Sialorrhea is often managed with off-label atropine eye drops, but rapid oral clearance can limit drug exposure and require frequent dosing. This study characterized a mucoadhesive atropine sulfate gel and evaluated its physicochemical properties, rheology, in vitro release, mucosal permeation, and relationship to in vivo pharmacokinetics. Atropine sulfate gels (0.01%, 0.05%, and 0.1% w/w) were evaluated using Franz diffusion cells and a dynamic flow-through system with porcine buccal mucosa and simulated saliva. The effects of drug concentration, application dose, salivary flow rate, and temperature were examined, and porcine buccal and sublingual tissues were used to evaluate mucosal retention and permeation. In dynamic testing, atropine eye drop solution released approximately 90% of the drug within 10 min, whereas the gel formulations required approximately 90 min to reach a similar extent of release. Application dose had a greater influence on release kinetics than formulation strength. Atropine was recovered from both buccal and sublingual mucosa but was not detected in the receiver medium during the 6-h permeation study, indicating tissue retention and limited permeation. In vitro release data were combined with clinical pharmacokinetic data to develop an in vitro-in vivo correlation. The model demonstrated a strong relationship between in vitro release and estimated in vivo absorption (R2 = 0.931), with absolute prediction errors of 3.96% and 2.70% for AUC and Cmax, respectively. These findings indicate that the atropine gel provides sustained local delivery and that the in vitro release method may support formulation optimization and prediction of in vivo performance.

The thermodynamic activity of an active pharmaceutical ingredient (API) is a key driver of permeation performance in topical formulations. This study investigated how solvent composition and evaporation impact the degree of saturation (DS) and skin permeation of three representative APIs: diclofenac sodium, metronidazole, and lidocaine. Model hydroxyethyl cellulose gels containing 1%, 10%, or 20% w/w Polyethylene Glycol (PEG-200) were prepared and characterized for solubility, pH, viscosity, and drying behavior. The solubility of all APIs increased with increasing PEG-200 concentration, whereas the DS varied correspondingly at a given drug load. Polystyrene substrate drying studies demonstrated that higher PEG-200 levels slowed solvent loss. The in situ drying studies on human cadaver skin using Franz cells enabled dynamic tracking of PEG-200 content and API saturation. Diclofenac sodium and lidocaine gels formulated with 1% PEG-200 showed progressively increasing DS over time and correspondingly higher permeation fluxes in in vitro permeation studies. In contrast, metronidazole gels showed little discrimination in DS and flux across PEG-200 concentrations, consistent with their hydrophilic nature and distinct solubility dynamics. The cumulative absorption confirmed a strong concordance between DS and permeation for diclofenac sodium and lidocaine, but not for metronidazole. Overall, the findings highlight that thermodynamic activity, modulated by solvent evaporation and shifts in solubility, governs the performance of topical formulations. These results underscore the value of monitoring DS profiles as predictive markers of drug delivery efficiency in topical product design.

The quality attributes of topical foams are critical in determining the rate and extent of drug absorption across the skin and mucous membranes. A generic product is required to match the reference-listed drug (RLD), with respect to its composition and characteristics. Time to break (TB) is one of the critical quality attributes to consider during the evaluation of some of the generic products, as per the product-specific guidance from the Food and Drug Administration (FDA). This paper proposes a slightly modified protocol for conducting TB studies to improve the robustness of the test and reduce the ambiguity in its assessment. The proposed modified method "Time to Break and Evaporation (TBE)" is a gravimetric method that considers the collapse and loss of solvents and other volatile components from the foam. A marketed salicylic acid foam product was used as a model to demonstrate the practicality of this modified approach.

