A review of FDA approved drugs and their formulations for the treatment of breast cancer.

Breast cancer is one of the most diagnosed solid cancers globally. Extensive research has been going on for decades to meet the challenges of treating solid tumors with selective compounds. This article aims to summarize the therapeutic agents which are either being used or are currently under approval for use in the treatment or mitigation of breast cancer by the US FDA, to date. A structured search of bibliographic databases for previously published peer-reviewed research papers on registered molecules was explored and data was sorted in terms of various categories of drugs used in first line/adjuvant therapy for different stages of breast cancer. We included more than 300 peer-reviewed papers, including both research and reviews articles, in order to provide readers an useful comprehensive information. A list of 39 drugs are discussed along with their current status, dose protocols, mechanism of action, pharmacokinetics, possible side effects, and marketed formulations. Another interesting aspect of the article included focusing on novel formulations of these drugs which are currently in clinical trials or in the process of approval. This exhaustive review thus shall be a one-stop solution for researchers who are working in the areas of formulation development for these drugs.

Review of industrially recognized polymers and manufacturing processes for amorphous solid dispersion based formulations.

Evolving therapeutic landscape through combinatorial chemistry and high throughput screening have resulted in an increased number of poorly soluble drugs. Drug delivery strategies quickly adapted to convert these drugs into successful therapies. Amorphous solid dispersion (ASD) technology is widely employed as a drug delivery strategy by pharmaceutical industries to overcome the challenges associated with these poorly soluble drugs. The development of ASD formulation requires an understanding of polymers and manufacturing techniques. A review of US FDA-approved ASD-based products revealed that only a limited number of polymers and manufacturing technologies are employed by pharmaceutical industries. This review provides a comprehensive guide for the selection and overview of polymers and manufacturing technologies adopted by pharmaceutical industries for ASD formulation. The various employed polymers with their underlying mechanisms for solution-state and solid-state stability are discussed. ASD manufacturing techniques, primarily implemented by pharmaceutical industries for commercialization, are presented in Quality by Design (QbD) format. An overview of novel excipients and progress in manufacturing technologies are also discussed. This review provides insights to the researchers on the industrially accepted polymers and manufacturing technology for ASD formulation that has translated these challenging drugs into successful therapies.

Innovative method for wound debridement in open globe injury.

Background: Open globe injury is a serious sight threatening condition. Full-thickness, non-selfsealing corneal lacerations require repair in the operating room. During repair, debridement of the wound is an important step. Incarceration of the intraocular structures in the wound eg. Iris, lens capsule, vitreous leads to improper healing if not removed properly. Purpose: To demonstrate the technique of wound debridement in open globe injury. Synopsis: : Manual removal of incarcerated tissue contents leads to incomplete cleaning & enormous traction on intra ocular contents. In this video, we have tried vitrectomy cutter with higher vacuum for cleaning the edges of the wound especially in the posterior aspect and debri removal, followed by easy suturing. All tissue in the wound edges are removed effectively without any traction on intraocular contents. Highlights: : Vitrectomy cutter is a very useful and effective tool to clean wound edges and good apposition & suturing of wound. Video link: https://youtu.be/y_kCxLdwhuQ.

A prospective cohort study on the epidemiology of ocular trauma associated with closed-globe injuries in pediatric age group.

Purpose: To study the epidemiology of mechanical ocular trauma and closed globe injury using the Birmingham Eye Trauma Terminology System in patients belonging to the pediatric age group. Methods: This work involved a prospective cohort study of all ocular trauma patients (pediatric age group) registered between 2002 and 2017 at the ocular trauma care center. The data were collected using the international ocular trauma society form through our online MIS data and exported to the Excel sheet. The statistical analyses including the univariate analysis and cross tabulation were carried out using SPSS 22 software. Results: Our cohort consisted of 12687 patients with mechanical ocular trauma. There were 7546 (59.4%) eyes with open globe ocular injuries and 5328 (41.9%) with closed globe injuries. Of all closed globe injury patients, 1010 (19.0%) belonged to the pediatric age group (0-18 years), including 690 males (68.3%) and 320 females (31.7%). The mean age of the patients was 10.2 ± 5.1 years. Of all closed globe injuries, 692 (68.5%) were closed globe contusion and 318 (31.5%) were lamellar laceration. Conclusion: Closed globe injury is an important in cause of vision loss in children (24% <1/60). The condition is more prevalent in males and >51.7% in children under 10 years of age. The treatment has significant impact on the visual outcome in patients belonging to the pediatric age group.

