The Effect of Process Parameters on the Microstructure, Stability, and Sensorial Properties of an Emulsion Cream Formulation.

A classical emulsion formulation based on petrolatum and mineral oil as the internal phase with emulsifier wax as a typical topical emulsion cream was investigated for the effect of process parameters on drug product quality and performance attributes. The Initial Design of Experiment (DoE) suggested that an oil phase above 15%, coupled with less than 10% emulsifying wax, resulted in less stable emulsions. Different processing parameters such as homogenization speed, duration, cooling rate, and final temperature showed minimal influence on properties and failed to improve stability. The final DoE suggested that the optimal emulsion stability was achieved by introducing a holding period midway through the cooling stage after solvent addition. Within the studied holding temperature range (25-35 °C), a higher holding temperature correlated with increased emulsion stability. However, the application of shear during the holding period, using a paddle mixer, adversely affected stability by disrupting the emulsion microstructure. IVRT studies revealed that the release of lidocaine was higher in the most stable emulsion produced at a holding temperature of 35 °C compared to the least stable emulsion produced at a holding temperature of 25 °C. This suggests that a holding temperature of 35 °C improves both the stability and active release performance. It appears that a slightly higher holding temperature, 35 °C, allows a more flexible and stable emulsifying agent film around the droplets facilitating stabilization of the emulsion. This study offers valuable insights into the relationship between process parameters at various stages of manufacture, microstructure, and various quality attributes of emulsion cream systems. The knowledge gained will facilitate improved design and optimization of robust manufacturing processes, ensuring the production of the formulations with the desired critical quality attributes.

Topical drug delivery by Sepineo P600 emulgel: Relationship between rheology, physical stability, and formulation performance.

The objective of this present work was to develop and optimize oil-in-water (O/W) emulsion-based gels, namely emulgels that allow maximum topical drug delivery while having desired microstructure and acceptable physical stability. Emulgels containing 2.0 wt% lidocaine were prepared using various concentrations (0.75-5.0 wt%) of Sepineo P600. Their droplet size distribution, physical stability, rheological behaviors, in vitro drug release, and skin permeation profiles were evaluated. Results show that the concentration of Sepineo P600 significantly influenced the microstructure, rheology, and physical stability of the emulgel formulations. The physico-chemical properties also reveals that at least 1.0 wt% Sepineo P600 was needed to produce stable emulgel formulations. All formulations exhibited non-Newtonian shear-thinning properties which are desirable for topical applications. Both the release and permeation rates decreased with increasing viscosity and rigidity of the formulation. The lower the complex modulus of the emulgels, the higher the steady-state flux of the drug through the skin. Adding Sepineo P600 to emulgel systems resulted in increased rheological properties, which in turn slowed the diffusion of the drug for in vitro release. Although as expected skin permeation was rate limiting since in vitro release was 3 to 4 log-fold faster than skin flux. However, an interesting finding was that the derived skin/vehicle partition coefficient suggested the ionic interaction between lidocaine and Sepineo polymer reducing the free drug, i.e., thermodynamic activity and hence the flux with increasing Sepineo P600 concentration. Overall, this study has provided us with valuable insights into understanding the relationship between the microstructure (rheology), physical stability and skin drug delivery properties which will help to design and optimize topical emulgel formulations.

Sustainable Alternatives to Petroleum-Derived Excipients in Pharmaceutical Oil-in-Water Creams.

Recently, vast efforts towards sustainability have been made in the pharmaceutical industry. In conventional oil-in-water (O/W) cream formulations, various petroleum-based excipients, namely mineral oil and petrolatum, are commonly used. Natural or synthetic excipients, derived from vegetable sources, were explored as alternatives to petroleum-based excipients in prototype topical creams, with 1% (w/w) lidocaine. A conventional cream comprised of petroleum-derived excipients was compared to creams containing sustainable excipients in terms of key quality and performance attributes, physicochemical properties, and formulation performance. The petrolatum-based control formulation had the highest viscosity of 248.0 Pa·s, a melting point of 42.7°C, a low separation index at 25°C of 0.031, and an IVRT flux of 52.9 µg/cm2/h. Formulation SUS-4 was the least viscous formulation at 86.9 Pa·s, had the lowest melting point of 33.6°C, the highest separation index of 0.120, and the highest IVRT flux of 139.4 µg/cm2/h. Alternatively, SUS-5 had a higher viscosity of 131.3 Pa·s, a melting point of 43.6°C, a low separation index of 0.046, and the lowest IVRT flux of 25.2 µg/cm2/h. The cumulative drug permeation after 12 h from SUS-4, SUS-5, and the control were 126.2 µg/cm2, 113.8 µg/cm2, and 108.1 µg/cm2, respectively. The composition of the oil-in-water creams had influence on physicochemical properties and drug release; however, skin permeation was not impacted. Sustainable natural or synthetic excipients in topical cream formulations were found to be suitable alternatives to petroleum-based excipients with comparable key quality attributes and performance attributes and should be considered during formulation development.

