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BACKGROUND: Diabetes mellitus is a global disease identified by hyperglycemia due to defects in insulin secretion, insulin action, or both. OBJECTIVE: The main objective of this research was to evaluate the ability of gelatinized Poly(ethylene glycol) (PEG) microparticles to be used as carriers for oral insulin delivery via double emulsion preparation. METHODS: Five different batches of the formulation consisting of gelatin:PEG were prepared as follows: 0:1 (W1), 1:0 (W2), 1:1 (W3), 1:3 (W4), and 3:1 (W5). The prepared microparticles (from insulin-loaded batches) had particle sizes ranging from 19.5 ± 0.32-23.9 ± 0.22 µm and encapsulation and loading capacities ranging from 78.8 ± 0.24-88.9 ± 0.95 and 22.2 ± 0.96-29.7 ± 0.86%, respectively. The minimum and maximum in vitro release rates were 8.0 and 66.0%, respectively, for batches W1 and W2 at 8 h. RESULTS: Insulin-loaded MPs induced a significant decrease in glucose levels, with a reduction from 100 to 33.35% in batch W5 at 9 h compared to that of subcutaneous insulin (100 to 22.63%). A liver function study showed that the formulation caused no obvious toxicity to the experimental rats. CONCLUSION: Gelatinized PEG-based microparticles as insulin delivery systems may open a new window into the development of oral insulin for diabetic treatment.

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[This retracts the article DOI: 10.1016/j.heliyon.2023.e16963.].

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OBJECTIVE: This study aimed to evaluate Cola acuminata gum (CAG) for the formulation of mucoadhesive sustained-release matrix tablets of diclofenac sodium. METHODS: Different batches of granules containing CAG and 100 mg of DS in ratios 0.5:1, 1:1, 2:1, and 3:1 were prepared, compressed into tablets, and evaluated for mucoadhesive strength, swelling index, and drug release in SGF (pH 1.2) and SIF (pH 7.4). RESULTS: Swelling indices and mucoadhesive strengths of the tablets were pH-dependent. Swelling indices of 56 ± 2.03 to 121 ± 2.19% and mucoadhesive strengths of 7.25 ± 1.45 to 15.43 ± 2.71 g/cm2 obtained at pH 7.4 were significantly higher (p<0.05) than swelling indices of 25 ± 2.43 to 47 ± 3.15% and mucoadhesive strengths of 5.52 ± 0.76 to 9.22 ± 1.95 g/cm2 obtained at pH 1.2. The percentage release of DS from the matrix tablets at pH 1.2 after 2 h (T2h) was insignificant. However, the percentage of drug release at pH 7.4 was significant for all the batches and dependent on the CAG concentration. The drug release was in the order of batches containing 3 g (80.44 ± 7.75) < 2 g (86.35 ± 5.65) < 1 g (90.08 ± 6.14) < 0.5 g (99.70 ± 3.90). The time for maximum drug release was 7 h (T7h) for CAG containing 0.5 g and 10 h (T10h) for other batches. CONCLUSION: This study showed that CAG could be useful for mucoadhesive sustained drug delivery.

Asunto(s)

Cola , Diclofenaco , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos , Comprimidos

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This research investigates the potentials of prodigiosin(PG) derived from bacteria and its formulations against triple-negative breast (TNB), lung, and colon cancer cells. The PG was extracted from S. marcescens using continuous batch culture, characterized, and formulated into lyophilized parenteral nanoparticles (PNPs). The formulations were characterized with respect to entrapment efficiency (EE), DSC, FT-IR, TEM, and proton nuclear magnetic resonance (1H NMR) spectroscopy. In vitro drug release was evaluated in phosphate buffer (pH 7.4) while acute toxicity, hematological and histopathological studies were performed on rats. The in vitro cytotoxicity was evaluated against TNB (MCF-7), lung (A-549), and colon (HT-29) cancer cell lines. High EE (92.3 ± 12%) and drug release of up to 89.4% within 8 h were obtained. DSC thermograms of PG and PG-PNPs showed endothermic peaks indicating amorphous nature. The FT-IR spectrum of PG-PNPs revealed remarkable peaks of pure PG, indicating no strong chemical interaction between the drug and excipients. The TEM micrograph of the PG-PNPs showed nano-sized formulations (20-30 nm) whose particles were mostly lamellar and hexagonal structures. The 1H NMR result revealed the chemical structure of PG showing all assigned proton chemical shifts. Toxicity results of the PG and its formulation up to a concentration of 5000 mg/kg showed insignificant vacuolar changes of hepatocytes in the liver, with normal renal medulla and cortex in the kidney. The PG and PG-PNPs inhibited the growth of breast, lung, and colon cell lines. The nano-sized lipid formulation (PG-PNPs) showed potential in PG delivery and cancer treatments.

