Challenges and Therapeutic Approaches for the Protein Delivery System: A Review.

The protein delivery system is one of the innovative or novel drug delivery systems in the present era. Proteins play an indispensable role in our body and are mainly found in every part, like tissue and cells of our body. It also controls various functions, such as maintaining our tissue, transportation, muscle recovery, enzyme production and acting as an energy source for our body. Protein therapeutics have big future perspectives, and their use in the treatment of a wide range of serious diseases has transformed the delivery system in the pharmaceutical and biotechnology industries. The chief advantage of protein delivery is that it can be delivered directly to the systemic circulation. So far, parenteral routes, such as intravenous, intramuscular, and subcutaneous, are the most often used method of administering protein drugs. Alternative routes like buccal, oral, pulmonary, transdermal, nasal, and ocular routes have also shown a remarkable success rate. However, as with all other types of delivery, here, several challenges are posed due to the presence of various barriers, such as the enzymatic barrier, intestinal epithelial barrier, capillary endothelial barrier, and blood-brain barrier. There are several approaches that have been explored to overcome these barriers, such as chemical modification, enzymatic inhibitors, penetration enhancers, and mucoadhesive polymers. This review article discusses the protein, its functions, routes of administration, challenges, and strategies to achieve ultimate formulation goals. Recent advancements like the protein Pegylation method and Depofoam technology are another highlight of the article.

Pharmaceutical Suspensions: An Updated Patent Review on Novel Suspending Agents and Recent Advancement.

A wide variety of dosage forms are used for the oral administration of drugs to humans and animals. Apart from solid dosage forms, it also includes liquid dosage forms, such as solutions, suspensions, and emulsions. The selection is based on the physiochemical attributes of the therapeutically active ingredient. Suspensions are classified as dispersed systems that are heterogeneous in nature and consist of two phases. One phase is the continuous phase, the dispersion medium, or the external phase, which is either liquid or semisolid; the other is a solid particle dispersed in the external phase and called an internal or dispersed phase. They have several advantages over other dosage forms, such as effectively delivering hydrophobic drugs, avoiding the need for cosolvents, masking unpleasant tastes, and providing resistance to degradation and easy swallowing for young or elderly patients. They also attain higher drug concentrations compared to solution forms. This review article aims to study and explore the advantages, novel suspending agents, patent preference, and innovations of pharmaceutical suspension. It was targeted to scrutinize the literature floating in the internet domain regarding pharmaceutical suspension for delivery of drugs by oral route. The literature survey is targeted at the novel herbal suspending agents used, their patents involved, and innovations in the dosage form. Further, the study gives an insight into various aspects of suspension, such as classification of suspension, theories of suspension, various components used in suspension formulation, formulation aspect of suspension, evaluation parameters of suspension, patents, innovations, and regulatory status.

Development, optimization and evaluation of solid lipid nanoparticles of Celecoxib.

BACKGROUND: As indicated by the biopharmaceutical classification system, Celecoxib is a class II moiety. Many endeavors have been made to improve its solubility and consequently its dissolution rate, thus enhancing its overall bioavailability. In the present investigation, the nano-lipid technology was exploited to control the release of celecoxib (CXB) to overcome its dissolution problem. Solid lipid nanoparticles (SLNs) have a small particle size (50-1000 nm) that results in a large surface area-to-volume ratio, which further enhances the contact between the drug and the dissolution medium. This leads to improved drug release and absorption. Moreover, SLNs can solubilize hydrophobic drugs within the lipid matrix, increasing their effective solubility and facilitating their dissolution in an aqueous environment. AIM AND OBJECTIVE: The objective of the study was to enhance the solubility and bioavailability of a BCS Class-II drug-celecoxib formulating it as solid lipid nanoparticles. In order to overcome all its limitations, solid lipid nanoparticles of Celecoxib were developed, optimized, and evaluated for in-vitro and in-vivo parameters. METHODS: The CXB loaded-SLNs were prepared by solvent emulsification-diffusion technique. SLN was characterized using Fourier transform infra spectroscopy (FTIR) and evaluated for entrapment efficiency, drug loading, particle size, Polydispersity index (PDI), zeta potential, In-vitro release studies as well as in- vivoanti-inflammatory studies using rat paw edema method. The SLN formulations were optimized by central composite design (Design Expert 11- trial version). RESULTS: On the basis of outcomes of CCD the optimized formulation OF1 was selected as a desirable formulation. Its particle size, PDI, and zeta potential were found to be 314 nm, 0.204, and -18.73 respectively. It exhibited high entrapment efficiency (79±0.18 %) and drug loading (44.38±0.21 %). In-vitro release studies of the optimized formulation displayed the Korsemeyer-Peppas model with a maximum drug release of 89.42 ±0.12 % in 24 h. In-vivo studies also revealed that OF1 formulation reduced the rat paw volume to a minimum (1±0.32) in 24 h when compared to pure API (2±0.62) and marketed preparation (2±0.42). CONCLUSION: The results revealed that in-vitro release studies of optimized formulation exhibited a sustained drug release delivery. In-vivo anti-inflammatory studies proved that the CXB-loaded SLNs enhance the oral bioavailability more than pure API.

