Thermoreversible Carbamazepine In Situ Gel for Intranasal Delivery: Development and In Vitro, Ex Vivo Evaluation.

Over the past decade, intranasal (IN) delivery has been gaining attention as an alternative approach to conventional drug delivery routes targeting the brain. Carbamazepine (CBZ) is available as an orally ingestible formulation. The present study aims to develop a thermoreversible in situ gelling system for delivering CBZ via IN route. A cold method of synthesis has been used to tailor and optimize the thermoreversible gel composition, using poloxamer 407 (P407) (15-20% w/v) and iota carrageenan (É©-Cg) (0.15-0.25% w/v). The developed in situ gel showed gelation temperatures (28-33°C), pH (4.5-6.5), rheological properties (pseudoplastic, shear thinning), and mucoadhesive strength (1755.78-2495.05 dyne/cm2). The in vitro release study has shown sustained release behavior (24 h) for gel, containing significant retardation of CBZ release. The release kinetics fit to the Korsmeyer-Peppas model, suggesting the non-Fickian diffusion type controlled release behavior. Ex vivo permeation through goat nasal mucosa showed sustained release from the gel containing 18% P407 with the highest cumulative drug permeated (243.94 µg/cm2) and a permeation flux of 10.16 µg/cm2/h. After treatment with CBZ in situ gel, the barrier function of nasal mucosa remained unaffected. Permeation through goat nasal mucosa using in situ gel has demonstrated a harmless nasal delivery, which can provide a new dimension to deliver CBZ directly to the brain bypassing the blood-brain barrier.

Formulation development of paracetamol instant jelly for pediatric use.

OBJECTIVE: Paracetamol is a common antipyretic and analgesic medicine used in childhood illness by parents and physicians worldwide. Paracetamol has a bitter taste that is considered as a significant barrier for drug administration. This study aimed to develop an oral dosage form that is palatable and easy to swallow by pediatric patients as well as to overcome the shortcomings of liquid formulations. METHODS: The paracetamol was encapsulated in beads, which were prepared mainly from alginate and chitosan through electrospray technique. The paracetamol beads were sprinkled on the instant jelly prepared from glycine, ι-carrageenan and calcium lactate gluconate. The paracetamol instant jelly characteristics, in terms of physical appearance, texture, rheology, in vitro drug release and palatability were assessed on a human volunteer. RESULTS: The paracetamol instant jelly was easily reconstituted in 20 mL of water within 2 min to form jelly with acceptable consistency and texture. The jelly must be ingested within 30 min after reconstitution to avoid the bitter taste. The palatability assessment carried out on 12 human subjects established the similar palatability and texture of the paracetamol instant jelly dosage comparable to the commercial paracetamol suspension and was found to be even better in overcoming the aftertaste of paracetamol. CONCLUSION: Such findings indicate that paracetamol instant jelly will compensate for the use of sweetening and flavoring agents as well as develop pediatric dosage forms with limited undesired excipients.

Assessment of preclinical pharmacokinetics and acute toxicity of pioglitazone and telmisartan combination.

The prevalence of hypertension is very common amongst the diabetic patients and is reported as the major cause of mortality in diabetes. Pioglitazone reported to have an ability to alter the blood cholesterol level and cardioprotective efficiency along with its antidiabetic activity. Telmisartan, through activation of PPAR-γ receptor exerts insulin sensitizing property in addition to its primary cardioprotective efficiency. Theoretically, a combination of pioglitazone and telmisartan may be beneficial to effectively control the high blood glucose level and management of coexisting cardiovascular complication in diabetes. The aim of this research was to experimentally evaluate the pharmacokinetic interaction of pioglitazone and telmisartan when are coadministered in rat. Pioglitazone and telmisartan were administered orally as a single dose individually and in combination to the rats. The plasma samples of the pharmacokinetic study were analyzed using a validated LCMS method. The acute toxicity of the combination with a high dose in rats was also evaluated as a part of the determination of its safety profile. There was no significant change in pharmacokinetic parameters were resulted due to the coadministration of pioglitazone and telmisartan in rat. Absence of major toxicological effect supports the in vivosafety of the combination.

Polymeric behavior evaluation of PVP K30-poloxamer binary carrier for solid dispersed nisoldipine by experimental design.

