QbD-Based Development and Evaluation of Pazopanib Hydrochloride Extrudates Prepared by Hot-Melt Extrusion Technique: In Vitro and In Vivo Evaluation.

BACKGROUND: Pazopanib hydrochloride (PZB) is a protein kinase inhibitor approved by the United States Food and Drug Administration and European agencies for the treatment of renal cell carcinoma and other renal malignancies. However, it exhibits poor aqueous solubility and inconsistent oral drug absorption. In this regard, the current research work entails the development and evaluation of the extrudates of pazopanib hydrochloride by the hot-melt extrusion (HME) technique for solubility enhancement and augmenting oral bioavailability. RESULTS: Solid dispersion of the drug was prepared using polymers such as Kollidon VA64, hydroxypropylmethylcellulose (HPMC), Eudragit EPO, and Affinisol 15LV in a 1:2 ratio by the HME process through a lab-scale 18 mm extruder. Systematic optimization of the formulation variables was carried out with the help of custom screening design (JMP Software by SAS, Version 14.0) to study the impact of polymer type and plasticizer level on the quality of extrudate processability by measuring the torque value, appearance, and disintegration time as the responses. The polymer blends containing Kollidon VA64 and Affinisol 15LV resulted in respective clear transparent extrudates, while Eudragit EPO and HPMC extrudates were found to be opaque white and brownish, respectively. Furthermore, evaluation of the impact of process parameters such as screw rpm and barrel temperature was measured using a definitive screening design on the extrude appearance, torque, disintegration time, and dissolution profile. Based on the statistical outcomes, it can be concluded that barrel temperature has a significant impact on torque, disintegration time, and dissolution at 30 min, while screw speed has an insignificant impact on the response variables. Affinisol extrudates showed less moisture uptake and faster dissolution in comparison to Kollidon VA64 extrudates. Affinisol extrudates were evaluated for polymorphic stability up to a 3-month accelerated condition and found no recrystallization. PZB-Extrudates using the Affinisol polymer (Test formulation A) revealed significantly higher bioavailability (AUC) in comparison to the free Pazopanib drug and marketed formulation.

Therapeutic Application of Microsponges-based Drug Delivery Systems.

Microsponges delivery systems (MDS) are highly porous, cross-linked polymeric systems that activate due to temperature, pH, or when rubbed. MDS offer a wide range of advantages, like controlled drug release, site-specific action, stability over a broad range of pH, less irritation, cost-effectiveness, and improved patient compliance. They can be transformed into various dosage forms like creams, gels, and lotions. MDS are suitable for the treatment of topical disorders like acne, psoriasis, dandruff, eczema, scleroderma, hair loss, skin cancer, and other dreadful diseases. The applications of MDS in drug delivery are not limited to topical drug delivery but are also explored for oral, parenteral, and pulmonary drug deliveries. Microsponges have been studied for colon targeting of drugs and genes. Additionally, MDS have several applications such as sunscreen, cosmetics, and over-the-counter (OTC) products. Furthermore, MDS do not actuate any irritation, genotoxicity, immunogenicity, or cytotoxicity. Therefore, this review extensively highlights microsponges, their advantages, key factors affecting their characteristics, their therapeutic applications in topical disorders and in cancer, their use as cosmetics, as well as recent advances in MDS and the associated challenges.

UPLC-MS/MS Method Validation for Estimation of Resveratrol in Rat Skin from Liposphere Gel Formulation and Its Application to Dermatokinetic Studies in Rats.

For the quantification of resveratrol (RV) in the Wistar rat skin, an ultra-performance liquid chromatography-mass spectrometric (UPLC-MS/MS) method was developed and validated on ACQUITY UPLC BEH C18 column (1.7 µm). The mobile phase ratio of methanol (A) and 2% formic acid (B) (ratio 10: 90% v/v, 80: 20 v/v) at isocratic elution with flow rate 0.3 mL/min, and run time 3 min was used for analysis. In addition, the use of multiple reaction monitoring (MRM)/ES+ mode to detect the analytes and to track parents to daughter ion transition of 229.17 > 107.04 m/z (time scan 3 min, retention time 1.48) for RV and curcumin as an internal standard shows 369.16 > 176.93m/z (scan time is 2.80 min, retention time is 1.11), respectively. Linearity was observed in the range of 2.5 to 2,000 ng/mL (R2 = 0.987). Precision and accuracy on rat skin were within the acceptability range (RE%: ±15; RSD%: ±15). Moreover, it showed a good percentage recovery and found within acceptance limit 90-110%. Lower limit of detection and quantitation for the method observed to be 2.5 and 20 ng.mL-1, respectively. Method application indicated successful determination of dermatokinetics parameters of RV from lipospheres gel and suspension in the rats.

