A local drug delivery system based on visible light-cured glycol chitosan and doxorubicin⋅hydrochloride for thyroid cancer treatment in vitro and in vivo

Systemic drug delivery systems (SDDSs) for thyroid cancer treatment are associated with serious side effects including nausea, anorexia, and hair loss as a result of damage to normal tissues. In this study, we investigated the feasibility of a local DDS (LDDS) based on visible light-cured glycol chitosan (GC) hydrogel and doxorubicin?hydrochloride (DOX?HCl), called GC10/DOX, on thyroid cancer treatment in vivo. Visible light irradiation increased the storage modulus and swelling ratio of the GC10/DOX hydrogel precursor. The release of DOX?HCl from GC10/DOX exhibited two unique patterns comprising an initial burst within 18?hours, followed by a controlled and sustained release thereafter. In vitro cell viability testing showed that GC10/DOX had a greater antitumor effect than free DOX?HCl and GC10 hydrogel controls. In vivo, local injection of GC10/DOX near tumor tissue led to a superior antitumor effect compared with controls consisting of free DOX?HCl intravenously injected to the tail vein of thyroid cancer-bearing mouse and GC10 hydrogel subcutaneously injected near the tumor. Altogether, our results suggest that GC10/DOX may have clinical potential for thyroid cancer treatment.     

TAT-based drug delivery system – new directions in protein delivery for new hopes?

There has been great progress in the use of TAT-based drug delivery systems for the delivery of different macromolecules into cells in vitro and in vivo, thus circumventing the bioavailability barrier that is a problem for so many drugs. There are many advantages to using this system, such as the ability to deliver these cargoes into all types of cells in culture and into all organs in vivo. This system can even deliver cargoes into the brain across the blood–brain barrier. In addition, the ability to target specific intracellular sub-localizations such as the nuclei, the mitochondria and lysosomes further expands the possibilities of this drug delivery system to the development of sub-cellular organelle-targeted therapy. The therapeutic applications seem almost unlimited, and the use of the TAT-based delivery system has extended from proteins to a large variety of cargoes such as oligonucleotides, imaging agents, low molecular mass drugs, nanoparticles, micelles and liposomes. In this review the most recent advances in the use of the TAT-based drug delivery system will be described, mainly discussing TAT-mediated protein delivery and the use of the TAT system for enzyme replacement therapy.     

In vitro and in vivo evaluation of pectin beads for the colon delivery of β-lactamases

The aim of the present study was to provide a “proof of concept” of colon delivery of β-lactamases by pectin beads aiming to degrade residual β-lactam antibiotics, in order to prevent the emergence of resistant bacterial strains.

Pectin beads were prepared according to ionotropic gelation method using CaCl₂ as a gelling agent. Particles were then washed and soaked in polyethylenimine (PEI). Coating beads with PEI considerably improved their stability in simulated intestinal medium. In vitro studies showed that β-lactamases were released from pectin beads in colonic medium due to the action of pectinolytic enzymes. When ampicillin was added to this medium, the release of β-lactamases induced, as expected, the antibiotic inactivation. Finally, after oral administration of loaded-beads to CD1 mice, β-lactamases were retrieved in high concentrations in faeces. Observation by SEM of beads extracted from mice intestinal tracts concluded the core degradation of beads without any modification of the PEI coating layer.

This study demonstrates that a multiparticulate system with suitable characteristics for site-specific colonic delivery can be prepared. This system could be used to target β-lactamases to the colon in order to hydrolyse antibiotic residues during treatment and prevent their impact on colonic microflora.     

Montmorillonite–alginate nanocomposite as a drug delivery system – incorporation and in vitro release of irinotecan

The scope of the present study was the preparation and characterization of irinotecan nanocomposite beads based on montmorillonite (Mt) and sodium alginate (AL) as drug carriers. After irinotecan (I) incorporation into Mt, the resulting hybrid was compounded with alginate, and I-Mt-AL nanocomposite beads were obtained by ionotropic gelation technique. The structure and surface morphology of the hybrid and composite materials were established by means of X-ray diffraction (XRD), IR spectroscopy (FT-IR), thermal analysis (TG-DTA) and scanning electron microscopy (SEM). Irinotecan incorporation efficiency in Mt and in alginate beads was determined both by UV–vis spectroscopy and thermal analysis and was found to be high. The hybrid and composite materials were tested in vitro in simulated intestinal fluid (pH 7.4, at 37 °C) in order to establish if upon administering the beads at the site of a resected colorectal tumor, the delivery of the drug is sustained and can represent an alternative to the existing systemic chemotherapy. The in vitro drug release test results clearly suggested that Mt, and Mt along with AL were able to control the release of irinotecan by making it sustained, without any burst effect, and by reducing the released amount and the release rate. The nanocomposite beads may be a promising drug delivery system in chemotherapy.     

