Browsing by Author "Singhvi, Gautam"

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Advanced Solid Oral Controlled-Release Formulations
(Elsevier, 2021) Singhvi, Gautam
Oral controlled release dosage forms have gained attention due to their numerous advantages that can overcome the limitations associated with conventional solid oral preparation to achieve the desired therapeutic efficacy. The pharmaceutical industry has extended patent lives through innovative repositioning and reformulation of existing drugs moieties. This has resulted in significant growth of the drug delivery market over the past few years. Advanced solid oral dosage forms belonging to the categories of gastro-retentive systems, pulsatile drug release, multiparticulate drug delivery systems, osmotic systems, colon-targeted systems, hydrodynamically balanced systems, and feedback-regulated drug delivery systems have been investigated extensively and have successfully hit the market. Patented technologies such as osmotic controlled-release oral delivery systems, liquid osmotic system, oral controlled absorption system, TIMERx, spheroidal oral drug absorption system, intestinal protective drug absorption system, and chronotherapeutic oral drug absorption system were also developed for targeting various parts of the gastrointestinal tract. This chapter discusses the factors influencing the fabrication of oral controlled formulations, mechanisms of drug release from oral controlled formulations, and their classification. With the upcoming automation in the pharma industry, ultra-long acting and 3D printing-based oral controlled preparation would be developed with better safety, efficacy, and lower cost, thereby benefitting the society at large.
Alginate: Drug Delivery and Application
(Taylor & Francis, 2021-03) Singhvi, Gautam
This new volume explores the latest research on the use of alginate as a biopolymer in various biomedical applications and therapeutics. The uses of alginates and modified alginates discussed in this book include tissue regeneration, encapsulation and delivery of drugs, nucleic acid materials, proteins and peptides, genes, herbal therapeutic agents, nutraceuticals, and more. This book also describes the synthesis and characterizations of various alginate and modified alginate systems, such as hydrogels, gels, composites, nanoparticles, scaffolds, etc., used for the biomedical applications and therapeutics. Alginate, a biopolymer of natural origin, is of immense interest for its variety of applications in pharmaceuticals (as medical diagnostic aids) and in materials science. It is the one of the most abundant natural biopolymers and is considered an excellent excipient because of its non-toxic, stable, and biodegradable properties. Several research innovations have been made on applications of alginate in drug delivery and biomedicines. There needs to be a thorough understanding of the synthesis, purification, and characterization of alginates and its derivatives for their utility in healthcare fields, and this volume offers an abundance of information toward that end.
Antibody–Drug Conjugates: Development and Applications
(Wiley, 2022-11) Taliyan, Rajeev; Singhvi, Gautam
Antibody–drug conjugates (ADCs) are relatively newly developed treatments but rapidly growing science. Theoretically, they are like a combination of payload (the drug that is to be delivered; often cytotoxic) and targeted drug-delivery system. In this type of system, the cytotoxic drug undergoes conjugation with a monoclonal antibody via a chemical linker. The fundamental design of ADCs imparts desired properties to the delivery system, such as physiochemical strength, biodegradable nature, and biocompatibility. This plays a crucial role in the management of diseases via offering numerous benefits, such as high drug loading, less incidence of adverse effects, site-specific release, and longer circulation time in the body. In this review, the recent advancements in the preparation of ADCs (including recently approved ADCs), pharmacokinetics, their applications, and regulatory consideration have been summarized. Further, it also provides a discussion on the future status of this therapy for the treatment and management of oncological conditions.
Application of QbD Principles in Nanocarrier-Based Drug Delivery Systems
(Elsevier, 2019) Singhvi, Gautam
Development of nanomedicines has become an attractive strategy in the delivery of therapeutics to overcome the problems associated with conventional therapy especially for cancer, skin infections, tuberculosis, and other long-term disorders. Preparation of nanocarriers includes multiple constituents and multiple steps which need to be understood in-depth. It is expected that the application of quality by design (QbD) approach can overcome the existing issues related to nanoformulation development and can provide wider acceptability for regulatory agencies to form constructive guidelines for their approval. The objective of QbD in nanocarrier drug delivery is to derive meaningful product specifications based on safety, efficacy, and clinical performance. It helps in investigation of variable factors with respect to materials and process involved and ultimately enhances the process capability with minimum product variability. This book chapter has compiled various QbD components which can be easily implemented for preparation and optimization of robust nanoformulations.
