Potential applications of carbomer in oral mucoadhesive controlled drug delivery system: a review

Carbomers are extensively being used in controlled drug delivery systems (CDDS). They are also finding numerous applications in oral mucoadhesive drug delivery because of their ability to interact with the mucus glycoprotein and to remain localized to a specific site. The present review aims at giving an insight into the potential application of carbomers in mucoadhesive CDDS. This review deals with the physicochemical properties of carbomers and various mechanisms of mucoadhesion. The mechanism for the release of the drug, both water soluble and water insoluble, is discussed. The use of carbomers in oral delivery of peptides or protein-based drugs is also covered.     

Development of phyllanthin-loaded self-microemulsifying drug delivery system for oral bioavailability enhancement

Phyllanthin, a poorly water-soluble herbal active component from Phyllanthus amarus, exhibited a low oral bioavailability. This study aims at formulating self-microemulsifying drug delivery systems (SMEDDS) containing phyllanthin and evaluating their in-vitro and in-vivo performances. Excipient screening was carried out to select oil, surfactant and co-surfactant. Formulation development was based on pseudo-ternary phase diagrams and characteristics of resultant microemulsions. Influences of dilution, pH of media and phyllanthin content on droplet size of the resultant emulsions were studied. The optimized phyllanthin-loaded SMEDDS formulation (phy-SMEDDS) and the resultant microemulsions were characterized by viscosity, self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. In-vitro dissolution and oral bioavailability in rats of phy-SMEDDS were studied and compared with those of plain phyllanthin. Phy-SMEDDS consisted of phyllanthin/Capryol 90/Cremophor RH 40/Transcutol P (1.38:39.45:44.38:14.79) in % w/w. Phy-SMEDDS could be emulsified completely within 6?min and formed fine microemulsions, with average droplet range of 27–42?nm. Phy-SMEDDS was robust to dilution and pH of dilution media while the resultant emulsion showed no phase separation or drug precipitation after 8?h dilution. The release of phyllanthin from phy-SMEDDS capsule was significantly faster than that of plain phyllanthin capsule irrespective of pH of dissolution media. Phy-SMEDDS was found to be stable for at least 6 months under accelerated condition. Oral absorption of phyllanthin in rats was significantly enhanced by SMEDDS as compared with plain phyllanthin. Our study indicated that SMEDDS for oral delivery of phyllanthin could be an option to enhance its bioavailability.     

Development of self-microemulsifying drug delivery system for oral delivery of poorly water-soluble nutraceuticals

The objective of the study was to develop a self-microemulsifying drug delivery system (SMEDDS), also known as microemulsion preconcentrate, for oral delivery of five poorly water-soluble nutraceuticals or bioactive agents, namely, vitamin A, vitamin K2, coenzyme Q₁₀, quercetin and trans-resveratrol. The SMEDDS contained a 1:1 mixture (w/w) of Capmul MCM NF (a medium chain monoglyceride) and Captex 355 EP/NF (a medium chain triglyceride) as the hydrophobic lipid and Tween 80 (polysorbate 80) as the hydrophilic surfactant. The lipid and surfactant were mixed at 50:50 w/w ratio. All three of the SMEDDS components have GRAS or safe food additive status. The solubility of nutraceuticals was determined in Capmul MCM, Captex 355, Tween 80, and the SMEDDS (microemulsion preconcentrate mixture). The solubility values of vitamin A palmitate, vitamin K2, coenzyme Q₁₀, quercetin, and trans-resveratrol per g of SMEDDS were, respectively, 500, 12, 8, 56, and 87?mg. Appropriate formulations of nutraceuticals were prepared and filled into hard gelatin capsules. They were then subjected to in vitro dispersion testing using 250?mL of 0.01 N HCl in USP dissolution apparatus II. The dispersion test showed that all SMEDDS containing nutraceuticals dispersed spontaneously to form microemulsions after disintegration of capsule shells with globule size in the range of 25 to 200?nm. From all formulations, except that of vitamin K2, >80–90% nutraceuticals dispersed in 5–10?min and there was no precipitation of compounds during the test period of 120?min. Some variation in dispersion of vitamin K2 was observed due to the nature of the material used (vitamin K2 pre-adsorbed onto calcium phosphate). The present report provides a simple and organic cosolvent-free lipid-based SMEDDS for the oral delivery of poorly water-soluble nutraceuticals. Although a 50:50 w/w mixture of lipid to surfactant was used, the lipid content may be increased to 70:30 without compromising the formation of microemulsion.     