Comparative Study of Dermal Pharmacokinetics Between Topical Drugs Using Open Flow Microperfusion in a Pig Model.

PURPOSE: Accurate methods to determine dermal pharmacokinetics are important to increase the rate of clinical success in topical drug development. We investigated in an in vivo pig model whether the unbound drug concentration in the interstitial fluid as determined by dermal open flow microperfusion (dOFM) is a more reliable measure of dermal exposure compared to dermal biopsies for seven prescription or investigational drugs. In addition, we verified standard dOFM measurement using a recirculation approach and compared dosing frequencies (QD versus BID) and dose strengths (high versus low drug concentrations). METHODS: Domestic pigs were topically administered seven different drugs twice daily in two studies. On day 7, drug exposures in the dermis were assessed in two ways: (1) dOFM provided the total and unbound drug concentrations in dermal interstitial fluid, and (2) clean punch biopsies after heat separation provided the total concentrations in the upper and lower dermis. RESULTS: dOFM showed sufficient intra-study precision to distinguish interstitial fluid concentrations between different drugs, dose frequencies and dose strengths, and had good reproducibility between studies. Biopsy concentrations showed much higher and more variable values. Standard dOFM measurements were consistent with values obtained with the recirculation approach. CONCLUSIONS: dOFM pig model is a robust and reproducible method to directly determine topical drug concentration in dermal interstitial fluid. Dermal biopsies were a less reliable measure of dermal exposure due to possible contributions from drug bound to tissue and drug associated with skin appendages.

Influence of Manufacturing Process on the Microstructure, Stability, and Sensorial Properties of a Topical Ointment Formulation.

The manufacturing process for ointments typically involves a series of heating, cooling, and mixing steps. Precise control of the level of mixing through homogenization and the cooling rate, as well as temperature at different stages, is important in delivering ointments with the desired quality attributes, stability, and performance. In this work, we investigated the influence of typical plant processing conditions on the microstructure, stability, and sensorial properties of a model ointment system through a Design of Experiments (DoE) approach. Homogenization speed at the cooling stage after the addition of the solvent (propylene glycol, PG) was found to be the critical processing parameter that affects stability and the rheological and sensorial properties of the ointment. A lower PG addition temperature was also found to be beneficial. The stabilization of the ointment at a lower PG addition temperature was hypothesized to be due to more effective encapsulation by crystallizing mono- and diglycerides at the lower temperature. The in vitro release profiles were found to be not influenced by the processing parameters, suggesting that for the ointment platform studied, processing affects the microstructure, but the effects do not translate into the release profile, a key performance indicator. Our systematic study represents a Quality-by-Design (QbD) approach to the design of a robust manufacturing process for delivering stable ointments with the desired performance attributes and properties.

Information Technology Tools for Mental Resilience Training in Sports: A Systematic Review / Herramientas de tecnología de la información para el entrenamiento de la resiliencia mental en los deportes: una revisión sistemática

The aim of this research study is to determine the information technology tools related to mental resilience training in sports. This research study determines the primary data for measuring the relation between dependent and independent. For this purpose, develop research questions related to information technology tools and mental resilience. Research determines through smart PLS software and generates informative results related to variables. The descriptive statistical analysis, the correlation coefficients, and the significant analysis also present the co-linearity statistical analysis between them. A systematic and deliberate procedure termed mental resilience training aims to increase a person's ability to deal with stress, obstacles, and adversity successfully. It entails developing the mental capacities and attitudes required to recover from failures, stay focused under duress, and persevere in the face of adversity. The overall research study found the significant and direct effect of information technology tools and mental resilience training in sports.(AU)

Assessing and Predicting Physical Stability of Emulsion-Based Topical Semisolid Products: A Review.