Crotamiton-loaded tea tree oil containing phospholipid-based microemulsion hydrogel for scabies treatment: in vitro, in vivo evaluation, and dermatokinetic studies.

Crotamiton (CRT) is a commonly approved drug prescribed for the scabies treatment in many countries across the globe. However, poor aqueous solubility and low bioavailability, and side effects restrict its use. To avoid such issues, an appropriate carrier system is necessary which can address the aforementioned challenges for attaining enhanced biopharmaceutical attributes. The current study intends to provide a detailed account on the development and evaluation of CRT-loaded microemulsion (ME) hydrogel formulation containing tea tree oil (TTO) for improved drug delivery for scabies treatment in a safe and effective manner. Pseudo-ternary phase diagrams were constructed with TTO as the oily phase, and Cremophor®EL was used as the surfactant in a mass ratio 2:1 with co-surfactants (mixture of phospholipid 90G and Transcutol®P), and aqueous solution as the external phase. The optimized drug-loaded ME formulation was evaluated for skin penetration, retention, compliance, and dermatokinetics. The nonirritant behavior of the formulation was revealed by skin histopathology, which showed no changes in normal skin histology. In comparison to the conventional product, dermatokinetic experiments revealed that CRT has greater penetration and distribution in the epidermis of the mice skin. The findings imply that the proposed lipid-based ME hydrogel can aid in the resolution of CRT issues by providing a better and safer delivery option to epidermis and deeper epidermis in substantial quantities.

Systematic development of lectin conjugated microspheres for nose-to-brain delivery of rivastigmine for the treatment of Alzheimer's disease.

The current study focuses on development of nasal mucoadhesive microspheres for nose-to-brain delivery of rivastigmine for Alzheimer treatment. A systematic development was employed for optimization of the formulation and process parameters influential on the quality attributes of the microspheres. The risk assessment study revealed major influence of the polymer concentration (ethylcellulose: chitosan), the concentration of surfactant solution (polyvinyl alcohol), and stirring speed as the critical factors for optimization of the microspheres. These factors were systematically optimized using Box-Behnken design and microspheres were evaluated for the particle size, entrapment efficiency, and in vitro drug release as the response variables. The optimized microspheres containing 4.4% wt/vol polymers, 1% wt/vol surfactant, and stirring speed at 1500 rpm showed particle size of 19.9 µm, entrapment efficiency of 77.8%, and drug release parameters as T80% of 7.3 h. The surface modification of microspheres was performed with lectin by carbodiimide activation reaction and confirmed by difference in surface charge before and after chemical functionalization by zeta potential measurement which was found to be - 25.7 mV and 20.5 mV, respectively. Ex vivo study for bioadhesion strength evaluation on goat nasal mucosa indicated a significant difference (p < 0.001) between the plain (29%) and lectin functionalized microspheres (64%). In vivo behavioral and biochemical studies in the rats treated with lectin functionalized microspheres showed markedly better memory-retention vis-à-vis test and pure drug solution treated rats (p < 0.001). In a nutshell, the present studies showed successful development of nasal microspheres for enhanced brain delivery of rivastigmine for Alzheimer's treatment.

Paclitaxel and naringenin-loaded solid lipid nanoparticles surface modified with cyclic peptides with improved tumor targeting ability in glioblastoma multiforme.

