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.

Topical foams are widely utilized in dermatology for both cosmetic and therapeutic purposes, owing to their superior spreadability, ease of application over large skin areas, and enhanced patient compliance. As with other topical products, generic foams must exhibit physicochemical properties comparable to their reference listed drug (RLD or innovator products) to establish pharmaceutical equivalence. However, foams possess distinct characteristics that set them apart from other topical formulations. This study aimed to develop and evaluate characterization methods specific to topical foams. A clobetasol propionate 0.05% hydro-alcoholic solution type foam, Olux (RLD), and its generic were used as model foams to develop characterization methods. Critical quality attributes such as pH, In-vitro drying study, time-to-break, foam firmness, work of adhesion, and rheological properties were characterized. The results showed no significant differences in quality attributes between the generic and RLD foams. This study clearly demonstrates the utility of simple, effective characterization techniques for assessing the similarity between generic foam products and their RLD counterparts.

The evaporation of the solvent induces significant changes in formulation, directly impacting its performance. The performance of topical products is determined by the interplay between their inherent quality attributes and the transformations that occur due to solvent evaporation when applied to the skin in clinically relevant doses. To accurately assess, in vivo performance, it is advisable to apply smaller doses to the skin and keep the donor compartment open to enable evaporation of solvents while carrying out in vitro permeation tests. This manuscript highlights the critical role of solvent evaporation in differentiating the performance of two compositionally distinct products. One gel formulation contained alcohol, while the other did not. Although both exhibited similar quality attributes, their drying profiles varied significantly. Permeation studies conducted with closed donor compartments (Evaporation-disabled (ED)) failed to reveal these differences. However, when the donor compartments were exposed to the atmosphere to allow evaporation (Evaporation-enabled (EN)), the performance differences between the two products became evident.

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.

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.

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.

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.

Efinaconazole is the first azole derivative approved by FDA for the topical treatment of onychomycosis. The objective of present study was to develop and validate HPLC method for estimation of efinaconazole in ex vivo human nail permeation study samples. The chromatographic analysis was performed on a HPLC system equipped with diode array detector. The efinaconazole and internal standard (IS) were extracted from the human nail samples by using the protein precipitation method. The samples were injected on to 5 μm Polar C18 100Å, 4.6 mm × 150 mm column. The mobile phase consisted of 0.01 M potassium dihydrogen phosphate: acetonitrile (36:64) and eluent was monitored at 205 nm. The chromatographic separation of drug and analyte was achieved using isocratic elution at flow rate of 1 mL/min with a total run time of 15 min. The efinaconazole and IS were eluted at 6.4 ± 0.5 and 8.3 ± 0.5 min, respectively. The developed method was validated as per FDA guidelines, and the results met with acceptance criteria. The method developed was specific, and the analyte concentrations were linear at range of 50 to 10000 ng/mL (R2 ≥ 0.9981). The validated HPLC method was applied for quantifying efinaconazole in human nail permeation study samples. The permeation of efinaconazole was increased by twofolds with Labarfac CC (15135.4 ± 2233.9 ng/cm2) compared to formulations containing Transcutol P (6892.0 ± 557.6 ng/cm2) and Labrasol (7266.1 ± 790.6 ng/cm2). The study results demonstrate that developed efinaconazole HPLC method can be employed for formulation evaluation and clinical studies.

Delta-9-tetrahydrocannabinol (THC) is one of the most effective antinociceptive agents used in the treatment of peripheral neuropathy. THC is highly lipophilic and susceptible to thermal and oxidative degradation. Identifying appropriate solvents in which THC is stable as well as adequately solubilized is crucial in developing topical dosage forms. Lipid solvent systems are of utmost utility and relevance for formulating highly lipophilic drugs. Hence, the objective of this project was to screen the solubility of THC in lipidic excipients, monitor THC content in the selected vehicles during stability, and study the influence of these excipients on permeation of THC across skin. The solubility of THC in liquid lipid excipients was in the range of 421 to 500 mg/g. The solubility of THC in solid lipid excipients was in the range of 250 to 750 mg/g. THC in its neat form was poorly stable, but when dissolved in lipid-based excipients, its stability improved significantly. THC in lipid excipients was more stable at 4 ± 3°C compared to samples stored at 25 ± 2°C. The antioxidants (butylated hydroxytoluene and ascorbyl palmitate) used in the excipients further improved the stability of THC. The results demonstrated that the liquid and solid lipid excipients used in the study could solubilize THC freely and mitigate the degradation of THC significantly. The binary combination of lipid excipients enhanced THC skin permeation and retention, demonstrating the potential for topical formulation development of THC.