Development of self-microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride

The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Berberine hydrochloride (BBH), an important bioactive compound from Chinese Medicines with poor water solubility. Pseudoternary phase diagrams were constructed using oil, surfactant and co-surfactant types to identify the efficient self-microemulsification region. SMEDDS was characterized by morphological observation, droplet size, zeta-potential determination, stability, in vitro release and in vivo bioavailability study. The optimal formulation with the best self-microemulsifying and solubilization ability consisted of 40% (w/w) of ethyl linoleate and oleic acid (2:1), 35% (w/w) Tween-80 and 25% (w/w) glycerol. The SMEDDS of BBH could exhibit good stability. In vitro release test showed a complete release of BBH from SMEDDS was in 5 h. In vivo results indicated that the peak plasma concentration (C_max) and the area under the curve (AUC_{0→12 h}) of SMEDDS of BBH were higher than the commercial tablet by 163.4% and 154.2%, respectively. The relative bioavailability of SMEDDS of BBH was enhanced about 2.42-fold compared with the commercial tablet in rats. The study confirmed that the SMEDDS formulation could be used as a possible alternative to traditional oral formulations of BBH to improve its bioavailability.     

Development and in vitro evaluation of alginate gel-encapsulated, chitosan-coated ceramic nanocores for oral delivery of enzyme

The successful administration of protein and peptide drugs by oral route maintaining their active conformation remains a key challenge in the field of pharmaceutical technology. In the present study, we propose the use of a nanosize ceramic core-based system for effective oral delivery of acid-labile model enzyme, serratiopeptidase (STP). Ceramic core was prepared by colloidal precipitation and sonication of disodium hydrogen phosphate solution and calcium chloride solution at room temperature. The core was coated with chitosan under constant stirring and Fourier-Transform Infra Red Spectroscopy (FTIR) confirmed phosphoric groups of calcium phosphate linked with ammonium groups of chitosan in the nanoparticles; then the enzyme was adsorbed over the preformed nanocore. Protein-loaded nanocore was further encapsulated into alginate gel for enzyme protection. Prepared system was characterized for size, shape, loading efficiency, and in vitro release profile (pH 1.2 and pH 7.4). The effect of processing variables on the size of the core was evaluated to form small, uniform, and discrete nanocores. Stability and integrity of enzyme during processing steps was assessed by in vitro proteolytic activity. The prepared system was examined to be spherical in shape with diameter 925 ± 6.81 nm using TEM. The in vitro release data followed the Higuchi model, showing a low amount (26% ± 2.4%) of diffusion-controlled drug release (R² = 0.9429) in acidic buffer up to a period of 2 to 6 hours, signifying the integrity of alginate gel in acid. In the alkaline medium sustained and nearly complete first order release of protein was observed up to a 6 hours. It is inferred that the protein-loaded ceramic core acts as a reservoir of the adsorbed enzyme and alginate gel provides protection to STP for controlled release in intestinal pH when compared to the enzyme solution.     

Preparation and characterization of novel sinomenine microcapsules for oral controlled drug delivery

