Sustained-release Pellets Research Articles

Fenofibrate modified-release pellets with lag phase and high oral bioavailability.

PurposeFenofibrate and statin combination therapy is highly recommended by the current clinical guidelines for treatment of mixed dyslipidemia. In this study, an innovative delayed-release preparation of fenofibrate was designed to reduce the risk of muscle toxicity, caused by simultaneous administration of this combination therapy, by altering the pharmacokinetic profile of fenofibrate, as well as to improve the oral bioavailability of the modified-release formulation.MethodsMicronized fenofibrate was used to prepare drug-loaded cores via a powder layering process before multiparticulate pellet coating. Different coating formulations (Eudragit® RS PO/E100, Eudragit® RS PO/RL PO, Eudragit® NE30D/HPMC, and EC/HPMC) were screened, and their in vitro release was compared with the commercial sustained-release pellets Lipilfen®. Two optimized formulations were evaluated in beagle dogs using two commercial preparations of fenofibrate (the immediate-release preparation Lipanthyl® and the sustained-release pellets Lipilfen®) as references.ResultsThe in vivo release of fenofibrate from R1 and R2 selected from in vitro tests exhibited a lag phase, and then rapid and complete drug release. The relative bioavailabilities of R1 and R2 were 100.4% and 201.1%, respectively, which were higher than that of Lipilfen® (67.2%).ConclusionThe modified fenofibrate pellets developed showed enhanced bioavailability and delayed-release properties. They have the potential to improve safety and compliance when co-administrated with statins. This is the first report of a delayed-release fenofibrate preparation.

Preparation and in vitro-in vivo evaluation of intestinal retention pellets of Berberine chloride to enhance hypoglycemic and lipid-lowing efficacy

Berberine chloride (BBR) is a pharmacokinetic profile of drug with poor bioavailability but good therapeutic efficacy, which is closely related to the discovery of BBR intestinal target. The major aim of this paper is to develop BBR intestinal retention type sustained-release pellets and evaluate their in vivo and in vitro behaviors base on the aspect of local action on intestinal tract. Here, wet milling technology is used to improve dissolution and dissolution rate of BBR by decreasing the particle size and increasing the wettability. The pellets are prepared by liquid layer deposition technology, and then the core pellets are coated with Eudragit® L30D-55 and Eudragit® NE30D aqueous dispersion. The prepared pellets show high drug loading capacity, and the drug loading up to 93%. Meanwhile, it possesses significant sustained drug release effect in purified water which is expected to improve the pharmacokinetic behavior of BBR. The pharmacokinetics results demonstrate that the half-life of BBR was increased significantly from 24 h to 36 h and the inter- and intra-subject variability are decreased compared to commercial BBR tablets. The retention test results indicate that the pellet size and Eudragit® NE30D plays an important role in retention time of the pellet, and it is found that the pellets with small particle size and high Eudragit® NE30D coating content can stay longer in the intestine than the pellets with large particle size. All in all, BBR intestinal retention type pellets are prepared successfully in this study, and the pellets show satisfactory in vivo and in vitro behaviors.

Changing muscle function with sustained glial derived neurotrophic factor treatment of rabbit extraocular muscle

Recent microarray and RNAseq experiments provided evidence that glial derived neurotrophic factor (GDNF) levels were decreased in extraocular muscles from human strabismic subjects compared to age-matched controls. We assessed the effect of sustained GDNF treatment of the superior rectus muscles of rabbits on their physiological and morphological characteristics, and these were compared to naïve control muscles. Superior rectus muscles of rabbits were implanted with a sustained release pellet of GDNF to deliver 2μg/day, with the contralateral side receiving a placebo pellet. After one month, the muscles were assessed using in vitro physiological methods. The muscles were examined histologically for alteration in fiber size, myosin expression patterns, neuromuscular junction size, and stem cell numbers and compared to age-matched naïve control muscles. GDNF resulted in decreased force generation, which was also seen on the untreated contralateral superior rectus muscles. Muscle relaxation times were increased in the GDNF treated muscles. Myofiber mean cross-sectional areas were increased after the GDNF treatment, but there was a compensatory increase in expression of developmental, neonatal, and slow tonic myosin heavy chain isoforms. In addition, in the GDNF treated muscles there was a large increase in Pitx2-positive myogenic precursor cells. One month of GDNF resulted in significant extraocular muscle adaptation. These changes are interesting relative to the decreased levels of GDNF in the muscles from subjects with strabismus and preliminary data in infant non-human primates where sustained GDNF treatment produced a strabismus. These data support the view that GDNF has the potential for improving eye alignment in subjects with strabismus.