A novel hydrogel plug of Sterculia urens for pulsatile delivery: in vitro and in vivo evaluation

The objective of this study was to investigate a novel hydrogel plug using isolated root mucilage of Sterculia urens to obtain a desired lag time for an oral chronotherapeutic colon-specific pulsatile drug delivery of indomethacin. Pulsatile drug delivery was developed using chemically treated hard gelatin capsule bodies filled with eudragit multiparticulates of indomethacin, and sealed with different hydrogel plugs (root mucilage of S. urens, xanthan gum, guar gum, HPMC K4M and combination of maltodextrin with guar gum). Indomethacin multiparticulates were prepared using extrusion spheronization, spray drying and solvent evaporation techniques with Eudragit? L-100 and S-100 (1:2) by varying drug-to-polymer ratio. After oral administration, the water-soluble cap of capsule dissolved in the intestinal fluid and the hydrogel plug swells. After a controlled time, the swollen plug subsequently ejected from the dosage form, releases the contents of the capsule. The formulation factors affecting the drug release were concentration and types of hydrogel plug used. In?vivo gamma scintigraphy study in healthy rabbits proved the capability of the system to release drug in lower parts of the gastrointestinal tract after a programmed lag time. This study demonstrates that the indomethacin multiparticulates could be successfully colon-targeted by the design of time and pH-dependent modified chronopharmaceutical formulation. In conclusion, the investigated novel hydrogel plug could be a valuable tool for achieving desired lag time.     

Renewable poly(δ-decalactone) based block copolymer micelles as drug delivery vehicle: in vitro and in vivo evaluation

Polymers from natural resources are attracting much attention in various fields including drug delivery as green alternatives to fossil fuel based polymers. In this quest, novel block copolymers based on renewable poly(δ-decalactone) (PDL) were evaluated for their drug delivery capabilities and compared with a fossil fuel based polymer i.e. methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL). Using curcumin as a hydrophobic drug model, micelles of PDL block copolymers with different orientation i.e. AB (mPEG-b-PDL), ABA (PDL-b-PEG-b-PDL), ABC (mPEG-b-PDL-b-poly(pentadecalactone) and (mPEG-b-PCL) were prepared by nanoprecipitation method. The size, drug loading and curcumin stability studies results indicated that mPEG-b-PDL micelles was comparable to its counterpart mPEG-b-PCL micelles towards improved delivery of curcumin. Therefore, mixed micelles using these two copolymers were also evaluated to see any change in size, loading and drug release. Drug release studies proposed that sustained release can be obtained using poly(pentadecalactone) as crystalline core whereas rapid release can be achieved using amorphous PDL core. Further, mPEG-b-PDL micelles were found to be non-haemolytic, up to the concentration of 40?mg/mL. In vivo toxicity studies on rats advised low-toxic behaviour of these micelles up to 400?mg/kg dose, as evident by histopathological and biochemical analysis. In summary, it is anticipated that mPEG-b-PDL block copolymer micelles could serve as a renewable alternative for mPEG-b-PCL copolymers in drug delivery applications.     

Prodrugs for transdermal drug delivery – trends and challenges

Prodrugs continue to attract significant interest in the transdermal drug delivery field. These moieties can confer favorable physicochemical properties on transdermal drug delivery candidates. Alkyl chain lengthening, pegylation are some of the strategies used for prodrug synthesis. It is usually important to optimize partition coefficient, water and oil solubilities of drugs. In this review, progress made in the field of prodrugs for percutaneous penetration is highlighted and the challenges discussed.     