CONTEXT: High melting point polymeric carrier without plasticizer is unacceptable for solid dispersion (SD) by melting method. Combined polymer-plasticizer carrier significantly affects drug solubility and tableting property of SD. OBJECTIVE: To evaluate and optimize the combined effect of a binary carrier consisting PVP K30 and poloxamer 188, on nisoldipine solubility and tensile strength of amorphous SD compact (SDcompact) by experimental design. MATERIALS AND METHODS: SD of nisoldpine (SDnisol) was prepared by melt mixing with different PVP K30 and poloxamer amount. A 32 factorial design was employed using nisoldipine solubility and tensile strength of SDcompact as response variables. Statistical optimization by design expert software, and SDnisol characterization using ATR FTIR, DSC and microscopy were done. RESULTS: PVP K30:poloxamer, at a ratio of 3.73:6.63, was selected as the optimized combination of binary polymeric carrier resulting nisoldipine solubility of 115 µg/mL and tensile strength of 1.19 N/m2. DISCUSSION: PVP K30 had significant positive effect on both responses. Increase in poloxamer concentration after a certain level decreased nisoldipine solubility and tensile strength of SDcompact. CONCLUSION: An optimized PVP K30-poloxamer binary composition for SD carrier was developed. Tensile strength of SDcompact can be considered as a response for experimental design to optimize SD.

Safety profiling of pioglitazone and telmisartan combination by sub-chronic toxicity study in rat.

It has been reported that the major cause of mortality in diabetes is cardiovascular diseases and contribution of hypertension is significant in this context. Pioglitazone, a thiazolidinedione class of therapeutic agent is used to treat type 2 diabetes mellitus. Telmisartan, an angiotensin receptor blocker antihypertensive has been reported to have beneficial effect if co-administered with pioglitazone for the management of diabetes complications. The present research work aims to evaluate the safety/toxicity profile of this combination in rat model. The investigation was carried out after co-administering the drugs to the rats for 28 days at three dose levels of 50, 100 and 150 mg/kg covering low to high dose ranges. Various hematological and biochemical parameters were studied in addition to the histopathology of the major organs in order to evaluate the toxicity profile of the combination. Absence of mortality and histopathological changes as well as unaltered hematological and biochemical parameters was observed. This preliminary investigation concludes that the combination of pioglitazone and telmisartan can primarily be stated as safe in animals, even at the dose level which is several folds higher than the intended human dose. Thus, this combination can be explored in future to develop a rational therapy regimen to treat hypertensive diabetic patients.

Lactoferrin Reduces Surfactant Content in the Self-Emulsifying Drug Delivery System.

Self-emulsifying drug delivery systems (SEDDSs) can effectively be employed to formulate drugs with poor oral bioavailability due to low aqueous solubility and high first-pass metabolism. High surfactant content is an existing challenge toward the successful application of SEDDS. A SEDDS is developed with lactoferrin, a natural emulsifier to reduce the Tween content of a fenofibrate (FEN) formulation. FEN SEDDS (SEDDS without lactoferrin) and FEN Lf-SEDDS (SEDDS with lactoferrin) were developed with 30% and 21% Tween content, respectively. Both formulations containing Crodamol GTCC as a lipid component were thermodynamically stable. No significant difference was observed in zeta potential (-9.25 to -12.63 mV), drug content (>85%), and percentage transmittance (>99%) between the two formulations. FEN Lf-SEDDS resulted in higher viscosity and larger particle size than FEN SEDDS. Solidified SEDDS with Aerosil 200 significantly improved in vitro drug release from both formulations than pure FEN. However, FEN SEDDS and FEN Lf-SEDDS did not show a significant difference in cumulative percent release or dissolution efficiency at 120 min. It can be concluded that lactoferrin containing SEDDS with 27% lesser synthetic surfactants (Tween 80 and Span 80) can result in similar physicochemical characteristics. Oral pharmacokinetic study of FEN Lf-SEDDS in a rat model resulted in 1.3 and 5.5 times higher relative bioavailability than marketed product and pure drug, respectively. The addition of lactoferrin could substitute synthetic surfactants in self-emulsifying drug delivery systems significantly.

