Development of Itraconazole Topical formulation in Skin Cancer Treatment

Overview: I, Praveen Kolimi, pursuing a first-year graduate program at the department of pharmaceutics and drug delivery. This Graduate Student Council (GSC) grant proposal focus on topical application of Itraconazole (ICZ) in skin cancer treatment. Intellectual Merit: 5.4 million skin cancer cases are reported each year in the United States. A study disclosed that one among five Americans are likely to develop skin cancer in their entire life. 9. Skin cancer can be distinguished into two types, malignant melanoma (MM) and non-melanoma skin cancer (NMSC) 1, 8. NMSC further classified into squamous cell carcinoma (SCC) and basal cell carcinoma (BCC)8, 10. It was estimated that every year 2 million people are suffering from BCC and 80 percent cases observed in NMSC4. Studies have demonstrated the hedgehog pathway is involved in BCC and melanoma development. 12, 16. Cyclopamine is a prototype drug which inhibits the hedgehog pathway in BCC and preclinical studies demonstrated cyclopamine as a potential drug for skin cancer treatment. 2. However, cyclopamine was not effective in skin cancer clinically due to its low solubility and toxicity profile. 2, 13. Recently, cyclopamine derivatives vismodegib and sonidegib hedgehog pathway inhibitors have been approved by USFDA for skin cancer through the oral route of administration. 6. Studies have reported oral vismodegib, and sonidegib produce adverse effects, including muscle spasms, alopecia and weight loss. 11. On the same lines, oral formulations are difficult to administer to unconscious patients, taste cannot be masked and they can be bulky making it difficult to ingest making oral formulations a discomfort to cancer patients. Topical anti-cancer drug treatment would better and effective option for topical (skin) cancer treatments. Topical products offer patient compliance which of utmost importance especially to the cancer patients. As of now, in the market, only 5-fluorouracil and imiquimod drugs are available for treating skin cancer through topical route 7. Although 5-fluorouracil and imiquimod beneficial for treating skin cancer, these drugs exhibit adverse effects including skin irritation, hair loss, pain and changes in skin color. Recent clinical studies have demonstrated ICZ oral dose are effective in the treatment of BCC and proposed mechanism of action is hedgehog pathway inhibition. The ICZ is high safety profile drug and extensively used as an anti-fungal agent for two decades. To our best knowledge, there is no effective topical formulation available for skin delivery of ICZ in skin cancer treatment, and therefore, it is required to develop ICZ topical formulation. The current study is designed to develop a topical formulation of ICZ and evaluate its potential effects in the treatment of skin cancer in athymic mice models. External Opportunity: Recently, many researchers are focusing on repurposing drugs, especially in cancer chemotherapy. 5, 15. Anti-fungal drugs, including ICZ and posaconazole, both drugs, were shown very positive results in skin cancer treatment 5, 14. Here, we conduct studies of ICZ via the topical route of administration in skin cancer induced athymic nude mice. After executing studies, will utilize this data and will write grant proposals to AAPS and other funding foundations

Developing Novel Topical Formulations for Azole drugs

Itraconazole is a broad-spectrum triazole antifungal agent used to prevent and treat fungal infections. Itraconazole is commercially available as an oral and intravenous formulation; however, its administration via these routes is associated with various side effects, such as hepatotoxicity, peripheral neuropathy, cardiac dysrhythmia, and hearing loss. Therefore, in this research, stable non-aqueous topical creams and gels loaded with itraconazole were investigated with the intent to prolong drug contact, improve drug permeation and penetration into skin layers, and overcome the side effects associated with other routes of administration for improved therapeutic outcomes. Chapter 1 discusses the development and characterization strategies during the development of the itraconazole non-aqueous creams while chapter 2 reports the preparation and optimization of the itraconazole non-aqueous gels. The lead cream formulation was stable over three months (the last time-point tested) during refrigeration and room-temperature storage. The cream formulation developed with 15% w/w Transcutol® P improved itraconazole permeation and deposition through the skin by 8.4- and 8.2-fold, compared to the drug solution, respectively. All lead gel formulations were found to have desirable physicochemical characteristics and showed three-month stability (the last time-point tested) during refrigeration, room temperature, and accelerated storage conditions. The gel formulation developed with 0.5% w/w Carbopol® 940 P improved itraconazole permeation and deposition through the skin by 5.1- and 6.8-fold, compared to the drug solution, respectively. Chapter 3 discusses the development and validation of HPLC method for the antifungal drug efinaconazole for application to human nail permeation studies. The developed method was validated as per FDA guidelines, and the results met the acceptance criteria. The method developed was specific, and the method was linear over the efinaconazole concentration range of 0.05 to 10 μg/mL (R2 ≥ 0.9981). In conclusion, the itraconazole-loaded non-aqueous creams and gels can serve as alternative drug delivery platforms for the treatment of fungal skin infections over oral/parenteral itraconazole formulations. Moreover, the developed efinaconazole HPLC method can be applied for formulation evaluation and clinical studies

