Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS) of Nimodipine

The ability of self-emulsifying drug delivery systems (SEDDS) to improve solubility, dissolution rate and bioavailability of a poorly water-soluble calcium channel blocker, nimodipine (NM) was evaluated in the present investigation. Solubility of NM in various oils, surfactants and cosurfactants was determined. The influence of the ratio of oil to surfactant + cosurfactant, pH of aqueous phase on mean globule size of resulting emulsions was studied by means of photon correlation spectroscopy. The NM loaded SEDDS selected for the in vitro and in vivo studies exhibited globule size less than 180 nm. In vitro dissolution studies indicated that NM loaded SEDDS could release complete amount of NM irrespective of the pH of the dissolution media. Pharmacokinetics of NM suspension, NM oily solution, NM micellar solution and NM SEDDS were evaluated and compared in rabbits. Relative bioavailability of NM in SEDDS was significantly higher than all the other formulations. NM loaded SEDDS were subjected to various conditions of storage as per ICH guidelines for 3 months. NM SEDDS successfully withstood the stability testing.     

Effect of chirality on PVP/drug interaction within binary physical mixtures of ibuprofen, ketoprofen, and naproxen: a DSC study

We report on the thermal behavior of freshly prepared binary drug/polymer physical mixtures that contained ibuprofen, ketoprofen, or naproxen as a drug, and polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC), or methylcellulose (MC) as excipient. At 6-10 degrees C/min heating rates the DSC detected a sharp, single endotherm that corresponds to the melting of drug. On heating physical mixtures of PVP and racemic ibuprofen or ketoprofen at lower heating rates, another endotherm was registered in front of the original one. To observe the additional endotherm, specific minimal values of the heating rate and of PVP weight fraction were needed; for ibuprofen and ketoprofen they were 1.5 and 2.0 degrees C/min, and 5 and 15% (w/w), respectively. At greater PVP weight fractions the top temperatures, T(mp), of both peaks were reduced almost linearly indicating strong solid-state interfacial reaction between the drug particles and PVP matrix. The additional endotherm was abolished at greater heating rates (2 degrees C/min for ibuprofen, 3 degrees C/min for ketoprofen), by replacing the racemate with respective S+-enantiomer and by replacing PVP with HEC and MC. Hence, the possible inclusion of enantioselective component within the PVP/drug interaction, responsible for the amorphization of physical mixture over storage, is assumed.     

Rice germ oil as multifunctional excipient in preparation of self-microemulsifying drug delivery system (SMEDDS) of tacrolimus

Surmounting the constraints of limited solubilization efficiency and prime requisite of antioxidant for conventional lipid formulations, the research work explores an edge over formulation utilizing potential applicability of rice germ oil (RGO) as a multifunctional excipient. Self-microemulsifying drug delivery system (SMEDDS) of tacrolimus (TAC) was formulated with RGO, an indigenous source of gamma-oryzanol. Being the same biological source, RGO and rice bran oil (RBO) were compared and it was found that RGO have more solubilization potential for TAC (2.2-fold) as well as higher antioxidant activity (8.06-fold) than the RBO. TAC-SMEDDS was prepared using RGO/Capmul PG8 (2:3) as an oil phase, Cremophore EL as a surfactant, and Transcutol P as a cosurfactant. The approximate particle size of TAC-SMEDDS was found to be 38 nm by dynamic light scattering and 12 nm by small angle neutron scattering. The in vitro dissolution studies showed complete and rapid drug release in 30 min compared to a plain drug (<5%) and marketed capsule (<50%). AUC and C _max were found to be 45.05 ± 15.64 ng h/ml and 3.91 ± 1.2 ng/ml for TAC-SMEDDS, 12.59 ± 5.54 ng h/ml and 0.48 ± 0.12 ng/ml for plain TAC, and 30.23 ± 10.34 ng h/ml and 2.31 ± 0.68 ng/ml for marketed formulation, respectively. The improved pharmacokinetic profile of TAC-SMEDDS is correlating to the dissolution results. Thus, gamma-oryzanol-enriched RGO acts as a potential multifunctional excipient for lipid formulations.     