Glyceryl behenate-based solid lipid nanoparticles as a carrier of haloperidol for nose to brain delivery: formulation development, in-vitro, and in-vivo evaluation

Abstract This study was aimed to develop the haloperidol (HPL) loaded solid lipid nanoparticles (SLNs) for brain targeting through the intranasal route. SLNs were fabricated by the emulsification diffusion technique using glyceryl behenate as lipid and tween 80 as a surfactant. SLNs were evaluated for particle size, zeta potential, structure, entrapment efficiency, solid state characterization by differential scanning calorimetry (DSC), and in-vitro release. In-vivo biological evaluation was performed on albino Wistar rats for the determination of pharmacokinetic as well as brain targeting parameters. Particle size, PDI, zeta potential, and entrapment efficiency of optimized formulation (HPL-SLNs 6) were found to be 103±09 nm, 0.190±0.029, -23.5±1.07 mV, and 79.46±1.97% respectively. In-vitro drug release studies exhibited that 87.21± 3.63% of the entrapped drug was released from the SLNs within 24 h. DSC curves confirmed that during entrapment in SLNs, the drug was solubilized in the lipid matrix and converted into the amorphous form. Enhanced HPL targeting to the brain was observed from HPL-SLNs as compared to HPL-Sol when administered intranasally. The value of AUC 0-∞ in the brain for HPL-SLNs i.n. was found to be nearly 2.7 times higher than that of HPL-Sol i.v., whereas 3.66 times superior to HPL-Sol administered i.n. Stability studies revealed that the formulation remains unchanged when stored at 4±2 °C (refrigerator) and 25±2 °C /60 ±5% RH up to six months. Finally, it could be concluded that SLN is a suitable carrier for HPL with enhanced brain targeting through i.n administration, as compared to the HPL-Sol, administered i.n. and i.v.

Luminescent naphthalimide-tagged ruthenium(ii)-arene complexes: cellular imaging, photocytotoxicity and transferrin binding.

Two water-soluble piano-stool shaped ruthenium(ii)-arene complexes, [RuII(η6-p-cymene)(L)Cl2] [RuLCl] and [RuII(η6-p-cymene)(L)(PTA)Cl] [RuLPTA], were designed as emissive photocytotoxic agents tagged with morpholine as the lysosome targeting moiety. Here, L = N-(2-morpholinoethyl)-4-(2-aminoethyl)amino-naphthalimide, and PTA = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane. The crystal structure of [RuLCl] exhibits the pseudooctahedral 'three-legged piano-stool' geometry, wherein Ru(ii) is bound to the η6-p-cymene moiety as a base and two chlorides and the amine-N of the ligand L occupies the three legs of the stool. The complexes exhibited both the possibility of covalent adduct formation via the hydrolyzed Ru-Cl bond and non-covalent intercalation binding through planar naphthalimide moieties. The complexes showed enhanced photo-cytotoxicity under low-power blue LED light irradiation (λmax = 448 nm) mediated by 1O2, thereby acting as potential PDT agents. Fluorescence microscopy studies revealed that luminescent complexes preferentially localized in both the lysosomes and nucleus for effectively targeting and damaging the nuclear DNA for PDT effects. Due to enhanced lipophilicity of [RuLCl], it showed higher internalization into MCF-7 cell, measured in terms of the ruthenium content using ICP-MS. The interaction of the complexes with human transferrin (hTf) proteins was studied through molecular docking calculations, suggesting favorable binding through histidine residues and possible internalization into cancer cells via TfR-mediated endocytosis. The luminescence properties of the complexes were well-utilized to study their cellular uptake mechanism via endocytosis using fluorescence microscopy.