The emulsion-based topical semisolid dosage forms present a high degree of complexity due to their microstructures which is apparent from their compositions comprising at least two immiscible liquid phases, often times of high viscosity. These complex microstructures are thermodynamically unstable, and the physical stability of such preparations is governed by formulation parameters such as phase volume ratio, type of emulsifiers and their concentration, HLB value of the emulsifier, as well as by process parameters such as homogenizer speed, time, temperature etc. Therefore, a detailed understanding of the microstructure in the DP and critical factors that influence the stability of emulsions is essential to ensure the quality and shelf-life of emulsion-based topical semisolid products. This review aims to provide an overview of the main strategies used to stabilize pharmaceutical emulsions contained in semisolid products and various characterization techniques and tools that have been utilized so far to evaluate their long-term stability. Accelerated physical stability assessment using dispersion analyzer tools such as an analytical centrifuge to predict the product shelf-life has been discussed. In addition, mathematical modeling for phase separation rate for non-Newtonian systems like semisolid emulsion products has also been discussed to guide formulation scientists to predict a priori stability of these products.

Crystallization and Rheology of Mono- and Diglycerides and Their Role in Stabilization of Emulsion Droplets in Model Topical Ointments.

The crystallization behavior of commercial mono- and diglycerides (MDG) in paraffin oil is studied to develop an in-depth understanding of the polymorphic transitions useful for the physical stability of petroleum oil-based topical emulsions. Optical microscopy and differential scanning calorimetry measurements showed the formation of plate-like and spherulite crystals at high and low temperatures, in sequence, while cooling a solution of MDG dissolved in oil. High-resolution NMR and X-ray scattering demonstrate that 1-monoglycerides (mixture of 1-glyceride monostearate and 1-glyceride monopalmitate) cocrystallize to an inverse-lamellar structure (Lα polymorph) that mainly forms plate-like crystals at a higher temperature. The Lα polymorph is seen to exist up to room temperature during the cooling process. At lower temperatures, 1,3-diglycerides (mixture of 1,3-glyceryl distearate and 1,3-glyceryl dipalmitate) crystallize into ß-polymorphs that form spherulites. The spherulites tend to assemble into elongated strands via aggregation, leading to the formation of a percolating network structure. The sizes of both types of crystals decrease with an increasing cooling rate, leading to a higher mechanical modulus due to the increased network connectivity of spherulites. In an emulsion, monoglycerides in the form of Lα polymorphs having plate-like crystal morphology show a higher affinity to the polar liquid/oil interface, thereby providing better interfacial stability compared to the spherulitic ß-polymorphs. However, diglycerides in the form of spherulites form bulk network structures which provide network stabilization to the suspended droplets. This work demonstrates that MDG, a commercially available ingredient that combines the differential functionality of monoglycerides and diglycerides, is an effective, bifunctional, emulsifying agent for petrolatum-based topical emulsions.

API-polymer interactions in Sepineo P600 based topical gel formulation- impact on rheology.

In the present study, topical gel and emulsion gel were formulated using Acrylamide/ Sodium Acryloyldimethyl taurate copolymer (Sepineo P600) as a gelling agent, and their rheological attributes and physical stability were evaluated upon incorporation of API. Lidocaine, a free base drug (pKa 7.92) was used as a model drug in all formulations. Medium- chain Triglycerides (MCT) was used as a dispersed phase to prepare the emulgel. Results show that the rheological properties of both gel and emulgel such as viscosity, elastic moduli and yield stress were significantly influenced by the pH of the topical formulations and API concentration. A lower pH (pH < pKa) leads to the increase in number of cationic species of lidocaine, which results in the weakening of the structure of the gel matrix by charge screening of polymer-polymer repulsions. Interactions between API and polymer chains through electrostatic attraction may play a major role in altering the rheology, which could potentially impact the physical stability against phase separation of the internal phase in emulsion gel samples. This study provides valuable insights into rheological behaviors of Sepineo P600 gel and emulgel which can be modified or tuned though the interplay of the API properties and critical formulation parameters such as pH. The tunable rheological properties with simpler manufacturing process make Sepineo P600 gel and emulsion gel very suitable systems for use in semisolid topical formulations.