Applications of 3D printing for the advancement of oral dosage forms
(Elsevier, 2020) Singhvi, Gautam
Three-dimensional (3D) printing was first described by Charles Hull in 1986. Three-dimensional printing is a unique technology for manufacturing 3D solid objects by deposition of many thin layers using computer-aided drafting technology and programming. Three-dimensional printing comprises a range of different technologies, such as fused deposition modeling, pressure-assisted microsyringes, stereolithography, and selective laser sintering. Compared with the traditional process of dosage form manufacturing, 3D printing can create robust, facile, and more complex products using a single manufacturing method. Moreover, 3D printing allows customized medications for individual patients with specialized medical needs. Based on the advantages offered by 3D printing, it became one of the latest interests for pharmaceutical and biomedical research which reflects in the increasing number of patents and scientific reports. Recently, in 2015, the USFDA has approved the first 3D-printed orally disintegrating tablet Spritam (levetiracetam) for the treatment of seizures in patients with epilepsy. Existing complex solid oral dosage form manufacturing technology combined with 3D printing has been studied for product development with several advantages. This chapter will provide an overview of 3D printing technology with detailed discussion on 3D printing methods applied to drug product manufacturing and will discuss the recent advances in 3D printing technology that affect drug product development.
Apremilast loaded lyotropic liquid crystalline nanoparticles embedded hydrogel for improved permeation and skin retention: An effective approach for psoriasis treatment
(Elsevier, 2023-06) Singhvi, Gautam; Roy, Aniruddha
The present work aimed to prepare and evaluate Apremilast loaded lyotropic liquid crystalline nanoparticles (LCNPs) formulation for skin delivery to enhance the efficacy with reduced adverse effects of the oral therapy in psoriasis treatment. The LCNPs were prepared using the emulsification using a high shear homogenizer for size reduction and optimized with Box Behnken design to achieve desired particle size and entrapment efficiency. The selected LCNPs formulation was evaluated for in-vitro release, in-vitro psoriasis efficacy, skin retention, dermatokinetic, in-vivo skin retention, and skin irritation study. The selected formulation exhibited 173.25 ± 2.192 nm (polydispersity 0.273 ± 0.008) particle size and 75.028 ± 0.235% entrapment efficiency. The in-vitro drug release showed the prolonged-release for 18 h. The ex-vivo studies revealed that LCNPs formulation exhibited drug retention up to 3.2 and 11.9-fold higher, in stratum corneum and viable epidermis compared to conventional gel preparation. In-vitro cell line studies performed on immortal keratinocyte cells (HaCaT cells) demonstrated non-toxicity of selected excipients used in designed LCNPs. The dermatokinetic study revealed the AUC0–24 of the LCNPs loaded gel was 8.4 fold higher in epidermis and 2.06 fold in dermis, respectively compared to plain gel. Further, in-vivo animal studies showed enhanced skin permeation and retention of Apremilast compared to conventional gel.
Bioanalytical methodologies for clinical investigation of endocrine-disrupting chemicals: a comprehensive update
(Future Science Group, 2021-01) Taliyan, Rajeev; Singhvi, Gautam
Endocrine-disrupting chemicals (EDCs) are xenobiotics that disrupt the endocrine system in humans at ecologically significant concentrations. Various substances are exposed to human health via routes including food, water, air and skin that result in disastrous maladies at low doses as well. Therefore EDCs need a meticulous strategy of analysis for dependable and consistent monitoring in humans. The management and risk assessment necessitate advancements in the detection methodologies of EDCs. Hyphenated MS-based chromatograph and other validated laboratory analysis methods are widely available and employed. Besides, in vitro bioassay techniques and biosensors are also used to conduct accurate toxicological tests. This article provides a revision of various bioanalytical detection methods and technologies for the clinical estimation of EDCs.