Background: Developing a sustained release drug to cure arthritis is needed. Sinomenine (SIN) is abstracted from sinomenium acutum and widely used in the treatment of various rheumatism and arrhythmia with few side effects. The primary aim of this study is to develop SIN microcapsules with polyelectrolyte multilayers for controlled drug release. Method: SIN microcrystals were encapsulated with chitosan, gelatin, and alginate by layer-by-layer technique, such as (gelatin/alginate)₄ and (chitosan/alginate)₆. The size distribution, zeta-potential, stability, and morphology of the microcapsules were characterized by a particle size analyzer, zetasizer, ultraviolet spectroscopy, and transmission electron microscope, respectively. The in vitro controlled release pattern of SIN was studied using a diffusion cell assembly at physiological pH of 6.8 or 1.4. Results: Light stability of these microcapsules was improved after microencapsulation. Compared with release rate of the SIN microcapsules coated by the poly(dimethyldiallyl ammonium chloride)/alginate and gelatin/alginate multilayers, release rate of the SIN microcapsules coated with chitosan/alginate multilayers was fast. Release rate progressively decreased with the increase of chitosan/alginate bilayer number and the decrease of pH value of release medium. Conclusion: These novel SIN microcapsules may be developed into oral controlled drug delivery for rheumatism and arthritis.     

Preparation and in vitro characterization of pluronic-attached polyamidoamine dendrimers for drug delivery

Context: Polyamidoamine (PAMAM) dendrimers have attracted lots of interest as drug carriers. And little study about whether pluronic-attached PAMAM dendrimers could be potential drug delivery systems has been carried on.

Objective: Pluronic F127 (PF127) attached PAMAM dendrimers were designed as novel drug carriers.

Methods: Two conjugation ratios of PF127-attached PAMAM dendrimers were synthesized. ¹H nuclear magnetic resonance (¹H-NMR), Fourier transform infrared spectrum (FTIR), element analysis and ninhydrin assay were used to characterize the conjugates. Size, zeta potential and critical micelle concentrations (CMC) were also detected. And DOX was incorporated into the hydrophobic interior of the conjugates. Studies on their drug loading and drug release were carried on. Furthermore, hemolysis and cytotoxicity assay were used to evaluate the toxicity of the conjugates.

Results and discussion: PF127 was successfully conjugated to the fifth generation PAMAM dendrimer at two molar ratios of 19% and 57% (PF127 to surface amine per PAMAM dendrimer molecular). The conjugates showed an increased size and a reduced zeta potential. And higher CMC values were obtained than pure PF127. Compared with unconjugated PAMAM dendrimer, PF127 conjugation significantly reduced the hemolytic toxicity and cytotoxicity of PAMAM dendrimer in vitro. The encapsulation results showed that the ability to encapsulate DOX by the conjugate of 19% conjugation ratio was better than that of 57% conjugation ratio. And the maximum is ～12.87 DOX molecules per conjugate molecule. Moreover, the complexes showed a sustained release behavior compared to pure DOX.

Conclusion: Findings from the in vitro study show that the PF127-attached PAMAM dendrimers may be potential carriers for drug delivery.     

Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation,optimization and in vivo evaluation

Objective: Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery.

Materials and methods: Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug–excipients interactions, powder X-ray diffraction analysis and drug release in vitro.

Results and discussion: The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100?nm, PDI 0.291, zeta potential of ?23.4?mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration.

Conclusion: In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.     

Development and in vitro characterization of chitosan-based microspheres for nasal delivery of promethazine

Conventional and composed promethazine-loaded microspheres were prepared by spray drying of chitosan solution systems and double water-in-oil-in-water (W/O/W) emulsion systems, respectively. Double emulsions were prepared in two different feed concentrations, with chitosan dissolved in both water phases, and ethylcellulose dissolved in oil phase. Swelling and bioadhesive properties of the microspheres depended on the chitosan content, type and the feed concentration of spray-dried system. Results obtained suggested that better ethylcellulose microcapsules with promethazine in the chitosan matrix were formed when less concentrated emulsion systems were spray-dried. Thus, in case of such a system, with ethylcellulose/chitosan weight ratio of 1:2, prolonged promethazine release was obtained.     