α-Tocopherol succinate-modified chitosan as a micellar delivery system for paclitaxel: preparation, characterization and in vitro/in vivo evaluations

α-Tocopherol succinate hydrophobically modified chitosan (CS-TOS) containing 17 α-tocopherol groups per 100 anhydroglucose units was synthesized by coupling reaction. The formation of CS-TOS was confirmed by ¹H NMR and FT-IR analysis. In aqueous medium, the polymer could self-aggregate to form micelles, and the critical micelle concentration (CMC) was determined to be 5.8 × 10⁻³ mg/ml. Transmission electron microscopy (TEM) observation revealed that both bare and paclitaxel-loaded micelles were near spherical in shape. The mean particle size and zeta potential of drug-loaded micelles were about 78 nm and +25.7 mV, respectively. The results of DSC and XRD analysis indicated that paclitaxel was entrapped in the micelles in molecular or amorphous state. In vitro cytotoxicity and hemolysis study revealed the effectiveness and safety of this delivery system, which was further confirmed by the in vivo antitumor evaluations. It can be concluded that the CS-TOS was a potential micellar carrier for paclitaxel.     

A novel vesicular transdermal delivery of nifedipine – preparation,characterization and in vitro/in-vivo evaluation

Abstract

Nifedipine is a calcium channel blocker extensively used in the treatment of anginal and hypertension. On oral administration it undergoes extensive first pass metabolism, which outweighs its absorbance through gastrointestinal tract (GIT) and bioavailability of the drug in systemic circulation. As an alternative to oral route transdermal route of drug delivery was developed. In the present investigation, proniosomes are prepared by varying the ratio of span-40, lecithin, aqueous phase and polymer. Formulation containing span-40, lecithin, isopropyl alcohol, 0.1% glycerol (5:5:4) and HPMC (2%) showed smaller vesicle size, high entrapment efficiency. The niosomal formation after hydration and their surface morphology of optimized formulation was studied by Motic and transmission electron microscopy. FTIR and differential scanning calorimetry studies were performed to unravel and understand the solid state properties of the drug and chemical interaction with formulation excipients. The ex-vivo Franz-diffusion studies were carried out in pH 6.8 using rat skin and the results showed better permeability of niosomes with good steady state flux and enhancement ratio suggesting the potential of proniosomal carriers for improved transdermal delivery of nifedipine. Skin irritation studies for 7 days, showed that the drug when formulated as proniosomes to be non-irritant with no erythemia development compared to pure drug. From the bio-distribution studies, the vesicles prepared with hydroxy propyl methyl cellulose with span-40 was found to be ideal batch as the concentration of drug at target site was higher.     

Which drug combination for colorectal cancer?

In Westernised countries, colorectal cancer (CRC) is second only to lung cancer as a cause of death from malignancy, with only 60% of patients alive at 5 years. In Stage II/III CRC, where the standard treatment is 5-fluorouracil (5-FU)/leucovorin, a recent clinical trial has shown that with the addition of oxaliplatin, fewer patients have relapsed or died at 40 months follow-up. The benefit was more pronounced in patients with Stage III than II CRC, and the addition of oxaliplatin to 5-FU/leucovorin should be considered in Stage III CRC. In metastatic CRC, where the standard treatment is 5-FU/leucovorin/irinotecan, a recent clinical trial has shown that the addition of bevacizumab, a mAb, to vascular endothelial growth factor, prolonged progression-free and overall survival. Bevacizumab is likely to become part of the standard therapy for metastatic CRC.     

Which drug combination for colorectal cancer?

In Westernised countries, colorectal cancer (CRC) is second only to lung cancer as a cause of death from malignancy, with only 60% of patients alive at 5 years. In Stage II/III CRC, where the standard treatment is 5-fluorouracil (5-FU)/leucovorin, a recent clinical trial has shown that with the addition of oxaliplatin, fewer patients have relapsed or died at 40 months follow-up. The benefit was more pronounced in patients with Stage III than II CRC, and the addition of oxaliplatin to 5-FU/leucovorin should be considered in Stage III CRC. In metastatic CRC, where the standard treatment is 5-FU/leucovorin/irinotecan, a recent clinical trial has shown that the addition of bevacizumab, a mAb, to vascular endothelial growth factor, prolonged progression-free and overall survival. Bevacizumab is likely to become part of the standard therapy for metastatic CRC.     

