Recent advances in nanomaterial-based drug delivery systems for melanoma therapy.

Background and Purpose: Safe and effective drug delivery is crucial for the treatment of cancer, which is quite impossible to achieve through traditional methods. Among all types of cancer, skin melanoma is known for its aggressive metastasizing ability and an unprecedented higher degree of lethalness, limiting the overall therapeutic efficacy. Here, we focus on the different types of nanomaterials (NMs) and their drug delivery applications against melanoma. Experimental Approach: All relevant publications, including research papers, reviews, chapters and patents, were assessed using search engines such as Scopus and PubMed, up to the end of August of 2023. The keywords used in the search were: nanomaterials, melanoma, drug delivery routes for melanoma, and nanomaterial-based drug delivery systems (DDS). Most of the publications out of 234 cited in this review are from the last five years. Key Results: The recent advancement and mechanism of action of various NMs against melanoma, including inorganic metallic and carbon-based NMs, organic polymeric and lipid-based NMs, and cell-derived vesicles are discussed. We also focus on the application of different NMs in the delivery of therapeutic agents for melanoma therapy. In addition, the skin and melanoma, genetic mutation and pathways for melanoma, conventional treatment options, and delivery routes for therapeutic agents are also discussed briefly. Conclusion: There are few NM-based DDS developed in the lab set up recently. The findings of this review will pave the path for the development of NM-based DDS on an industrial scale and help in the better management of skin melanoma.

QbD enabled optimization of solvent shifting method for fabrication of PLGA-based nanoparticles for promising delivery of Capecitabine for antitumor activity.

The key objective of the current research was to fabricate and optimize Capecitabine (Cap)-loaded [poly(lactic-co-glycolic acid)] PLGA-based nanoparticles (NPs) by enabling quality by design (QbD) approach for enhancing antitumor activity by promising delivery of the drug at the colonic site. The current research was based on fabricating PLGA-based nanoparticles along with Eudragit S100 as enteric polymer employing solvent shifting method followed by optimization using QbD approach. This approach was found to be useful for understanding the multiple factors and their interaction influencing the product by utilizing Design of Experiment (DOE). Box-Behnken design (BBD) was adopted to achieve the required critical quality attributes (CQAs), i.e., minimizing particle size, maximizing entrapment efficiency, and minimizing PDI value. The optimized nanoparticles were lyophilized and characterized by FT-IR, DSC, TEM, DLS, MTT assay using HT-29 cell lines, and in vivo pharmacokinetic studies. The optimized PLGA-based nanoparticles were found to possess average particle size, PDI, zeta potential, and entrapment efficiency of 195 nm, 0.214, -6.65 mV, and 65%, respectively. TEM analysis revealed the spherical nature of nanoparticles. The FT-IR and DSC studies revealed no interaction. The bioavailability of Cap-loaded nanoparticles was found to be two fold increased than the pure drug, and also, it exhibited significantly more cytotoxic to tumor cells as compared to pure drug as confirmed by MTT assay. The optimized PLGA-based nanoparticles found to possess enhanced bioavailability and significantly more cytotoxic potential as compared to pure drug.

An updated review on application of 3D printing in fabricating pharmaceutical dosage forms.

The concept of "one size fits all" followed by the conventional healthcare system has drawbacks in providing precise pharmacotherapy due to variation in the pharmacokinetics of different patients leading to serious consequences such as side effects. In this regard, digital-based three-dimensional printing (3DP), which refers to fabricating 3D printed pharmaceutical dosage forms with variable geometry in a layer-by-layer fashion, has become one of the most powerful and innovative tools in fabricating "personalized medicine" to cater to the need of therapeutic benefits for patients to the maximum extent. This is achieved due to the tremendous potential of 3DP in tailoring various drug delivery systems (DDS) in terms of size, shape, drug loading, and drug release. In addition, 3DP has a huge impact on special populations including pediatrics, geriatrics, and pregnant women with unique or frequently changing medical needs. The areas covered in the present article are as follows: (i) the difference between traditional and 3DP manufacturing tool, (ii) the basic processing steps involved in 3DP, (iii) common 3DP methods with their pros and cons, (iv) various DDS fabricated by 3DP till date with discussing few research studies in each class of DDS, (v) the drug loading principles into 3D printed dosage forms, and (vi) regulatory compliance.

