Development and approval of novel injectables: enhancing therapeutic innovations.

INTRODUCTION: Novel injectables possess applications in both local and systemic therapeutics delivery. The advancement in utilized materials for the construction of complex injectables has tremendously upgraded their safety and efficacy. AREAS COVERED: This review focuses on various strategies to produce novel injectables, including oily dispersions, in situ forming implants, injectable suspensions, microspheres, liposomes, and antibody-drug conjugates. We herein present a detailed description of complex injectable technologies and their related drug formulations permitted for clinical use by the United States Food and Drug Administration (USFDA). The excipients used, their purpose and the challenges faced during manufacturing such formulations have been critically discussed. EXPERT OPINION: Novel injectables can deliver therapeutic agents in a controlled way at the desired site. However, several challenges persist with respect to their genericization. Astronomical costs incurred by innovator companies during product development, complexity of the product itself, supply limitations with respect to raw materials, intricate manufacturing processes, patent evergreening, product life-cycle extensions, relatively few and protracted generic approvals contribute to the exorbitant prices and access crunch. Moreover, regulatory guidance are grossly underdeveloped and significant efforts have to be directed toward development of effective characterization techniques.

A Quality by Design Approach for Developing SNEDDS Loaded with Vemurafenib for Enhanced Oral Bioavailability.

Vemurafenib (VMF) is a practically insoluble (< 0.1 µg/mL) and least bioavailable (1%) drug. To enhance its oral bioavailability and solubility, we formulated a reliable self-nano emulsifying drug delivery system (SNEDDS). A Quality by Design (QbD) approach was used to optimize the ratio of Capryol 90, Tween 80, and Transcutol HP. VMF-loaded SNEDDS was characterized for its size, polydispersity index (PDI), zeta potential, drug content, and transmittance. The in vitro release profile of the drug loaded in SNEDDS was compared to the free drug in two media, pH 6.8 and 1.2, and the data obtained were analyzed with different mathematical models. A reverse-phase ultra-pressure liquid chromatography (UPLC) technique with high sensitivity and selectivity was developed and validated for the quantification of VMF in analytical and bioanalytical samples. Dissolution efficiency for SNEDDS was estimated using different models, which proved that the developed novel SNEDDS formulation had a better in vitro dissolution profile than the free drug. A 2.13-fold enhanced oral bioavailability of VMF-loaded SNEDDS compared to the free drug demonstrates the superiority of the developed formulation. This work thus presents an overview of VMF-loaded SNEDDS as a promising alternative to improve the oral bioavailability of the drug.

Ophthalmic nano-bioconjugates: critical challenges and technological advances.

Ophthalmic disease can cause permanent loss of vision and blindness. Easy-to-administer topical and systemic treatments are preferred for treating sight-threatening disorders. Typical ocular anatomy makes topical and systemic ophthalmic drug delivery challenging. Various novel nano-drug delivery approaches are developed to attain the desired bioavailability in the eye by increasing residence time and improved permeability across the cornea. The review focuses on novel methods that are biocompatible, safe and highly therapeutic. Novelty in nanocarrier design and modification can overcome their drawbacks and make them potential drug carriers for eye disorders in both the anterior and posterior eye segments. This review briefly discussed technologies, patented developments, and clinical trial data to support nanocarriers' use in ocular drug delivery.

Recent Update on Pharmacokinetics and Drug Metabolism in CNS-based Drug Discovery.

Despite significant advancements in CNS research, CNS illnesses are the most important and serious cause of mental disability worldwide. These facts show a tremendous unmet demand for effective CNS medications and pharmacotherapy since it accounts for more hospitalizations and extended care than practically all other disorders combined. The site-targeted kinetics of the brain and, pharmacodynamics of CNS effects are determined/regulated by various mechanisms after the dose, including blood-brain barrier (BBB) transport and many other processes. These processes are condition-dependent in terms of their rate and extent because they are dynamically controlled. For effective therapy, drugs should access the CNS "at the right place, time, and concentration". Details on inter-species and inter-condition variances are required to translate target site pharmacokinetics and associated CNS effects between species and illness states, improving CNS therapeutics and drug development. The present review encircles a short discussion about the barriers that affect effective CNS treatment and precisely focuses on the pharmacokinetics aspects of efficient CNS therapeutics.

