Cutaneous Pharmacokinetics of Topically Applied Novel Dermatological Formulations.

Novel formulations are developed for dermatological applications to address a wide range of patient needs and therapeutic challenges. By pushing the limits of pharmaceutical technology, these formulations strive to provide safer, more effective, and patient-friendly solutions for dermatological concerns, ultimately improving the overall quality of dermatological care. The article explores the different types of novel dermatological formulations, including nanocarriers, transdermal patches, microsponges, and microneedles, and the techniques involved in the cutaneous pharmacokinetics of these innovative formulations. Furthermore, the significance of knowing cutaneous pharmacokinetics and the difficulties faced during pharmacokinetic assessment have been emphasized. The article examines all the methods employed for the pharmacokinetic evaluation of novel dermatological formulations. In addition to a concise overview of earlier techniques, discussions on novel methodologies, including tape stripping, in vitro permeation testing, cutaneous microdialysis, confocal Raman microscopy, and matrix-assisted laser desorption/ionization mass spectrometry have been conducted. Emerging technologies like the use of microfluidic devices for skin absorption studies and computational models for predicting drug pharmacokinetics have also been discussed. This article serves as a valuable resource for researchers, scientists, and pharmaceutical professionals determined to enhance the development and understanding of novel dermatological drug products and the complex dynamics of cutaneous pharmacokinetics.

Transmucosal Delivery of Peptides and Proteins Through Nanofibers: Current Status and Emerging Developments.

Advancements in recombinant DNA technology have made proteins and peptides available for diagnostic and therapeutic applications, but their effectiveness when taken orally leads to poor patient compliance, requiring clinical administration. Among the alternative routes, transmucosal delivery has the advantage of being noninvasive and bypassing hepato-gastrointestinal clearance. Various mucosal routes-buccal, nasal, pulmonary, rectal, and vaginal-have been explored for delivering these macromolecules. Nanofibers, due to their unique properties like high surface-area-to-volume ratio, mechanical strength, and improved encapsulation efficiency, serve as promising carriers for proteins and peptides. These nanofibers can be tailored for quick dissolution, controlled release, enhanced encapsulation, targeted delivery, and improved bioavailability, offering superior pharmaceutical and pharmacokinetic performance compared to conventional methods. This leads to reduced dosages, fewer side effects, and enhanced patient compliance. Hence, nanofibers hold tremendous potential for protein/peptide delivery, especially through mucosal routes. This review focuses on the therapeutic application of proteins and peptides, challenges faced in their conventional delivery, techniques for fabricating different types of nanofibers and, various nanofiber-based dosage forms, and factors influencing nanofiber generation. Insights pertaining to the precise selection of materials used for fabricating nanofibers and regulatory aspects have been covered. Case studies wherein the use of specific protein/peptide-loaded nanofibers and delivered via oral/vaginal/nasal mucosa for diagnostic/therapeutic use and related preclinical and clinical studies conducted have been included in this review.

Investigation on Potential of Chitosan Nanoparticles for Oral Bioavailability Enhancement of Risedronate Sodium.

Risedronate sodium (RS) is used in osteoporosis for bone reabsorption. It is a BCS class III drug having poor oral bioavailability (<0.63%) due to low permeability. In the present study, RS-loaded chitosan nanoparticles were developed to increase oral bioavailability and evaluated for various parameters. The DSC study indicated compatibility of RS with excipients in their physical mixture. The nanoparticles were prepared by ionotropic gelation technique and lyophilized. The optimized batch (RS-CNs) was found to have particles of size 268.7 nm and zeta potential of 24.9 mV. The TEM image of RS-CNs revealed discrete spherical particles. Angle of repose of 27.02 indicates good flow property of nanoparticles. FT-IR spectra of RS-CNs showed characteristic peaks of RS indicating compatibility of RS with the excipients. The mucin binding efficiency of RS-CNs was obtained as 63.42%. The in vitro release study of RS indicated controlled delivery from RS-CNs over 22 h. The release mechanism was found to be diffusion- and erosion-controlled release. Ex vivo study using rat intestine revealed faster permeation of 32.78% in 6 h from RS-CNs compared to plain drug solution. In vivo pharmacokinetic study in rats showed increased Cmax (1.8 fold) from RS-CNs compared to marketed formulation. The relative bioavailability of 193% from RS-CNs indicated significant enhancement in bioavailability upon nanoparticle formulation. The RS-CNs were found to be stable at room and refrigerated conditions. In conclusion, developed RS-loaded chitosan nanoparticles seem to be a promising approach to increase oral bioavailability and can avoid upper GI tract side effects.