Innovative cost-effective method to repair lacrimal cannaliculi laceration - finding proximal end and stent.

Purpose: To explore a new technique to find out the proximal end of lacerated canaliculi and a new material for the stent. Methods: Surgery was performed on 9 eyes of 9 patients using a 5/0 prolene suture needle as a modified probe. Prolene suture was inserted as a stent and left in place for two months. All the data were analyzed. Results: The surgery was successful in all cases and the prolene were removed after two months. The mean follow-up time after the tube removal was 3.8 months (range 3-6 months). No other complications associated with the prolene sutures were noticed except for epiphora and corneal irritation in three cases. All the tubes were removed successfully without any difficulty. No iatrogenic injuries occurred during prolene removal. Conclusions: The reported surgical technique is a very cost-effective option for lacrimal canalicular laceration repair.

Systematic Development and Optimization of an in-situ Gelling System for Moxifloxacin Ocular Nanosuspension using High-pressure Homogenization with an Improved Encapsulation Efficiency.

BACKGROUND: The objective of this study was to apply Quality by Design (QbD) principles on process parameter optimization for the development of hybrid delivery system (combination of (SLNs) and In-situ gelling system) for hydrophilic drug Moxifloxacin Hydrochloride (MOX) to achieve its controlled delivery, which otherwise may not be possible through single type of technology. METHODS: Risk assessment studies were carried out to identify probable risks influencing CQAs on the product. In design of experiments (DoE), the process parameters (independent variables) i.e., chiller temperature X1, High Pressure Homogenization (HPH) pressure X2, and HPH cycles X3 were optimized using a three-factor two level face-centered central composite design to streamline the influence on three responses, namely encapsulation efficiency Y1, particle size Y2 and outlet temperature Y3. Independent and dependent variables were analyzed to establish a full-model second-order polynomial equation. F value is used to confirm the omission of insignificant parameters/interactions to derive a reduced-model polynomial equation to predict the Y1, Y2 and Y3 for optimized moxifloxacin in situ gelled nanosuspension. RESULTS: Desirability plots showed the effects of X1, X2, and X3 on Y1, Y2 and Y3, respectively. The design space is generated to obtain optimized process parameters viz. chiller temperature (-5°C), HPH pressure 800 - 900 bar and 8 cycles that resulted in nanosuspension with ≈ 500 nm size, encapsulation efficiency >65% and final formulation temperature <23°C that were necessary to maintain the formulation in a liquid state. CONCLUSION: Quality by Design (QbD) approach is recently been encouraged by regulatory bodies to improve the quality of the finished product. This approach proved to be a useful tool in the development of robust nanosuspension of highly hydrophilic drugs with improved efficiency. Results indicate that such hybrid gel systems can be used to control the release of SLNs from application site and prolong their action in a sustained manner.

Role of P-Glycoprotein Inhibitors in the Bioavailability Enhancement of Solid Dispersion of Darunavir.