Enhanced apoptosis and mitochondrial cell death by paclitaxel-loaded TPP-TPGS1000-functionalized nanoemulsion.

Background: The present research was designed to develop a nanoemulsion (NE) of triphenylphosphine-D-α-tocopheryl-polyethylene glycol succinate (TPP-TPGS1000) and paclitaxel (PTX) to effectively deliver PTX to improve breast cancer therapy. Materials & methods: A quality-by-design approach was applied for optimization and in vitro and in vivo characterization were performed. Results: The TPP-TPGS1000-PTX-NE enhanced cellular uptake, mitochondrial membrane depolarization and G2M cell cycle arrest compared with free-PTX treatment. In addition, pharmacokinetics, biodistribution and in vivo live imaging studies in tumor-bearing mice showed that TPP-TPGS1000-PTX-NE had superior performance compared with free-PTX treatment. Histological and survival investigations ascertained the nontoxicity of the nanoformulation, suggesting new opportunities and potential to treat breast cancer. Conclusion: TPP-TPGS1000-PTX-NE improved the efficacy of breast cancer treatment by enhancing its effectiveness and decreasing drug toxicity.

Chitosan/HPMC-based mucoadhesive film co-loaded with fluconazole and ofloxacin for management of polymicrobial keratitis.

Bacterial and fungal co-infection leads to polymicrobial keratitis (PMK). The current study produced swellable mucoadhesive biopolymeric films composed of chitosan, HPMC, and glycerol using cast drying method. The film was dual-loaded with fluconazole (FCZ) and ofloxacin (OFX) to treat PMK. The prepared film exhibited excellent thickness, folding endurance, surface pH, tensile strength, and stability characteristics. In addition, it also exhibited good in vitro antimicrobial activity, ex-vivo mucoadhesion, and corneal permeation. AUC (0-∞) and MRT were 6.5 and 5.2-fold higher for a film containing FCZ and 22.5 and 2.5-fold higher for a film containing OFX than their marketed formulations. PK-PD simulation study supports desired efficacy of the proposed dosage form. Thus, the film exhibits longer pre-corneal drug residence time and enhanced ocular bioavailability, most likely resulting in high patient compliance. The proposed film could be a prominent replacement for the existing dosage form and may present a viable alternative for the treatment of PMK.

HPLC method for simultaneous estimation of paclitaxel and baicalein: pharmaceutical and pharmacokinetic applications.

Aim: A novel HPLC method was developed and validated for the simultaneous estimation of paclitaxel (PTX) and baicalein (BAC). Materials & methods: The analytes were resolved in a C18 column using the aqueous solution of formic acid (0.10% v/v) and MeOH (30:70 v/v). Results: The developed method was found to be linear over the concentration ranges 0.039-10 µg/ml and 0.019-10 µg/ml for PTX and BAC, respectively. The lower limits of quantification obtained were 0.042 µg/ml and 0.361 µg/ml for PTX and BAC, respectively. Conclusion: The developed method was found to be precise and accurate as per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines, for simultaneous estimation of PTX and BAC, having an application in formulation development and bioanalytical studies.

Poly-L-lysine Coated Oral Nanoemulsion for Combined Delivery of Insulin and C-Peptide.