Preparation, Characterization and Pharmacokinetics Evaluation of the Compound Capsules of Ibuprofen Enteric-Coated Sustained-Release Pellets and Codeine Phosphate Immediate-Release Pellets.

The objective of this study was to prepare ibuprofen enteric-coated sustained-release pellets (IB-SRPs) and codeine phosphate immediate-release pellets (CP-IRPs) to play a synergistic role in analgesia. The pellets were developed by extrusion-spheronization and fluidized bed coating technology. The single-factor investigation was used to determine the optimal prescription and process. The sustained-release membrane of IB-SRPs was water-insoluble ethyl cellulose (EC), triethyl citrate (TEC) was used as plasticizer, and hydroxypropyl methylcellulose (HPMCP) was chose as porogen. Besides, the immediate-release layer of CP-IRPs was gastric-soluble coating film. The ibuprofen and codeine phosphate compound capsules (IB-CP SRCs) were prepared by IB-SRPs and CP-IRPs packed together in capsules with the optimum doses of 200 and 13mg, respectively. The prepared pellets were evaluated by scanning electron microscopy and dissolution test. Pharmacokinetic studies in beagle dogs indicated that the optimized IB-CP SRCs had smaller individual differences and better reproducibility comparing with commercial available tablets. Additionally, IB-CP SRCs achieved consistency with in vivo and in vitro tests. Therefore, IB-CP SRCs could play a great role in rapid and long-term analgesic.

Quality Criteria Establishment for Dissolution of Ascorbic Acid from Sustained Release Pellets

Quality Criteria Establishment for Dissolution of Ascorbic Acid from Sustained Release Pellets

Multiple response optimisation of processing and formulation parameters of pH sensitive sustained release pellets of capecitabine for targeting colon

Purpose: To optimise the Eudragit/Surelease®-coated pH-sensitive pellets for controlled and target drug delivery to the colon tissue and to avoid frequent high dosing and associated side effects which restrict its use in the colorectal-cancer therapy.Methods: The pellets were prepared using extrusion-spheronisation technique. Box–Behnken and 32 full factorial designs were applied to optimise the process parameters [extruder sieve size, spheroniser-speed, and spheroniser-time] and the coating levels [%w/v of Eudragit S100/Eudragit-L100 and Surelease®], respectively, to achieve the smooth optimised size pellets with sustained drug delivery without prior drug release in upper gastrointestinal tract (GIT).Results: The design proposed the optimised batch by selecting independent variables at; extruder sieve size (X1 = 1 mm), spheroniser speed (X2 = 900 revolutions per minute, rpm), and spheroniser time (X3 = 15 min) to achieve pellet size of 0.96 mm, aspect ratio of 0.98, and roundness 97.42%. The 16%w/v coating strength of Surelease® and 13%w/v coating strength of Eudragit showed pH-dependent sustained release up to 22.35 h (t99%). The organ distribution study showed the absence of the drug in the upper part of GIT tissue and the presence of high level of capecitabine in the caecum and colon tissue. Thus, the presence of Eudragit coat prevent the release of drug in stomach and the inner Surelease® coat showed sustained drug release in the colon tissue.Conclusion: The study demonstrates the potential of optimised Eudragit/Surelease®-coated capecitabine-pellets for effective colon-targeted delivery system to avoid frequent high dosing and associated systemic side effects of drug.

Increased bioavailability of tylosin phosphate as in-feed medication formulated for long-action pellets in broiler chickens

Circadian variation of serum concentrations of tylosin in broiler chickens after in-feed medication prompted a comparison study of the serum profiles of this drug after in-feed medication with standard tylosin phosphate (Tprf reference formulation group), and after in-feed medication with a sustained-release pellet formulation (Tpsr group), based on Patent No.MX/a/2012/013222 and PCT/MX2013/000137, in broiler chickens. Six hundred 4-week-old Ross broiler chickens were in-feed medicated with tylosin phosphate at an approximate dose of 25.2 mg/kg/d, based on daily feed consumption values and a final concentration of tylosin in feed of 200 mg/kg of feed. Approximately 2 to 3 mL of blood were obtained per 5 chickens every 2 h, avoiding the sampling of a bird more than once and during 72 h after making medicated feed available for the first time. Serum concentrations of tylosin were determined by HPLC. Gaussian multi-peak regressions were then fitted to serum concentration vs. time profiles. Day by d areas under the serum concentration vs. time profiles (AUC0–24), as well as overall AUC0–72, were statistically higher for the Tpsr group (P < 0.001). Also, maximum serum concentrations obtained and relative bioavailability for the Tpsr formulation were statistically higher (382.8%) as compared to the Tprf group (P < 0.01). Considering the referred improved values of AUC observed in the Tpsr formulation, as well as the fact that tylosin is a time-dependent antibacterial drug, better clinical responses are postulated with this pharmaceutical preparation intended for chickens. Tissue deposition studies for this new formulation of tylosin are required.