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The current study was to improve and control aceclofenac delivery prepared as biopolymer-based microparticles for effective colon-targeted drug delivery using modified gelatin capsules (MGCs) at different time intervals developed in two batches (C1 and C2). Microparticles were formulated with extracted mucuna gum using liquid paraffin oil (AC.LPO) and soybean oil (AC.SO) and evaluated in vitro for physicochemical performance and in vivo in rats. Encapsulation efficiency ranges from 54.48 ± 0.21% to 82.83 ± 0.22% for AC.LPO and 52.64 ± 0.11% to 80.36 ± 0.22% for AC.SO. SEM showed oblong and irregular shapes with porous and cracked surfaces. DSC showed low enthalpy and a very broad endothermic peak depicting high amorphous property. Delayed drug release was observed in the upper gastrointestinal tract with sustained release depicted in the lower gastrointestinal tract (GIT) using 3 and 9-h batch C1 of MGCs. AC.SO exhibited significantly (p < 0.05) higher anti-inflammatory activity (86%) than AC.LPO (77%). Hence, aceclofenac colon delivery could be improved and controlled using biopolymer-based colon-targeted microparticles delivered with MGCs.

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Metformin hydrochloride (MH) is a widely used oral biguanide antihyperglycemic (antidiabetic) drug with poor bioavailability which necessitates the development of novel drug delivery systems such as PEGylated solid lipid nanoparticles for improving its therapeutic activity. The aim of this study was to formulate, characterize and evaluate in vitro and in vivo pharmacodynamic properties of metformin-loaded PEGylated solid lipid nanoparticles (PEG-SLN) for improved delivery of MH. The lipid matrices (non-PEGylated lipid matrix and PEGylated lipid matrices) used in the formulation of both non-PEGylated (J0) and PEGylated SLNs (J10, J20, J40) were prepared by fusion using beeswax and Phospholipon ® 90H at 7:3 ratio with or without polyethylene glycol (PEG) 4000 (0, 10, 20 and 40% w/w), respectively. Representative lipid matrices (LM and PEG-LM) were loaded with MH by fusion and then characterized by differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. The PEG-SLNs were prepared by high shear hot homogenization using the lipid matrices (5% w/w), drug (MH) (1.0% w/w), sorbitol (4% w/w) (cryoprotectant), Tween ® 80 (2% w/w) (surfactant) and distilled water (q.s to 100% w/w) (vehicle). The non-PEGylated and PEGylated SLNs (J0, J10, J20, J40)) were characterized with respect to encapsulation efficiency (EE%), loading capacity (LC), morphology by scanning electron microscopy (SEM), mean particle size (Zav) and polydispersity indices (PDI) by photon correlation spectroscopy (PCS), compatibility by FT-IR spectroscopy and in vitro drug release in biorelevant medium. Thereafter, in vivo antidiabetic study was carried out in alloxanized rats' model and compared with controls (pure sample of MH and commercial MH- Glucophage®)). Solid state characterizations indicated the amorphous nature of MH in the drug loaded-lipid matrices. The PEG-SLNs were mostly smooth and spherical nanoformulations with Zav and PDI of 350.00 nm and 0.54, respectively, for non-PEGylated SLNs, and in the range of 386.80-783.10 nm and 0.592 to 0.752, respectively, for PEGylated SLNs. The highest EE% and LC were noted in batch J20 and were 99.28% and 16.57, respectively. There was no strong chemical interaction between the drug and excipients used in the preparation of the formulations. The PEGylated SLN (batch J40) exhibited the highest percentage drug released (60%) at 8 h. The PEGylated SLNs showed greater hyperglycemic control than the marketed formulation (Glucophage ®) after 24 h. This study has shown that metformin-loaded PEGylated solid lipid nanoparticles could be employed as a potential approach to improve the delivery of MH in oral diabetic management, thus encouraging further development of the formulations.