The pH of the formulation can affect the pH of the skin surface. However, the skin's pH is known to recover rapidly due to the substantial buffer capacity associated with the skin. The objective of the project was to investigate the effect of the buffer capacity of skin on the pH of the formulation. A few custom-made gel and cream formulations were used as test products in the study. Custom-made gel and cream formulations were prepared and applied to human skin, with parallel applications on an inert substrate serving as controls to isolate the effect of solvent evaporation. In the control group, pH changes due to evaporation were negligible across all formulations. In vivo application revealed that the skin's buffering capacity significantly modulates the pH of the applied formulation. When formulations had a pH higher than the skin’s basal level, the skin responded by reducing the formulation pH. For instance, a cream adjusted to pH 9 showed a drop of more than one pH unit within 30 min post-application. Conversely, formulations with pH lower than the skin’s baseline exhibited an increase in pH; creams adjusted to pH 4 increased by over 0.5 units in the same timeframe. This bidirectional shift highlights the skin's active role in restoring pH homeostasis. The incorporation of buffers with varying ionic strengths into the formulations reduced the extent of pH drift, offering greater resistance to skin-driven pH changes compared to unbuffered formulation.

The emergence of novel long-acting and antiretroviral (ARV) drug delivery systems has reshaped the landscape of HIV pre-exposure prophylaxis (PrEP). Intravaginal delivery platforms are increasingly recognised for their ability to deliver ARVs directly at the portal of viral entry. These systems are well retained at the portal, ensuring sustained local inhibitory levels, minimising systemic exposure. Compared to oral PrEP, these systems offer better protection against viral transmission, reduce dosing frequency and minimise systemic side effects. Among these systems, polymeric nanoparticles (NPs) stand out due to their customisable surface chemistry, mucoadhesive potential and sustained drug release profiles, ensuring enhanced mucosal retention and minimal systemic absorption. Recent innovations integrate these NPs into versatile platforms such as in situ gelling systems, bioadhesive films, microneedles, vaginal rings and electrospun nanofibres. These specialised platforms have demonstrated superior user acceptance, stability and pharmacokinetics compared to traditional vaginal formulations. Cell-based HIV challenge models using engineered TZM-bl and PHA-stimulated peripheral blood mononuclear cells (PBMCs) have emerged as reliable in silico tools for evaluation of viral inhibition, cytotoxicity and mucosal interaction of NPs. This review critically highlights recent advances in intravaginal polymeric NP-based carrier systems for effective and sustained HIV prevention.

Topical dermatological formulations undergo profound compositional, physicochemical, and microstructural transformations upon application to the skin. This process, termed evaporative metamorphosis, alters critical quality attributes (CQAs) such as drug concentration, pH, viscosity, interfacial properties, phase distribution, substantivity, globule size, particle size, and solid-state behavior. These shifts, driven primarily by solvent evaporation, consequently, affect the dermal absorption of active pharmaceutical ingredients (API). This review systematically examines the foundational role of critical quality attributes (CQAs) in topical drug delivery and explores how evaporative metamorphosis affects these attributes at the site of application. A comprehensive understanding of the dynamic processes involved in the formulation at the applied site is crucial for the rational development of robust topical formulations that can maintain therapeutic performance throughout the metamorphosis phase and beyond.

Zaltoprofen (ZAL) is a non-steroidal anti-inflammatory drug (NSAID) with a short half-life (similar to 2.8 h) due to extensive first pass metabolism. In this context, 16 different polymeric film forming solutions (PFFS) of ZAL were developed using different grades of Eudragits, Polyvinylpyrrolidones, Kollicoat MAE 100 P and Hydroxypropyl cellulose as film formers, and polyethylene glycol 400 as a plasticizer in equal parts of ethanol and isopropyl alcohol used as solvents. Of these solutions, F13 composed of Kollicoat MAE 100 P emerged as an optimal PFFS as it quickly formed a saturated film (10.25 +/- 0.75 min) that displayed low drying time (3.00 +/- 0.46 min), and high in vitro adhesion (2.67 +/- 0.58). Ex vivo permeation studies conducted in Franz diffusion cell across porcine skin indicated that F13 displayed significantly higher (p < 0.001) steady state flux (8.64 +/- 1.72 g.cm(-2).h(-1)), shorter lag time (similar to 3 h) and better skin content (2.55 +/- 0.62 mu g/mg) compared to other PFFS. Fourier Transform Infrared Spectroscopy (FT-IR) proved the chemical integrity of ZAL in polymeric film formed from F13, while Differential scanning calorimetry (DSC) and X-ray Diffractometry (XRD) proved the "anti-recrystallization potential" of PFFS. Anti-inflammatory studies in rats indicated that F13 significantly inhibited (ANOVA, p < 0.001) carrageenan induced paw edema for nearly 12 h compared to topical diclofenac used as standard. In addition, significantly elevated (ANOVA, p < 0.001) analgesic effect was noted in the hot plate test in rats treated with F13 compared to the standard for 12 h proving the superior efficacy of F13. Thus, PFFS by virtue of "in situ evaporative metamorphosis" induced supersaturation can be an attractive platform to deliver ZAL transdermally.