Studies in formulation and pharmacotechnical evaluation of controlled release transdermal delivery system of bupropion

The objective of the present study was to design and evaluate unilaminate transdermal adhesive matrix systems capable of diffusing bupropion base at a constant rate over an extended period of time as an alternative route of administration. Unilaminate transdermal adhesive matrices have been fabricated with different concentrations of Eudragit E as the adhesive and rate-controlling polymer. The in vitro release and epidermal flux through human cadaver skin were studied. The release of drug from the matrices obeyed zero order release kinetics (r ²=0.9810 to 0.9960). The delivery rate of bupropion ranged from 10.5 mg to 31.4 mg per day from a 3.14 cm² area of matrix. The relation between concentration of bupropion base in matrix and epidermal flux, concentration of drug in matrix, and epidermal adsorption of bupropion during diffusion follow hyperbolic fashion. Triethylcitrate (TEC) and dibutylphthalate (DBP) have no influence on the diffusion of bupropion through human cadaver skin when used as plasticizers. Incorporation of succinic acid in the adhesive matrix retarded diffusion due to the formation of rigid cross linking of the polymer, while propylene glycol and myristic acid, alone or in combination, significantly enhanced the flux of bupropion through human cadaver skin.     

Gastroretentive drug delivery system of ranitidine hydrochloride: Formulation and in vitro evaluation

The purpose of this research was to prepare a gastroretentive drug delivery system of ranitidine hydrochloride. Guar gum, xanthan gum, and hydroxypropyl methylcellulose were evaluated for gel-forming properties. Sodium bicarbonate was incorporated as a gas-generating agent. The effects of citric acid and stearic acid on drug release profile and floating properties were investigated. The addition of stearic acid reduces the drug dissolution due to its hydrophobic nature. A 3² full factorial design was applied to systemically optimize the drug release profile. The amounts of citric acid anhydrous (X₁) and stearic acid (X₂) were selected as independent variables. The times required for 50% (t₅₀) and 80% drug dissolution (t₈₀), and the similarity factor f₂ were selected as dependent variables. The results of the full factorial design indicated that a low amount of citric acid and a high amount of stearic acid favors sustained release of ranitidine hydrochloride from a gastroretentive formulation. A theoretical dissolution profile was generated using pharmacokinetic parameters of ranitidine hydrochloride. The similarity factor f₂ was applied between the factorial design batches and the theoretical dissolution profile. No significant difference was observed between the desired release profile and batches F2, F3, F6, and F9. Batch F9 showed the highest f2 (f2=75) among all the batches, and this similarity is also reflected in t₅₀ (∼214 minutes) and t₈₀ (∼537 minutes) values. These studies indicate that the proper balance between a release rate enhancer and a release rate retardant can produce a drug dissolution profile similar to a theoretical dissolution profile.     

Evaluation of polymerized rosin for the formulation and development of transdermal drug delivery system: A technical note

Conclusions  Results from the present study conclude that PR in combination with PVP and with incorporation of dibutyl phthalate (30% wt/wt) produces smooth flexible films with improved tensile strength and percentage elongation. The release rate of drug from films and permeation across skin increases with increase in drug and PVP loading but is independent of film thickness. Patches containing PR:PVP (7:3) show promise for pharmacokinetic and pharmacodynamic performance evaluation in a suitable animal model. In view of the overall results reported in the present study, it may be proposed that PR can be used in the design of a matrix type transdermal drug delivery system to prolong the drug release. Published: December 27, 2005     

Effect of Salmonella minnesota R595 LPS on the dipalmitoylphosphatidyl-ethanolamine (DPPE)-dipalmitoylglycerol (DPG)-water model membrane system

The effect of Salmonella minnesota R595 lipopolysaccharide (LPS) on model membrane consisting of a mixture of fully hydrated lipids (dipalmitoylphosphatidylethanolamine (DPPE) and dipalmitoylglycerol (DPG)) was investigated by differential scanning calorimetry (DSC), small-angle X-ray scattering (SAXS) and freeze–fracture methods. The DPPE–DPG/water system forms a multilamellar arrangement in the gel phase which transforms into a mixture of inverted hexagonal and cubic structures. By the presence of LPS the thermotropic behaviour of the system was affected significantly only at its high concentration (1:1 mol/mol LPS/DPPE–DPG) in the gel phase, while above the chain melting transition the ratio of the inverted cubic and the hexagonal structures was changed and at the 1:1 mol/mol LPS/DPPE–DPG ratio a complex and amorphous phase was formed. The structural parameters of the inverted hexagonal and cubic phases are modified by the temperature and also by the LPS concentration, as deduced from the characteristic SAXS curves. Summarizing the effects of the LPS molecules on the DPPE–DPG/water vesicle system a schematic phase diagram was constructed.     