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Metformin hydrochloride (MTH) has been associated with poor/incomplete absorption (50-60%), low bioavailability, short half-life (0.4-0.5 h), high dosage and dose-related side effects. To overcome these barriers and improve oral bioavailability and efficacy of MTH, surface-modified nanostructured lipid carriers (NLCs) were developed. Lipid matrices composed of rational blends of beeswax and Phospholipon® 90H (as solid lipids) and Capryol-PGE 860 (as liquid lipid) were prepared by fusion, and the resultant lipid matrices were PEGylated to give 10, 20 and 40% PEGylated lipid matrices. MTH-loaded non-PEGylated and PEGylated NLCs were prepared via high-shear hot homogenization and characterized regarding particle properties and physicochemical performance. The encapsulation efficiencies (EE%) and loading capacities (LC) of the MTH-loaded NLCs were determined while the in vitro drug release was evaluated in phosphate buffered saline (PBS, pH 7.4). Antidiabetic and pharmacokinetics properties of the NLCs were ascertained in an alloxan-induced diabetic rats model after oral administration. The MTH-loaded NLCs were nanomeric (particle size: 184.8-882.50 nm) with low polydispersity index (0.368-0.687) and zeta potential (26.5-34.2 mV), irregular shape, amorphous nature with reduced crystallinity. The EE% and LC were >90 % and 16%, respectively. The formulations showed >65 % release over 12 h in a greater sustained manner than marketed MTH formulation (Glucophage®) as well as enhanced pharmacokinetics properties and sustained blood glucose lowering effect, even at reduced doses with PEGylated NLCs than Glucophage®. Thus, PEGylated NLC is a promising approach for improved delivery and oral bioavailability of MTH thus encouraging further development of the formulation.

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PURPOSE: To assess the improvement in oral bioavailability and efficacy in systemic candidiasis treatment of miconazole nitrate (MN) formulations in murine models of candidiasis. METHODS: Selected formulations containing 5% of Softisan + Phospholipon 90H lipid matrix with 3% of MN (A 1), 5% of stearic acid + Phospholipon 90H lipid matrix with 3% of MN (B 1), and 5% Softisan + stearic acid + Phospholipon 90H with 3% of MN (C 1) from the in vitro investigation were used for the study. Their acute toxicity was assessed using Lorke's method (with slight modification) while bioavailability was determined using the bioassay method. The optimized batch (A 1) was tested in murine systemic candidiasis induced in cyclophosphamide-immunosuppressed mice. The mice were treated with a single oral dose (100 mg/kg) of the formulations for five days. Serum fungal counts (cfu/mL) were determined on days 1, 3, and 5 of the treatment period. Haematological assessments were done. RESULTS: The lipid formulations were safer than MN powder with LD50 values of 3162.8 and 1118.3 mg/kg. Bioavailability determination revealed a higher area under the curve (AUC) value for formulations A 1 (6.11 µg/hr/mL) and B 1 (4.91 µg/hr/mL) while formulation C 1 (1.80 µg/hr/mL) had a lower AUC than MN (4.46 µg/hr/mL). Fungi were completely cleared from the blood of animals treated with the optimized formulation by day 3 as opposed to the controls (MN and Tween® 20) which still had fungi on day 5. No significant increase (p > 0.05) in haematological parameters was observed in mice treated with A 1. CONCLUSION: Formulation A 1 successfully cleared Candida albicans from the blood within a shorter period than miconazole powder. This research has shown the potential of orally administered MN-loaded SRMS-based microparticles in combating systemic candidaemia.