Novel and investigational therapies for wet and dry age-related macular degeneration

Funding Information: The authors are thankful to the Institute of Chemical Technology, Mumbai, India for providing facilities to carry out this work. V.J.is supported by a personal research grant from the Finnish Cultural Foundation (Ingrid, Toini and Olavi Martelius foundation), and thanks Arto Urtti for suggestions that improved the manuscript. Publisher Copyright: © 2022 The AuthorsAge-related macular degeneration (AMD) is a macular degenerative eye disease, the major cause of irreversible loss of central vision. In this review, we highlight current progress and future perspectives of novel and investigational therapeutic strategies in the drug pipeline, including anti-vascular endothelial growth factor (VEGF) agents, bispecific antibodies, biosimilars, small molecules, gene therapy, and long-acting drug delivery strategies for both dry and wet AMD. We anticipate that biologics with dual functionalities and combined therapies with long-acting capabilities will lead the wet AMD pipeline. Sustained-release platforms also show potential. However, significant breakthroughs are yet to be made for dry AMD. The personalized approach might be well suited in the scenario of diverse genetic variations in both conditions.Peer reviewe

Polymeric Micelles for Breast Cancer Therapy: Recent Updates, Clinical Translation and Regulatory Considerations

With the growing burden of cancer, parallel advancements in anticancer nanotechnological solutions have been witnessed. Among the different types of cancers, breast cancer accounts for approximately 25% and leads to 15% of deaths. Nanomedicine and its allied fields of material science have revolutionized the science of medicine in the 21st century. Novel treatments have paved the way for improved drug delivery systems that have better efficacy and reduced adverse effects. A variety of nanoformulations using lipids, polymers, inorganic, and peptide-based nanomedicines with various functionalities are being synthesized. Thus, elaborate knowledge of these intelligent nanomedicines for highly promising drug delivery systems is of prime importance. Polymeric micelles (PMs) are generally easy to prepare with good solubilization properties; hence, they appear to be an attractive alternative over the other nanosystems. Although an overall perspective of PM systems has been presented in recent reviews, a brief discussion has been provided on PMs for breast cancer. This review provides a discussion of the state-of-the-art PMs together with the most recent advances in this field. Furthermore, special emphasis is placed on regulatory guidelines, clinical translation potential, and future aspects of the use of PMs in breast cancer treatment. The recent developments in micelle formulations look promising, with regulatory guidelines that are now more clearly defined; hence, we anticipate early clinical translation in the near future

Fast-Fed Variability: Insights into Drug Delivery, Molecular Manifestations, and Regulatory Aspects

Among various drug administration routes, oral drug delivery is preferred and is considered patient-friendly; hence, most of the marketed drugs are available as conventional tablets or capsules. In such cases, the administration of drugs with or without food has tremendous importance on the bioavailability of the drugs. The presence of food may increase (positive effect) or decrease (negative effect) the bioavailability of the drug. Such a positive or negative effect is undesirable since it makes dosage estimation difficult in several diseases. This may lead to an increased propensity for adverse effects of drugs when a positive food effect is perceived. However, a negative food effect may lead to therapeutic insufficiency for patients suffering from life-threatening disorders. This review emphasizes the causes of food effects, formulation strategies to overcome the fast-fed variability, and the regulatory aspects of drugs with food effects, which may open new avenues for researchers to design products that may help to eliminate fast-fed variability

Review on the Scale-Up Methods for the Preparation of Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) are an alternate carrier system to liposomes, polymeric nanoparticles, and inorganic carriers. SLNs have attracted increasing attention in recent years for delivering drugs, nucleic acids, proteins, peptides, nutraceuticals, and cosmetics. These nanocarriers have attracted industrial attention due to their ease of preparation, physicochemical stability, and scalability. These characteristics make SLNs attractive for manufacture on a large scale. Currently, several products with SLNs are in clinical trials, and there is a high possibility that SLN carriers will quickly increase their presence in the market. A large-scale manufacturing unit is required for commercial applications to prepare enough formulations for clinical studies. Furthermore, continuous processing is becoming more popular in the pharmaceutical sector to reduce product batch-to-batch differences. This review paper discusses some conventional methods and the rationale for large-scale production. It further covers recent progress in scale-up methods for the synthesis of SLNs, including high-pressure homogenization (HPH), hot melt extrusion coupled with HPH, microchannels, nanoprecipitation using static mixers, and microemulsion-based methods. These scale-up technologies enable the possibility of commercialization of SLNs. Furthermore, ongoing studies indicate that these technologies will eventually reach the pharmaceutical market

Progress on Thin Film Freezing Technology for Dry Powder Inhalation Formulations

The surface drying process is an important technology in the pharmaceutical, biomedical, and food industries. The final stage of formulation development (i.e., the drying process) faces several challenges, and overall mastering depends on the end step. The advent of new emerging technologies paved the way for commercialization. Thin film freezing (TFF) is a new emerging freeze-drying technique available for various treatment modalities in drug delivery. TFF has now been used for the commercialization of pharmaceuticals, food, and biopharmaceutical products. The present review highlights the fundamentals of TFF along with modulated techniques used for drying pharmaceuticals and biopharmaceuticals. Furthermore, we have covered various therapeutic applications of TFF technology in the development of nanoformulations, dry powder for inhalations and vaccines. TFF holds promise in delivering therapeutics for lung diseases such as fungal infection, bacterial infection, lung dysfunction, and pneumonia