Formulation and in vitro–in vivo evaluation of ketoprofen-loaded albumin microspheres for intramuscular administration

Abstract

The objective of this work was to prepare and evaluate ketoprofen-loaded albumin microspheres for intramuscular administration. Microspheres were prepared by emulsion cross-linking method using a 2³ factorial design and the effect of different factors on entrapment efficiency was determined. Microspheres were evaluated for entrapment efficiency, percentage yield, particle size and release behaviour. Selected formulations were then tested by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Further they were analysed for residual solvents, syringeability and stability. Microspheres were then sterilized and bioavailability studies were carried out in New Zealand white rabbits. The physical characteristics of microspheres showed that they were suitable for IM administration. The sterilization technique adopted was adequate to maintain sterility. In vivo studies showed increase in C_max, AUC, t_1/2 and MRT (p < 0.05) administered in the form of microspheres. MRT of ketoprofen was almost 3.2-times in the form of microspheres. From these results it was concluded that the developed albumin microspheres of ketoprofen is a potential delivery system for once-a-day intramuscular administration.     

Self-microemulsifying drug delivery system (SMEDDS) – challenges and road ahead

Abstract

Self-microemulsifying drug delivery system (SMEDDS) has emerged as a vital strategy to formulate poor water soluble compounds for bioavailability enhancement. However, certain limitations are associated with SMEDDS formulations which include in vivo drug precipitation, formulation handling issues, limited lymphatic uptake, lack of predictive in vitro tests and oxidation of unsaturated fatty acids. These limitations restrict their potential usage. Inclusion of polymers or precipitation inhibitors within lipid based formulations helps to maintain drug supersaturation after dispersion. This, thereby, improves the bioavailability and reduces the variability on exposure. Also, formulating solid SMEDDS helps to overcome liquid handling and stability problems. Usage of medium chain triglycerides (MCT) and suitable antioxidants to minimize oxidation of unsaturated fatty acids are few of the steps to overcome the limitations associated with SMEDDS. The review discussed here, in detail, the limitations of SMEDDS and suitable measures that can be taken to overcome them.     

Medicated chewing gum – a potential drug delivery system

Importance of the field: Over the years, patient convenience and patient compliance-orientated research in the field of drug delivery has resulted in bringing out potential innovative drug delivery options. Out of which, medicated chewing gum (MCG) offers a highly convenient patient-compliant way of dosing medications, not only for special population groups with swallowing difficulties such as children and the elderly, but also for the general population, including the young generation.

Areas covered in this review: In this review, various formulation ingredients, different manufacturing processes, and assessment of in vivo and in vitro drug release from MCG are thoroughly discussed along with the therapeutic potential and limitations of MCG.

What the reader will gain: Readers will gain knowledge about the rationale and prominent formulation and performance evaluation strategies behind chewing gum as a drug delivery system.

Take home message: The availability of directly compressible co-processed gum material enables rapid, safe and low-cost development of MCG as a drug delivery option. By MCG formulation, revitalization of old products and reformulation of new patented products is possible, to differentiate them from upcoming generics competition in the market.     

Preparation and in vitro–in vivo evaluation of surface-modified poly(lactide-co-glycolide) nanoparticles as controlled release carriers for flutamide delivery

Abstract

This investigation explores the use of methoxy polyethylene glycol (mPEG) functionalised poly(d,l-lactide-co-glycolide) (PLGA) nanocrystals of flutamide (FLT) with enhanced solubility, bioavailability and blood circulation time for targeting prostate cancer. FLT had Log P 3.27, short half life 5–6?h, low water solubility, permeability and bioavailability with extensive first-pass metabolism. FLT-loaded nanocrystals were prepared using nanoprecipitation method with surface coating by mPEG and characterised through differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray powder diffraction, scanning electronic microscopy, particle size, zeta potential, percent entrapment efficiency (% EE), in vitro dissolution, haemolysis, sterility, bioavailability and stability studies. The percent cumulative drug release and % EE of optimised formulation was found to be 95.21?±?1.18 and 88.36?±?1.20, respectively, for 48?h. In addition, FLT-loaded PEGylated PLGA nanocrystals exhibited significantly delayed blood clearance with drug level of about 766.71?ng/mL at 48?h. In conclusion, PEGylated PLGA FLT nanocrystals could be demonstrated as a novel approach to enhance solubility, bioavailability and blood circulation time.     