Design of experiments assisted the development of inclusion complexes of ramipril using hydrophilic carriers for enhancement of solubility and dissolution rate

Abstract The goal of the present study was to develop inclusion complexes and polymers dispersions of ramipril prepared by physical mixing, kneading, co-evaporation, and solvent evaporation methods to enhance drug solubility and dissolution rate, and thereby to reduce drug dose and side effects using selected hydrophilic carriers such as β-CD, PVP-K25, PEG 4000, and HPMC K100M. The prepared formulations were characterized for solubility and in-vitro drug release studies. The systematic optimization of formulations was performed using I-Optimal experimental design by selecting factors such as type of carriers (X1), drug: carrier ratio (X2), and method of preparation (X3), and response variables including percent yield (Y1), solubility (Y2), Carr's index (Y3) and drug release in 30 min (Y4). Mathematical modeling was carried out using a quadratic polynomial model. The inclusion complex formulation (F27) was selected as an optimized batch by numerical desirability function and graphical optimization with the help of design space. The inclusion complex prepared by the co-evaporation method showed maximum drug solubility and released in pH 6.8 phosphate buffer compared to pure and other formulations. The inclusion complex is a feasible approach to improve the solubility, dissolution rate, bioavailability, and minimization of drugs' gastrointestinal toxicity upon oral administration of ramipril.

Applications of polysaccharides in topical and transdermal drug delivery: A recent update of literature

Abstract The main aim of transdermal drug delivery (TDD) is to deliver a specific dose of drug across the skin and to reach systemic circulation at a controlled rate. On the other hand skin is the target for topical drug delivery. Mentioned drug delivery systems (DDS) have numerous advantages compared to oral and parenteral routes. Avoidance of first-pass metabolism, prevent drug degradation due to harsh environment of the stomach, allow controlled drug delivery, provide patient compliance, and pain-free administration are a few of them. To achieve all of them, a DDS with suitable polymer is the primary requisite. Based on the recent trends, natural polymers have been more popular in comparison to synthetic polymers because the former possesses favourable properties including nontoxic, biodegradable, biocompatible, low cost, sustainable and renewable resources. In this context polysaccharides, composed of chains of monosaccharides bound together by glycosidic bonds, have been successfully employed to augment drug delivery into and across the skin with various formulations such as gel, membrane, patches, nanoparticles, nanofibres, nanocomposite, and microneedles. In this chapter, various polysaccharides such as cellulose, chitosan, and their semisynthetic derivatives, alginate, pectin, carrageenan etc, were discussed with their diverse topical and TDD applications. In addition, various formulations based on polysaccharides and limitations of polysaccharides were also briefly discussed.

Enhancement of skin permeability with thermal ablation techniques: concept to commercial products.

Traditionally, the skin is considered as a protective barrier which acts as a highly impermeable region of the human body. But in recent times, it is recognized as a specialized organ that aids in the delivery of a wide range of drug molecules into the skin (intradermal drug delivery) and across the skin into systemic circulation (transdermal drug delivery, TDD). The bioavailability of a drug administered transdermally can be improved by several penetration enhancement techniques, which are broadly classified into chemical and physical techniques. Application of mentioned techniques together with efforts of various scientific and innovative companies had made TDD a multibillion dollar market and an average of 2.6 new transdermal drugs are being approved each year. Out of various techniques, the thermal ablation techniques involving chemicals, heating elements, lasers, and radiofrequency (RF) are proved to be more effective in terms of delivering the drug across the skin by disrupting the stratum corneum (SC). The reason behind it is that the thermal ablation technique resulted in improved bioavailability, quick treatment and fast recovery of the SC, and more importantly it does not cause any damage to underlying dermis layer. This review article mainly discussed about various thermal ablation techniques with commercial products and patents in each classes, and their safety aspects. This review also briefly presented anatomy of the skin, penetration pathways across the skin, and different generations of TDD. Graphical abstract.