Development and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for curcumin transdermal delivery: an anti-inflammatory exposure

The purpose of this work is to develop novel lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) as carriers for transdermal delivery of curcumin. SNEDDS containing black seed oil, medium chain mono- and diglycerides and surfactants, were prepared as curcumin delivery vehicles. Their formation spontaneity, morphology, droplet size, and drug loading were evaluated. Gel preparation containing two of the SNEDDS formulations were used in the carrageenan induced paw edema to evaluate the anti-inflammatory effect. Results showed droplet size as low as 71?nm. The highest drug loading was observed with SNEDDS-F6 of ～45?mg/g. In in-vivo investigation, SNEDDS-F6 exhibited significant anti-inflammatory activities in terms of 80% reduction in paw edema when compared with positive control. The prepared SNEDDS with the elevated entrapment efficiency, good transdermal penetration ability could be a suitable candidate for effective transdermal curcumin skin delivery.     

Development and in vitro characterization of chitosan-coated polymeric nanoparticles for oral delivery and sustained release of the immunosuppressant drug mycophenolate mofetil

Objective: To develop an oral sustained release formulation of mycophenolate mofetil (MMF) for once-daily dosing, using chitosan-coated polylactic acid (PLA) or poly(lactic-co-glycolic) acid (PLGA) nanoparticles. The role of polymer molecular weight (MW) and drug to polymer ratio in encapsulation efficiency (EE) and release from the nanoparticles was explored in vitro.

Methods: Nanoparticles were prepared by a single emulsion solvent evaporation method where MMF was encapsulated with PLGA or PLA at various polymer MW and drug: polymer ratios. Subsequently, chitosan was added to create coated cationic particles, also at several chitosan MW grades and drug: polymer ratios. All the formulations were evaluated for mean diameter and polydispersity, EE as well as in vitro drug release. Differential scanning calorimetry (DSC), surface morphology, and in vitro mucin binding of the nanoparticles were performed for further characterization.

Results: Two lead formulations comprise MMF: high MW, PLA: medium MW chitosan 1:7:7 (w/w/w), and MMF: high MW, PLGA: high MW chitosan 1:7:7 (w/w/w), which had high EE (94.34% and 75.44%, respectively) and sustained drug release over 12?h with a minimal burst phase. DSC experiments revealed an amorphous form of MMF in the nanoparticle formulations. The surface morphology of the MMF NP showed spherical nanoparticles with minimal visible porosity. The potential for mucoadhesiveness was assessed by changes in zeta potential after incubation of the nanoparticles in mucin.

Conclusion: Two chitosan-coated nanoparticles formulations of MMF had high EE and a desirable sustained drug release profile in the effort to design a once-daily dosage form for MMF.     

Development and in vitro evaluation of a nanoemulsion for transcutaneous delivery

Objective: The purpose of this study is to develop a nanoemulsion formulation for its use as a transcutaneous vaccine delivery system.

Materials and methods: With bovine albumin-fluorescein isothiocyanate conjugate (FITC-BSA) as a vaccine model, formulations were selected with the construction of pseudo-ternary phase diagrams and a short-term stability study. The size of the emulsion droplets was furthered optimized with high-pressure homogenization. The optimized formulation was evaluated for its skin permeation efficiency. In vitro skin permeation studies were conducted with shaved BALB/c mice skin samples with a Franz diffusion cell system. Different drug concentrations were compared, and the effect of the nanoemulsion excipients on the permeation of the FITC-BSA was also studied.

Results: The optimum homogenization regime was determined to be five passes at 20?000?psi, with no evidence of protein degradation during processing. With these conditions, the particle diameter was 85.2?nm?±?15.5?nm with a polydispersity index of 0.186?±?0.026 and viscosity of 14.6 cP?±?1.2 cP. The optimized formulation proved stable for 1 year at 4?°C. In vitro skin diffusion studies show that the optimized formulation improves the permeation of FITC-BSA through skin with an enhancement ratio of 4.2 compared to a neat control solution. Finally, a comparison of the skin permeation of the nanoemulsion versus only the surfactant excipients resulted in a steady state flux of 23.44?μg/cm²/h for the nanoemulsion as opposed to 6.10?μg/cm²/h for the emulsifiers.

Conclusion: A novel nanoemulsion with optimized physical characteristics and superior skin permeation compared to control solution was manufactured. The formulation proposed in this study has the flexibility for the incorporation of a variety of active ingredients and warrants further development as a transcutaneous vaccine delivery vehicle.     