Preparation,optimisation, and in vitro–in vivo evaluation of febuxostat ternary solid dispersion

Abstract

The research aimed to prepare febuxostat (FEB) solid dispersion through solvent evaporation. Optimised solid dispersion composed of FEB, polyvinylpyrrolidone (PVP K30) and poloxamer at a ratio of 1:3:3 was characterised. Powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) indicated FEB was transformed from crystalline into the amorphous state in solid dispersion and scanning electron microscopy (SEM) revealed the morphology. Fourier transform infrared spectroscopy (FT-IR) suggested the interactions formed between FEB and polymers. A remarkable increase was observed of the optimised formulation in saturation solubility, dissolution studies (96.17?±?0.79% in pH 6.0), and bioavailability (C_max 18.25?±?2.44 vs. 7.72?±?0.48?μg/mL and AUC_0–∞ 53.62?±?7.63 vs. 34.76?±?2.45?μg·h/mL). Besides, the FEB solid dispersion showed great stability after 90 days storage. Thus, the present study supports the rationality of PVP K30 and poloxamer188 as co-carriers for the preparation of FEB solid dispersion.     

Poly (ε-caprolactone) nanocapsules for oral delivery of raloxifene: process optimization by hybrid design approach,in vitro and in vivo evaluation

Abstract

Raloxifene HCl (RLX), a selective oestrogen receptor modulator, has low oral bioavailability (<2%) in humans due to its poor aqueous solubility and extensive first-pass metabolism in gut. In this study, we optimised the method of preparation for poly (ε-caprolactone) (PCL) based nanocapsules of RLX by double emulsion method (w/o/w). A hybrid design approach, Plackett–Burman design followed by rotatable central composite design, was used to arrive at the optimised formulation. The optimised formulation was subjected to in vitro and in vivo evaluation. RLX loaded nanocapsules were spherical in shape with particle size less than 200?nm and high encapsulation efficiency (>80%). RLX-loaded nanocapsules showed 2.1-fold increase in oral bioavailability compared to free RLX. IV pharmacokinetic studies indicated that RLX loaded into nanocapsule had significantly low clearance in comparison with free RLX. Designed nanocapsules showed promise as delivery systems to enhance oral bioavailability and in reducing clearance of raloxifene.     

Novel in situ gelling ocular inserts for voriconazole-loaded niosomes: design,in vitro characterisation and in vivo evaluation of the ocular irritation and drug pharmacokinetics

This work aimed to develop voriconazole in situ gelling ocular inserts loaded with niosomal suspension. Niosomes and mixed niosomes were prepared using span 40 and span 60 with pluronic L64 and pluronic F127. The entrapment efficiency percentages (EE%), mean vesicle size, polydispersity index (PI), zeta potential and in vitro drug release of these niosomes were evaluated. F3-mixed niosomes prepared with span 60 and pluronic L64 was selected, due to its highest EE; optimum vesicle size with smallest PdI and suitable release pattern of the drug (63% after 8?h). In situ ocular inserts were prepared using sodium carboxymethylcellulose (CMC Na) and sodium alginate (ALG) and characterised for surface morphology, surface pH, water uptake, mucoadhesion and in vitro release. ALG in situ ocular insert (S₂) was selected for further in vivo evaluation of the ocular irritation and drug pharmacokinetics in the aqueous humour of rabbit's eyes. S₂ in situ gelling ocular insert was non-irritant and showed significantly (p?<?0.01) higher C_max, delayed T_max and increased bioavailability.     

Preparation and in vitro–in vivo evaluation of Witepsol® H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q10

Coenzyme Q₁₀ (CoQ₁₀) was formulated into self-nanoemulsifying drug delivery systems (SNEDDS) to overcome low bioavailability attributed to hydrophobic nature of the drug. Screening of oil phase, surfactants and co-surfactants were performed to select Witepsol^® H35, Solutol^® HS15 and Lauroglycol^® FCC, respectively. Ternary phase diagrams were drawn to identify nanoemulsifying region followed by optimization of SNEDDS formulation. The optimized formulation, CoQ₁₀, Witepsol^® H35, Solutol^® HS15 and Lauroglycol^® FCC in the weight ratio of 1:0.7:4:2, respectively, emulsified readily at 37 °C with mean emulsion droplet size of 32.4 nm. The stability test of the optimized formulation in pH 1.2 and 6.8 buffers confirmed no pH effect on emulsion droplet size. In vitro dissolution (emulsification) test and in vivo animal study of the formulation elucidated the complete emulsification of drug and improved oral bioavailability of poorly soluble CoQ₁₀.