The present work describes the systematic development of paclitaxel and naringenin-loaded solid lipid nanoparticles (SLNs) for the treatment of glioblastoma multiforme (GBM). So far only temozolomide therapy is available for the GBM treatment, which fails by large amount due to poor brain permeability of the drug and recurrent metastasis of the tumor. Thus, we investigated the drug combination containing paclitaxel and naringenin for the treatment of GBM, as these drugs have individually demonstrated significant potential for the management of a wide variety of carcinoma. A systematic product development approach was adopted where risk assessment was performed for evaluating the impact of various formulation and process parameters on the quality attributes of the SLNs. I-optimal response surface design was employed for optimization of the dual drug-loaded SLNs prepared by micro-emulsification method, where Percirol ATO5 and Dynasan 114 were used as the solid lipid and surfactant, while Lutrol F188 was used as the stabilizer. Drug loaded-SLNs were subjected to detailed in vitro and in vivo characterization studies. Cyclic RGD peptide sequence (Arg-Gly-Asp) was added to the formulation to obtain the surface modified SLNs which were also evaluated for the particle size and surface charge. The optimized drug-loaded SLNs exhibited particle size and surface charge of 129 nm and 23 mV, drug entrapment efficiency >80% and drug loading efficiency >7%. In vitro drug release study carried out by micro dialysis bag method indicated more than 70% drug was release observed within 8 h time period. In vivo pharmacokinetic evaluation showed significant improvement (p < 0.05) in drug absorption parameters (Cmax and AUC) from the optimized SLNs over the free drug suspension. Cytotoxicity evaluation on U87MG glioma cells indicated SLNs with higher cytotoxicity as compared to that of the free drug suspension (p < 0.05). Evaluation of uptake by florescence measurement indicated superior uptake of SLNs tagged with dye over the plain dye solution. Overall, the dual drug-loaded SLNs showed better chemoprotective effect over the plain drug solution, thus construed superior anticancer activity of the developed nanoformulation in the management of glioblastoma multiforme.

Novel therapeutic interventions in cancer treatment using protein and peptide-based targeted smart systems.

Cancer, being the most prevalent and resistant disease afflicting any gender, age or social status, is the ultimate challenge for the scientific community. The new generation therapeutics for cancer management has shifted the approach to personalized/precision medicine, making use of patient- and tumor-specific markers for specifying the targeted therapies for each patient. Peptides targeting these cancer-specific signatures hold enormous potential for cancer therapy and diagnosis. The rapid advancements in the combinatorial peptide libraries served as an impetus to the development of multifunctional peptide-based materials for targeted cancer therapy. The present review outlines benefits and shortcomings of peptides as cancer therapeutics and the potential of peptide modified nanomedicines for targeted delivery of anticancer agents.

Functionalized mesoporous silica nanoparticles in anticancer therapeutics.

The application of nanomedicines in tumor targeting and attaining meaningful therapeutic benefits for the treatment of cancers has been going on for almost two decades. Beyond the lipidic and polymeric nanomedicines-based passive and active targeting, the quest for inventing the new generation of carriers has no end. This has lead to the evolution of some of the unique carrier systems with supramolecular assembly structures. Mesoporous nanoparticulate systems (MSNPs) are the recently explored substances with favorable potential for drug delivery and drug targeting applications especially in cancer chemotherapeutics. Notwithstanding their physical properties that makes them a suitable carrier for cancer treatment, but their outstanding ability towards chemical functionalization helps in delivering the imaging agents for diagnostic applications. MSNPs can improve the dissolution rate and systemic availability of the poorly water soluble drugs due to their mesoporous structures. Besides, guest molecules including targeting ligands, biomimetic agents, fluorescent dyes, and biocompatible polymers can be efficiently encapsulated in their tunable porous structure for targeting purpose. Some special features of the MSNPs which make them one of the highly effective nanocarrier systems include their ability to encapsulate non-crystalline drugs in their mesopores, high dispersion ability as a function of large surface area and wetting properties. For anticancer drug delivery, MSNPs are worthful to provide excellent drug loading capacity and endocytotic behavior. Moreover, the external surface of MSNPs can be precisely modified for tumor-recognition and developing sensitivity of the antitumor agents towards the cancer cells. Owing to the innumerable applications of MSNPs till now in cancer treatment, the present article particularly focuses to provide an overview account with complete details on the topic to make the readers abreast with details on physiochemical and material properties of MSNPs, their applications and current innovations for the purpose.

Nanomedicinal strategies as efficient therapeutic interventions for delivery of cancer vaccines.

The applications of gene therapy-based treatment of cancers were started almost two decades back as a boon over the chemotherapeutic treatment strategies. Gene therapy helps in correcting the genetic sequences for treatment of cancers, thus also acts like a vaccine to induce the cellular and humoral immunity. However, the cancer vaccines typically suffer from a series of biopharmaceutical challenges due to poor solubility, low systemic availability and lack of targeting ability. Owing to these challenges, the physicians and pharmaceutical scientists have explored the applications of nanocarriers as quite promising systems for effective treatment against the tumors. A series of nanotherapeutic systems are available to date for diverse drug therapy applications. Systematic understanding on the preparation, evaluation and application of nanomedicines as a carrier system for delivering the cancer vaccines is highly important. The present review article provides an in-depth understanding on the challenges associated with cancer vaccine delivery and current opportunities with diverse nanomedicinal carriers being available for treatment of cancers.