Self-emulsifying drug delivery system for enhanced solubility of asenapine maleate: design,characterization, in vitro,ex vivo and in vivo appraisal

Self-emulsifying drug delivery systems (SES) were developed to improve oral bioavailability of asenapine maleate (ASM), an antipsychotic drug with challenging amphiphobic nature and extensive pre-systemic metabolism. ASM-SES was prepared by choosing the proportion of oil, surfactant, co-surfactant from constructed phase diagram. The in vitro and ex vivo evaluation was done. In vivo evaluation was done through pharmacokinetic and pharmacodynamic studies. Role of lymphatic absorption was studied by lymphatic absorption inhibition study. A formulation consisting of 9.9%, 59.4%, 29.7% and 1% of oil, surfactant, co-surfactant, and drug respectively was considered as optimized formulation. After various evaluation test, the globule size and zeta potential for optimized formulation (SES₄) were found to be 137.9?nm and ?28.8?mV respectively. A maximum of 99.64?±?0.16% of ASM was released from SES₄ in 60?minutes of time. The flux (ex vivo study) increased by 2.33 folds, which prove the enhanced release and permeation of ASM when loaded into SES. The animals administered with SES₄ showed higher activity and good pharmacodynamic response than the control and ASM-Suspension, which may be due to the greater availability of the drug. The maximum pharmacodynamic response was observed at the t_max determined by Pharmacokinetic studies. The bioavailability increased by 1.64 folds with 16.55?±?3.11% as extend of lymphatic absorption (r?=?0.9732). Good in vitro in vivo correlation was observed. ASM-SES is a novel approach to effectively deliver ASM and improve the oral bioavailability.     

Preformulation characterization and in vivo absorption in beagle dogs of JFD,a novel anti-obesity drug for oral delivery

JFD (N-isoleucyl-4-methyl-1,1-cyclopropyl-1-(4-chlorine)phenyl-2-amylamine·HCl) is a novel investigational anti-obesity drug without obvious cardiotoxicity. The objective of this study was to characterize the key physicochemical properties of JFD, including solution-state characterization (ionization constant, partition coefficient, aqueous and pH-solubility profile), solid-state characterization (particle size, thermal analysis, crystallinity and hygroscopicity) and drug-excipient chemical compatibility. A supporting in vivo absorption study was also carried out in beagle dogs. JFD bulk powders are prismatic crystals with a low degree of crystallinity, particle sizes of which are within 2–10?μm. JFD is highly hygroscopic, easily deliquesces to an amorphous glass solid and changes subsequently to another crystal form under an elevated moisture/temperature condition. Similar physical instability was also observed in real-time CheqSol solubility assay. pK_a (7.49?±?0.01), log?P (5.10?±?0.02) and intrinsic solubility (S₀) (1.75?μg/ml) at 37?°C of JFD were obtained using potentiometric titration method. Based on these solution-state properties, JFD was estimated to be classified as BCS II, thus its dissolution rate may be an absorption-limiting step. Moreover, JFD was more chemically compatible with dibasic calcium phosphate, mannitol, hypromellose and colloidal silicon dioxide than with lactose and magnesium stearate. Further, JFD exhibited an acceptable pharmacokinetic profiling in beagle dogs and the pharmacokinetic parameters T_max, C_max, AUC_0–t and absolute bioavailability were 1.60?±?0.81?h, 0.78?±?0.47?μg/ml, 3.77?±?1.85?μg·h/ml and 52.30?±?19.39%, respectively. The preformulation characterization provides valuable information for further development of oral administration of JFD.     