The in vitro permeation testing (IVPT) of topical products is performed across the human cadaver skin, which is stored frozen for a prolonged duration. The cryo-preservation technique is not economical and is a cumbersome process. Moreover, prolonged skin preservation in a frozen state and frequent freeze-thawing are known to affect the integrity of the skin barrier. Therefore, lyophilization was explored as an alternative to protect the skin tissue from microbial contamination and degeneration. Notably, the project's objective was to investigate the impact of the freeze-drying process on the skin's barrier properties. The morphometrics of the lyophilized skin were measured. Histological studies did not reveal any notable changes in the organization and intactness of the layers due to the freeze-drying process. The biophysical attributes of the skin, such as transepidermal water evaporation rate and transepidermal electrical resistivity (TEER), were not significantly different between the control skin (not subjected to the freeze-drying process) and the freeze-dried skin (FDS). The permeability of caffeine, a hydrophilic model permeant, and nicotine, a lipophilic model permeant, were consistent across the control and the FDS. It is evident from the studies that the lyophilization process did not significantly impact the barrier properties and permeability of the skin.

Natural products are generally preferred medications owing to their low toxicity and irritancy potential. However, a good number of herbal therapeutics (HT) exhibit solubility, permeability and stability issues that eventually affect oral bioavailability. Transdermal administration has been successful in resolving some of these issues which has lead in commercialization of a few herbal transdermal products. Polymeric Microneedles (MNs) has emerged as a promising platform in transdermal delivery of HT that face problems in permeating the skin. Several biocompatible and biodegradable polymers used in the fabrication of MNs have been discussed. MNs have been exploited for cutaneous delivery of HT in management of skin ailments like skin cancer, acne, chronic wounds and hypertrophic scar. Considering the clinical need, MNs are explored for systemic delivery of potent HT for management of diverse disorders like asthma, disorders of central nervous system and nicotine replacement as it obviates first pass metabolism and elicits a quicker onset of therapeutic response. MNs of HT have found good number of aesthetic applications in topical delivery of HT to the skin. Interestingly, MNs have emerged as an attractive option as a minimally invasive diagnostic aid in sampling biomarkers from plants, skin and ocular interstitial fluid. The review updates the progress made by MN technology of HT for multiple therapeutic interventions along with the future challenges. An attempt is made to illustrate the challenging formulation strategies employed in the fabrication of polymeric MNs of HT. Efforts are on to extend the potential applications of polymeric MNs to HT for diverse therapeutic applications.

Pharmaceutical industries and drug regulatory agencies are inclining towards continuous manufacturing due to better control over the processing conditions and in view to improve product quality. In the present work, continuous manufacturing of O/W emulgel by melt extrusion process was explored using lidocaine as an active pharmaceutical ingredient. Emulgel was characterized for pH, water activity, globule size distribution, and in vitro release rate. Additionally, effect of temperature (25°C and 60°C) and screw speed (100, 300, and 600 rpm) on the globule size and in vitro release rate was studied. Results indicated that at a given temperature, emulgel prepared under screw speed of 300 rpm resulted in products with smaller globules and faster drug release.

The objective of the project was to investigate the plausibility of active pharmaceutical ingredients (APIs) to undergo sublimation from topical application following evaporation of solvent. Topical formulations with different APIs were subjected to a sublimation screening test. The APIs in the selected topical products were found to undergo sublimation to a different extent. The salicylic acid topical product was found to undergo a significant loss due to sublimation. The extent of sublimation of salicylic acid was significantly greater at skin temperature compared to room temperature. When the APIs were subjected to the sublimation screening test in their neat form at 32 ± 1 °C, the natural log of the rate of sublimation decreased linearly with the standard enthalpy of sublimation of compound (R2 = 0.89). The formulation composition was found to have a significant impact on the extent of sublimation of the representative API, salicylic acid. The sublimation of APIs from the topical product was found to affect the mass balance studies in the case of the salicylic acid ointment. Furthermore, the results of the human studies agreed with the in vitro experimental results demonstrating the plausibility of loss of API due to sublimation from the site of application.