Darunavir-Loaded Lipid Nanoparticles for Targeting to HIV Reservoirs.

Darunavir has a low oral bioavailability (37%) due to its lipophilic nature, metabolism by cytochrome P450 enzymes and P-gp efflux. Lipid nanoparticles were prepared in order to overcome its low bioavailability and to increase the binding efficacy of delivery system to the lymphoid system. Darunavir-loaded lipid nanoparticles were prepared using high-pressure homogenization technique. Hydrogenated castor oil was used as lipid. Peptide, having affinity for CD4 receptors, was grafted onto the surface of nanoparticles. The nanoparticles were evaluated for various parameters. The nanoparticles showed size of less than 200 nm, zeta potential of - 35.45 mV, and a high drug entrapment efficiency (90%). 73.12% peptide was found conjugated to nanoparticles as studied using standard BSA calibration plot. Permeability of nanoparticles in Caco-2 cells was increased by 4-fold in comparison to plain drug suspension. Confocal microscopic study revealed that the nanoparticles showed higher uptake in HIV host cells (Molt-4 cells were taken as model containing CD4 receptors) as compared to non-CD4 receptor bearing Caco-2 cells. In vivo pharmacokinetic in rats showed 569% relative increase in bioavailability of darunavir as compared to plain drug suspension. The biodistribution study revealed that peptide-grafted nanoparticles showed higher uptake in various organs (also in HIV reservoir organs namely the spleen and brain) except the liver compared to non-peptide-grafted nanoparticles. The prepared nanoparticles resulted in increased binding with the HIV host cells and thus could be promising carrier in active targeting of the drugs to the HIV reservoir.

Effect of particle size on oral bioavailability of darunavir-loaded solid lipid nanoparticles.

The present investigation aimed to study the effect of particle size of solid lipid nanoparticles (SLNs) on oral bioavailability of darunavir. High pressure homogenisation technique was used to prepare SLNs. Three different sized SLNs loaded with darunavir were developed with mean particle sizes of around 100 nm, 200 nm and 500 nm, respectively. The in vivo pharmacokinetics in rats showed a significant increase in oral bioavailability of darunavir from all the three formulations in comparison to plain drug suspension and reference tablet. The results revealed insignificant difference between SLNs of 100 and 200 nm and these had significantly higher bioavailability in comparison to SLNs of 500 nm. However, more number of homogenisation cycles is required for obtaining 100 nm and thus we selected 200 nm as an optimum size for oral bioavailability enhancement of darunavir. The optimised SLN formulation was stable for a period of 6 months at 25 ± 2 °C/60 ± 5% relative humidity (RH).

Formulation Development of Spherical Crystal Agglomerates of Itraconazole for Preparation of Directly Compressible Tablets with Enhanced Bioavailability.

The objective of the present work was to formulate tablet dosage form of itraconazole with enhanced bioavailability. Spherical crystal agglomerates (SCA) of itraconazole prepared by quasi emulsification solvent diffusion method using Soluplus and polyethylene glycol 4000 (PEG 4000) showed increased solubility (540 µg/ml) in 0.1 N hydrochloric acid as compared to pure drug (12 µg/ml). A Fourier transform infrared (FTIR) study indicated compatibility of drug with the excipients. The developed SCA were spherical with smooth surface having an average size of 412 µm. The significantly improved micromeritic properties compared to the plain drug suggested its suitability for direct compression. The antifungal activity of itraconazole was retained in the SCA form as evidenced from the results of the disc diffusion method. The optimized SCA formulation could be easily compressed into tablet with desirable characteristics of hardness (5 kg/cm(2)) and disintegration time (6.3 min). The in vitro dissolution studies showed significant difference in the dissolution profiles of pure drug (21%) and SCA formulation (85%) which was even greater than that of marketed preparation (75%). In vivo pharmacokinetic showed significant enhancement in C max and AUC0-t with relative bioavailability of 225%. The SCA formulation seems to be promising for enhancement of oral bioavailability of itraconazole.

Caprylate-conjugated Cisplatin for the development of novel liposomal formulation.