Synthesis and characterization of star poly(epsilon-caprolactone)-b-poly(ethylene glycol) and poly(L-lactide)-b-poly(ethylene glycol) copolymers: evaluation as drug delivery carriers

Two types of 32 arm star polymers incorporating amphiphilic block copolymer arms have been synthesized and characterized. The first type, stPCL-PEG 32, is composed of a polyamidoamine (PAMAM) dendrimer as the core with radiating arms having poly(epsilon-caprolactone) (PCL) as an inner lipophilic block in the arm and poly(ethylene glycol) (PEG) as an outer hydrophilic block. The second type, stPLA-PEG 32, is similar but with poly(L-lactide) (PLA) as the inner lipophilic block. Characterization with SEC, (1)H NMR, FTIR, and DSC confirmed the structure of the polymers. Micelle formation by both star copolymers was studied by fluorescence spectroscopy. The stPCL-PEG 32 polymer exhibited unimolecular micelle behavior. It was capable of solubilizing hydrophobic molecules, such as pyrene, in aqueous solution, while not displaying a critical micelle concentration. In contrast, the association behavior of stPLA-PEG 32 in aqueous solution was characterized by an apparent critical micelle concentration of ca. 0.01 mg/mL. The hydrophobic anticancer drug etoposide can be encapsulated in the micelles formed from both polymers. Overall, the stPCL-PEG 32 polymer exhibited a higher etoposide loading capacity (up to 7.8 w/w % versus 4.3 w/w % for stPLA-PEG 32) as well as facile release kinetics and is more suitable as a potential drug delivery carrier.     

In vitro evaluation of dissolution behavior for a colon-specific drug delivery system (CODES) in multi-pH media using United States Pharmacopeia apparatus II and III

United States Pharmacopeia dissolution apparatus II (paddle) and III (reciprocating cylinder) coupled with automatic sampling devices and software were used to develop a testing procedure for acquiring release profiles of colon-specific drug delivery system (CODES^™) drug formulations in multi-pH media using acetaminophen (APAP) as a model drug. System suitability was examined. Several important instrument parameters and formulation variables were evaluated. Release profiles in artificial gastric fluid (pH 1.2), intestinal fluid (pH 6.8), and pH 5.0 buffer were determined. As expected, the percent release of APAP from coated core tablets was highly pH dependent. A release profile exhibiting a negligible release in pH 1.2 and 6.8 buffers followed by a rapid release in pH 5.0 buffer was established. The drug release in pH 5.0 buffer increased significantly with the increase in the dip or paddle speed but was inversely related to the screen mesh observed at lower dip speeds. It was interesting to note that there was a close similarity (f ₂=80.6) between the release profiles at dip speed 5 dpm and paddle speed 100 rpm. In addition, the release rate was reduced significantly with the increase in acid-soluble Eudragit E coating levels, but lactulose loading showed only a negligible effect. In conclusion, the established reciprocating cylinder method at lower agitation rates can give release profiles equivalent to those for the paddle procedure for CODES^™ drug pH-gradient release testing. Apparatus III was demonstrated to be more convenient and efficient than apparatus II by providing various programmable options in sampling times, agitation rates, and medium changes, which suggested that the apparatus II approach has better potential for in vitro evaluation of colon-specific drug delivery systems.     

Synthesis and evaluation of a star amphiphilic block copolymer from poly(epsilon-caprolactone) and poly(ethylene glycol) as a potential drug delivery carrier

A star polymer composed of amphiphilic block copolymer arms has been synthesized and characterized. The core of the star polymer is polyamidoamine (PAMAM) dendrimer, the inner block in the arm is lipophilic poly(epsilon-caprolactone) (PCL), and the outer block in the arm is hydrophilic poly(ethylene glycol) (PEG). The star-PCL polymer was synthesized first by ring-opening polymerization of epsilon-caprolactone with a PAMAM-OH dendrimer as initiator. The PEG polymer was then attached to the PCL terminus by an ester-forming reaction. Characterization with SEC, (1)H NMR, FTIR, TGA, and DSC confirmed the star structure of the polymers. The micelle formation of the star copolymer (star-PCL-PEG) was studied by fluorescence spectroscopy. Hydrophobic dyes and drugs can be encapsulated in the micelles. A loading capacity of up to 22% (w/w) was achieved with etoposide, a hydrophobic anticancer drug. A cytotoxicity assay demonstrated that the star-PCL-PEG copolymer is nontoxic in cell culture. This type of block copolymer can be used as a drug delivery carrier.     