An attempt of co-delivery of insulin and C-peptide enclosed in linseed oil globules has been made employing a protective coating of positively charged poly-L-lysine to manage diabetes-associated complications. Oral water in oil in water (w/o/w) nanoemulsion manufactured by double emulsification method showed good entrapment efficiency of 87.6 ± 7.48% for insulin and 73.4 ± 6.44% for C-peptide. The optimized uncoated nanoemulsion showed a mean globule size of 210.6 ± 9.87 nm with a good PDI of 0.145 ± 0.033 and -21.7 ± 4.5 mV ZP. The poly-L-lysine coating of the nanoemulsion resulted in the reversal of surface charge to positive i.e. 18.3 ± 2.7 mV due to the cationic nature of poly-L-lysine. In vitro drug release showed an initial burst of 15-20% release within 4 h followed by controlled release up to 24 h. The poly-L-lysine coated nanoemulsion showed an 8.28-fold higher uptake than fluorescein isothiocyanate (FITC) solution in HCT116 intestinal cell lines. In vivo studies confirmed that orally administered insulin and C-peptide bearing coated nanoemulsion has the potential to improve glycemic control confirmed by blood glucose level under 200 mg/dL for 12 h compared to that of subcutaneous administration of insulin. The formulation was found stable at 25 °C as well as 4°C for up to 3 months. These findings show a promising approach for delivering oral insulin along with C-peptide for effective glycemic control and management of complications associated with diabetes.

Risk Reversal of Oral, Pharyngeal and Oesophageal Cancers after Cessation of Betel Quid Users: A Systematic Review and Meta-Analysis.

BACKGROUND: Areca nut (AN), the principal ingredient of betel quid (BQ) has been categorized as a human carcinogen associated with various cancers of upper aerodigestive tract. However, there has been no attempt at summarizing the risk reversal of oral and other cancers after cessation of BQ with or without tobacco (BQ+T/BQ-T). OBJECTIVE: To analyze the effect of cessation of betel quid without tobacco (BQ-T) and with tobacco (BQ+T) on reversal of the risk of oral, pharyngeal and oesophageal cancers. METHODS: A systematic literature search was conducted for publications evaluating risk of these three cancers among current and former users of BQ-T or BQ+T. The overall as well as subgroup meta-relative risks (meta-RR) were estimated using random-effect models. RESULTS: A total of 14 studies, seven each providing estimates for BQ-T and BQ+T, were identified. For BQ-T and oral cancer, a 28.9% risk reversal was observed among former users (meta-RR 5.61, 95% CI 2.24-14.04) compared to current users (meta-RR 7.89, 95% CI 3.90-15.98). A risk reversal of 48% was noted for pharyngeal cancer - former users (meta-RR 2.50, 95% CI 1.43-4.38), current users (meta-RR 4.81, 95% CI 2.05-11.30). For oesophageal cancer, no appreciable difference in risk was observed between current and former users.For BQ+T and oral cancer the overall meta-RR indicated a higher risk in former than in current users. However, sensitivity analysis including only better-quality studies showed a modestly lower cancer risk in former than in current users. Compared to current users, the risk in former users who quit less than 10 years ago (meta-RR 1.21, 95% CI 0.90-1.63) was increased, but decreased in former users who quit more than 10 years ago (meta-RR 0.72, 95% CI 0.48-1.07). CONCLUSION: Our analysis highlights for the first time the potential of risk reversal for oral and pharyngeal cancers following cessation of BQ-T and for oral cancer in long-term quitters (greater than 10 years) of BQ+T. The suggestive evidence from this systematic review further supports the imperative need of a strong policy to reduce the initiation of BQ use and inclusion of interventions for BQ cessation in cancer control efforts especially in geographic regions where BQ chewing is prevalent.

Inflammatory Markers and Mortality in Diabetic Versus Idiopathic Gastroparesis.

INTRODUCTION: Markers of systemic inflammation have been shown to be elevated in patients with gastroparesis (Gp). We hypothesized the presence of elevated markers of inflammation and/or coagulation can predict death in gastroparesis. METHODS: Retrospective evaluation of 396 patients with symptoms of gastroparesis with baseline measures of inflammation and coagulation, using a database of patients from 2001 through 2011 followed for an additional 5 plus years. Patients were divided into two groups; diabetic (DM; n=137) and non-diabetic (non-DM; n=259). Inflammation, evaluated by C-reactive protein (CRP), and coagulation by fibrinogen by factor VIII assays, was compared to patient mortality, reported as death during the follow-up period. RESULTS: Six DM and 13 non-DM patients died during the study period. DM patients had higher fibrinogen, CRP, and factor VIII levels of 454.0±135.2, 4.0±6.3, and 168±63.5, versus non-DM whose levels were 410.4±127.9, 2.6±4.9, 140.4±127.9, p=0.03, 0.001, and <0.001 respectively. Hypercoagulability risk differed by DM status (37% Vs. 29%, p=0.08). Compared to living non-DM, deceased non-DM/idiopathic patients had lower factor VIII (142.3±51.2 vs 117.7±40.3, p=0.07). The majority of deceased non-DM patients had abnormal fibrinogen (62%) but CRP and factor VIII were normal (80% and 85% respectively). CONCLUSIONS: In this sample of 396 patients with symptoms of gastroparesis, systemic inflammation and coagulopathy appear related to diabetes mellitus. Patients who died had markers of inflammation and coagulation that differed from those still alive. Further analysis may suggest a link between inflammation, hypercoagulability, and the mechanism for mortality in gastroparesis or as a marker of disease severity.