Cisplatin, first (platinum) compound to be evolved as an anticancer agent, has found its important place in cancer chemotherapy. However, the dose-dependent toxicities of cisplatin, namely nephrotoxicity, ototoxicity, peripheral neuropathy, and gastrointestinal toxicity hinder its widespread use. Liposomes can reduce the toxicity of cisplatin and provide a better therapeutic action, but the low lipid solubility of cisplatin hinders its high entrapment in such lipid carrier. In the present investigation, positively charged reactive aquated species of cisplatin were complexed with negatively charged caprylate ligands, resulting in enhanced interaction of cisplatin with lipid bilayer of liposomes and increase in its encapsulation in liposomal carrier. Prepared cisplatin liposomes were found to have a vesicular size of 107.9 ± 6.2 nm and zeta potential of -3.99 ± 3.45 mV. The optimized liposomal formulation had an encapsulation efficiency of 96.03 ± 1.24% with unprecedented drug loading (0.21 mg cisplatin / mg of lipids). The in vitro release studies exhibited a pH-dependent release of cisplatin from liposomes with highest release (67.55 ± 3.65%) at pH 5.5 indicating that a maximum release would occur inside cancer cells at endolysosomal pH. The prepared liposomes were found to be stable in the serum and showed a low hemolytic potential. In vitro cytotoxicity of cisplatin liposomes on A549 lung cancer cell line was comparable to that of cisplatin solution. The developed formulation also had a significantly higher median lethal dose (LD50) of 23.79 mg/kg than that of the cisplatin solution (12 mg/kg). A promising liposomal formulation of cisplatin has been proposed that can overcome the disadvantages associated with conventional cisplatin therapy and provide a higher safety profile.

Innovative Fusion of Probiotics and Mouth Fresheners: Investigating Unaltered Growth, Microscopic Analysis, and Mucoadhesive Strength.

Since ancient times, mouth fresheners in many different forms have been used throughout the world. Traditional knowledge describes the health benefits of mouth fresheners, and contemporary science is now investigating their benefits. Claims have been made that mouth fresheners not only improve digestion but also promote oral health. Similar, but in a more profound sense, probiotics offer astounding advantages in treating many disorders. In certain cases, probiotics also offer prophylactic effects. Numerous benefits for dental health are being studied for B. coagulans (MB-BCM9) and B. subtilis (MB-BSM12). In this current study, a probiotic and a mouth freshener were combined to ameliorate the impacts of both. The oral residence of probiotics was enhanced by employing mucoadhesive polymers. Numerous compositions were developed and evaluated for the unaltered growth of probiotics, along with other evaluations like microscopy, in vitro mucoadhesive strength, and stability studies. Xanthan gum and hydroxypropyl methylcellulose were used in the development of mucoadhesive probiotic powder by employing the lyophilization technique. More than five hours of residence time were observed in the in vitro study with goat oral mucosa. The enumeration study validated the label claims of MB-BCM9 and MB-BSM12. It also concluded that none of the components of the formulation had a detrimental effect on probiotics. In essence, the present work discloses the novel and stable formulation of a probiotic-based mouth freshener.

Nanomaterials as drug delivery agents for overcoming the blood-brain barrier: A comprehensive review.

Background and Purpose: The blood-brain barrier (BBB), a critical interface of specialized endothelial cells, plays a pivotal role in regulating molecular and ion transport between the central nervous system (CNS) and systemic circulation. Experimental Approach: This review aims to delve into the intricate architecture and functions of the BBB while addressing challenges associated with delivering therapeutics to the brain. Historical milestones and contemporary insights underscore the BBB's significance in protecting the CNS. Key Results: Innovative approaches for enhanced drug transport include intranasal delivery exploiting olfactory and trigeminal pathways, as well as techniques like temporary BBB opening through chemicals, receptors, or focused ultrasound. These avenues hold the potential to reshape conventional drug delivery paradigms and address the limitations posed by the BBB's selectivity. Conclusion: This review underscores the vital role of the BBB in maintaining CNS health and emphasizes the importance of effective drug delivery through this barrier. Nanoparticles emerge as promising candidates to overcome BBB limitations and potentially revolutionize the treatment of CNS disorders. As research progresses, the application of nanomaterials shows immense potential for advancing neurological therapeutics, albeit with careful consideration of safety aspects.

Lipid-based amphotericin B gel treatment eradicates vulvovaginal candidiasis in patients who failed to azole therapy.