Dynamic and cellular interactions of nanoparticles in vascular-targeted drug delivery (review)

Abstract

Vascular-targeted drug delivery systems could provide more efficient and effective pharmaceutical interventions for treating a variety of diseases including cardiovascular, pulmonary, inflammatory, and malignant disorders. However, several factors must be taken into account when designing these systems. The diverse blood hemodynamics and rheology, and the natural clearance process that tend to decrease the circulation time of foreign particles all lessen the probability of successful carrier interaction with the vascular wall. An effective vascular-targeted drug delivery system must be able to navigate through the bloodstream while avoiding immune clearance, attach to the vascular wall, and release its therapeutic cargo at the intended location. This review will summarize and analyze current literature reporting on (1) nanocarrier fabrication methods and materials that allow for optimum therapeutic encapsulation, protection, and release; (2) localization and binding dynamics of nanocarriers as influenced by hemodynamics and blood rheology in medium-to-large vessels; (3) blood cells' responses to various types of nanocarrier compositions and its effects on particle circulation time; and (4) properties that affect nanocarrier internalization at the target site.     

Dynamic and cellular interactions of nanoparticles in vascular-targeted drug delivery (review)

Abstract

Vascular-targeted drug delivery systems could provide more efficient and effective pharmaceutical interventions for treating a variety of diseases including cardiovascular, pulmonary, inflammatory, and malignant disorders. However, several factors must be taken into account when designing these systems. The diverse blood hemodynamics and rheology, and the natural clearance process that tend to decrease the circulation time of foreign particles all lessen the probability of successful carrier interaction with the vascular wall. An effective vascular-targeted drug delivery system must be able to navigate through the bloodstream while avoiding immune clearance, attach to the vascular wall, and release its therapeutic cargo at the intended location. This review will summarize and analyze current literature reporting on (1) nanocarrier fabrication methods and materials that allow for optimum therapeutic encapsulation, protection, and release; (2) localization and binding dynamics of nanocarriers as influenced by hemodynamics and blood rheology in medium-to-large vessels; (3) blood cells' responses to various types of nanocarrier compositions and its effects on particle circulation time; and (4) properties that affect nanocarrier internalization at the target site.     

Preparation of konjac glucomannan-based pulsatile capsule for colonic drug delivery system and its evaluation in vitro and in vivo

The current study aims to develop and evaluate a colon-specific, pulsatile drug delivery system based on an impermeable capsule. A pulsatile capsule was prepared by sealing a 5-aminosalicylic acid rapid-disintegrating tablet inside an impermeable capsule body with a konjac glucomannan (KGM)-hydroxypropyl methylcellulose (HPMC)-lactose plug. The drug delivery system showed a typical pulsatile release profile with a lag time followed by a rapid release phase. The lag time was determined by the KGM/HPMC/lactose ratio, the type of HPMC, and the plug weight. The addition of β-glucanase and rat cecal contents into the release medium shortened the lag time significantly, which predicted the probable enzyme sensitivity of the KGM plug. The in vivo studies show that the plasma drug concentration can only be detected 5 h after oral administration of the capsule, which indirectly proves the colon-specific characteristics. These results indicate that the pulsatile capsule may have therapeutic potential for colon-specific drug delivery.     

Pinocytic uptake and intracellular degradation of N-(2-hydroxypropyl)methacrylamide copolymers a potential drug delivery system

Synthetic ¹²⁵I-labelled N-(2-hydroxypropyl)methacrylamide copolymers containing four different, potentially degradable peptidyl side chains were incubated with rat visceral yolk sacs cultured in vitro. All copolymers were captured by fluid-phase pinocytosis and three of the side chains were susceptible to lysosomal hydrolysis, resulting in release of [¹²⁵I]iodotyrosine back into the culture medium. Uptake and degradation was completely inhibited by 2,4-dinitrophenol. The thiol-proteinase inhibitor leupeptin did not affect the rate of pinocytosis, but caused different degrees of inhibition of hydrolysis depending on side chain composition.     

Development and in vitro evaluation of thiolated chitosan--Poly(methacrylic acid) nanoparticles as a local mucoadhesive delivery system

The main objective of this study was to develop a local, oral mucoadhesive metronidazole benzoate (MET) delivery system that can be applied and removed by the patient for the treatment of periodontal diseases. The results of present study revealed that the retention time of MET at its absorption site could be increased by formulating it into nanoparticles using thiolated chitosan (TCS)-poly(methacrylic acid) (PMAA). The nanoparticles of MET prepared from TCS-PMAA may represent a useful approach for targeting its release at its site of absorption, sustaining its release and improving its oral availability.     