Global trends in nature's contributions to people.

Declining biodiversity and ecosystem functions put many of nature's contributions to people at risk. We review and synthesize the scientific literature to assess 50-y global trends across a broad range of nature's contributions. We distinguish among trends in potential and realized contributions of nature, as well as environmental conditions and the impacts of changes in nature on human quality of life. We find declining trends in the potential for nature to contribute in the majority of material, nonmaterial, and regulating contributions assessed. However, while the realized production of regulating contributions has decreased, realized production of agricultural and many material commodities has increased. Environmental declines negatively affect quality of life, but social adaptation and the availability of substitutes partially offset this decline for some of nature's contributions. Adaptation and substitutes, however, are often imperfect and come at some cost. For many of the contributions of nature, we find differing trends across different countries and regions, income classes, and ethnic and social groups, reinforcing the argument for more consistent and equitable measurement.

Nanostructured Lipid Carriers: A Groundbreaking Approach for Transdermal Drug Delivery.

Nanostructured lipid carriers (NLCs) are novel pharmaceutical formulations which are composed of physiological and biocompatible lipids, surfactants and co-surfactants. Over time, as a second generation lipid nanocarrier NLC has emerged as an alternative to first generation nanoparticles. This review article highlights the structure, composition, various formulation methodologies, and characterization of NLCs which are prerequisites in formulating a stable drug delivery system. NLCs hold an eminent potential in pharmaceuticals and cosmetics market because of extensive beneficial effects like skin hydration, occlusion, enhanced bioavailability, and skin targeting. This article aims to evoke an interest in the current state of art NLC by discussing their promising assistance in topical drug delivery system. The key attributes of NLC that make them a promising drug delivery system are ease of preparation, biocompatibility, the feasibility of scale up, non-toxicity, improved drug loading, and stability.

Fate of GdF3 nanoparticles-loaded PEGylated carbon capsules inside mice model: a step toward clinical application.

The successful translation of nanostructure-based bioimaging and/or drug delivery system needs extensive in vitro and in vivo studies on biocompatibility, biodistribution, clearance, and toxicity for its diagnostic applications. Herein, we have investigated the in vitro cyto-hemocompatibility, in vivo biodistribution, clearance, and toxicity in mice after systemic administration of GdF3 nanoparticles loaded PEGylated mesoporous carbon capsule (GdF3-PMCC)-based theranostic system. In vitro cyto-hemocompatibility study showed a very good biocompatibility up to concentration of 500 µg/ml. Biodistribution studies carried out from 1 h to 8 days showed that GdF3-PMCC was found in major organs, such as liver, kidney, spleen, and muscle till 4th day and it was negligible in any tissue after 8th day. The clearance study was carried out for a period of 8 days and it was observed that the urinary system is the main route of excretion of GdF3-PMCC. The tissue toxicity study was done for 15 days and histopathological analysis indicated that the GdF3-PMCC based theranostic system does not have any adverse effect in tissues. Thus, PMCCs are nontoxic and can be applied as theranostic agents in contrast to the other carbon-based systems (PEGylated carbon nanotubes and PEGylated graphene oxide) which showed significant toxicity.

Self-Emulsifying Drug Delivery System of Simvastatin: Formulation Development, Optimization by Box- Behnken Design, In-Vitro and In-Situ Single-Pass Intestinal Perfusion (SPIP) Studies.

