Overcoming Challenges in Pediatric Formulation with a Patient-Centric Design Approach: A Proof-of-Concept Study on the Design of an Oral Solution of a Bitter Drug.

Designing oral formulations for children is very challenging, especially considering their peculiarities and preferences. The choice of excipients, dosing volume and palatability are key issues of pediatric oral liquid medicines. The purpose of the present study is to develop an oral pediatric solution of a model bitter drug (ranitidine) following a patient centric design process which includes the definition of a target product profile (TPP). To conclude on the matching of the developed solution to TPP, its chemical and microbiological stability was analyzed over 30 days (stored at 4 °C and room temperature). Simulation of use was accomplished by removing a sample with a syringe every day. Taste masking was assessed by an electronic tongue. The developed formulation relied on a simple taste masking strategy consisting in a mixture of sweeteners (sodium saccharine and aspartame) and 0.1% sodium chloride, which allowed a higher bitterness masking effectiveness in comparison with simple syrup. The ranitidine solution was stable for 30 days stored at 4 °C. However, differences were noted between the stability protocols (unopened recipient and in-use stability) showing the contribution of the simulation of use to the formation of degradation products. Stock solution was subjected to acid and alkali hydrolysis, chemical oxidation, heat degradation and a photo degradation stability assessment. The developed pediatric solution matched the TPP in all dimensions, namely composition suitable for children, preparation and handling adapted to hospital pharmaceutical compounding and adequate stability and quality. According to the results, in-use stability protocols should be preferred in the stability evaluation of pediatric formulations.

Formulation and evaluation of transdermal nanogel for delivery of artemether.

Artemether (ART) is second to artesunate in being the most widely used derivatives of artemisinin in combination therapy of malaria. Nanostructured lipid carrier (NLC) formulations were prepared following our previous report using optimized ART concentration of 0.25 g dissolved in 5% w/v mixture of solid (Gelucire 43/01 and Phospholipon 85G) and liquid (Transcutol) lipids at 90 °C. An aqueous surfactant phase at 90 °C was added (dropwise) under magnetic stirring (1000 rpm) for 5 min. The pre-emulsion was speedily homogenized at 28,000 rpm for 15 min and further probe sonicated at 60% amplitude (15 min). Resultant sample was cooled at room temperature and frozen at - 80 °C prior to lyophilization. The freeze-dried sample was used for solid-state characterization as well as in the formulation of transdermal nanogels using three polymers (Carbopol 971P, Poloxamer 407, and Prosopis africana peel powder) to embed the ART-NLC, using ethanol as a penetration enhancer. Transdermal ART-nanogels were characterized accordingly (physical examination, pH, drug content, rheology, spreadability, stability, particle size and morphology, skin irritation, in vitro and ex vivo skin permeation, and analysis of permeation data), P < 0.05. Results indicated that ART nanogels showed good encapsulation, drug release, pH-dependent swelling, stability, and tolerability. Overall, ART nanogels prepared from Poloxamer 407 showed the most desirable drug permeation, pH, swellability, spreadability, viscosity, and transdermal antiplasmodial properties superior to PAPP-ANG > C971P-ANG. A two-patch/week concurrent application of the studied nanogels could offer 100% cure of malaria as a lower-dose (50 mg ART) patient-friendly regimen devoid of the drug's many side effects.

Insulin-loaded mucoadhesive nanoparticles based on mucin-chitosan complexes for oral delivery and diabetes treatment.

In this study, insulin-loaded nanoparticles (NPs) were prepared via self-gelation method using chitosan and aqueous soluble snail mucin as natural polymers. Herein, mucins were ionically interacted with chitosan at different concentrations to obtained insulin-loaded NPs, labelled as A1 (1:1) (i.e., chitosan 2 % w/v + mucin 2 % w/v) and A2 (2:1) (chitosan 4 % w/v + mucin 2 % w/v), using poloxamer and poly vinyl alcohol as solid surfactant. Such formulation was selected to provide the necessary dynamics for the formation of the nanoparticles while maintaining the surface properties that will favor the encapsulation of insulin. Each system was characterized in terms of their particle size distribution, morphology, zeta potential, and polydispersity index. In vitro release of insulin was evaluated in acidic solution (pH 1.2) and phosphate buffer solution (pH 7.4), and the hypoglycaemic activity was evaluated in diabetes rats. The prepared insulin-loaded NPs displayed particles with relatively smooth surfaces and an average particle size of 479.6 and 504.1 nm for A1 and A2, respectively. Zeta potential and polydispersity index, ranged from 22.1 to 31.2 mV and 0.155-0.185, respectively. The encapsulating efficiency for the systems A1 and A2 were 88.6 and 92.5, respectively, and a self-sustained release of encapsulated insulin was observed for over a period of 8 h. In vivo studies revealed a pronounced hypoglycaemic effect in diabetic rats after peroral administration of the insulin-loaded NPs compared to the effect caused by free oral insulin solution. In addition, both the pharmacokinetic and toxicity results showed low plasma clearance of insulin and no signs of toxicity on the liver enzyme and cell viability, which suggested good biocompatibility of the NPs formulations. Overall, the formation of NPs of insulin with chitosan and snail mucin represents a potentially safe and promising approach to protect insulin and enhance its peroral delivery.