Asunto(s)

Antifúngicos , Miconazol , Animales , Antifúngicos/farmacología , Disponibilidad Biológica , Candida albicans , Candidiasis , Lípidos/farmacología , Ratones , Micelas , Miconazol/farmacología , Tamaño de la Partícula , Polvos

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Aim: Anterior eye segment disorders are treated with eye drops and ointments, which have low ocular bioavailability necessitating the need for improved alternatives. Lipid microsuspension of gentamicin sulphate was developed for the treatment of susceptible eye diseases. Materials & methods: Lipid microsuspensions encapsulating gentamicin sulphate were produced by hot homogenization and evaluated. Ex vivo permeation and ocular irritancy tests were also conducted. Results & conclusion: Stable microsuspensions with high entrapment efficiency and satisfactory osmolarities were obtained. Release studies achieved 49-88% in vitro release at 12 h with sustained permeability of gentamicin compared with conventional gentamicin eye drop (Evril®). No irritation was observed following Draize's test. The microsuspensions have great potential as ocular delivery system of gentamicin sulphate.

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Ojo , Gentamicinas , Disponibilidad Biológica , Sistemas de Liberación de Medicamentos , Lípidos , Soluciones Oftálmicas

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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.

Asunto(s)

Portadores de Fármacos , Lípidos , Administración Cutánea , Arteméter , Portadores de Fármacos/química , Humanos , Lípidos/química , Nanogeles , Tamaño de la Partícula , Piel

RESUMEN

Bio-inspired nanotechnology-based strategies are potential platforms for enhanced dissolution and oral biovailability of poorly water-soluble drugs. In this study, a recently patented green biopolymer (Prosopis africana gum, PG) was compatibilized with microcrystalline cellulose (MCC), a conventional polysaccharide, via thermo-regulated coacervation to obtain PG-MCC (1:0, 1:1, 1:2, 2:1, and 0:1) rational blends and the nanoparticles developed with optimized (1:1) biocomposites (termed "prosopisylated cellulose") by combined homogenization-nanoprecipitation technique was engineered as a high circulating system for improved oral bioavailability of griseofulvin (GF), a model Biopharmaceutics Classification System (BCS) Class-II drug. The effects of biopolymer interaction on morphological and microstructural properties of drug-free biocomposites obtained were investigated by Fourier transform infra-red spectroscopy, scanning electron microscopy and x-ray diffractometry, while the physicochemical properties and in-vivo pharmacokinetics of GF-loaded nanoparticles were also ascertained. Optimized biocomposites revealed inter-molecular and intra-molecular hydrogen bonding between the hydroxyl group of MCC and polar components of PG, as well as reduction in crystallinity of MCC. Griseofulvin-loaded nanoparticles were stable, displayed particles with relatively smooth surfaces and average size of 26.18 ± 0.94 . nm, with zeta potential and polydispersity index of 32.1 ± 0.57 mV and 0.173 ± 0.06, respectively. Additionally, the nanoparticles showed good entrapment efficiency (86.51 ± 0.93 %), and marked improvement in griseofulvin dissolution when compared to free drug, with significantly (p < 0.05) higher GF release in basic than acidic PEG-reinforced simulated bio-microenvironments. Besides, x-ray diffractogram of GF-loaded nanoparticles showed amorphization with few characteristic peaks of GF while infra-red spectrum indicated broader principal peaks of GF and components compatibility. Furthermore, GF-loaded nanoparticles showed low plasma clearance with three-fold increase in systemic bioavailability of griseofulvin compared with free drug. These results showed that prosopisylated cellulose nanoparticles would be a facile approach to improve oral bioavailability of BCS class-II drugs and can be pursued as a new versatile drug delivery platform.