Higher coronavirus disease-19 mortality linked to comorbidities: A comparison between low-middle income and high-income countries.

BACKGROUND: Global burden of disease (GBD) provides the estimates of mortality and morbidity, while case fatality rate (CFR) helps in understanding the severity of the disease. People infected with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) with underlying medical conditions have shown higher levels of unfavorable outcomes including mortality. We assessed the association of SARS-CoV-2 CFR with disability-adjusted life years (DALY) of various comorbidities in the low-middle income countries (LMIC) and high-income countries (HIC) to study the relationship of coronavirus disease-19 (COVID-19) mortality with GBDs and to understand the linkage between COVID-19 mortality and comorbidities. MATERIALS AND METHODS: This was an ecological study with secondary data analysis comparing the DALY of various morbidities from GBD with CFR of COVID-19. Gross domestic product was the basis of stratifying 177 countries into low-middle income (LMIC) and high-income groups (HIC). The mortality was analyzed using Pearson correlation and linear regression. RESULTS: The median global CFR of SARS-CoV-2 was 2.15. The median CFR among LMIC (n = 60) and HIC (n = 117) was 2.01 (0.00-28.20) and 2.29 (0.00-17.26), respectively. The regression analysis found that, in both LMIC and HIC, maternal disorders were associated with higher SARS-CoV-2 CFR, while tuberculosis, mental health disorders, and were associated with lower CFR. Further, in LMIC, musculoskeletal disorders and nutritional deficiencies were associated with higher CFR, while respiratory disorders were associated with lower CFR. CONCLUSIONS: SARS-CoV-2 infection appears to be a systemic disease. Individuals with comorbidities, such as maternal disorders, neurological diseases, musculoskeletal disorders, and nutritional deficiencies, have poorer outcomes with COVID-19, leading to higher mortality.

Barriers and facilitators in implementing population based common cancer screening through community health workers.

Population based cancer screening was initiated in India in 2016 owing to an increased burden of cancers. A feasibility health system study was done by utilising community health workers (CHWs) to conduct the cancer screening. The current study is a qualitative study to elicit the barriers and facilitators in implementing population based cancer screening through CHWs. The study was conducted at three subcentres of Dholai block of Cachar district, Assam, India and Cachar Cancer Hospital and Research Center, Silchar. The participants of the study were CHWs, master trainer nurses and women from community. Three focus group discussions (FGDs) and one in-depth interview (IDI) were conducted at the provider level and seven IDIs of women from the community. The FGDs and IDIs were audio recorded after taking verbal consent from the participants. The verbatims were prepared following translation and transcription and data analysis using ATLAS ti ver 8. The major barrier faced by the community was a lack of motivation to get screened which stemmed from various factors such as personal beliefs, attitudes and fear. The major facilitators were accessibility of tests, family support and CHWs as screening service providers. The major barriers for CHWs were difficulty in motivating the community, lack of support from supervisors and lack of motivation to work. The major facilitators were convenience of screening during home visits, empowerment, skill enhancement and teamwork. Population based cancer screening was a new concept for the community under study. Cancer screening by CHWs was well accepted by the community. Awareness generation among the community was a major factor in improving screening coverage. The study highlights that training and motivation of CHWs can improve the uptake of cancer screening services. CHWs felt empowered with the new skills imparted and were able to carry out screening.