Vaginal yeast infection is one of the most common diseases caused by vulvovaginal candidiasis (VVC). Effective therapy for VVC is needed. A lipid-based amphotericin B gel 0.1% (LAB) was developed and evaluated for the treatment of VVC patients and those who failed to azole therapy. LAB was applied topically twice daily for 7 days to 64 moderate patients and 14 days to 55 severely infected VVC patients. Additionally, 66 patients who failed to azole therapy were treated twice daily with LAB for 14 days. A 91.5% clinical response and 93.16% mycological response was observed in VVC patients. The patients treated with LAB who failed to azole therapy showed a 75% clinical, 95.3% mycological response and 83% remission was observed.Overall, the LAB was found to be efficacious and safe for the treatment of VVC patients. Clinical Trial Registration All the trials were registered at Clinical Trial Registry of India (CTRI/2013/02/003378, CTRI/2014/02/004409).

Preservation of bioavailability of ingredients and lack of drug-drug interactions in a novel five-ingredient polypill (polycap): a five-arm phase I crossover trial in healthy volunteers.

BACKGROUND: The Polycap (polypill; aspirin [acetylsalicylic acid], ramipril, simvastatin, atenolol, and hydrochlorothiazide) was found to be safe and effective for reducing multiple cardiovascular risk factors in The Indian Polycap Study (TIPS). OBJECTIVE: We evaluated the bioavailability of each ingredient of the Polycap and determined any drug-drug interactions relative to single component reference preparations. METHODS: The bioavailability of the ingredients of the Polycap (T; test) when formulated as a single capsule was compared with that of identical capsules with each of its ingredients administered separately (R; reference) in a five-arm, randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial with at least a 2-week washout period in a total of 195 healthy volunteers. Plasma concentrations of each drug and, where applicable, its active metabolite were measured using validated liquid chromatography-tandem mass spectrometry and ultra-performance liquid chromatography. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte. RESULTS: Comparative bioavailability was computed and no drug-drug interactions and no difference in comparative bioavailability were concluded for each ingredient based on point estimates of the T/R ratio of the geometric means falling within 80-125% for peak plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC(t)), and AUC from time zero to infinity (AUC(infinity)). The T/R ratio for C(max), AUC(t) and AUC(infinity) was within 80-125% for atenolol, hydrochlorothiazide, ramipril, ramiprilat and dose-normalized salicylic acid. However, for simvastatin, the T/R point estimates for C(max), AUC(t) and AUC(infinity) for Ln-transformed data were significantly lower ( approximately 3-4%) than the lower bound of 80%. For its active metabolite, simvastatin acid, these estimates were significantly higher ( approximately 25-35%) than the higher bound of 125%. Thus, the increased bioavailability of active simvastatin acid appeared to compensate for the loss of bioavailability of simvastatin. CONCLUSION: The Polycap was found to be effective and safe in the previously published TIPS trial. The present study in healthy volunteers establishes that Polycap is safe (no serious adverse events) and well tolerated, and that there is no indication of pharmacokinetic drug-drug interactions for any of the ingredients, with their bioavailabilities being well preserved.

Enhanced oral bioavailability and brain uptake of Darunavir using lipid nanoemulsion formulation.

The present work aimed to formulate Darunavir loaded lipid nanoemulsion to increase its oral bioavailability and enhance brain uptake. Various batches of lipid nanoemulsion of Darunavir were prepared by high pressure homogenization using soya bean oil, egg lecithin and Tween 80. The optimized batch DNE-3 had globule size of 109.5 nm, zeta potential of -41.1 mV, entrapment efficiency 93% and creaming volume 98%. The batch remained stable at 4 °C for 1 month with an insignificant change in globule size and zeta potential (P > 0.05). In-vivo pharmacokinetics male wistar rats indicated 223% bioavailability of Darunavir relative to drug suspension. Cmax of DNE-3 was twofold higher than suspension form. The organ biodistribution study indicated 2.65 fold higher brain uptake for DNE-3 than that for suspension. The higher bioavailability of Darunavir from nanoemulsion could lessen the dose related side effects. Moreover, high organ distribution results in passive uptake of Darunavir to HIV reservoir organs.

Formulation and evaluation of tacrolimus-loaded galactosylated Poly(lactic-co-glycolic acid) nanoparticles for liver targeting.