Innovative Treatment Strategies to Accelerate Wound Healing: Trajectory and Recent Advancements

Wound healing is highly specialized dynamic multiple phase process for the repair of damaged/injured tissues through an intricate mechanism. Any failure in the normal wound healing process results in abnormal scar formation, and chronic state which is more susceptible to infections. Chronic wounds affect patients’ quality of life along with increased morbidity and mortality and are huge financial burden to healthcare systems worldwide, and thus requires specialized biomedical intensive treatment for its management. The clinical assessment and management of chronic wounds remains challenging despite the development of various therapeutic regimens owing to its painstakingly long-term treatment requirement and complex wound healing mechanism. Various conventional approaches such as cell therapy, gene therapy, growth factor delivery, wound dressings, and skin grafts etc., are being utilized for promoting wound healing in different types of wounds. However, all these abovementioned therapies are not satisfactory for all wound types, therefore, there is an urgent demand for the development of competitive therapies. Therefore, there is a pertinent requirement to develop newer and innovative treatment modalities for multipart therapeutic regimens for chronic wounds. Recent developments in advanced wound care technology includes nanotherapeutics, stem cells therapy, bioengineered skin grafts, and 3D bioprinting-based strategies for improving therapeutic outcomes with a focus on skin regeneration with minimal side effects. The main objective of this review is to provide an updated overview of progress in therapeutic options in chronic wounds healing and management over the years using next generation innovative approaches. Herein, we have discussed the skin function and anatomy, wounds and wound healing processes, followed by conventional treatment modalities for wound healing and skin regeneration. Furthermore, various emerging and innovative strategies for promoting quality wound healing such as nanotherapeutics, stem cells therapy, 3D bioprinted skin, extracellular matrix-based approaches, platelet-rich plasma-based approaches, and cold plasma treatment therapy have been discussed with their benefits and shortcomings. Finally, challenges of these innovative strategies are reviewed with a note on future prospects

Polymeric micelles for breast cancer therapy: recent updates, clinical translation and regulatory considerations

With the growing burden of cancer, parallel advancements in anticancer nanotechnological solutions have been witnessed. Among the different types of cancers, breast cancer accounts for approximately 25% and leads to 15% of deaths. Nanomedicine and its allied fields of material science have revolutionized the science of medicine in the 21st century. Novel treatments have paved the way for improved drug delivery systems that have better efficacy and reduced adverse effects. A variety of nanoformulations using lipids, polymers, inorganic, and peptide-based nanomedicines with various functionalities are being synthesized. Thus, elaborate knowledge of these intelligent nanomedicines for highly promising drug delivery systems is of prime importance. Polymeric micelles (PMs) are generally easy to prepare with good solubilization properties; hence, they appear to be an attractive alternative over the other nanosystems. Although an overall perspective of PM systems has been presented in recent reviews, a brief discussion has been provided on PMs for breast cancer. This review provides a discussion of the state-of-the-art PMs together with the most recent advances in this field. Furthermore, special emphasis is placed on regulatory guidelines, clinical translation potential, and future aspects of the use of PMs in breast cancer treatment. The recent developments in micelle formulations look promising, with regulatory guidelines that are now more clearly defined; hence, we anticipate early clinical translation in the near future

Twin Screw Melt Granulation: A Single Step Approach for Developing Self-Emulsifying Drug Delivery System for Lipophilic Drugs

The current research aims to improve the solubility of the poorly soluble drug, i.e., ibuprofen, by developing self-emulsifying drug delivery systems (SEDDS) utilizing a twin screw melt granulation (TSMG) approach. Gelucire® 44/14, Gelucire® 48/16, and Transcutol® HP were screened as suitable excipients for developing the SEDDS formulations. Initially, liquid SEDDS (L-SEDDS) were developed with oil concentrations between 20–50% w/w and surfactant to co-surfactant ratios of 2:1, 4:1, 6:1. The stable formulations of L-SEDDS were transformed into solid SEDDS (S-SEDDS) using a suitable adsorbent carrier and compressed into tablets (T-SEDDS). The S-SEDDS has improved flow, drug release profiles, and permeability compared to pure drugs. The existence of the drug in an amorphous state was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction analysis (PXRD). The formulations with 20% w/w and 30% w/w of oil concentration and a 4:1 ratio of surfactant to co-surfactant have resulted in a stable homogeneous emulsion with a globule size of 14.67 ± 0.23 nm and 18.54 ± 0.55 nm. The compressed tablets were found stable after six months of storage at accelerated and long-term conditions. This shows the suitability of the TSMG approach as a single-step continuous manufacturing process for developing S-SEDDS formulations