Asunto(s)

Administración Oral , Materiales Biocompatibles/química , Celulosa/química , Nanopartículas/química , Solubilidad , Agua/química , Animales , Disponibilidad Biológica , Tampones (Química) , Portadores de Fármacos/química , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Femenino , Griseofulvina/química , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Masculino , Nanotecnología/métodos , Tamaño de la Partícula , Conejos

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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.

Asunto(s)

Quitosano/química , Diabetes Mellitus/tratamiento farmacológico , Portadores de Fármacos/química , Insulina/química , Mucinas/química , Membrana Mucosa/química , Nanopartículas/química , Adhesividad , Administración Oral , Animales , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/farmacología , Liberación de Fármacos , Femenino , Insulina/administración & dosificación , Insulina/uso terapéutico , Masculino , Ratas , Ratas Wistar

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BACKGROUND: Artemether and lumefantrine display low aqueous solubility leading to poor release profile; hence the need for the use of lipid-based systems to improve their oral bioavailability so as to improve their therapeutic efficacy. AIM AND OBJECTIVE: The objective of this work was to utilize potentials of nanostructured lipid carriers (NLCs) for improvement of the oral bioavailability of artemether and lumefantrine combination and to evaluate its efficacy in the treatment of malaria. This study reports a method of formulation, characterization and evaluation of the therapeutic efficacies of caprol-based NLC delivery systems with artemether and lumefantrine. METHOD: The artemether-lumefantrine co-loaded NLCs were prepared using the lipid matrix (5% w/w) (containing beeswax and Phospholipon® 90H and Caprol-PGE 860), artemether (0.1%w/w) and lumefantrine (0.6%w/w), sorbitol (4%w/w), Tween® 80(2%w/w as surfactant) and distilled water (q.s to 100%) by high shear homogenization and evaluated for physicochemical performance. The in vivo antimalarial activities of the NLC were tested in chloroquine-sensitive strains of Plasmodium berghei (NK-65) using Peter´s 4-day suppressive protocol in mice and compared with controls. Histopathological studies were also carried out on major organs implicated in malaria. RESULTS: The NLC showed fairly polydispersed nano-sized formulation (z-average:188.6 nm; polydispersity index, PDI=0.462) with no major interaction occurring between the components while the in vivo study showed a gradual but sustained drug release from the NLC compared with that seen with chloroquine sulphate and Coartem®. Results of histopathological investigations also revealed more organ damage with the untreated groups than groups treated with the formulations. CONCLUSION: This study has shown the potential of caprol-based NLCs for significant improvement in oral bioavailability and hence antimalarial activity of poorly soluble artemether and lumefantrine. Importantly, this would improve patient compliance due to decrease in dosing frequency as a sustained release formulation.

Asunto(s)

Antimaláricos/administración & dosificación , Antimaláricos/farmacología , Combinación Arteméter y Lumefantrina/administración & dosificación , Combinación Arteméter y Lumefantrina/farmacología , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Lípidos , Ratones , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Tamaño de la Partícula

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Erythromycin-loaded solid lipid microparticles (SLM) based on solidified reverse micellar solution (SRMS) as an oral delivery formulation was studied. Hot homogenization technique was employed to prepare erythromycin stearate-loaded SLMs using blends of Softisan® 154 and Phospholipon® 90H or beeswax in the ratio of 1:2, and characterized in vitro. Antibacterial evaluation of the formulations was carried out by agar diffusion technique against some selected clinical isolates of bacterial. Preliminary pharmacokinetic study was performed after oral administration in male Albino rats. The results of matrix contain Softisan® 154 and phospholipon® 90H (1:2) showed that erythromycin-loaded SLM was smooth; particle size ranged from 10.3 ±â€¯11.24 µm to 18.1 ±â€¯10.11 µm and maximum encapsulation efficiency and loading capacity were 95.11 ±â€¯0.3% and 43.22 ±â€¯0.1 mg, respectively. While that of beeswax- containing matrix showed maximum particle size of 18.9 ±â€¯21.10 µm, maximum encapsulation efficiency of 89.01 ±â€¯0.11% and loading capacity of 39.02 ±â€¯0.12 mg. All the formulations had prolonged release and antibacterial activity. Significantly (p > 0.05), prolonged plasma erythromycin concentration was obtained in the optimized formulation (>14 h) compared with commercial sample of erythromycin tablet (10h). Erythromycin stearate-loaded SLMs formulation could serve as an alternative to conventional oral formulation of erythromycin.