Semisolid Pharmaceutical Product Characterization Using Non-invasive X-ray Microscopy and AI-Based Image Analytics.

This work reports the use of X-ray microscopy (XRM) imaging to characterize the microstructure of semisolid formulations containing multiple immiscible phases. For emulsion-based semisolid formulations, the disperse phase globule size and its distribution can be critical quality attributes of the product. Optical microscopy and light diffraction techniques are traditionally used to characterize globule size distribution. These techniques are subjected to sample preparation bias and present challenges from matrix interference and data processing. XRM imaging is an emergent technique that when combined with intelligent data processing has been used to characterize microstructures of pharmaceutical dosage forms including oral solid formulations, controlled release microspheres, and lyophilized products. This work described our first attempt to use XRM imaging to characterize two complex emulsion-based semisolid formulations, a petrolatum-based ointment with a dispersed phase comprising a hydrophilic liquid, and an oil-in-water cream. This initial assessment of technology showed that microstructure details such as globule size distribution, volume fraction, spatial distribution uniformity, inter-globule spacing, and globule sphericity could be obtained and parameterized. It was concluded that XRM imaging, combined with artificial intelligence-based image processing is feasible to generate advanced characterization of semisolid formulation microstructure through 3D visualization and parameterization of globule attributes. This technique holds promise to provide significantly richer microstructure details of semisolid formulations. When fully developed and validated, it is potentially useful for quantitative comparison of microstructure equivalence of semisolid formulations.

Interplay of Aging and Lot-to-Lot Variability on the Physical and Chemical Properties of Excipients: A Case Study of Mono- and Diglycerides.

The present study investigates the chemical composition governing the physical properties of mono- and diglycerides (MDGs) at the microstructural level, as a function of aging and lot-to-lot variability. The physical structure of the MDG plays a vital role in ameliorating the emulsion stability and is widely explored in diverse research horizons related to the pharmaceutical, cosmetic, and food industries. In an effort to understand the mechanism of emulsion stabilization, physical properties were extensively evaluated in selective commercial lots to determine if there is a correlation between the chemical composition of MDG and physical properties. The solid state of the MDG samples with different aging profiles was characterized using X-ray scattering, differential scanning calorimetry, attenuated total reflection-Fourier transform infrared spectroscopy, and NMR relaxometry. Moreover, the kinetic aspect of solid-state transformation was also evaluated via treating MDG samples with a heat-cool cycle. The chemical composition of MDGs was quantified using a quantitative NMR (qNMR) method. Interestingly, the X-ray scattering results demonstrated a change in the MDG polymorphic form and an increase in the %ß content as a function of aging. The increase in the %ß content led to the formation of rigid crystal structures of MDG, as evident from the NMR relaxometry. Chemical quantification of isomeric composition revealed chemical composition change as a potentially critical factor responsible for the altered physical structures of MDG with respect to aging and lot-to-lot variability. The findings correlated the solid-state transformation with the change in the chemical composition of the MDG as a combined effect of aging and lot-to-lot variability. This work serves as a basis to better understand the interdependency of the physicochemical properties of MDG. Furthermore, the present work can also be used as guidance for setting up the specifications of MDG, as per the required polymorphic form for a multitude of applications.

Quantitative Chemical Profiling of Commercial Glyceride Excipients via 1H NMR Spectroscopy.

Glycerides are the main components of oils, and fats, used in formulated products in the food and cosmetic industry as well as in the pharmaceutical product industry. However, there is limited literature available on the analysis of the chemical composition of glycerides. The lack of a suitable analytical method for complete chemical profiling of glycerides is one of the bottlenecks in understanding and controlling the change in chemical composition during processing, formulation, and storage. Thus, the aim of the present study is to develop a calibration-free quantitative proton nuclear magnetic resonance (qHNMR) method for the simultaneous quantification of different components of glycerides. The qHNMR method was developed for the quantification of mono-, di-, and triglycerides; their positional isomers; free fatty acids; and glycerol content. The accuracy, precision, and robustness of the developed method were evaluated and were found suitable for the quantitative analysis of five batches of marketed excipient. The study demonstrates the potential of qHNMR method for the quantification of different components of glycerides in various marketed products. The method has the ability to identify the variability of glycerides among different batches and suppliers in terms of chemical composition and also to discern the changes during storage.