A Novel Approach for Dry Powder Coating of Pellets with Ethylcellulose. Part II: Evaluation of Caffeine Release.

The objective of this study was to assess the efficacy and the capability of a novel ethylcellulose-based dry-coating system to obtain prolonged and stable release profiles of caffeine-loaded pellets. Lauric and oleic acids at a suitable proportion were used to plasticize ethylcellulose. The effect of coating level, percentage of drug loading, inert core particle size, and composition of the coating formulation including the anti-sticking agent on the drug release profile were fully investigated. A coating level of 15% w/w was the maximum layered amount which could modify the drug release. The best controlled drug release was obtained by atomizing talc (2.5% w/w) together with the solid plasticizer during the dry powder-coating process. SEM pictures revealed a substantial drug re-crystallization on the pellet surface, and the release studies evidenced that caffeine diffused through the plasticized polymer acting as pore former. Therefore, the phenomenon of caffeine migration across the coating layer had a strong influence on the permeability of the coating membrane. Comparing dry powder-coated pellets to aqueous film-coated ones, drug migration happened during storage, though more sustained release profiles were obtained. The developed dry powder-coating process enabled the production of stable caffeine sustained release pellets. Surprisingly, the release properties of the dry-coated pellets were mainly influenced by the way of addition of talc into the dry powder-coating blend and by the drug nature and affinity to the coating components. It would be interesting to study the efficacy of novel coating system using a different API.

Curcumin Pellets of Carboxymethylated Tamarind Seed Polysaccharide for the Treatment of Inflammatory Bowel Disease

Background and Objectives: Inflammatory Bowel Disease (IBD) is a group of inflammatory conditions of the colon and small intestine. Crohn's disease and ulcerative colitis are the principal types of inflammatory bowel disease. IBD is a complex disease which arises as a result of the interaction of environmental and genetic factors leading to immunological responses and inflammation in the intestine. Curcumin, a yellow coloring agent is used as a remedy for the treatment and prevention of inflammatory disease. Curcumin is safe, non-toxic, and mediates its anti-inflammatory effects through the down-regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes that all promote inflammation. Methods: An attempt was made to formulate sustained release pellets of curcumin using Carboxymethyl Tamarind Seed Polysaccharide (CMTSP). Solid dispersion of curcumin prepared using soluplus and incorporated into pellets for enhanced solubility and bioavailability. A central composite design was applied to study the effect of independent variables (amount of microcrystalline cellulose MCC and CMTSP) on crushing strength and drug release of pellets. In vivo study of solid dispersion loaded pellets revealed the presence of more amount of drug in plasma than pure drug loaded pellets. Result: Dissolution and absorption of curcumin were found to be increased by 1.5 and 2 fold, respectively. Conclusion: Carboxymethyl tamarind seed polysaccharide can be used successfully for colon targeted drug delivery system in the form of pellets. The percent permeability of pellets prepared by using solid dispersion was found to be more than pellets prepared by using pure drug. Curcumin has an advantageous safety profile as well as low relativecost, making it an attractive option for IBD patients. Keywords: Soluplus, carboxymethyl tamarind seed polysaccharide, extrusion-spheronization, solid dispersion pellets, inflammatory bowel disease, curcumin.