Asunto(s)

Antibacterianos/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Eritromicina/análogos & derivados , Lípidos/química , Administración Oral , Animales , Antibacterianos/farmacocinética , Rastreo Diferencial de Calorimetría , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Portadores de Fármacos/administración & dosificación , Liberación de Fármacos , Eritromicina/administración & dosificación , Eritromicina/farmacocinética , Eritromicina/farmacología , Concentración de Iones de Hidrógeno , Masculino , Micelas , Pruebas de Sensibilidad Microbiana , Tamaño de la Partícula , Ratas , Ceras/química

RESUMEN

The aim of this study was to investigate the potential of microparticles based on biocompatible phytolipids [Softisan® 154 (SF) (hydrogenated palm oil) and super-refined sunseed oil (SO)] and polyethylene glycol- (PEG-) 4000 to improve intravaginal delivery of miconazole nitrate (MN) for effective treatment of vulvovaginal candidiasis (VVC). Lipid matrices (LMs) consisting of rational blends of SF and SO with or without PEG-4000 were prepared by fusion and characterized and employed to formulate MN-loaded solid lipid microparticles (SLMs) by melt-homogenization. The SLMs were characterized for physicochemical properties, anticandidal activity, and stability. Spherical discrete microparticles with good physicochemical properties and mean diameters suitable for vaginal drug delivery were obtained. Formulations based on SO:SF (1:9) and containing highest concentrations of PEG-4000 (4 %w/w) and MN (3.0 %w/w) were stable and gave highest encapsulation efficiency (83.05-87.75%) and inhibition zone diameter (25.87±0.94-26.33±0.94 mm) and significantly (p<0.05) faster and more powerful fungicidal activity regarding killing rate constant values (7.10 x 10-3-1.09 x 10-2 min-1) than commercial topical solution of MN (Fungusol®) (8.00 x 10-3 min-1) and pure MN sample (5.160 x 10-3 min-1). This study has shown that MN-loaded SLMs based on molecularly PEGylated lipid matrices could provide a better option to deal with VVC.

Asunto(s)

Antifúngicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Miconazol/administración & dosificación , Femenino , Humanos , Tamaño de la Partícula , Vagina

RESUMEN

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.

Asunto(s)

Candidiasis Vulvovaginal/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Miconazol/uso terapéutico , Adhesividad , Administración Intravaginal , Animales , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Preparaciones de Acción Retardada/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Concentración de Iones de Hidrógeno , Lípidos , Miconazol/administración & dosificación , Distribución Aleatoria , Ratas

RESUMEN

OBJECTIVE: To develop and evaluate solidified-reverse-micellar-solution (SRMS)-based oromucosal nano lipid gels for improved localised delivery of miconazole nitrate (MN). METHODS: Phospholipon® 90G and Softisan® 154 (3:7) were used to prepare SRMS by fusion. Solid lipid nanoparticles (SLNs, 0.25-1.0% w/w MN) formulated with the SRMS by high shear homogenisation were employed to prepare mucoadhesive nano lipid gels. Physicochemical characterisation, drug release in simulated salivary fluid (SSF) (pH 6.8) and anti-candidal activity were carried out. RESULTS: The SLNs were spherical nanoparticles, had mean size of 133.8 ± 6.4 to 393.2 ± 14.5 nm, low polydispersity indices, good encapsulation efficiency (EE) (51.96 ± 2.33-67.12 ± 1.65%) and drug loading (DL) (19.05 ± 2.44-24.93 ± 1.98%). The nano lipid gels were stable, spreadable, pseudoplastic viscoelastic mucoadhesive systems that exhibited better prolonged release and anti-candidal properties than marketed formulation (Daktarin® oral gel) (p < 0.05). CONCLUSION: This study has shown that SRMS-based nano lipid gels could be employed to prolong localised oromucosal delivery of MN.