CD44 receptor-targeted novel drug delivery strategies for rheumatoid arthritis therapy
(Taylor & Francis, 2021-07) Singhvi, Gautam
Rheumatoid arthritis (RA) is a chronic systemic inflammatory condition that mainly affects the lining of the synovial joints. It can progressively cause disability and even premature death. Moreover, it is associated with substantial socioeconomic burdens [Citation1]. Currently, RA affects more than 23 million people globally, including 12.6 million Indians [Citation1]. Recent findings have suggested the involvement of genetic factors in the development of RA. The HLA-DRB1 alleles that code shared epitopes (conserved sequence of amino acids in positions 70–74 of HLA-DRβ chains) are associated with the structural severity of RA. It was reported that more than 80% of the RA-affected individuals carry the HLA-DRB1*04 cluster, in which *04 signifies the allele group which corresponds to the serological type [Citation1]
Chitosan-based microneedles as a potential platform for drug delivery through the skin: Trends and regulatory aspects
(Elsevier, 2021-08) Singhvi, Gautam
Microneedles (MNs) fabrication using chitosan has gained significant interest due to its ability of film-forming, biodegradability, and biocompatibility, making it suitable for topical and transdermal drug delivery. The presence of amine and hydroxyl functional groups on chitosan permits the modification with tunable properties and functionalities. In this regard, chitosan is the preferred material for fabrication of MNs because it does not produce an immune response in the body and can be tailored as per required strength and functionalities. Therefore, many researchers have attempted to use chitosan as a drug delivery vehicle for hydrophilic drugs, peptides, and hormones. In 2020, the FDA has issued “Regulatory Considerations for Microneedling Products”. This official guidance is a sign for future opportunities in the development of MNs. The present review focuses on properties, and modifications of chitosan used in the fabrication of MNs. The therapeutic and diagnostic applications of different types of chitosan-based MNs have been discussed. Further, the regulatory aspects of MN-based devices, and patents related to chitosan-based MNs are discussed.
Curcumin loaded nanostructured lipid carriers for enhanced skin retained topical delivery: optimization, scale-up, in-vitro characterization and assessment of ex-vivo skin deposition
(Elsevier, 2020-09) Singhvi, Gautam; Roy, Aniruddha
Nanostructured lipid carriers (NLC) have become a promising drug delivery system for topical delivery of drugs. Delivery of lipophilic drugs with improved stability and entrapment efficiency is one of the foremost benefits of NLC based formulations. The objective of the present study was to improve the permeation of poorly soluble curcumin into topical skin layers for the treatment of chronic inflammatory disorder psoriasis and microbial mediated acne vulgaris. Hot emulsification followed by probe sonication method was employed for the preparation of the curcumin loaded NLC. Further, in-vitro and ex-vivo characterization was performed for designed NLC. The designed NLC showed a mean particle size 96.2 ± 0.9 nm, entrapment efficiency of 70.5 ± 1.65% and zeta potential of -15.2 ± 0.566 mV. Curcumin-NLC showed extended in-vitro release upto 48 hours, whereas free curcumin showed 100% drug release within 4 hours. Ex-vivo skin permeation studies revealed 3.24 fold improved permeation and skin retention in the case of curcumin loaded NLC gel compared to free curcumin gel. The cell viability studies demonstrated the formulation components showed no toxicity towards keratinocyte cells. In keratinocyte cells, improved cell uptake was observed for curcumin-NLC compared to free curcumin dispersion. The results suggested that the NLC based formulation had potential to improve the efficacy of curcumin.