Effect of poly (ethylene glycol) molecular weight and microparticle size on oral insulin delivery from P(MAA-g-EG) microparticles

Five years of successful work in our lab have shown that graft copolymer networks of poly(methacrylic acid-g-ethylene) [P(MAA-g-EG)], are very promising candidates for oral drug delivery. In an acidic environment, these copolymers form interpolymer complexes, protecting the active agent from the harsh environment of the gastrointestinal tract. At high pH, these complexes dissociate, causing the polymer to swell and release the drug. Films of P(MAA-g-EG) with a monomer ratio of 1:1 (MAA:EG) were prepared by free radical solution UV-polymerization, washed in order to remove the unreacted monomer, and crushed to form microparticles with different particle size distribution. Previous studies in our lab have focused on using polymer disks in their swelling studies. The swelling properties of polymer disks vs. crushed particles were investigated via equilibrium swelling experiments in this study. Another goal in this study is to compare different PEG chain length (MW-400 and MW-1000) and different particle size (150-212 microns, 90-150 microns and 25-90 microns) in their loading and release behavior. After 6 hours of exposing the polymer with the insulin solution we achieved approximately 90% of insulin loading.     

Development of isradipine loaded self-nano emulsifying powders for improved oral delivery: in vitro and in vivo evaluation

Isradipine (ISR) is a potent calcium channel blocker with low oral bioavailability due to low aqueous solubility, extensive first-pass metabolism and P-glycoprotein (P-gp)-mediated efflux transport. In the present investigation, an attempt was made to develop isradipine-loaded self-nano emulsifying powders (SNEP) for improved oral delivery. The liquid self-nano emulsifying formulations (L-SNEF/SNEF) of isradipine were developed using vehicles with highest drug solubility, i.e. Labrafil® M 2125 CS as oil phase, Capmul® MCM L8 and Cremophor® EL as surfactant/co-surfactant mixture. The developed formulations revealed desirable characteristics of self-emulsifying system such as nano-size globules ranging from 32.7 to 40.2?nm, rapid emulsification (around 60?s), thermodynamic stability and robustness to dilution. The optimized stable self-nano emulsifying formulation (SNEF₂) was transformed into SNEP using Neusilin US2 (SNEP_N) as adsorbent inert carrier, which exhibited similar characteristics of liquid SNEF. The solid state characterization of SNEP_N by Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopic studies shown transformation of crystalline drug into amorphous form or molecular state without any chemical interaction. The in vitro dissolution of SNEP_N compared to pure drug was indicated by 18-fold increased drug release within 5?min. In vivo pharmacokinetic studies in Wistar rats showed significant improvement of oral bioavailability of isradipine from SNEP_N with 3- and 2.5-fold increments in peak drug concentration (C_max), area under curve (AUC_0–∞) compared to pure isradipine. In conclusion, these results signify the improved oral delivery of isradipine from developed SNEP.     

Thermodynamic modeling for solubility prediction of indomethacin in self-nanoemulsifying drug delivery system (SNEDDS) and its individual components

For the development of an effective self-nanoemulsifying drug delivery system (SNEDDS) of poorly soluble drugs, the knowledge of the solubility in its oil phase and SNEDDS are one of the most important factors to avoid possibility of drug to get phase separated or precipitated upon dilution with gastrointestinal fluids. With this background, this study was undertaken to determine the equilibrium saturated solubility as well as mole fraction solubility of indomethacin in prepared SNEDDS and its individual components at the temperature range of 295.15 to 320.15?K. The equilibrium solubilities of indomethacin in each sample matrices were determined by an isothermal mechanical shaking method and the resulting data was analyzed by regression analysis. The experimental mole fraction solubility data of indomethacin at various temperatures was well correlated with the modified Apelblat model. The equilibrium saturated solubility as well as mole fraction solubility of indomethacin was found to be increased with increase in temperature in SNEDDS as well as in its individual components. The mole fraction solubility of indomethacin was found to be significantly higher in Tween-80 than SNEDDS, Labrafil-M1944CS and Transcutol-HP. These preliminary studies on solubility could be a useful tool for the development of an efficient and thermodynamically stable SNEDDS formulation of various poorly soluble drugs to enhance their solubility/dissolution and oral bioavailability.     

