower than estimates from Brinkman model. The differences were attributed to the high partition coefficient of about 150, which implies that a majority of the drug in the gel is bound to the polymer. The bound drug can diffuse along the surface or desorb and diffuse. The diffusivity estimates match the measured values after binding is taken into consideration. Light transmittance was measured to determine whether particle incorporation reduces the transparency. Results showed that the drug release duration could be controlled by increasing the drug loading but the transmittance was significantly reduce particularly at high drug loadings, which suggest that this approach may have limited applicability for contact lenses, but could be useful in other applications where light transmission is not critical.

Development of a Convenient In Vitro Gel Diffusion Model for Predicting the In Vivo Performance of Subcutaneous Parenteral Formulations of Large and Small Molecules.

Parenteral delivery remains a compelling drug delivery route for both large- and small-molecule drugs and can bypass issues encountered with oral absorption. For injectable drug products, there is a strong patient preference for subcutaneous administration due to its convenience over intravenous infusion. However, in subcutaneous injection, in contrast to intravenous administration, the formulation is in contact with an extracellular matrix environment that behaves more like a gel than a fluid. This can impact the expected performance of a formulation. Since typical bulk fluid dissolution studies do not accurately simulate the subcutaneous environment, improved in vitro models to help better predict the behavior of the formulation are critical. Herein, we detail the development of a new model system consisting of a more physiologically relevant gel phase to simulate the rate of drug release and diffusion from a subcutaneous injection site using agarose hydrogels as a tissue mimic. This is coupled with continuous real-time data collection to accurately monitor drug diffusion. We show how this in vitro model can be used as an in vivo performance differentiator for different formulations of both large and small molecules. Thus, this model system can be used to improve optimization and understanding of new parenteral drug formulations in a rapid and convenient manner.

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.

Effects of fluid shear stress on polyelectrolyte multilayers by neutron scattering studies.

The structure of layer-by-layer (LbL) deposited nanofilm coatings consists of alternating polyethylenimine (PEI) and polystyrenesulfonate (PSS) films deposited on a single crystal quartz substrate. LbL-deposited nanofilms were investigated by neutron reflectomery (NR) in contact with water in the static and fluid shear stress conditions. The fluid shear stress was applied through a laminar flow of the liquid parallel to the quartz/polymer interface in a custom-built solid-liquid interface cell. The scattering length density profiles obtained from NR results of these polyelectrolyte multilayers (PEM), measured under different shear conditions, showed proportional decrease of volume fraction of water hydrating the polymers. For the highest shear rate applied (ca. 6800 s(-1)) the water volume fraction decreased by approximately 7%. The decrease of the volume fraction of water was homogeneous through the thickness of the film. Since there were not any significant changes in the total polymer thickness, it resulted in negative osmotic pressures in the film. The PEM films were compared with the behavior of thin films of thermoresponsive poly(N-isopropylacrylamide) (pNIPAM) deposited via spin-coating. The PEM and pNIPAM differ in their interactions with water molecules, and they showed opposite behaviors under the fluid shear stress. In both cases the polymer hydration was reversible upon the restoration of static conditions. A theoretical explanation is given to explain this difference in the effect of shear on hydration of polymeric thin films.

Aggregation and transport of Brij surfactants in hydroxyethyl methacrylate hydrogels.

Surfactant loaded polymeric hydrogels find applications in several technological areas including drug delivery. Drug transport can be attenuated in surfactant loaded gels through partitioning of the drug in the surfactant aggregates. The drug transport depends on the type of the aggregates and also on the surfactant transport because diffusion of the surfactant leads to dissolution of the aggregates. The drug and the surfactant transport can be characterized by the surfactant monomer diffusivity Ds. and the critical aggregation concentration C(*). Here we focus on the transport in hydroxyethyl methacrylate (HEMA) hydrogels loaded with three different types of Brij surfactants. We measure transport of a hydrophobic drug cyclosporine and the surfactant for surfactant loadings ranging from 0.1% to 8%, and utilize the data to predict the values of Ds. and C(*). We show that the predictions based on surfactant transport are significantly different from those based on modeling the drug transport. The differences are attributed to the assumption of just one type of aggregate in the gel irrespective of the total concentration. The transport data suggests existence of multiple types of aggregates and this hypothesis is validated for Brij 98 by imaging of the microstructure with free fracture SEM.