The polymer coated polymeric (PCP) microneedles (MNs) is a novel approach for controlled delivery of drugs (without allowing release of the excipients) to the target site. PCP MNs was explored as an approach to deliver the drug intravitreally to minimize the risks associated with conventional intravitreal injections. The core MNs was fabricated with polyvinyl pyrrolidone K30 (PVP K30) and coating was with Eudragit E100. Preformulation studies revealed that the films prepared using Eudragit E 100 exhibited excellent integrity in the physiological medium after prolonged exposure. FTIR studies were performed to investigate the possible interaction between the API and the polymer. The PCP MNs fabricated with different drug loads (dexamethasone sodium phosphate) were subjected to in vitro drug release studies. The drug release from uncoated MNs was instantaneous and complete. On the other hand, a controlled release profile was observed in case of PCP MNs. Likewise, even in the ex vivo porcine eye model, the drug release was gradual into the vitreous humor in case of PCP MNs. The uncoated microneedles released all the drug instantaneously where the PCP MNs retarded the release up to 3 h.

Aim: Negatively charged deformable liposomes (DL) of ketoprofen were formulated to enhance transdermal delivery of ketoprofen (KP) under the influence of iontophoresis for intraarticular delivery. Methods: Conventional and deformable KP liposomes were prepared using thin film hydration, characterized and intraarticular delivery of KP was evaluated using Sprague-Dawley rats. Results: Vesicles displayed entrapment efficiency (>71%); zeta potential <-25 mV; size between 152.4 ± 12.42 nm to 220.4 ± 6.22 nm, KP-DL were stable under iontophoresis. Conventional and deformable liposomes exhibited relatively higher iontophoretic flux values than passive flux; Iontophoretic delivery enhanced KP availability in the synovial fluid (1.34 ± 0.12 μg.h/ml) fourfold over passive delivery (0.329 ± 0.15 μg.h/ml). Conclusion: Iontophoretic mediated transport of deformable liposomes could improve transdermal delivery of ketoprofen into the synovial joints than conventional liposomes.

Peripheral neuropathy (PN) is a condition of peripheral nerve damage leading to severe pain. The first line therapies are associated with adverse psychotropic effects (PSE) and second line therapies are not efficient enough to relieve pain. There is an unmet drug need for relieving pain effectively without PSE in PN. Anandamide, an endocannabinoid activates cannabinoid receptors to relieve the pain due to peripheral neuropathy (PN). Anandamide has a very short biological half-life as they are extensively metabolized by fatty acid amide hydrolase enzyme (FAAH). Regional delivery of safe FAAH inhibitor (FI) with anandamide would be beneficial for PN without PSE. The objective of the study is to identify a safe FI and deliver the anandamide in combination with the FI topically for the management of PN. The FAAH inhibition potential of silymarin constituents was evaluated by molecular docking and in vitro studies. The topical gel formulation was developed to deliver anandamide and FI. The formulation was assessed in chemotherapeutic agent-induced PN rat models to relieve mechanical-allodynia and thermal-hyperalgesia. The molecular docking studies demonstrated that the Prime MM-GBSA free energy of silymarin constituents were in the order of silybin > isosilybin > silychristin > taxifolin > silydianin. In in vitro studies, silybin 20 & mu;M inhibited > 61.8% of FAAH activity and increased the half-life of anandamide. The developed formulation increased permeation of anandamide and silybin across the porcine skin. Furthermore, on the application of anandamide and anandamide-silybin gel to rat paws, there was a significant increase in the pain threshold for allodynic and hyperalgesic stimulus up to 1 h and 4 h, respectively. The topical anandamide with silybin delivery approach could serve to alleviate PN efficiently and thus could minimize unwanted CNS side effects of synthetic or natural cannabinoids in patients.