Biomedical Application of Chitosan and Chitosan Derivatives: A Comprehensive Review.

Chitosan (CS) is a widely known naturally occurring polysaccharide made of chitin. The Low solubility of chitosan in water restricts its use in medical applications. However, several chemical modifications have made chitosan superior in solubility, biocompatibility, biodegradability, stability, and easy functionalization ability. All these favourable properties have increased chitosan's application in drug delivery and biomedical fields. Chitosan-based nanoparticles or biodegradable controlled-release systems are of great interest to scientists. Layer -by-layer technique is employed to develop hybrid chitosan composites. Such modified chitosan is widely used in wound healing and several tissue engineering approaches. This review brings together the potential of chitosan and its modified form in biomedical applications.

Comparison of Two Grafted Copolymers, Soluplus and Kollicoat IR, as Solid Dispersion Carriers of Arteether for Oral Delivery Prepared by Different Solvent-Based Methods.

Arteether (ART), an antimalarial drug, belongs to BCS class II and has very low oral bioavailability. Clinically, it is given as a solution in oil by the intramuscular route. Solid dispersion in Soluplus or Kollicoat IR, two commonly used grafted copolymers, may improve its in vitro dissolution and oral bioavailability. ART solid dispersion was prepared by three solvent-based methods: rotary evaporation (ethanol as solvent), spray drying (hydro-alcoholic solvent), and freeze-drying (aqueous solvent). ART-polymer miscibility increases with increasing polymeric concentrations up to 4% or 6%. Spray drying resulted in the highest increment of ART saturation solubility (476.01 ± 10.01 mg/L) than that of rotary evaporation (432.22 ± 15.76 mg/L) or freeze-drying (122.97 ± 2.94 mg/L) in the drug-Soluplus (1:1 w/w) ratio. Also, with Kollicoat IR-based solid dispersion, the same trend was observed. The drug-polymer ratio of 1:3 (w/w) showed a decrease in saturation solubility. Spray-dried products were better for flow properties (Carr index: 21.27 ± 0.98 for the 1:1 ratio of drug-Soluplus solid dispersion) than the other two methods. An enteric-coated capsule was prepared with an ART-Soluplus (1:1) ratio, selected based on the saturation solubility and downstream feasibility compared with those of Kollicoat IR. Eudragit L-100-coated enteric capsules containing 100 mg equivalent ART showed 88.88 ± 2.9% drug release in phosphate buffer pH 6.8 medium, which is significantly higher than that in raw drug (<10%) and a physical mixture of the exact composition of solid dispersion (44%). The study concluded that Soluplus possesses better properties as a solid dispersion carrier than those of Kollicoat IR. A stable, partially amorphous solid dispersion of ART was developed that can provide improved oral bioavailability.

Role of angiotensin receptor blockers in the context of Alzheimer's disease.

As the world's population ages, the prevalence of age-related neurological disorders such as Alzheimer's disease (AD) is increasing. There is currently no treatment for Alzheimer's disease, and the few approved medications have a low success rate in lowering symptoms. As a result, several attempts are underway worldwide to identify new targets for the therapy of Alzheimer's disease. In preclinical studies of Alzheimer's disease, it was recently found that inhibition of angiotensin-converting enzyme (ACE) and blocking of the angiotensin II receptors reduce symptoms of neurodegeneration, Aß plaque development, and tau hyperphosphorylation. Angiotensin II type I (AT1) blockers, such as telmisartan, candesartan, valsartan, and others, have a wide safety margin and are commonly used to treat hypertension. Renal and cardiovascular failures are reduced due to their vascular protective actions. Inhibition of AT1 receptors in the brain has a neuroprotective impact in humans, reducing the risk of stroke, increasing cognition, and slowing the progression of Alzheimer's disease. The review focuses on the mechanisms via which AT1 blockers may act beneficially in Alzheimer's disease. Although their effect is evident in preclinical studies, clinical trials, on the other hand, are in short supply to validate the strategy. More dose-response experiments with possible AT1 blockers and brain-targeted administration will be needed in the future.

Role of Fine Silica as Amorphous Solid Dispersion Carriers for Enhancing Drug Load and Preventing Recrystallization- A Comprehensive Review.