Vulvodynia is a chronic clinical condition associated with vulvar pain that can impair the sexual, social, and psychological life of women. There is a need for more research to develop novel strategies and therapies for the treatment of vulvodynia. Vulvodynia in experimental animal models induced via infections, allergens, and diabetes are tedious and with lessor induction rate. The objective of the study was to explore the possibility of inducing vulvodynia using a chemotherapeutic agent in a rodent model. Paclitaxel is commonly used in treating breast and ovarian cancer, whose dose-limiting side effect is peripheral neuropathy. Studies have shown that peripheral neuropathy is one of the etiologies for vulvodynia. Following paclitaxel administration (2 mg/kg i.p.), the intensity of vulvar hypersensitivity was assessed using a series of von Frey filaments (0.008 to 1 g) to ensure the induction of vulvodynia. Vulvodynia was induced from day 2 and was well sustained for 11 days. Furthermore, the induced vulvodynia was validated by investigating the potentiation of a flinch response threshold, upon topical application and systemic administration of gabapentin, a commonly used medication for treating neuropathic pain. The results demonstrate that vulvodynia was induced due to administration of paclitaxel. The fact that chemotherapeutic agent-induced vulvodynia was responsive to topical and parenterally administered gabapentin provides validity to the model. The study establishes a new, relatively simple and reliable animal model for screening drug molecules for vulvar hypersensitivity.

The use of hot-melt extrusion (HME) technique in the preparation of semi-solid products offers several advantages over conventional processes. However, the optimization of the technique for preparation of semi-solid pharmaceuticals is challenging due to involvement of ingredients with different physical properties. Hence, a simple tool to optimize the mixing of ingredients that results in a target ratio and drug content uniformity is utmost important. In this study, a handheld colorimeter has been explored to optimize the process variables of twin screw processor for preparation of hydrophilic PEG-based ointment. The process parameters which were optimized with use of handheld colorimeter have been used for preparation of polyethylene glycol–based metronidazole ointment. The metronidazole ointment prepared by twin screw processor was compared with commercially available metronidazole gel for in vitro release testing and ex vivo permeation. The flux, ex vivo bioavailability, and Tmax of polyethylene glycol-based metronidazole ointment was found to be similar to that of marketed metronidazole gel.

Cystic fibrosis is diagnosed in infants by estimating the levels of chloride ions present in the sweat induced by iontophoresis of pilocarpine solution. Elevated levels of chloride (≥60 mMol/L) in sweat are indicative of cystic fibrosis. However, the iontophoretic method of delivering pilocarpine is cumbersome and usually is associated with several side effects such as skin burn, skin rashes, erythema, and so forth. The objective of this study was therefore to develop a topical formulation that delivers adequate amount of pilocarpine. The drug delivery of formulation was compared with iontophoresis of aqueous solution of pilocarpine nitrate in vitro using porcine skin model. The pilocarpine levels in the skin exposed to topical pilocarpine solution under mild hyperthermia was 152.04 ± 52.23 μg/cm2 after 10 min of application, whereas it was 97.05 ± 27.93 μg/cm2 in the skin after 10 min of iontophoresis. The topical formulation was subjected to clinical evaluation to assess the efficacy of the product to induce sweat production. The average amount of the sweat secreted on application of topical formulation was found to be 77.28 ± 18.97 mg. Based on these results, it was found that the topical formulation was successful in delivering pilocarpine and to stimulate sweat secretion.