OBJECTIVE: The aim of the present study was to improve bioavailability of an important antiretroviral drug, Darunavir (DRV), which has low water solubility and poor intestinal absorption through solid dispersion (SD) approach incorporating polymer with P-glycoprotein inhibitory potential. METHODS: A statistical approach where design of experiment (DoE) was used to prepare SD of DRV with incorporation of P-glycoprotein inhibitors. Using DoE, different methods of preparation, like melt, solvent evaporation, and spray drying method, utilizing carriers like Kolliphor TPGS and Soluplus were evaluated. The optimized SD was characterized by DSC, FTIR, XRD, and SEM and further evaluated for enhancement in absorption using everted gut sac model, effect of food on absorption of DRV, and in vivo prospect. RESULTS AND DISCUSSION: DSC, FTIR, XRD, and SEM confirmed the amorphicity of drug in SD. Oral bioavailability studies revealed better absorption of DRV when given with food. Absorption studies and in vivo study findings demonstrated great potential of Kolliphor TPGS as P-glycoprotein inhibitor for increasing intestinal absorption and thus bioavailability of DRV. CONCLUSION: It is concluded that SD of DRV with the incorporation of Kolliphor TPGS was potential and promising approach in increasing bioavailability of DRV as well as minimizing its extrusion via P-glycoprotein efflux transporters.

Clinical trials in "emerging markets": regulatory considerations and other factors.

Clinical studies are being placed in emerging markets as part of global drug development programs to access large pool of eligible patients and to benefit from a cost effective structure. However, over the last few years, the definition of "emerging markets" is being revisited, especially from a regulatory perspective. For purposes of this article, countries outside US, EU and the traditional "western countries" are discussed. Multiple factors are considered for placement of clinical studies such as adherence to Good Clinical Practice (GCP), medical infrastructure & standard of care, number of eligible patients, etc. This article also discusses other quantitative factors such as country's GDP, patent applications, healthcare expenditure, healthcare infrastructure, corruption, innovation, etc. These different factors and indexes are correlated to the number of clinical studies ongoing in the "emerging markets". R&D, healthcare expenditure, technology infrastructure, transparency, and level of innovation, show a significant correlation with the number of clinical trials being conducted in these countries. This is the first analysis of its kind to evaluate and correlate the various other factors to the number of clinical studies in a country.

Effects of ionization and penetration enhancers on the transdermal delivery of 5-fluorouracil through excised human stratum corneum.

The purpose of this study was to determine the effects of ionization and penetration enhancers on the transdermal delivery of 5-fluorouracil (5-FU) through excised human stratum corneum. The in vitro transport of 5-FU was determined at three physiologically relevant pH values of 5.0, 7.4 and 8.0, and in the presence of suitable penetration enhancers, namely Azone (AZ), lauryl alcohol (LA), and isopropyl myristate (IPM). The results showed that passive permeation of 5-FU is dependent upon the pH of the donor solution, although did not fully conform to the pH-partition hypothesis. A further analysis of data suggested an inverse relationship (i.e., negative correlation) between steady-state flux and aqueous solubility of 5-FU at these pH values (correlation coefficient = -0.4205), although correlation was not statistically significant (p = 0.7237). In the absence of a penetration enhancer, the in vitro permeability of 5-FU was quite low (0.82+/-0.06 x 10(4) cm/h). This delivery rate was enhanced by approximately by 3, 4 and 24-fold, respectively, when IPM, LA, and AZ were incorporated into the donor solution. All these enhancements were statistically significant (p < 0.05) compared to control, and occurred regardless of the polarity (solubility parameters) of these enhancers. Out of three examined enhancers, AZ appears to be a suitable enhancer for enhancing transport of 5-FU, which merits in vivo investigation in a suitable animal model. Possible mechanisms of enhancement by these penetration enhancers are also discussed.

Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma.

The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 microCi) of [(3)H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n = 6) and plasma was collected over 26 weeks in study B (n = 7). Supportive data were obtained from a single-dose [(3)H]caspofungin tissue distribution study in rats (n = 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t(1/2) = 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at approximately 92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.

Optimization of the indolyl quinolinone class of KDR (VEGFR-2) kinase inhibitors: effects of 5-amido- and 5-sulphonamido-indolyl groups on pharmacokinetics and hERG binding.

Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.