Surface-modified mucoadhesive microgels as a controlled release system for miconazole nitrate to improve localized treatment of vulvovaginal candidiasis.

The use of conventional vaginal formulations of miconazole nitrate (MN) in the treatment of deep-seated VVC (vulvovaginal candidiasis) is limited by poor penetration capacity and low solubility of MN, short residence time and irritation at the application site. Surface-modified mucoadhesive microgels were developed to minimize local irritation, enhance penetration capacity and solubility and prolong localized vaginal delivery of MN for effective treatment of deep-seated VVC. Solid lipid microparticles (SLMs) were prepared from matrices consisting of hydrogenated palm oil (Softisan® 154, SF) and super-refined sunseed oil (SO) with or without polyethylene glycol (PEG)-4000, characterized for physicochemical performance and used to prepare mucoadhesive microgels (MMs) encapsulating MN, employing Polycarbophil as bioadhesive polymer. The MMs were evaluated for physicochemical performance and in vitro drug release in simulated vaginal fluid (pH=4.2), whereas mucoadhesive, rheological and stability tests, anticandidal efficacy in immunosuppressed estrogen-dependent female rats and vaginal tolerance test in rabbits were performed with optimized formulation. The amorphicity of 1:9 phytolipid blend (SO:SF) was increased in the presence of PEG-4000. The physicochemical properties of the SLMs and MMs indicated their suitability for vaginal drug delivery. Overall, MN-loaded PEGylated MMs exhibited significantly (p<0.05) more prolonged drug release than non-PEGylated MMs. Additionally, optimized PEGylated MMs was stable at 40±2°C over a period of 6months, viscoelastic, mucoadhesive, non-sensitizing, histopathologically safe and gave remarkably (p<0.05) higher reduction in Candida albicans load (86.06%) than Daktarin® (75.0%) and MN-loaded polymeric-hydrogel (47.74%) in treated rats in 12days. Thus, PEGylated MMs is promising for effective and convenient treatment of VVC.

Improved dissolution and anti-inflammatory activity of ibuprofen-polyethylene glycol 8000 solid dispersion systems.

BACKGROUND: The purpose of this study was to develop ibuprofen (IB)-polyethylene glycol (PEG) 8000 solid dispersions (SDs) and investigate them for in vitro dissolution and in vivo anti-inflammatory activity. MATERIALS AND METHODS: IB-PEG 8000 SDs were prepared by fusion method using varying combination ratios of IB and PEG 8000. Characterization based on surface morphology, particle size, absolute drug content, and Fourier transform infrared (FT-IR) spectroscopy was carried out on the SDs. The in vitro release of IB from the SDs was performed in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.4) without enzymes, whereas the anti-inflammatory activity was evaluated using egg albumin-induced rat paw edema model. RESULTS: Greenish brown, discrete, and irregularly shaped SDs of mean particle size range 113.5 ± 2.5-252.5 ± 1.9 µm, which were stable over 3 months, were obtained. The drug content of the SDs ranged from 73.4 ± 2.9 % to 83.5 ± 2.7%. Although the drug content increased with increased concentration of PEG 8000 in the SDs, the mean particle size decreased with increased concentration of PEG 8000 in the SDs. The FT-IR results indicate no strong chemical interaction of IB and PEG 8000 in the SDs. There was marked increase in the dissolution rate of IB from the SDs (P < 0.05) as compared to pure IB and physical mixture. The dissolution was better in SIF than in SGF. The increased dissolution rate of IB may be due to the formation of microcrystals, increased wettability and dispersibility in PEG 8000. The SDs showed good anti-inflammatory properties achieving up to 90% edema inhibition at 6 h while the pure sample of IB had 77% edema inhibition at 6 h. CONCLUSION: SDs based on IB-PEG 8000 is a good approach to enhance the dissolution rate and anti-inflammatory activity of IB, thus, encouraging further development of the SDs.

Design of novel miconazole nitrate transdermal films based on Eudragit RS100 and HPMC hybrids: preparation, physical characterization, in vitro and ex vivo studies.