Dermatokinetic assessment of luliconazole-loaded nanostructured lipid carriers (NLCs) for topical delivery: QbD-driven design, optimization, and in vitro and ex vivo evaluations
(Springer, 2021-04) Singhvi, Gautam
The present study is concerned with the QbD-based design and development of luliconazole-loaded nanostructured lipid carriers (NLCs) hydrogel for enhanced skin retention and permeation. The NLCs formulation was optimized employing a 3-factor, 3-level Box-Behnken design. The effect of formulation variable lipid content, surfactant concentration, and sonication time was studied on particle size and % EE. The optimized formulation exhibited particle size of 86.480 ± 0.799 nm; 0.213 ± 0.004 PDI, ≥ − 10 mV zeta potential and 85.770 ± 0.503% EE. The in vitro release studies revealed sustained release of NLCs up to 42 h. The designed formulation showed desirable occlusivity, spreadability (0.748 ± 0.160), extrudability (3.130 ± 1.570), and the assay was found to be 99.520 ± 0.890%. The dermatokinetics assessment revealed the Cmax Skin to be ~ 2-fold higher and AUC0–24 to be ~ 3-fold higher in the epidermis and dermis of NLCs loaded gel in contrast with the marketed cream. The Tmax of both the formulations was found to be 6 h in the epidermis and dermis. The obtained results suggested that luliconazole NLCs can serve as a promising formulation to enhance luliconazole’s antifungal activity and also in increasing patient compliance by reducing the frequency of application.
Design and dermatokinetic evaluation of Apremilast loaded nanostructured lipid carriers embedded gel for topical delivery: A potential approach for improved permeation and prolong skin deposition
(Elsevier, 2021-10) Singhvi, Gautam; Roy, Aniruddha
The present study aimed to develop Apremilast loaded nanostructured lipid carriers (NLCs) for topical delivery to overcome the limitations of oral therapy and increase the efficacy. Apremilast loaded NLCs were prepared by hot emulsification technique. The developed formulation was optimized by Box Behnken design and characterized for size, entrapment efficiency, and zeta potential. The selected formulation was investigated for in-vitro release, ex-vivo skin retention, dermatokinetic, psoriasis efficacy, in-vivo skin retention and skin irritation study. The NLCs characterization results showed its spherical shape with the particle size of 157.91 ± 1.267 nm (0.165 ± 0.017 PDI). The entrapment efficiency and zeta potential were found to be 69.144 ± 0.278% and -16.75 ± 1.40 mV, respectively. The in-vitro release study revealed a controlled release of Apremilast from NLCs up to 24 h. The ex-vivo study showed 3-fold enhanced skin retention compared to conventional gel preparation. The formulation depicted improved psoriasis efficacy indicating reduced TNF-α mRNA expression. The cytotoxicity and skin irritation study revealed the prepared formulation has no toxicity or irritation. The study depicts the NLCs loaded Apremilast can be explored for the topical delivery for treatment of psoriasis with improved skin retention and efficacy.
Design and Evaluation of Oral Controlled Release Tablets of Milnacipran Hydrochloride
(BITS Pilani, 2014-08) Singhvi, Gautam
Design and Evaluation of Rapidly Disintegrating Tablets of Racecadotril with Enhanced in-vitro Dissolution Achieved by Solid Dispersion Technique
(IJPER, 2013-11) Singhvi, Gautam
Racecadotril is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. It is a solubility-limited compound and thus the bioavailability can be improved by increasing its aqueous solubility. Solid dispersions of racecadotril were prepared using polymers β-cyclodextrin, poloxamer 188 (Lutrol F 68) and poloxamer 407 (Lutrol F127) in different proportions (1:1, 1:3, 1:5 and 1:10). Solvent evaporation method was employed using methanol as solvent. The solid dispersion complexes were also characterized using FT-IR, DSC and XRD. The optimized dispersions were formulated into rapid disintegrating tablets using Kollidon® CL-SF and sodium starch glycolate (SSG) as disintegrants with proportion of 2%, 3%, and 4%. The disintegration time, mean dissolution time (MDT), T50 and T90 of the formulated tablets were evaluated and compared with the marketed formulation. The pure drug showed aqueous solubility of 18.89 μg/ml while the solid dispersions with poloxamer 188 and poloxamer 407 in ratios 1:5 showed solubility of 70.75 μg/ml and 58.07 μg/ml. There was a 3 fold increase in drug solubility. The disintegration time of all the formulations were found to be less than 42 sec. Both Kollidon® CL-SF and SSG decreased the T50 and T90 values but Kollidon® CL-SF at a concentration of 4% was found to show the best results (T50 = 10.63 ± 0.17, T90 = 35.31 ± 0.57 and MDT = 13.85 ± 0.27 min). This was further compared with marketed formulation. The difference (f1) and similarity (f2) factors was found to be 89.91 and 21.11 respectively. The results suggest that the designed formulation is improved than the marketed formulation. The improved solubility, dissolution and drug release may be highly beneficial in improving the overall bioavailability of RDT.