Preparation and enantioseparation characteristics of two chiral stationary phases based on mono(6(A)-azido-6(A)-deoxy)-perphenylcarbamoylated alpha- and gamma-cyclodextrin

Two chiral stationary phases, ph-alpha-CD and ph-gamma-CD, were prepared from mono(6(A)-azido-6(A)-deoxy)perphenylcarbamoylated alpha- and gamma-cyclodextrin immobilized onto silica gel via the Staudinger reaction. The chromatographic characteristics of these two chiral stationary phases were evaluated. The influence of different cyclodextrins (CDs) on the enantioselectivities was also investigated in this study. Compared to ph-gamma-CD, ph-alpha-CD exhibited quite good enantioselectivity toward the analytes with bulky molecular structures. It was found that the formation of inclusion complex might play a quite important role in the chiral recognition not only under reverse phases but also under normal phases.     

Effect of treatment with silver(I) complex of metronidazole on ocular rosacea: Design and formulation of new silver drug with potent antimicrobial activity

BackgroundMetronidazole with well-soluble silver nitrate forms a complex with potent activity (synergism) against bacterial strains and fungi with simultaneous lower side effect than in the case of the two agents administered separately.This study aimed to establish effectiveness in the treatment of ocular rosacea with new formulation of drops and ointment with silver(I) complex of metronidazole.MethodsThree patients suffering from serious ophthalmic complications of acne rosacea were treated with drops and ointments applied 3 times a day for 3 months. The uncorrected visual acuity testing (UCVA), pachymetry as well as subjective and objective tear film assessment were evaluated.ResultsIn all patients, we have improved UCVA as well as objective and subjective evaluation of the tear film parameters. No significant differences in corneal thickness were observed.ConclusionWell soluble silver(I) complex of metronidazole might be an alternative method in ophthalmic complications of acne rosacea treatment.     

Effect of dithiocarbamate pesticide zineb and its commercial formulation, azzurro. III. Genotoxic evaluation on Chinese hamster ovary (CHO) cells

The in vitro genotoxicity exerted by the dithiocarbamate fungicide zineb, and its commercial formulation azzurro, were studied in Chinese hamster ovary (CHO) cells by the analysis of the sister chromatid exchange (SCE), cell-cycle progression and single cell gel electrophoresis (SCGE) assays. Both zineb and azzurro activities were tested within the range of 0.1-100.0 microg/ml. Concentrations of 0.1-25.0 microg/ml of zineb or azzurro induced a significant dose-dependent increase in SCE frequency over control values. For both test compounds, while doses ranging from 0.1 to 1.0 microg/ml did not alter the rate of cell proliferation, a significant delay in cell-cycle progression was observed within the 5.0-25.0 microg/ml dose-range. A regression test showed that either the proliferative replication index or the mitotic activity of cultures decreased as a function of the pesticide concentration within the 1.0-25.0 microg/ml dose-range. Doses higher than 50.0 microg/ml were cytotoxic. SCGE assay revealed an increase in zineb-induced DNA damage by enhancing the proportion of slightly damaged cells in the 25.0-100.0 microg/ml dose-range and by increasing in a dose-dependent manner the proportion of damaged cells within the 1.0-100.0 microg/ml dose-range. Overall, image analysis showed statistically significant positive relationships between zineb concentration and DNA damage (expressed by image length and width) and between length and width of the damaged cells. In azzurro-treated cells, only when 100.00 microg/ml was employed a significant increase in the frequency of damaged cells over control values affecting the totality of the cells was observed only when 100.0 microg/ml was employed. When lower doses were employed, no DNA damage was revealed. Based on these results, the evaluation of zineb as a genotoxic/non-genotoxic compound for human health should be reconsidered. Even though we demonstrate that the pesticide induces large DNA alterations in vitro, does no necessarily mean that the chemical should be considered clastogenic.notoxic     

Effect of silicon dioxide on expression of poly (ADP-Ribose) polymerase mRNA and protein

Silicon dioxide induces acute injury and chronic pulmonary fibrosis. International Agency for Research on Cancer (IARC) listed it as a human carcinogen in 1996. However, the molecular mechanisms to induce cancer are not understood yet. The content of poly (ADP-ribose) polymerases (PARP) mRNA and protein in Hela cells treated with concentrations of silicon dioxide up to 400 μg/ml was determined by real-time fluorogenetic quantitative PCR (RQ-PCR) and immunofluorescence assay, respectively. MTT assay was used to determine cell viability. The results showed that viability at 400 μg/ml silica was significantly decreased but not at lower concentrations. The protein content of γ-H2AX in silica-treated group was significantly higher than the controls. The PARP mRNA and protein levels were significantly reduced with a dose response manner from the lowest silicon dioxide level. Our findings suggested that silicon dioxide increased the expression of γ-H2AX and inhibited the expression of PARP mRNA and protein in Hela cells.