OBJECTIVE: The aim of this investigation was to formulate liver targeted tacrolimus-loaded nanoparticles for reducing renal distribution and thereby decreasing nephrotoxicity. METHOD: Poly lactic-co-glycolic acid (PLGA) was galactosylated, and confirmation of galactosylation was performed by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. Tacrolimus-loaded PLGA nanoparticles (Tac-PLGA NP) and galactosylated PLGA nanoparticles (Tac-Gal-PLGA NPs) were prepared by ultrasonic emulsification solvent evaporation technique and characterized. KEY FINDINGS: The size of both the formulations was below 150 nm and negative zeta potential indicated the stability and reticuloendothelial system targeting efficiency. The in-vitro release and pharmacokinetics showed sustained release of tacrolimus from nanoparticles in comparison to plain drug solution. The biodistribution studies revealed the potential of both the nanoparticulate systems to target tacrolimus to the liver for prolonged periods of time compared with the plain drug solution. However, significantly higher liver and spleen targeting efficiency of Tac-Gal-PLGA NPs compared with Tac-PLGA NPs was evident indicating its active targeting. Significantly lower distribution in the kidney from nanoparticles indicated the possibility of reduced nephrotoxicity - the principal reason for patient non-compliance. Both nanoparticles showed stability at refrigerated condition (5°C ± 3°C) upon storage for 1 month. CONCLUSION: Galactosylated PLGA nanoparticles seem to be a promising carrier for liver targeting of tacrolimus.

Gemcitabine hydrochloride-loaded functionalised carbon nanotubes as potential carriers for tumour targeting.

The objective of the present work was to formulate gemcitabine hydrochloride loaded functionalised carbon nanotubes to achieve tumour targeted drug release and thereby reducing gemcitabine hydrochloride toxicity. Multiwalled carbon nanotubes were functionalised using 1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000. Optimised ratio 1:2 of carbon nanotubes:1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000 was taken for loading of gemcitabine hydrochloride. The formulation was evaluated for different parameters. The results showed that maximum drug loading efficiency achieved was 41.59% with an average particle size of 188.7 nm and zeta potential of -10-1 mV. Scanning electron microscopy and transmission electron microscopy images confirmed the tubular structure of the formulation. The carbon nanotubes were able to release gemcitabine hydrochloride faster in acidic pH than at neutral pH indicating its potential for tumour targeting. Gemcitabine hydrochloride release from carbon nanotubes was found to follow Korsmeyer-Peppas kinetic model with non-Fickian diffusion pattern. Cytotoxic activity of formulation on A549 cells was found to be higher in comparison to free gemcitabine hydrochloride. Stability studies indicated that lyophilised samples of the formulation were more stable for 3 months under refrigerated condition than at room temperature. Thus carbon nanotubes can be promising carrier for the anticancer drug gemcitabine hydrochloride.

Design, development and optimization of self-microemulsifying drug delivery system of an anti-obesity drug.

The aim of the present work was to formulate a self-microemulsifying drug delivery system (SMEDDS) containing orlistat. The oil, surfactant and co-surfactant were decided based on the solubility studies. Pseudoternary phase diagrams were plotted, microemulsification area was determined and different formulations were prepared. Particle size, zeta potential, dispersibility test and thermodynamic stability studies were measured. In-vitro dissolution test of thermodynamically stable formulations OS-B and OS-C were carried and results were compared with those of plain drug and suspension formulation. Stability studies performed indicated that formulation OS-C remained stable over 12 months period. Thus this investigation concluded that hydrophobic drugs like orlistat can be delivered effectively through the formulation of SMEDDS.

Physiologically activated phase transition systems for improved ocular retention of ketorolac tromethamine.

In present investigation, novel physiologically activated phase transition systems for Ketorolac Tromethamine was developed. In-situ gelling systems: pH sensitive gel using carbopol 980 and HPMC K100LV, ion sensitive gel using gallan gum and temperature sensitive gel using Poloxamer 407 and Poloxamer 188 were developed. The drug content, content uniformity, pH, optical transmittance, rheological property, bioadhesive strength, in-vitro drug release, ocular irritation and stability study were evaluated. Characterization revealed that gels were conforming to all criteria required for ocular delivery in terms of stability on sterilization, long residence time, non-irritability and sustained drug release without affecting vision. Thus, In-situ gels can be a promising alternative to the prevalent market formulations.