Amorphous solid dispersion (ASD) is a popular concept for improving the dissolution and oral bioavailability of poorly water-soluble drugs. ASD faces two primary challenges of low drug loading and recrystallization upon storage. Several polymeric carriers are used to fabricate a stable ASD formulation with a high drug load. The role of silica in this context has been proven significant. Different types of silica, porous and nonporous, have been used to develop ASD. Amorphous drugs get entrapped into silica pores or adsorbed on their surface. Due to high porosity and wide surface area, silica provides better drug dissolution and high drug loading. Recrystallization of amorphous drugs is inhibited by limited molecular ability inside the delicate pores due to hydrogen bonding with the surface silanol groups. A handful of researches have been published on silica-based ASD, where versatile types of silica have been used. However, the effect of different kinds of silica on product stability and drug loading has been rarely addressed. The present study analyzes multiple porous and nonporous silica types and their distinct role in developing a stable ASD. Emphasis has been given to various types of silica which are commonly used in the pharmaceutical industry.

Refinement of safety and efficacy of anti-cancer chemotherapeutics by tailoring their site-specific intracellular bioavailability through transporter modulation.

Low intracellular bioavailability, off-site toxicities, and multi drug resistance (MDR) are the major constraints involved in cancer chemotherapy. Many anticancer molecules fail to become a good lead in drug discovery because of their poor site-specific bioavailability. Concentration of a molecule at target sites is largely varied because of the wavering expression of transporters. Recent anticancer drug discovery strategies are paying high attention to enhance target site bioavailability by modulating drug transporters. The level of genetic expression of transporters is an important determinant to understand their ability to facilitate drug transport across the cellular membrane. Solid carrier (SLC) transporters are the major influx transporters involved in the transportation of most anti-cancer drugs. In contrast, ATP-binding cassette (ABC) superfamily is the most studied class of efflux transporters concerning cancer and is significantly involved in efflux of chemotherapeutics resulting in MDR. Balancing SLC and ABC transporters is essential to avoid therapeutic failure and minimize MDR in chemotherapy. Unfortunately, comprehensive literature on the possible approaches of tailoring site-specific bioavailability of anticancer drugs through transporter modulation is not available till date. This review critically discussed the role of different specific transporter proteins in deciding the intracellular bioavailability of anticancer molecules. Different strategies for reversal of MDR in chemotherapy by incorporation of chemosensitizers have been proposed in this review. Targeted strategies for administration of the chemotherapeutics to the intracellular site of action through clinically relevant transporters employing newer nanotechnology-based formulation platforms have been explained. The discussion embedded in this review is timely considering the current need of addressing the ambiguity observed in pharmacokinetic and clinical outcomes of the chemotherapeutics in anti-cancer treatment regimens.

A review on taste masked multiparticulate dosage forms for paediatric.

Taste refers to those sensations perceived through taste buds on the tongue and oral cavity. The unpleasant taste of drugs leads to the refusal of taking the medicine in the paediatric population. It is widely known that a pharmaceutical product's general acceptability is the result of numerous contributing components such as swallowability, palatability (taste, flavour, texture, and mouthfeel), appearance, ease of administration, and patient characteristics. Multiparticulate as a dosage form is a platform technology for overcoming paediatrics' incapacity to swallow monolithic dosage forms, masking many medications' inherent nasty taste, and overcoming the obstacles of manufacturing a commercially taste masked dosage form. This review will discuss the considerations that must be taken into account to prepare taste masked multiparticulate dosage forms in the best way for paediatric use.

Strategies to improve the stability of amorphous solid dispersions in view of the hot melt extrusion (HME) method.

Oral administration of drugs is preferred over other routes for several reasons: it is non-invasive, easy to administer, and easy to store. However, drug formulation for oral administration is often hindered by the drug's poor solubility, which limits its bioavailability and reduces its commercial value. As a solution, amorphous solid dispersion (ASD) was introduced as a drug formulation method that improves drug solubility by changing the molecular structure of the drugs from crystalline to amorphous. The hot melt extrusion (HME) method is emerging in the pharmaceutical industry as an alternative to manufacture ASD. However, despite solving solubility issues, ASD also exposes the drug to a high risk of crystallisation, either during processing or storage. Formulating a successful oral administration drug using ASD requires optimisation of the formulation, polymers, and HME manufacturing processes applied. This review presents some important considerations in ASD formulation, including strategies to improve the stability of the final product using HME to allow more new drugs to be formulated using this method.