Self-microemulsifying drug delivery systems (SMEDDS) for improving in vitro dissolution and oral absorption of Pueraria lobata isoflavone

The aim of our investigation was to develop and characterize self-microemulsifying drug delivery systems (SMEDDS) of Pueraria lobata isoflavone to improve its in vitro dissolution and oral absorption in beagle dogs. SMEDDS consisted of oil (ethyl oleate), a surfactant (Tween 80), and a cosurfactant (Transcutol P). In all the SMEDDS, the level of Pueraria lobata isoflavone was fixed at 20% w/w of the vehicle. The in vitro self-microemulsification properties and droplet size analysis of SMEDDS were studied following their addition to water under mild agitation. A pseudoternary phase diagram was constructed identifying the efficient self-microemulsification region. From these investigations, an optimized formulation was selected and its dissolution and bioavailability were compared with a tablet formulation in beagle dogs. The in vitro dissolution rate of puerarin from SMEDDS was more than threefold faster than that from Yufengningxin tablets (Pueraria lobata isoflavone tablets). A 2.5-fold increase in the relative bioavailability was observed for the SMEDDS compared with Yufengningxin tablets. The absolute bioavailability of the SMEDDS was 82.32 +/- 15.51%, which was significantly improved compared with that of Yufengningxin tablets. These results demonstrate the potential of SMEDDS as an efficient way of improving the oral absorption of Pueraria lobata isoflavone.     

Temperature-responsive, Pluronic-g-poly(acrylic acid) copolymers in situ gels for ophthalmic drug delivery: rheology, in vitro drug release, and in vivo resident property

To prolong the precorneal resident time and improve ocular bioavailability of the drug, Pluronic-g-poly(acrylic acid) copolymers were studied as a temperature-responsive in situ gelling vehicle for an ophthalmic drug delivery system. The rheological properties and in vitro drug release of Pluronic-g-PAA copolymer gels, as well as the in vivo resident properties of such in situ gel ophthalmic formulations, were investigated. The rheogram and in vitro drug release studies indicated that the drug release rates decreased as acrylic acid/Pluronic molar ratio and copolymer solution concentration increased. It was also shown that the drug concentration had no obvious effect on drug release. The release rates of drug from such copolymer gels were mainly dependent on the gel dissolution. In vivo resident experiments showed the drug resident time and the total resident amount increased by 4-fold and 1.2-fold for in situ gel compared with eye drops. These in vivo experimental results, along with the rheological properties and in vitro drug release studies, demonstrated that in situ gels containing Pluronic-g-PAA copolymer may significantly prolong the drug resident time and thus improve bioavailability. The results showed that the Pluronic-g-PAA copolymer can be a promising in situ gelling vehicle for ophthalmic drug delivery.     

Preparation and in vitro evaluation of pH, time-based and enzyme-degradable pellets for colonic drug delivery

The preparation of pH-dependent, time-based and enzyme degradable pellets was investigated for use as an oral colonic drug delivery system. It was expected that drug would be released immediately once the pellets reached the colon. The pellets were prepared using extrusion-spheronizing equipment and subsequently coated with three layers of three functional polymers by an air-suspension technique. The core consisted of 5-aminosalicylic acid (5-ASA) as a model drug, CaP as an enzyme-degradable material and microcrystalline cellulose (MCC) as an additive. As far as the three coated layers were concerned, the outer layer was coated with Eudragit L30D-55 for protection against gastrointestinal juices, the intermediate layer was coated with ethylcellulose (EC) to inhibit drug release during passage through the small intestine, and the inner film was coated with pectin for swelling and enzyme-degradation, which required a 30, 10, and 12% weight gain, respectively. Several micromeritic properties of the core pellets, including particle size distribution, particle size, degree of circularity, and friability, were evaluated to investigate the effects of the formulations of the cores and preparation conditions. Also, dissolution testing of the cores showed that the presence of calcium pectinate (CaP) markedly increased the drug release rate from the cores, as determined by scanning electron microscopy (SEM). In-vitro release studies indicated that the coated pellets completely protected the drug release in 0.1 mol/L HCl, while the drug release was delayed for 3-4 hr in pH 6.8 PBS. A synergistic effect of enzyme dependence for the coated pellets was seen following removal of the coated layer and during contact with colonic enzymes. Consequently, it was possible to achieve colon-specific drug delivery using this triple-dependence system.