Liposome assay for evaluating ocular toxicity of surfactants.

PURPOSE: The ocular toxicity of various compounds is typically determined by the Draize eye test, which has been criticized in the past for its lack of reproducibility and the cruelty associated with harsh testing conditions for animals. In this study, a liposome-based assay was developed for estimating ocular toxicity of surfactants. METHODS: The release of calcein dye from liposomes induced by interactions with surfactants was studied and correlated to Draize eye scores. First, the liposome assay was conducted for various surfactants at identical concentrations and correlated to the Draize scores. Next, mechanistic and geometric considerations were used to determine the appropriate surfactant concentration that should be used in the liposome assay. RESULTS: Correlations between the percentage of dye released and the Draize scores were drastically improved after surfactant concentrations were chosen based on CMC/200, where CMC is the critical micelle concentration of the surfactants. With this choice of surfactant concentration, excellent correlations were obtained with Draize scores from three separate sources and two different ocular surfactant loadings (Pearson = 0.99, 0.82, 0.78, and 0.74; Spearman = 0.94, 0.79, 0.79, and 0.85). Subsequently, the ocular toxicities of six nonionic surfactants, Brij 700, -58, -56, -78, -97, and -98 were shown to be minimal based on the proposed correlations. CONCLUSIONS: The modified liposome assay developed in this study could be used in conjunction with other in vitro assays to obtain initial estimates for ocular toxicities and thus minimize the need for the Draize test.

Surfactant-laden soft contact lenses for extended delivery of ophthalmic drugs.

Eye drops are inefficient means of delivering ophthalmic drugs because of limited bioavailability and these can cause significant side effects due to systemic uptake of the drug. The bioavailability for ophthalmic drugs can be increased significantly by using contact lenses. This study focuses on the development of surfactant-laden poly-hydroxy ethyl methacrylate (p-HEMA) contact lenses that can release Cyclosporine A (CyA) at a controlled rate for extended periods of time. We focus on various Brij surfactants to investigate the effects of chain length and the presence of an unsaturated group on the drug release dynamics and partitioning inside the surfactant domains inside the gel. The gels were imaged by cryogenic scanning electron microscopy (cryo-SEM) to obtain direct evidence of the presence of surfactant aggregates in the gel, and to investigate the detailed microstructure for different surfactants. The images show a distribution of nano pores inside the surfactant-laden hydrogels which we speculate are regions of surfactant aggregates, possibly vesicles that have a high affinity for the hydrophobic drug molecule. The gels are further characterized by studying their mechanical and physical properties such as transparency, surface contact angle and equilibrium water content to determine their suitability as extended wear contact lenses. Results show that Brij surfactant-laden p-HEMA gels provide extended release of CyA, and possess suitable mechanical and optical properties for contact lens applications. The gels are not as effective for extended release of two other hydrophobic ophthalmic drugs, dexamethasone (DMS) and dexamethasone 21 acetate (DMSA) because of insufficient partitioning inside the surfactant aggregates.

Ophthalmic delivery of Cyclosporine A from Brij-97 microemulsion and surfactant-laden p-HEMA hydrogels.