Design and optimization of film-forming gel of etoricoxib using research surface methodology.

The present investigation is focused on the development of transdermal film-forming gel (FFG) loaded with etoricoxib employing research surface methodology (RSM). Box-Behnken surface design method was used to develop experimental run using different concentrations of etoricoxib, hydroxypropyl methylcellulose (HPMC K100M), and eudragit RL100 as independent variables, and Derringer's optimization tool was employed to optimize best possible formulation. The dependent variables considered in this study were viscosity and drug permeation at 24 h (Q24, µg/cm2). Anti-inflammatory study was performed on Wistar albino rats for 8 h. Skin irritation studies and accelerated stability studies were performed for validated FFG formulations. Quadratic model was found to be best fit model (p < 0.0001) for both the responses. The influence of HPMC concentration on the viscosity was found to be highest whereas concentration of etoricoxib was maximum for Q24. The optimum composition of the FFG was observed to be 4% of etoricoxib, 1.1246% of HPMC, and 0.4% of eudragit. Above composition resulted in viscosity of 1549.5 mPa.s and maximum Q24 of 4639.11 µg/cm2 with desirability 0.918. The in vivo anti-inflammatory study demonstrated better sustained release effect (for 8 h) of optimized FFG compared to orally administered drug suspension. An average irritation score of 0.555 was observed on Draize scoring system. The validated FFG formulation was found to be stable for the 3 months in accelerated conditions. It can be concluded from the above investigations that the validated FFG formulation of etoricoxib is well tolerated and could provide sustained drug release for 8 h. Graphical abstract.

Quality by Design: Concept to Applications.

BACKGROUND: Quality by Design (QbD) is associated with a modern, systematic, scientific and novel approach which is concerned with pre-distinct objectives that not only focus on product, process understanding but also lead to process control. It predominantly signifies the design and product improvement and the manufacturing process in order to fulfill the predefined manufactured goods or final products quality characteristics. It is quite essential to identify the desired and required product performance report, such as Target Product Profile, typical Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQA). METHODS: This review highlighted the concepts of QbD design space, for critical material attributes (CMAs) as well as the critical process parameters that can totally affect the CQAs within which the process shall be unaffected thus, consistently manufacturing the required product. Risk assessment tools and design of experiments are its prime components. RESULTS: This paper outlines the basic knowledge of QbD, the key elements; steps as well as various tools for QbD implementation in pharmaceutics field are presented briefly. In addition to this, quite a lot of applications of QbD in numerous pharmaceutical related unit operations are discussed and summarized. CONCLUSION: This article provides a complete data as well as the roadmap for universal implementation and application of QbD for pharmaceutical products.

Transdermal Evaporation Drug Delivery System: Concept to Commercial Products.

Since two decades or so transdermal route established itself as better alternative to traditional oral route. This is possible due to continuous innovations in transdermal drug delivery (TDD), which not only enables researchers from academia and industry to successfully develop and launch many new pharmaceuticals but also allow to include new classes of drugs that can be developed into transdermal formulations. These successes are achieved due to the use of novel techniques based on either physical or chemical approaches. However, both of these techniques suffer due to their own disadvantages. Comparatively, a simple method of supersaturation to enhance drug permeation across skin has created a new wave of interest. Even though the application supersaturated principle in topical and TDD has been used from 1960s, but proper control of drug release and formation of stable supersaturated states has been the core of intense research in the last decade. Out of various methods used to get supersaturated system, evaporation method is considered as most efficient and practically feasible for TDD. Therefore, in this review concept of supersaturation, selection of solvent system and the mechanism of inhibition of crystallization are discussed. Application of evaporation systems in the development of transdermal formulations such as solutions, semisolids and metered dose therapeutic systems (MDTS) and the commercial evaporative systems are also discussed in this review.