Ex vivo (human skin) and in vivo (minipig) permeation of propylene glycol applied as topical crisaborole ointment, 2.

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. It contains 9% w/w propylene glycol (PG). Although PG is generally considered to be safe when used as a pharmaceutical excipient or food additive, the European Medicines Agency has recommended maximum daily limits for PG exposure. To determine the potential skin permeation of PG from crisaborole ointment, ex vivo human skin (normal abdominal skin from healthy volunteers without atopic dermatitis) and in vivo minipig experiments (dermal application on unabraded or abraded skin) were performed. Over a 24-h period, the extent of PG permeation in the ex vivo human skin experiment was 3.7% for crisaborole ointment. In the in vivo minipig study, the bioavailability of PG after dermally applied crisaborole ointment was 3.56% for unabraded skin and 3.65% for abraded skin. Experimental values from this study can serve to provide scientific justification for using a product's specific absorption value, as opposed to a maximum absorption of 100%, when attempting to estimate systemic exposure of PG from a topical product.

Enhancing the Dissolution Stability of Hard Gelatin Capsules Using Activated Carbon as a Packaging Component.

Hard gelatin capsule (HGC) shells are widely used to encapsulate drugs for oral delivery but are vulnerable to gelatin cross-linking, which can lead to slower and more variable in vitro dissolution rates. Adding proteolytic enzymes to the dissolution medium can attenuate these problems, but this complicates dissolution testing and is only permitted by some regulatory authorities. Here, we expand the scope of our previous work to demonstrate that canisters containing activated carbon (AC) or polymeric films embedded with AC particles can be used as packaging components to attenuate gelatin cross-linking and improve the dissolution stability of hard gelatin-encapsulated products under accelerated International Council for Harmonisation conditions. We packaged acetaminophen and diphenhydramine HCl HGCs with or without AC canisters in induction-sealed high-density polyethylene bottles and with or without AC films in stoppered glass vials and stored these samples at 50°C/75% relative humidity through 3 months and at 40°C/75% relative humidity for 6 months. Samples packaged with AC canisters or AC films dissolved more rapidly than samples packaged without AC when differences were observed. These results demonstrate that different sources and formats of AC can enhance the dissolution stability of HGCs packaged in bottles and other potential packaging systems such as blister cards.

Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin.

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.

Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example.

PURPOSE: Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM). METHODS: Latrepirdine transdermal solution was prepared extemporaneously. The solution was applied with occlusive dressing to upper or middle back for 24 h. Each subject received a single dose of 8.14 mg oral, 5 mg transdermal, and 10 mg transdermal (EMs only) latrepirdine free base in a fixed sequence. RESULTS: Twelve EMs and 7 PMs (50-79 years) enrolled and completed the study. Latrepirdine was well tolerated following both routes of administration. Dose-normalized latrepirdine total exposures were approximately 11-fold and 1.5-fold higher in EMs and PMs, respectively following administration of transdermal relative to oral. Differences between EM and PM latrepirdine exposures were decreased, with PMs having 1.9- and 2.7-fold higher peak and total exposures, respectively, following transdermal administration compared to 11- and 20-fold higher exposures, respectively, following oral administration. CONCLUSION: Transdermal delivery can potentially mitigate the large intersubject differences observed with compounds metabolized primarily by CYP2D6. Transdermal delivery was readily accomplished in the clinic using an extemporaneously prepared solution [NCT00990613].

Current opportunities and challenges in intradermal vaccination.

The skin is an attractive site for immunization in humans and animals, owing to its resident population of dendritic cells and macrophages along with extensive vascularization by lymphatic vessels and blood capillaries. In addition to these physiological attributes, the intradermal route for vaccine delivery also presents a less-invasive alternative to conventional subcutaneous or intramuscular injections. This may offer compliance and convenience advantages for a wide range of stakeholders including patients, healthcare providers, veterinarians, animal owners and animal producers. This review discusses the current developments in intradermal vaccination for human and veterinary applications, with particular focus on the skin immunology, vaccine antigens and adjuvants and delivery systems.

Current landscape and trends in transdermal drug delivery systems.

"Generic pharmaceutical marketers are increasingly keen to have a presence in generic patches as they represent high-margin, high entry-barrier opportunities with a smaller field of competition".