Tobacco use among urban slum dwellers attending a cancer screening clinic in the National Capital Region of India: a cross-sectional study.

BACKGROUND: Tobacco consumption in India varies based on the place of residence (urban/rural). Minimal, exclusive information exists regarding the same for 'urban slum' dwellers. The current study determines the tobacco use pattern among such individuals in Noida, Uttar Pradesh (India). METHODS: A cross-sectional study was conducted among the urban slum residents visiting the institutional clinic between December 2016 and June 2019. Apart from tobacco history, routine recording of the basic demographic details and oral visual examination was carried out for the participants. For categorical data, the percentage of different parameters was calculated and for quantitative data, descriptive statistics were calculated. Chi-square or Fisher's exact tests were employed to determine the association between the two categorical variables. To find the strength of association between tobacco use and the socio-demographic factors, univariate and multivariable binary logistic regression was used. RESULTS: Among 2,043 urban slum respondents (602 male, 1441 female), 15.0% (n = 308) currently consumed tobacco. The majority were smokeless tobacco (SLT) users (among both males and females). Among males, khaini (42.1%) and gutkha (32.5%) and among females gul (36.1%) were the most widely used tobacco products. CONCLUSION: The majority of the Noida urban slum population attending the screening clinic consumed SLT. Gender variation in the tobacco form and product-specific consumption patterns indicates that the undertaking of urban slums-specific surveys is essential. Tobacco control programmes must incorporate appropriate strategies addressing such subgroups of tobacco users.

Spongy wound dressing of pectin/carboxymethyl tamarind seed polysaccharide loaded with moxifloxacin beads for effective wound heal.

An attempt was made to formulate moxifloxacin loaded alginate beads incorporated into spongy wound dressing to heal chronic wounds as well as to reduce frequency of painful dressing change. Moxifloxacin loaded beads (sodium alginate:pectin, 1:1) were prepared by ionic gelation method, with entrapment efficiency 94.52%, crushing strength 25.30 N and drug release 90.52%. Beads were further incorporated into wound dressing, made of pectin and carboxymethyl tamarind seed polysaccharide (CMTSP). Spongy wound dressing was obtained by freeze drying technology, which showed good folding endurance, high wound fluid absorption and good crushing strength. Drug release was found to be 85.09%. Dressing made of CMTSP:pectin (1.5:2) showed good water vapour transmission and antibacterial activity. Porous nature of dressing absorbed exudates of wound. Excision wound model in rats revealed wound healing within 17 days: groups I (control), II (moxifloxacin beads loaded wound dressing), III (moxifloxacin beads), IV (pectin film) and V (sodium alginate film) showed 65.28, 99.09, 86.90, 66.84 and 64.30% wound closure, respectively. To conclude, moxifloxacin beads loaded spongy wound dressing has good healing and wound closing potential compared to pectin film and moxifloxacin beads. Thus, the formulation is novel for biomedical application which reduced the frequency of painful dressing change.

Association of metabolic NCD risk factors with oral, breast and cervical precancers and cancers in India.