Controlled-release domperidone pellets compressed into fast disintegrating tablets forming a multiple-unit pellet system (MUPS)

Controlled release dosage forms are essential when the drug release rate impacts the effectiveness of therapy. In the present study, a modified-release dosage form of domperidone was developed in the form of pellets, which were subsequently compressed into a tablet to disintegrate and be swallowed by patients, without changing the release profile. Sustained-release pellets of domperidone prepared by the extrusion-spheronization and layering technique using Celphere® 102 (microcrystalline cellulose spheres) and Suglet® (sugar spheres) as core seed, subsequently coated with Kollicoat® SR 30 D (polyvinyl acetate dispersion) as rate controlling polymer, were developed using the multiple unit pellet system (MUPS) as a plateform technology. Then, 2ˆ3 full factorial design (two level and three parameters) was applied to assess the impact of the different variables on the properties of the resulting pellets prepared by extrusion-spheronization. Different types of tableting excipients were combined for better pellet compressibility. The combination of Ceolus® granules (granules prepared using a fibrous grade of microcrystalline cellulose) and Ludipess® (lactose based co-processed excipient) was found as a suitable tableting excipient for MUPS preparation. The MUPS based sustained-release domperidone formulation prepared using Celphere® 102 was found to possess rapid disintegration properties, hardness, and unaltered release profile even after compression.

Development of Sustained Release Pellets of Galantamine HBr by Extrusion Spheronization Technique Incorporating Risk based QbD Approach

Objective: The present research aims to integrate the concept of quality by design (QbD) to develop galantamine HBr modified release pellets and to scrutinize the critical factors that can affect the quality of the pellets prepared by extrusion spheronization technique. Materials and Methods: Modified release pellets of galantamine HBr were prepared using Compritol 888 ATO and ethyl cellulose (EC) as release retardants. Avicel pH 101 was selected as an extruder aid. Before converting the wet extrudates in pellets, pregelatinized starch was sprinkled on them to improve the physical properties of the pellets. Qualitative risk analysis was performed to screen and identify the significant factors using Failure Mode Effect Analysis (FMEA) model. Central composite design was adopted to optimize the formulation. Concentration of Compritol and concentration of ethyl cellulose were selected as independent factors and drug release at 2, 6, and 10 h were selected as dependent variables. The pellets were evaluated for size, shape, flow, % yield, % friability and drug content. Results and Discussion: Concentration of Compritol and concentration of EC were found to be critical factors from FMEA model. All the batches of central composite design showed excellent flowability, spherical shape, desired size, yield, friability and drug content. Multiple linear regression analysis and analysis of variance were performed to identify the effect of independent variables on different responses. Design space was generated from the data. In vivo plasma concentration time profile was predicted from in vitro data. Conclusion: Concentration of Compritol and EC were found to be significant for the development of modified release pellets. Innovative finding of the present research is to explore the potential use of pregelatinized starch as a dry binder in the post wet extrusion step.

Formulation and in vivo pharmacokinetic evaluation of ethyl cellulose-coated sustained release multiple-unit system of tacrolimus

A novel once-a-day sustained-release (SR) system of tacrolimus (FK506), a poorly water-soluble immunosuppressive agent, was designed employing ethyl cellulose (EC) polymer as release retardant. Drug (5 mg) was layered onto sugar spheres (518.3 mg) with hypromellose (5 mg), to transform the drug from a crystalline to an amorphous form. Subsequently, the drug-layered pellets were recoated with EC polymer (0.5-1.5 mg) using a fluid bed granulator. Drug release from the reservoir-type pellets was markedly impeded by the outer EC-based coating layer (EC 1 mg), displaying about 60% of drug release after 8 h, regardless of the acidity of the media. In an in vivo pharmacokinetic study in fasted Cynomolgus monkeys, the drug level in blood was gradually increased over 4.7 h and high drug concentration was maintained until 24 h, with an elimination half-life of 16.6 h. There were no statistical differences between the novel SR pellets and the recently marketed SR capsule (Advagraf®, Astellas Pharma, Japan) in terms of maximum blood concentration, area under the curve, and half-life values, in both fasted and fed states. Therefore, the novel EC-coated pellets are expected to be bioequivalent to the commercial SR capsule, providing a once-daily dosing regimen in patients with allogenic rejection.

Aneurysmal Subarachnoid Hemorrhage: Strategies for Preventing Vasospasm in the Intensive Care Unit.

This article addresses the intensive care unit (ICU) management of patients with aneurysmal subarachnoid hemorrhage (SAH), with an emphasis on the prevention of cerebral vasospasm and delayed cerebral ischemia (DCI), which are major contributors to morbidity and mortality. Interventions addressing various steps in the development of vasospasm have been attempted, with variable success. Enteral nimodipine remains the only approved measure to potentially prevent DCI. Since oral and intravenous administrations are limited by hypotension, direct administration via sustained-release pellets and intraventricular administration of sustained-release microparticles are being investigated. Studies of other calcium channel blockers have been disappointing. Efforts to remove blood from the subarachnoid space via cisternal irrigation, cisternal or ventricular thrombolysis, and lumbar cerebrospinal fluid drainage have met with limited and variable success, and they remain an area of active investigation. Several interventions that had early promise have failed to show benefit when studied in large trials; these include tirilazad, magnesium, statins, clazosentan, transluminal angioplasty, and hypervolemia.