Cross-Linked Hydrogel for Pharmaceutical Applications: A Review.

Hydrogels are promising biomaterials because of their important qualities such as biocompatibility, biodegradability, hydrophilicity and non-toxicity. These qualities make hydrogels suitable for application in medical and pharmaceutical field. Recently, a tremendous growth of hydrogel application is seen, especially as gel and patch form, in transdermal drug delivery. This review mainly focuses on the types of hydrogels based on cross-linking and; secondly to describe the possible synthesis methods to design hydrogels for different pharmaceutical applications. The synthesis and chemistry of these hydrogels are discussed using specific pharmaceutical examples. The structure and water content in a typical hydrogel have also been discussed.

Transdermal delivery of Diltiazem HCl from matrix film: Effect of penetration enhancers and study of antihypertensive activity in rabbit model.

The present investigation focused on the development of Diltiazem HCl (DTH) matrix film and its characterization by in-vitro, ex-vivo and in-vivo methods. Films were prepared by solvent casting method by taking different ratios of hydroxypropyl methylcellulose K4M (HPMC K4M) and Eudragit RS100. Various parameters of the films were analyzed such as mechanical property using tensile tester, interaction study by Fourier transform infrared spectroscopy (FTIR) and Thermogravimetric analysis (TGA), in-vitro drug release through cellulose acetate membrane, ex-vivo permeation study using abdominal skin of rat employing Franz diffusion cell, and in-vivo antihypertensive activity using rabbit model. The FTIR studies confirmed the absence of interaction between DTH and selected polymers. Thermal analysis showed the shifting of endothermic peak of DTH in film, indicating the dispersion of DTH in molecular form throughout the film. Incorporation of 1,8-cineole showed highest flux (89.7 µg/cm(2)/h) of DTH compared to other penetration enhancers such as capsaicin, dimethyl sulfoxide (DMSO), and N-methyl pyrrolidone (NMP). Photomicrographs of histology study on optimized formulation (DF9) illustrated disruption of stratum corneum (SC) supporting the ex-vivo results. The in-vivo antihypertensive activity results demonstrated that formulation DF9 was effective in reducing arterial blood pressure in normotensive rabbits. SEM analysis of films kept for stability study (40 ± 2 °C/75% ± 5%RH for 3 months) revealed the formation of drug crystals which may be due to higher temperature. The findings of the study provide a better alternative dosage form of DTH for the effective treatment of hypertension with enhanced patient compliance.

Pluronic lecithin organogel (PLO) of diltiazem hydrochloride: effect of solvents/penetration enhancers on ex vivo permeation.

In the present study, pluronic lecithin organogel (PLO) of diltiazem hydrochloride (DZH) was developed by taking different ratios of organic phase to aqueous phase (1:3, 1:4, and 1:5) with varying concentration of soya lecithin (20, 30, and 40 % w/w) in organic phase (isopropyl myristate, IPM) and pluronic (20, 25, and 30 % w/w) in aqueous phase, respectively, and characterized for in vitro parameters and ex vivo permeation study. The results of in vitro parameters were found to be within permissible limit and all the PLOs were physically stable at refrigeration and ambient temperature. The influence of phase ratio and different concentrations of soya lecithin on DZH release from the PLOs was found to be significant (p < 0.05), whereas the influences of different concentrations of pluronic were insignificant. The effect of different solvents/penetration enhancers viz. IPM, propylene glycol (PG), dimethyl sulphoxide (DMSO), and D-limonene, in combination and alone, on the permeation of DZH across the dorsal skin of rat was studied. Among all, formulation containing IPM (PLO6) exhibited highest flux of 147.317 µg/cm(2)/h. Furthermore, histopathology section of treated skin sample illustrated that lipid bilayer disruption was the mechanism for the DZH permeation. The above results indicated that PLO6 may serve as a promising alternative delivery system for DZH in the effective treatment of hypertension.

Application of Response Surface Methodology for Design and Optimization of Reservoir-type Transdermal Patch of Simvastatin.