Asunto(s)

Antifúngicos/administración & dosificación , Candidiasis Bucal/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Miconazol/administración & dosificación , Nanopartículas/administración & dosificación , Química Farmacéutica , Estabilidad de Medicamentos , Geles , Micelas , Miconazol/química , Tamaño de la Partícula

RESUMEN

The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether-lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol® ATO 5/Transcutol® HP and tallow fat/Transcutol® HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected with Plasmodium berghei berghei (NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol® ATO 5/Transcutol® HP batch, then 81% and 95% for tallow fat/Transcutol® HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol® ATO 5/Transcutol® HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol® HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem® tablets (86%) and chloroquine phosphate tablets (66%). No significant difference (P<0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms.

Asunto(s)

Artemisininas/uso terapéutico , Etanolaminas/uso terapéutico , Fluorenos/uso terapéutico , Malaria/tratamiento farmacológico , Cooperación del Paciente , Animales , Antimaláricos/administración & dosificación , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Combinación Arteméter y Lumefantrina , Artemisininas/administración & dosificación , Artemisininas/química , Artemisininas/farmacología , Rastreo Diferencial de Calorimetría , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/uso terapéutico , Portadores de Fármacos/química , Combinación de Medicamentos , Liberación de Fármacos , Etanolaminas/administración & dosificación , Etanolaminas/química , Etanolaminas/farmacología , Fluorenos/administración & dosificación , Fluorenos/química , Fluorenos/farmacología , Humanos , Concentración de Iones de Hidrógeno , Cinética , Lípidos/química , Malaria/parasitología , Ratones , Nanoestructuras/química , Tamaño de la Partícula , Plasmodium berghei/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier , Comprimidos

RESUMEN

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.

RESUMEN

CONTEXT: Poor aqueous solubility of artemether and lumefantrine makes it important to seek better ways of enhancing their oral delivery and bioavailability. OBJECTIVE: To formulate and carry out in vitro and anti-malarial pharmacodynamic evaluations of solidified reverse micellar solutions (SRMS)-based solid lipid microparticles (SLMs) of artemether and lumefantrine for oral delivery and improved bioavailability. MATERIALS AND METHODS: Rational blends of Softisan(®)154 and Phospholipon(®)90H lipid matrices, and different concentrations of artemether and lumefantrine were used to formulate several batches of SLMs. Drug-free SLMs were also formulated. Morphology, particle size, encapsulation efficiency (EE%) and pH studies were performed. In vitro release studies were performed in alcoholic buffer, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Anti-malarial pharmacodynamic studies were conducted in mice. RESULTS: Stable, smooth and spherical particles with sizes ranging from 4.2 ± 0.02 to 9.3 ± 0.8 µm were formed. EE% of 92.2-97.3% and 30.2-84.7% and pH of 3.0 ± 0.02 to 4.9 ± 0.12 and 3.0 ± 0.02 to 5.8 ± 0.05 were obtained for artemether and lumefantrine SLMs, respectively. Release of 100, 88.28 and 75.49%, as well as 63.26, 34.31 and 56.17% were recorded for artemether and lumefantrine in alcoholic buffer, SGF and SIF, respectively. Pharmacodynamic studies indicated very significant (p < 0.05) clearance of parasitaemia in plasmodium-infected mice by the drug-loaded SLMs. CONCLUSION: Oral delivery and bioavailability of artemether and lumefantrine could be improved using SRMS-based SLMs.

Asunto(s)

Antimaláricos/administración & dosificación , Artemisininas/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Etanolaminas/administración & dosificación , Fluorenos/administración & dosificación , Lípidos/química , Administración Oral , Animales , Antimaláricos/química , Arteméter , Artemisininas/química , Disponibilidad Biológica , Diseño de Fármacos , Etanolaminas/química , Fluorenos/química , Lumefantrina , Ratones , Microesferas , Tamaño de la Partícula , Solubilidad