Metronidazole topical formulations such as gels, creams, and lotions are used in the treatment of bacterial vaginosis and inflammation lesions of rosacea. Metronidazole precipitating from a Carbopol-based gel resulted in the formation of unique, highly branched, curvilinear microstructures. In contrast, metronidazole precipitated as linear, acicular crystals from drug solutions. The reason for the change in crystal habit was investigated by preparing different custom-made solutions and gels. Custom-made solutions were prepared using different solvent systems. Custom-made gels were prepared using different concentration of pH modifier, carbopol and other excipients. Characterization studies were carried out on the recrystallized metronidazole using bright-field microscopy, polarized microscopy, scanning electron microscopy (SEM), Differential Scanning Calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and Powder X-Ray Diffractometry (PXRD). The results indicated that the change in crystal habit was likely due to the interactions between the nitro-imidazole moiety of metronidazole and the polymer without a change in the polymorphic form.

Silymarin constituents are extensively investigated in the treatment of skin disorders. The main constituents of silymarin include taxifolin (TX), silychristin (ST), silydianin (SDN), silybin A (SA), silybin B (SB), isosilybin A (ISA) and isosilybin B (ISB). The objective of the present study was to determine in-vitro dermal kinetics of individual silymarin constituents in human skin models and to develop a silymarin topical formulation. In-vitro studies indicate human skin binding of silymarin was in the range of 2.09 to 12.3% and half-life of silymarin constituents was > 15.5 h in epidermal and dermal cells. Topical silymarin cream was prepared using sulfobutylether ss-cyclodextrins as solubilizer and propylene glycol as permeation enhancer. The cream was subjected to ex-vivo human skin permeation studies. In ex-vivo studies, cumulative amount of TX, ST, SDN, SA, SB, ISA and ISB permeated across human cadaver skin at 24 h was 921 +/- 13.5, 1992 +/- 67.6, 345 +/- 39.2, 1089 +/- 45.0, 1770 +/- 100, 1469 +/- 81.5 and 1285 +/- 33.1 ng/cm2, respectively. The amount TX, ST, SDN, SA, SB, ISA and ISB retained after 24 h was 60.7 +/- 8.2, 376 +/- 45.5, 72.3 +/- 6.9, 66.4 +/- 8.0, 208 +/- 31.3, 154 +/- 12.4 and 102 +/- 6.3 ng/mg of human cadaver skin, respectively. The study results demonstrate silymarin topical formulation could deliver significant amount of silymarin constituents into skin. The developed silymarin formulation could be beneficial for treatment or management of a broad spectrum of dermatological disorders.

For more than five decades, pharmaceutical manufacturers have been relying heavily on batch manufacturing that is a sequential, multistep, laborious, and time-consuming process. However, late advances in manufacturing technologies have prompted manufacturers to consider continuous manufacturing (CM) is a feasible manufacturing process that encompasses fewer steps and is less tedious and quick. Global regulatory agencies are taking a proactive role to facilitate pharmaceutical industries to adopt CM that assures product quality by employing robust manufacturing technologies encountering fewer interruptions, thereby substantially reducing product failures and recalls. However, adopting innovative CM is known to pose technical and regulatory challenges. Hot melt extrusion (HME) is one such state-of-the-art enabling technology that facilitates CM of diverse pharmaceutical dosage forms, including topical semisolids. Efforts have been made to continuously manufacture semisolids by HME integrating the principles of Quality by Design (QbD) and Quality Risk Management (QRM) and deploying Process Analytical Technologies (PAT) tools. Attempts have been made to systematically elucidate the effect of critical material attributes (CMA) and critical process parameters (CPP) on product critical quality attributes (CQA) and Quality Target Product Profiles (QTPP) deploying PAT tools. The article critically reviews the feasibility of one of the enabling technologies such as HME in CM of topical semisolids. The review highlights the benefits of the CM process and challenges ahead to implement the technology to topical semisolids. Once the CM of semisolids adopting melt extrusion integrated with PAT tools becomes a reality, the process can be extended to manufacture sterile semisolids that usually involve more critical processing steps.