The objective of the present investigation was to develop and optimize reservoir-type of transdermal drug delivery system of Simvastatin using response surface methodology. A total of 17 experimental runs were conducted according to three-factor, three-level Box-Behnken design employing Design expert®2 software to determine the effect of independent variables (simvastatin concentration, percentage of poloxamer 407, and concentration of D-limonene) on cumulative amount of simvastatin permeation through human cadaver skin in 48 h (dependent variable). The experimental data was fitted to different response surface models using multiple regression analysis and observed quadratic model was the best fit model with significant p-value (p꞊0.0003) and coefficient of determination value of 0.9949. The second-order polynomial equation and response surface plots indicated the significant influence of concentration of simvastatin and D-limonene on the simvastatin permeation in 48 h. The highest simvastatin permeation value of 76.94 µg/cm2 was observed in case of experimental number 10 with 1.5% (w/w) of simvastatin, 25% (w/w) of poloxamer 407, and 10% (w/w) of D-limonene. Using Derringer's desirability functional tool for optimization, the highest simvastatin permeation value of 78.7684 µg/cm2 in 48 h was predicted under optimum condition of; simvastatin concentration of 1.4893% (w/w), poloxamer 407 percentage of 22.43% (w/w), and D-limonene concentration of 9.8541% (w/w) with optimum desirability value. The in-vivo hypolipidemic study conducted for 14 days in hyperlipidemia induced Sprague-Dawley rats revealed that the optimized patch exhibited significant lowering of blood lipid profile. Finally, histology study was performed on skin sample used in permeation study of optimized formulation and compared with untreated skin sample. The treated skin sample showed a significant distortion in stratum corneum, which supported the ex-vivo permeation result. Thus, the patch may serve as an alternative therapy to oral dosage form of simvastatin with outmost patient compliance.

Formulation optimization and characterization of transdermal film of simvastatin by response surface methodology.

Matrix type of simvastatin transdermal film (SSTF) was developed with poly(vinyl alcohol) (PVA) and eudragit RL100 (EG) using response surface methodology (RSM) to investigate combined effect of the selected process variables like SS concentration, PVA:EG ratio and the dibutyl phthalate (DBT) concentration at different levels on dependent variables such as tensile strength and flux, with an aim to optimize a suitable combination of drug, polymer and plasticizer ratio. The study reveals that the effect of DBT concentration was highest on tensile strength, while SS concentration exhibited pronounced effect on SS flux through the abdominal skin of rat. According to Derringer's desirability prediction tool, the composition of optimized film was found to be 2% of SS, 2:1 ratio of PVA:EG and 40% of DBT. Under these conditions, the SSTF exhibited a predicted value of tensile strength and flux of 11.871 MPa and 43.569 µg/cm(2)/h, respectively. The in vivo hypolipidemic study conducted for 14 days in hyperlipidemia induced Sprague-Dawley rats reveals that the optimized SSTF exhibited significant lowering of blood lipid level. The absence of skin irritation indicates that the prepared film was safe and well tolerated as transdermal formulation. Thus, the film may serve as an alternative therapy to oral dosage form of SS.

Physical means of stratum corneum barrier manipulation to enhance transdermal drug delivery.

Since the approval of first transdermal patch (Transderm Scop(®)) containing scopolamine in 1979, the improvement in systemic drug delivery through skin remains incremental. The traditional methods based on passive diffusion of drug molecules in to the skin are unable to deliver macromolecules, such as peptides, proteins, DNA and vaccines, due to the barrier properties of stratum corneum (SC). During the course of approximately 35 years, the focuses are not only to overcome the above barrier property of the skin but also the safety, accuracy and patient compliance aspect of the traditional methods. The former limitation can be overcome by altering the SC barrier function by different active methods such electrically assisted methods (sonophoresis, iontophoresis, electroporation, magnetophoresis, pressure waves, electron beam irradiation), SC abruption (microneedles, high-velocity jet) and SC removal (tape-stripping, suction, microdermabrasion, ablation). This review summarizes basic principles, mechanisms, advantages, limitations and recent development of above physical techniques along with skin anatomy and drug transport pathways across skin.