The use of opioids for treating acute and chronic pain condition is a common clinical practice. When delivered systemically, the analgesic activity is mediated through the central pathway, which although effective, leads to various adverse effects such as dependence, abuse and respiratory depression. Fentanyl is an opioid analgesic that is available as injection and transdermal patch products for the management of acute and chronic pain. These products require stringent regulatory controls and label warnings on disposal due to the abuse potential associated. This research project evaluated the regional antinociceptive efficacy of fentanyl delivered from soluble microneedles. The microneedle patches were formulated with relatively less drug loading as compared to patches intended for systemic delivery and were tested for their antinociceptive activity in rats by measuring the paw withdrawal latency when exposed to a thermal stimulus. The results indicate that regional delivery of fentanyl mediated through soluble microneedles provides an effective antinociceptive activity. The onset of analgesic activity was faster with microneedle patch (0.5 h) when compared to the adhesive dermal patch (6 h). This study thus demonstrates the effectiveness of microneedle mediated pain management for immediate pain relief.

Second-degree burn injury is the most common type of burn injury, which usually takes 2-3 weeks for complete healing. However, such patients suffer with intense pain associated with development of hyperalgesia and allodynia. Here, we prepare a silver clay patch using montmorillonite clay, betaine, and silver nitrate. Later, the silver clay patches were loaded with fentanyl. Furthermore, the patches were fabricated into burn wound dressings. The dressings were first subjected to ex vivo skin penetration studies and were later evaluated for thermal hyperalgesia and mechanical allodynia using second-degree burn injury rodent model. Our results show that application of fentanyl-loaded dermal clay (FLDC) dressings for 3 h showed significant increase of paw withdrawal latency (p <0.001) against hyperalgesia starting from 30 min after removal of patch to up to 6 h. Similarly, the FLDC dressings also potentiated the paw withdrawal threshold for up to 4 h after application (p <0.001). From these studies, we can conclude that FLDC dressings are ideal topical formulations for better management of pain in second-degree burns.

The analgesic activity was assessed using hot plate method, formalin induced paw licking test, acetic acid induced writhing test. Preliminary investigations were carried out with water, DMSO and chloroform for solubility. For analgesic activity 1, 2, 3-triazine-4-ones series of compounds CP1, CP2, CP3 showed significant increase in jumping time of mice in hot plate method at only higher dose level (50 mg/kg). In acetic acid induced writhing test in mice at higher dose levels CP1, CP2, CP3, (50 mg/kg) significantly inhibited the number of writhing in mice. 1, 2, 3-triazine-4-ones series of compounds CP1, CP2, CP3 at (25 and 50 mg/kg) significantly inhibited formalin induced paw licking at both early and late phases. These results indicate that compound possessed both central and peripheral analgesic actions. It was found that the CP1, CP2, CP3 compounds shown good analgesic activity in formalin induced paw licking test at both dose levels (25 and 50 mg/kg) but in other two model hot plate method and acetic acid induced writhing model; shown good analgesic activity at higher dose level only (50 mg/kg).

The sensorial characteristic of topical products determines the patient acceptability of the topical products. The primary focus of the present study was to assess the feasibility of using Infrared (IR) thermal imaging technique to measure the skin cooling effect of topical creams. The secondary objective was to investigate the effect of microstructure of topical creams on the skin cooling effect of topical cream products that are identical in composition. The results showed that IR thermal measurement technique was found to be a sensitive and reliable for quantitative evaluation of skin cooling effect of topical products. The globule size of the creams was found to influence the skin cooling effect caused by creams despite their sameness in composition.

The objective was to evaluate anti-nociceptive activity of a novel clay based dermal patch system for potential use in first degree burn wounds. First, clay patches with silver were formulated for antisepsis. Subsequently they were loaded with 5 mg/cm(2) of lidocaine. The skin penetration studies were performed to ensure the delivery of drug into the skin. Finally, the lidocaine loaded silver clay patches were screened for in vivo anti-nociception using hot plate analgesiometer in rats. The lidocaine loaded silver clay patches did not show anti-nociception after 6hrs of application despite significant amount of drug release observed in in vitro studies. To discover the reason for failure of the patch system in thermally induced pain model, mechanistic studies were performed using clay patches not loaded with silver colloid. When lidocaine loaded clay patches, devoid of silver were subjected to in-vivo evaluation, a significant anti-nociceptive activity was observed. The reason for masking of anti-nociceptive activity of lidocaine in the silver loaded patches was potentially due to coating of silver on the paw rendering the skin more conductive. Often, additional mechanistic studies are required to be performed to critically assess the in-vivo data. (C) 2017 Elsevier B.V. All rights reserved.