PURPOSE: The purpose of the study was formulation development, optimization and evaluation of a Self-Emulsifying Drug Delivery System (SEDDS) of Simvastatin (SIM) for improvement in dissolution and bioavailability of SIM. Solubility enhancement of Biopharmaceutical Classification System (BCS) Class-II drugs is a burning topic and attracting various publications and patents regarding different strategies employed for improvement of dissolution viz., USOO5340591A (Solid dispersion), US005472954A, US005646131A (complexation), USOO5858410A (Nanosuspensions), USOO5874029A (micronization) US2008.00095O2A1 (Solid composites), US2008O146640A1 (Prodrug) US 2009001 1009 A1 (nanocapsules), etc. Methods: SEDDS was prepared on the basis of solubility studies employing Capmul MCM EP as lipid and Cremophor ELP as surfactant. Box-Behnken design was implemented for optimization by using lipid concentration, surfactant concentration and mixing time as dependent variables and their impact was observed on particle size, poly dispersity index (PDI) and drug released in 15min. Optimized formulation was evaluated for particle size, PDI, zeta potential, emulsification time, transmittance, invitro drug release and in situ Single-Pass Intestinal Perfusion (SPIP) studies. RESULTS: For optimized formulation, OF1 value of particle size, PDI, zeta potential, emulsification time, transmittance and percent in-vitro release were 162±14.32nm, 0.19±0.01, -22.3 ±1.1mV, 93±3.11 sec, 99.45±4.35 % and 99.43± 5.6 % in 30 min respectively. In-situ SPIP studies were performed on Wistar rats and the value of predicted fraction absorbed for humans was found to be 0.98. CONCLUSION: SIM SEDDS was successfully developed and evaluated for in-vitro & in-vivo parameters. All the evaluated parameters were in tolerable limits. In vitro release studies from optimized formulation, OF1, exhibited maximum drug release when compared to SIM API and marketed preparation. Moreover, the predicted value of fraction absorbed (Fa) in humans by in-situ SPIP method was also in agreement with in-vitro dissolution studies thus, confirming SEDDS as a suitable drug delivery system for solubility enhancement of SIM.

Photoactive platinum(II) complexes of nonsteroidal anti-inflammatory drug naproxen: Interaction with biological targets, antioxidant activity and cytotoxicity.

The effect on the therapeutic efficacy of Pt(II) complexes on combining non-steroidal anti-inflammatory drugs (NSAIDs) is an attractive strategy to circumvent chronic inflammation mediated by cancer and metastasis. Two square-planar platinum(II) complexes: [Pt(dach)(nap)Cl] (1) and [Pt(dach)(nap)2] (2), where dach = (1R,2R)-dichloro(cyclohexane-1,2-diamine) and NSAID drug naproxen (nap), have been designed for studying their biological activity. The naproxen bound to the Pt(II) centre get released upon photoirradiation with low-power UV-A light as confirmed by the significant enhancement in emission intensities of the complexes. The compounds were evaluated for their photophysical properties, photostability, reactivity with 5'-guanosine monophophosphate (5'-GMP), interactions with CT-DNA and BSA, antioxidant activity and reactive oxygen species mediated photo-induced DNA damage properties. ESI-MS studies demonstrated the formation of bis-adduct with 5'-GMP and the formation of PtII-DNA crosslinks by gel electrophoretic mobility shift assay and ITC studies. The interaction of the complexes 1 and 2 with the CT-DNA exhibits potential binding affinity (Kb âˆ¼ 104 M-1, Kapp∼ 105 M-1), implying intercalation to CT-DNA through planar naphthyl ring of the complexes. Both the complexes also exhibit strong binding affinity towards BSA (KBSA∼ 105 M-1). The complexes exhibit efficient DNA damage activity on irradiation at 365 nm via formation of singlet oxygen (1O2) and hydroxyl radical (•OH) under physiological conditions. Both the complexes were cytotoxic in dark and exhibit significant enhancement of cytotoxicity upon photo-exposure against HeLa and HepG2 cancer cells giving IC50 values ranging from 8 to 12 µM for 1 and 2. The cellular internalization data showed cytosolic and nuclear localization of the complexes in the HeLa cells.

Dual Role of Subepithelial Connective Tissue Grafting in Regeneration of Periodontal Attachment Apparatus.

Periodontal plastic and aesthetic surgery are gaining significant momentum owing to the increasing aesthetic demands by patients. Along with the fulfilment of aesthetic needs, it is imperative that clinicians also enhance function. From these two important viewpoints, subepithelial connective tissue grafting remains an optimum treatment choice for periodontists when treating gingival recession defects accompanied by periodontal attachment apparatus breakdown. Clinical relevance: Subepithelial connective tissue grafting is a successful procedure in its dual role of gingival recession coverage and predictable periodontal regeneration.

Assessment and management of halitosis.

Halitosis is an unpleasant condition that may be the origin of concern not only for a possible health condition but also for frequent psychological alterations which may lead to social and personal isolation. The most frequent sources of halitosis that exist in the oral cavity include bacterial reservoirs such as the dorsum of the tongue, saliva and periodontal pockets. Volatile sulphur compounds (VSCs) are the prominent elements of oral malodour. Genuine halitosis and pseudo-halitosis should be in the treatment realm of dental practitioners. Clinical Relevance: Halitosis can be a symptom of underlying systemic disease, therefore the exact diagnosis and its source (oral or non-oral) is important in the proper approach to its management.