Preparation and characterization of solid lipid nanoparticles-a review.

In the present scenario, most of the developed and new discovered drugs are posing real challenge to the formulation scientists due to their poor aqueous solubility which in turn is responsible for poor bioavailability. One of the approach to overcome above problem is the packaging of the drug in to particulate carrier system. Among various carriers, lipid emerged as very attractive candidate because of its unique property of enhancing the bioavailability of poorly water soluble drugs. Solid lipid, one of the physical forms of lipid, is used to formulate nanoparticles, popularly known as Solid lipid nanoparticles (SLNs), as an alternative carrier system to emulsions, liposomes and polymeric micro- and nano-particles. SLNs combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews numerous production techniques for SLNs along with their advantages and disadvantages. Special attention is paid to the characterization of the SLNs by using various analytical tools. It also emphasizes on physical state of lipid (supercooled melts, different lipid modifications).

Novel penetration enhancers for skin applications: a review.

The use of topical formulation is popular over the past decade due to extensive researches made in the field of transdermal drug delivery. As a result, an increasing number of drugs are being added to the list of therapeutic agents that can be delivered to systemic circulation through the skin. Commonly available dosage forms for the topical application are creams, ointments, gels, patches etc. The therapeutic benefits of the above topical formulations are limited due to barrier property of stratum corneum (SC). The use of chemical penetration enhancers (CPEs) is one of the long standing approach to overcome the barrier property of SC. Numerous class of novel compounds have been evaluated for penetration enhancement activity, including soft enhancement for percutaneous absorption (SEPA), for example, 2 N-nonyl-1,3- dioxolanes, N-acetyle prolinate esters (such as pentyl- and octyl-N-acetyle prolinate), alkyldiloxanes (e.g., 1-Alkyl-3-b-D glucopyranosyl-1,1,3,3-tetramethyl disiloxanes), transcarbam (such as 5-(dodecyloxycarbonyl) pentylammonium-5- (dodecyloxycarbonyl) pentylcarbamate), iminosulfurane (like N-hexyl,N-benzoyl-S,S-dimethylimino-sulfuranes), capsaicin derivatives (e.g., Nonivamide), cinnamene compounds (such as cinnamic acid, cinnamaldehyde etc), terpenes (like clove and basil oil) and synergestic combination of penetration enhancers (SCOPE). We briefly describe about the anatomy of skin. Potential mechanisms of action of above novel PEs along with adverse reactions associated with traditional PEs are also considered in this review.

Formulation of topical bioadhesive gel of aceclofenac using 3-level factorial design.

The objective of this work was to develop bioadhesive topical gel of Aceclofenac with the help of response-surface approach. Experiments were performed according to a 3-level factorial design to evaluate the effects of two independent variables [amount of Poloxamer 407 (PL-407 = X1) and hydroxypropylmethyl cellulose K100 M (HPMC = X2)] on the bioadhesive character of gel, rheological property of gel (consistency index), and in-vitro drug release. The best model was selected to fit the data. Mathematical equation was generated by Design Expert® software for the model which assists in determining the effect of independent variables. Response surface plots were also generated by the software for analyzing effect of the independent variables on the response. Quadratic model was found to be the best for all the responses. Both independent variable (X1 and X2) were found to have synergistic effect on bioadhesion (Y1) but the effect of HPMC was more pronounced than PL-407. Consistency index was enhanced by increasing the level of both independent variables. An antagonistic effect of both independent variables was found on cumulative percentage release of drug in 2 (Y3) and 8 h (Y4). Both independent variables approximately equally contributed the antagonistic effect on Y3 whereas antagonistic effect of HPMC was more pronounced than PL-407. The effect of formulation variables on the product characteristics can be easily predicted and precisely interpreted by using a 3-level factorial experimental design and generated quadratic mathematical equations.