Design of temozolomide-loaded proliposomes and lipid crystal nanoparticles with industrial feasible approaches: comparative assessment of drug loading, entrapment efficiency, and stability at plasma pH
(Taylor & Francis, 2021-06) Singhvi, Gautam
Temozolomide is a drug approved for treating glioblastomas, which has 100% oral bioavailability but gets degraded at physiological pH thus having very short half-life and only 20–30% brain bioavailability. Due to its amphiphilic nature, reported nanoformulations exhibits poor drug loading. The objective of this work was to formulate lipid-based drug delivery systems to enhance the brain bioavailability by prolonging the drug release and circulation time of the drug to overcome the limitations of the existing therapies and possible reduction of side effects. The size of the nanocarriers obtained was less than 300 nm and the PDI obtained was less than 0.3. The designed formulation showed higher entrapment efficiency as compared to the other reported nanocarriers of temozolomide. The designed formulations showed prolonged drug release from 12 to 20 h compared to 6 h for the pure drug. About 95% of the pure drug was degraded at plasma pH at the end of 12 h, whereas only 68% and 77% was degraded when entrapped inside the lipid crystal nanoparticles and proliposomes respectively. Further, pharmacokinetic and animal studies can confirm the potential of these for improvement of brain bioavailability.
Determination of Venlafaxine in Bulk and Pharmaceutical Formulations Using Stability Indicating RP-HPLC Method with UV Detector
(Bentham Science, 2019) Singhvi, Gautam
A robust and validated analytical method is a key component at various stages of pharmaceutical product development to ensure identity, purity and quality of drugs and formulations
Development of a new, rapid and sensitive HPTLC method for estimation of Milnacipran in bulk, formulation and compatibility study
(Elsevier, 2017-05) Singhvi, Gautam
A simple, sensitive and rapid high performance thin layer chromatographic (HPTLC) method has been developed and validated for quantitative determination of Milnacipran Hydrochloride (MIL) in bulk and formulations. The chromatographic development was carried out on HPTLC plates precoated with silica gel 60 F254 using a mixture of acetonitrile, water and ammonia (6:0.6:1.6) (v/v/v) as mobile phase. Detection was carried out densitometrically at 220 nm. The Rf value of drug was found to be 0.63 ± 0.02. The method was validated as per ICH guideline with respect to linearity, accuracy, precision, robustness etc. The calibration curve was found to be linear over a range of 100–1000 ng μL−1 with a regression coefficient of 0.999. The accuracy was found to be very high (99.12–100.87%). %RSD values for intra-day and inter-day variation were not more than 1.43. The method has demonstrated high sensitivity and specificity. The method was applied for compatibility studies also. The method is new, simple and economic for routine estimation of MIL in bulk, preformulation studies and pharmaceutical formulation to help the industries as well as researchers for their sensitive determination of MIL rapidly at low cost in routine analysis.