Amorphization of Drugs for Transdermal Delivery-a Recent Update.

Amorphous solid dispersion is a popular formulation approach for orally administered poorly water-soluble drugs, especially for BCS class II. But oral delivery could not be an automatic choice for some drugs with high first-pass metabolism susceptibility. In such cases, transdermal delivery is considered an alternative if the drug is potent and the dose is less than 10 mg. Amorphization of drugs causes supersaturation and enhances the thermodynamic activity of the drugs. Hence, drug transport through the skin could be improved. The stabilization of amorphous system is a persistent challenge that restricts its application. A polymeric system, where amorphous drug is dispersed in a polymeric carrier, helps its stability. However, high excipient load often becomes problematic for the polymeric amorphous system. Coamorphous formulation is another approach, where one drug is mixed with another drug or low molecular weight compound, which stabilizes each other, restricts crystallization, and maintains a single-phase homogenous amorphous system. Prevention of recrystallization along with enhanced skin permeation has been observed by the transdermal coamorphous system. But scalable manufacturing methods, extensive stability study and in-depth in vivo evaluation are lacking. This review has critically studied the mechanistic aspects of amorphization and transdermal permeation by analyzing recent researches in this field to propose a future direction.

Self-emulsifying Drug Delivery System for Oral Anticancer Therapy: Constraints and Recent Development.

Oral anticancer therapy faces several drawbacks: low aqueous solubility, poor and irregular absorption from gastrointestinal sites, high first-pass metabolism, food-influenced absorption, non-targeted delivery, severe systemic and local adverse effects, etc. Enhancement of oral bioavailability could reduce the drug load and associated adverse effects. Self-emulsifying drug delivery systems (SEDDS) can enhance in-vivo solubility and drug absorption from the gastrointestinal tract, bypass liver metabolism by lymphatic absorption and inhibit efflux transport. All these phenomena ultimately result in improved oral bioavailability. Anticancer drug delivery using the SEDDS has shown promising results for bioavailability and pharmacodynamic response. A handful of research studies have produced evidence of the successful loading of anticancer agents in SEDDS-based formulations. Various potent and established chemotherapeutic agents such as docetaxel, paclitaxel, etoposide, 5 Fluorouracil, doxorubicin etc., have been successfully formulated and evaluated. Improved bioavailability and reduction of dose might be possible by SEDDS. It could be effective for low-dose drugs. But, excessive surfactant- cosurfactant concentration, lacking predictive in-vitro models and adequate IVIVC, and unavailability of toxicity data are certain challenges for future researchers. No clinical trials have been recorded with anticancer drug-loaded SEDDS. Overcoming the challenges and further progression to clinical studies are required to avail the benefits of anticancer SEDDS.

Biocompatible Supramolecular Mesoporous Silica Nanoparticles as the Next-Generation Drug Delivery System.

Supramolecular mesoporous silica nanoparticles (MSNs) offer distinct properties as opposed to micron-sized silica particles in terms of their crystal structure, morphology-porosity, toxicity, biological effects, and others. MSN biocompatibility has touched the pharmaceutical realm to exploit its robust synthesis pathway for delivery of various therapeutic molecules including macromolecules and small-molecule drugs. This article provides a brief review of MSN history followed by special emphasis on the influencing factors affecting morphology-porosity characteristics. Its applications as the next-generation drug delivery system (NGDDS) particularly in a controlled release dosage form via an oral drug delivery system are also presented and shall be highlighted as oral delivery is the most convenient route of drug administration with the economical cost of development through to scale-up for clinical trials and market launch.

Exploring the role of mesoporous silica nanoparticle in the development of novel drug delivery systems.