Cyclosporine A (CyA) is an immunosuppressant drug that is used for treating a variety of ocular diseases and disorders. CyA is commonly delivered via eye drops, which is highly inefficient due to a low bioavailability of less than 5%. The bioavailability of ophthalmic drugs can be substantially improved to about 50% by delivering them via contact lenses. This paper focuses on the development of nanostructured poly (2-hydroxyethyl methacrylate) (p-HEMA) hydrogels containing microemulsions or micelles of Brij 97 (C(18)H(35)(OCH(2)CH(2))(10)) for extended delivery of CyA. Release of CyA from these nanostructured hydrogels was performed in vitro to explore the mechanisms of release and the effects of surfactant concentration, processing conditions and storage on the release kinetics. Results show that the surfactant and microemulsion-laden gels can deliver CyA at therapeutic dosages for a period of about 20 days. Release of the drug is diffusion controlled with effective diffusivities decreasing with increasing surfactant loading. The release kinetics are relatively similar for both surfactant and microemulsion-laden gels with comparable surfactant loading. The results also show that these hydrogels retain their effectiveness even after exposure to all the relevant processing conditions including unreacted monomer extraction, autoclaving and packaging, and so these materials seem to be very promising for ophthalmic delivery of CyA and perhaps other drugs.

Drug and surfactant transport in Cyclosporine A and Brij 98 laden p-HEMA hydrogels.

Surfactants are commonly incorporated into hydrogels to increase solute loading and attenuate the release rates. In this paper we focus on understanding and modeling the mechanisms of both surfactant and drug transport in hydrogels. Specifically, we focus on Brij 98 as the surfactant, Cyclosporine A (CyA) as the hydrophobic drug, and poly-hydroxy ethyl methacrylate (p-HEMA) as the polymer. The models developed here are validated by experiments conducted with gels of different thicknesses and surfactant loadings. Also the model is compared with prior experimental studies in literature. The model predicts that the percentage surfactant as well as drug release scales as 1/(surfactant loading)(0.5), and thus a four fold increase in surfactant loading leads to a two fold reduction in percentage release for both drug and surfactant at a given time. The models for the surfactant and drug release are fitted to the experimental data to obtain values of 1.44 x 10(-14) m(2)/s for CyA diffusivity and 414.4 for the partition coefficient between drug concentration inside the micelle and that in the gel. These models can be very helpful in tuning the drug release rates from hydrogels by controlling the surfactant concentration. The results also show that Brij 98 loaded p-HEMA exhibit an extended release of CyA and so contact lenses made with this material can be used for extended ocular delivery of CyA, which is an immunosuppressant drug commonly used for treatment of various ocular ailments.

Timolol transport from microemulsions trapped in HEMA gels.

Approximately 90% of all ophthalmic drug formulations are now applied as eye-drops. While eye-drops are convenient and well accepted by patients, about 95% of the drug contained in the drops is lost due to absorption through the conjunctiva or through the tear drainage. A major fraction of the drug eventually enters the blood stream and may cause side effects [J.C. Lang, Adv. Drug Delivery Rev. 16 (1995) 39-43; C. Bourlais, L. Acar, H. Zia, P.A. Sado, T. Needham, R. Leverge, Prog. Retinal Eye Res. 17 (1998) 33-58; M.P. Segal, FDA Consumer Mag. (1991)]. The drug loss and the side effects can be minimized by using microemulsion-laden soft contact lenses for ophthalmic drug delivery [D. Gulsen, A. Chauhan, Invest. Ophthalmol. Vis. Sci. 45 (2004) 2342-2347; D. Gulsen, A. Chauhan, Abstr. Pap. Am. Chem. Soc. 227 (2004) U875]. In order for microemulsion-laden gels to be effective, these should load sufficient quantities of drug and should release it a controlled manner. The presence of a tightly packed surfactant at the oil-water interface of microemulsions may provide barrier to drug transport, and this could be used to control the drug delivery rates. In this paper we focus on trapping ethyl butyrate in water microemulsions stabilized by Pluronic F127 surfactant in 2-hydroxyethyl methacrylate (HEMA) gels and measuring the transport rates of timolol, which is a beta-blocker drug that is used for treating a variety of diseases including glaucoma. The results described here show that microemulsion-laden gels could have high drug loadings, particularly for drugs such as timolol base which can either be dissolved in the oil phase or form the oil phase of the microemulsions. However, the surfactant covered interface of the Pluronic microemulsions does not provide sufficient barrier to impede the transport of timolol, perhaps due to the small size of this drug.