Development of a tumor extracellular pH-responsive nanocarrier by terminal histidine conjugation in a star shaped poly(lactic-co-glycolic acid)
(Elsevier, 2021-06) Roy, Aniruddha; Singhvi, Gautam
The present work aimed to develop topical solid lipid nanocarriers (SLN) loaded hydrogel of apremilast (API) for psoriasis therapy to minimize the systemic adverse effects. The quality by design approach was implemented for the optimization of API loaded SLN using Box-Behnken design. SLN were prepared using hot emulsification followed by size reduction using probe sonication. The size and entrapment were found to be 167.70 nm ± 1.5 (0.238 PDI) and 63.84 ± 0.93%, respectively. The FESEM images of SLN dispersion portrayed the spherical shape of nanocarriers. The in vitro drug release of SLN dispersion showed extended-release up to 18 h and followed the Korsmeyyar-Peppas model with a regression value of 0.958 (n = 0.330), and Akaike index criteria was 63.69. In vitro cell line study, the MTT assay depicted the formulation excipients had minimal effect, and high internalization was observed with SLN dispersion (1.4-fold). The Ct value reduction in the relative expression of TNF-α miRNA was 3-fold higher with SLN dispersion compared to the positive control. The ex vivo skin retention and dermal distribution study by Coumarin-6 dye depicted an increase in permeation and retention with SLN formulation compared to free drug-loaded gel. The dermato-pharmacokinetic study of SLN formulation exhibited 2-fold higher drug retention in the epidermis and 5-fold higher in the dermis compared to free drug. This were stable for 3 months without significant changes. The results suggest that API loaded SLN can be utilized for topical delivery for effective treatment of psoriasis by targeting skin layers. The API loaded SLN based topical gel formulation showed improved permeation, skin deposition and prolonged release compared to conventional preparation. The designed preparation can signify a potential alternative for psoriasis treatment after clinical evaluation in near future.
Development of Bioanalytical HPLC Method for Estimation of Milnacipran Hydrochloride in Rabbit Plasma Using Solid Phase Extraction Technique and its Application in Pharmacokinetic Investigation
(Bentham Science, 2017) Singhvi, Gautam
The availability of a low-cost bioanalytical method, easy to transfer and to set up, represents an advantage in therapeutic drug monitoring and industrial research.
Development of gene expression inhibitors for the treatment of cutaneous carcinomas
(Taylor & Francis, 2025-07) Roy, Aniruddha; Singhvi, Gautam
Cutaneous carcinoma is one of the most common cancers worldwide, with rising incidence and mortality rates, especially among white Caucasians. It primarily includes non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC), which together account for over 90% of all skin cancers. The main cause is the abnormal proliferation of skin cells due to genetic mutations and environmental damage [Citation1]. Basal cell carcinoma (BCC) arises from mutations in the Ptch1 tumor suppressor gene caused by UV-radiations, leading to dysregulated hedgehog signaling, while Squamous cell Carcinoma (SCC), which originates in keratinocytes, is driven by TP53 mutations and epigenetic changes. In melanoma, mutations in genes like B-Raf proto-oncogene, serine/threonine kinase (BRAF), Neuroblastoma RAS Viral Oncogene Homolog (NRAS), Neurofibromin 1 (NF1), or proto-oncogene receptor tyrosine kinase (KIT) activate the MAPK pathway, leading to cellular proliferation and invasion. Traditional treatments, such as surgery, chemotherapy, and immunotherapies, face challenges like resistance, side effects, and don’t address widespread epigenetic alterations that activate oncogenes and silence tumor suppressors, emphasizing the need for targeted genetic therapies to inhibit skin cancer growth [Citation2]. Several gene expression inhibitors are being explored for cutaneous carcinomas, such as DNMT inhibitors (guadecitabine and decitabine, etc), which reverses abnormal DNA methylation to reactivate tumor suppressor genes, while EZH2 inhibitors (CPI-1205) block H3K27 trimethylation to prevent oncogenic gene silencing. HDAC inhibitors (entinostat, mocetinostat, and panobinostat), enhance histone acetylation to promote tumor suppressor expression and improve immune responses, and siRNA-based therapies (STP705 and c-Myc siRNA, etc) or antisense oligonucleotides targeting lncRNAs like MALAT1 and TINCR directly silence cancer-promoting genes and disrupt oncogenic pathways [Citation3]. Therefore, recent investigations focused on the regulation of gene expression and the development of their inhibitors as effective targeted therapeutic strategies for the treatment of cutaneous carcinoma.