The biocompatible nature of mesoporous silica nanoparticles (MSN) attracted researchers' attention to deliver therapeutic agents in the treatment of various diseases, where their porous nature, high drug loading efficiency, and suitability to functionalize with a specific ligand of MSN helped to obtain the desired outcome. The application of MSN has been extended to deliver small chemicals to large-sized peptides or proteins to fight against complex diseases. Recently, formulation researches with MSN have been progressed for various non-conventional drug delivery systems, including liposome, microsphere, oro-dispersible film, 3D-printed formulation, and microneedle. Low bulk density, retaining mesoporous structure during downstream processing, and lack of sufficient in vivo studies are some of the important issues towards the success of mesoporous silica-based advanced drug delivery systems. The present review has aimed to evaluate the application of MSN in advanced drug delivery systems to critically analyze the role of MSN in the respective formulation over other functionalized polymers. Finally, an outlook on the future direction of MSN-based advanced drug delivery systems has been drawn against the existing challenges with this platform.

Exploring the Effect of Glycerol and Hydrochloric Acid on Mesoporous Silica Synthesis: Application in Insulin Loading.

Mesoporous silica (MPS), a carrier for active pharmaceutical ingredients, has a wide range of particle and pore morphology. A thorough understanding of ingredients used in MPS synthesis is an important prerequisite for optimizing its physicochemical characteristics. The present study aimed to evaluate the effect of glycerol and hydrochloric acid on the characteristics of synthesized MPS. Ordered MPS materials were synthesized using the pluronic P123 template and tetraethyl orthosilicate (TEOS) precursor. A three-level factorial design was employed to study the interaction between glycerol and hydrochloric acid. The optimized MPS particles were reasonably uniform in shape (short and rod-shaped) and < 1 µm in size with a smooth surface morphology. The nitrogen adsorption-desorption analysis revealed that the uniform cylindrical pores of the prepared MPS had a diameter > 5 nm and a total surface area > 500 m2/g. With increasing acid and glycerol concentrations, the particle size of MPS decreased. However, while the glycerol increased the heterogeneity of the synthesized particles, the acid decreased it. The developed MPS was successfully loaded with a biological drug (insulin) with a 21.94% encapsulation efficiency. The MPS prepared in this study exhibits potential applications as a drug delivery carrier for drugs with a large molecular weight.

Identifying Underlying Issues Related to the Inactive Excipients of Transfersomes based Drug Delivery System.

Transfersomes are bilayer vesicles composed of phospholipid and edge activators, which are mostly surfactant. Transfersomes based drug delivery system has gained a lot of interest of the pharmaceutical researchers for their ability to improve drug penetration and permeation through the skin. Transdermal drug delivery via transfersomes has the potential to overcome the challenge of low systemic availability. However, this complex vesicular system has different issues to consider for developing a successful transdermal delivery system. One of the major ingredients, phospholipid, has versatile sources and variable effect on the vesicle size and drug entrapment in transfersomes. The other one, termed as edge activators or surfactant, has some crucial consideration of skin damage and toxicity depending upon its type and concentration. A complex interaction between type and concentration of phospholipid and surfactant was observed, which affect the physicochemical properties of transfersomes. This review focuses on the practical factors related to these two major ingredients, such as phospholipid and surfactant. The origin, purity, desired concentration, the susceptibility of degradation, etc. are the important factors for selecting phospholipid. Regarding surfactants, the major aspects are type and desired concentration. A successful development of transfersomes based drug delivery system depends on the proper considerations of these factors and practical aspects.

Transdermal Delivery of Macromolecules Using Nano Lipid Carriers.

Skin being the largest external organ, offers an appealing procedure for transdermal drug delivery, so the drug needs to reach above the outermost layer of the skin, i.e., stratum corneum. Small molecular drug entities obeying the Lipinski rule, i.e., drugs having a molecular weight less than 500 Da, high lipophilicity, and optimum polarity, are favored enough to be used on the skin as therapeutics. Skin's barrier properties prevent the transport of macromolecules at pre-determined therapeutic rates. Notable advancements in macromolecules' transdermal delivery have occurred in recent years. Scientists have opted for liposomes, the use of electroporation, low-frequency ultrasound techniques, etc. Some of these have shown better delivery of macromolecules at clinically beneficial rates. These physical technologies involve complex mechanisms, which may irreversibly incur skin damage. Majorly, two types of lipid-based formulations, including Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs), are widely investigated as transdermal delivery systems. In this review, the concepts, mechanisms, and applications of nanostructured lipid carriers used to transport macromolecules via transdermal routes are thoroughly reviewed and presented along with their clinical perspective.