OBJECTIVE: To find an association between metabolic non-communicable disease (NCD) risk factors (high blood pressure (BP), high random blood sugar (RBS) and overweight /obesity) and oral, breast, cervical cancers/precancerous or potentially malignant conditions. DESIGN: This is an observational study using convenience sampling. The participants were screened through opportunistic or population-based screening. SETTING: The study was conducted at a health promotion clinic (HPC) located in Northern India under the Indian Council of Medical Research. HPC is a screening clinic where screening is done for hypertension (HT), diabetes mellitus (DM), obesity, and oral, breast and cervical cancers. The study was conducted between December 2016 and January 2019. PARTICIPANT: The number of participants screened was 8352 (6712 women and 1640 men). All consenting men and women above 18 years were included. All participants were screened for oral cancer, DM, HT and obesity. All women were also screened for breast and cervical cancers. Cervical screening was done for non-pregnant women 21 years and above with history of sexual activity. RESULT: Oral potentially malignant disease (OPMD) was the most prevalent, followed by breast cancer, oral cancer, cervical cancer and cervical precancer. High RBS had a strong association with oral cancer (OR=2.29, 95% CI 1.09 to 4.82, p=0.03) and breast cancer (OR=1.95, 95% CI 1.01 to 3.76, p=0.05). High BP had a strong association with breast cancer (OR=2.50, 95% CI 1.43 to 4.35, p<0.0001). An inverse association was noted between oral cancer and overweight/obesity (OR=0.20, 95% CI 0.08 to 0.48, p<0.0001). Current tobacco use was strongly associated with oral cancer (OR=6.51, 95% CI 3.63 to 11.67, p<0.0001) and OPMD (OR=9.82, 95% CI 8.13 to 11.86, p<0.0001). No association was elicited between the metabolic NCD risk factors and cervical cancer/precancer. CONCLUSIONS: The study reaffirms that NCD metabolic risk factors determine oral and breast cancers. Besides NCD risk factors, current tobacco use was a strong determinant of OPMD and oral cancer. Hence, primary and primordial prevention measures to control NCD metabolic risk factors and tobacco use should move along with secondary prevention of breast and oral cancers.

Trichophyton tonsurans induced recurrent onychomadesis in a very young infant.

Onychomadesis, or nail shedding, is rarely seen in children and can be due to stress, systemic illnesses, trauma, and drug therapy or may be idiopathic. Fungal infection of the nail is only rarely reported as a cause of onychomadesis. We present here a case of Trichophyton tonsurans-induced onychomycosis and resultant onychomadesis in a 9-month-old boy with onset of lesions at 2 weeks of life.

Efficacy of oral prednisolone use in the treatment of infantile hemangiomas in Indian children.

Approximately 10% to 15% of patients with infantile hemangioma (IH) require treatment that needs to be individualized according to the size, location, and type of IH. Oral corticosteroids [CS] have been the mainstay of therapy, but dose and duration of therapy have been variably reported in literature. The possible side effects with high dose CS is a constant deterrant. Twenty infants with IH requiring therapy were treated with prednisolone at a dose of 3 to 4 mg/kg/day. Response to therapy, adverse effects, and risk of rebound growth were monitored. All of the treated lesions responded to prednisolone at 3.1 mg/kg/day given for a mean duration of 9.16 weeks by showing a cessation of active growth; 90% of patients showed partial to excellent response (Grade 2 to Grade 4 improvement). In the remaining 10% of patients there was <25% regression in the lesion. The total duration of therapy with tapering doses was 29.9 weeks. No cases of rebound growth were seen. The incidence of adverse effects was low, with one patient developing CS-induced hypertension (5%). Oral CS, given at appropriate doses, are a reasonably safe and highly efficacious treatment modality for IH. To prevent the risk of rebound growth, adequate prolongation of therapy is required.

Combination of oral corticosteroids and polidocanol sclerotherapy in the management of infantile hemangiomas.

BACKGROUND: Infantile hemangiomas (IHs) are the most common benign tumors of infancy and may need to be treated in some cases. Oral corticosteroids are the mainstay of therapy but are not without their attendant side effects. OBJECTIVES: To evaluate the efficacy of combination therapy with oral corticosteroids and polidocanol sclerotherapy in hemangiomas needing treatment. PATIENTS AND METHODS: Eight children with IHs were started on oral prednisolone 3 to 4 mg/kg per day and fortnightly sclerotherapy with 3% polidocanol solution. The outcome was evaluated on the basis of color, turgidity of the lesion, ongoing growth, and assessment by parents and physician. Serial photographic records were maintained. The response was graded as excellent, good, poor, or nil. Complications were recorded. RESULTS: Four male and four female patients presented at a mean age of 4.6 months. The average area of the lesions was 40.6 cm(2) . The mean duration of treatment with steroids at full dose was 8.2 weeks and mean total duration of treatment was 28.6 weeks. Mean number of sclerotherapy sessions required was 4.7. Complications included ischemic necrosis, rebound growth, and ulceration. CONCLUSION: Combining oral corticosteroids with polidocanol sclerotherapy produced excellent results in the patients treated, with minimal attendant side effects.