The objective of this study was to formulate and evaluate transdermal films containing miconazole nitrate (MN), a poorly water-soluble imidazole antifungal agent, with a view to enhancing its delivery across intact skin. Transdermal films of MN were formulated by solvent casting technique using admixtures of film-forming polymers - Eudragit RS100 and hydroxypropylmethylcellulose (HPMC) (2:8, 4:6, 5:5, 6:4 and 8:2) with polyethylene glycol 8000 (plasticizer and permeation enhancer) and Tween 80 (mobile surfactant). The films were evaluated for weight uniformity, folding endurance, thickness, moisture loss and uptake, bioadhesive strength, drug content, skin irritation on rabbits and time-resolved stability. The ex vivo release of MN from the films was carried out using a modified Franz diffusion apparatus while the microbiological evaluation was conducted using a clinical isolate of Candida albicans. Overall results indicate that films made with two portions of Eudragit RS100 and eight portions of HPMC (batch T-1) had the least weight variation (57.33 ± 0.27 mg), folding endurance (307.90 ± 4.17), moisture uptake (1.37 ± 0.28%) and thickness (145.9 ± 2.08 µm), but highest drug content (97.50 ± 2.43%) and bioadhesive strength (81.40 ± 2.03 dyne/cm2), best bioactivity and in vitro skin permeation through rat skin with highest permeation flux (5.161 µg/cm2 h) and permeation coefficient (1.032 × 10-6 cm/h) compared to all other formulations. This study has established that transdermal films based on 2:8 admixtures of Eudragit RS100 and HPMC could offer a promising approach for the treatment of skin infections caused by MN-susceptible fungi.

Development and Evaluation of Novel Self-Nanoemulsifying Drug Delivery Systems Based on a Homolipid from Capra hircus and Its Admixtures with Melon Oil for the Delivery of Indomethacin.

In this study, goat fat (Capra hircus) and melon oil were extracted and used to formulate self-nanoemulsifying drug delivery systems (SNEDDS) based on either goat fat alone or its admixture with melon oil by employing escalating ratios of oil(s), surfactant blend (1 : 1 Tween 60 and Tween 80), and cosurfactant (Span 85), with or without carbosil, a glidant, for the delivery of indomethacin. The formulations were encapsulated in hard gelatin capsules and then assessed using isotropicity test, aqueous dilution stability and precipitation propensity, absolute drug content, emulsification time, in vitro drug release, and anti-inflammatory activity. The SNEDDS exhibited low precipitation propensity and excellent stability on copious dilution, as well as high drug release in vitro and in vivo. The inhibition produced by the SNEDDS was comparable to that of indomethacin injection (positive control) for much of the 5 h test period, indicating a high degree of bioavailability of the administered SNEDDS. The absolute drug contents and emulsification times fell within narrow limits. This study has shown that a 1 : 1 ratio of melon oil and goat fat could confer favourable properties with respect to drug release and anti-inflammatory activity on SNEDDS for the delivery of indomethacin, thus encouraging further development of the formulations.

In vitro evaluation of the antiviral activity of extracts from the lichen Parmelia perlata (L.) Ach. against three RNA viruses.

BACKGROUND: Substances extracted from lichens have previously been reported to possess antimicrobial activities against various groups of bacteria, fungi and viruses. Due to the high abundance of Parmelia perlata in the Eastern parts of Nigeria, we decided to explore whether it possesses antiviral activity against some common animal and human viruses. METHODOLOGY: The dried and powdered lichen was extracted with acetone, water and 4% (v/v) NaOH (to yield a crude polysaccharide fraction) using standard methods. The cytotoxicity of the extracts was investigated on HEP-2, Vero and L20 cell lines. The antiviral properties were determined against yellow fever, poliomyelitis and infectious bursal disease virus of chickens using the end-point cytopathic effect assay. Phytochemical evaluations of the extracts were also carried out. RESULTS: Phytochemical tests showed the presence of flavonoids, saponins, tannins, glycosides, steroidal aglycone, carbohydrates and also the presence, in trace amounts, of some oligodynamic elements. Cytotoxicity tests revealed that while L20 was susceptible to the extracts at a concentration of 50 microg/ml, the extracts were generally toxic to the cell lines at concentrations above 500 microg/ml. The order of sensitivity of the cell lines was L20 > HEP-2 > Vero. The water and acetone extracts showed no activity against the viruses when tested at concentrations below the cytotoxic level while the crude polysaccharide fraction showed activity against yellow fever virus with an IC50 of 15 microg/ml. The time of addition of the test extracts to the infected cells did not have significant effect on cytopathic effect inhibition. CONCLUSIONS: The results showed that the crude polysaccharide fraction from Parmelia perlata possesses specific antiviral activity against yellow fever virus. It is postulated that a major mechanism of inhibition of yellow fever infection by the crude polysaccharide fraction of the lichen could be by attack on the viral envelope.