Self-Emulsifying Granules and Pellets: Composition and Formation Mechanisms for Instant or Controlled Release.

Many articles have been published in the last two decades demonstrating improvement in the dissolution and absorption of low solubility drugs when formulated into self-emulsifying drug delivery systems (SEDDS). Several such pharmaceutical products have appeared in the market for medium dose (Neoral® for Cyclsoprin A, Kaletra® for Lopinavir and Ritonavir), or low dose medications (Rocaltrol® for Calcitriol and Avodart® for Dutasteride). However, these are in the form of viscous liquids or semisolid presentations, characterized by the disadvantages of high production cost, stability problems and the requirement of large quantities of surfactants. Solid SEDDS (S-SEDDS), as coarse powders, granules or pellets, besides solubility improvement, can be filled easily into capsules or processed into tablets providing a handy dosage form with instant release, which can be further developed into controlled release by mixing with suitable polymers or coating with polymeric films. In this review, the materials used for the preparation of S-SEDDS, their properties and role in the formulations are detailed. Factors affecting the physical characteristics, mechanical properties of S-SEDDS as well as their in vitro release and in vivo absorption are discussed. The mechanisms involved in the formation of instant and sustained release self-emulsifying granules or pellets are elucidated. Relationships are demonstrated between the characteristics of S-SEDDS units (size, shape, mechanical properties, re-emulsification ability, drug migration and drug release) and the properties of the submicron emulsions used as massing liquids, with the aim to further elucidate the formation mechanisms. The influence of the composition of the powdered ingredients forming the granule or pellet on the properties of S-SEDDS is also examined. Examples of formulations of S-SEDDS that have been reported in the literature in the last thirteen years (2004–2017) are presented.

Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome

Volume retention in nephrotic syndrome has been linked to activation of the epithelial sodium channel (ENaC) by proteolysis of its γ-subunit following urinary excretion of serine proteases such as plasmin. Here we tested whether pharmacological inhibition of urinary serine protease activity might protect from ENaC activation and volume retention in nephrotic syndrome. Urine from both nephrotic mice (induced by doxorubicin injection) and nephrotic patients exhibited high aprotinin-sensitive serine protease activity. Treatment of nephrotic mice with the serine protease inhibitor aprotinin by means of subcutaneous sustained-release pellets normalized urinary serine protease activity and prevented sodium retention, as did treatment with the ENaC inhibitor amiloride. In the kidney cortex from nephrotic mice, immunofluorescence revealed increased apical γ-ENaC staining, normalized by aprotinin treatment. In Xenopus laevis oocytes heterologously expressing murine ENaC, aprotinin had no direct inhibitory effect on channel activity but prevented proteolytic channel activation. Thus, our study shows that volume retention in experimental nephrotic syndrome is related to proteolytic ENaC activation by proteasuria and can be prevented by treatment with aprotinin. Hence, inhibition of urinary serine protease activity might become a therapeutic approach to treat patients with nephrotic-range proteinuria.

A novel release kinetics evaluation of Chinese compound medicine: Application of the xCELLigence RTCA system to determine the release characteristics of Sedum sarmentosum compound sustained-release pellets

Purpose: To establish a novel release kinetics evaluation method of Chinese compound medicine (Sedum Sarmentosum compound) with xCELLigence Real-Time Cell-based Assay (RTCA) system. Methods: Cell lines sensitive to Sedum Sarmentosum compound are screened, and cell index-time (CI-T) graphs and cell index release kinetics models are established based on the cell index (CI) monitored. The methodological studies of precision and repeatability were processed by the cell monitors system. The release profiles of the sustained-release Sedum Sarmentosum compound were determined. Consequently, the sustained-release property was characterized by the kinetic parameters based on the cell-index. Results: The accumulative release rate based on cell index of Sedum sarmentosum compound sustained-release preparation was determined and it had a good correlation with time, fitting better with First-order model, Higuchi model and Ritger-Peppas model, and fitting best with Weibull model. It indicated that the release rate is proportional with the diffusion coefficient. Conclusion: The new method of cell-index release kinetics may provide a quantitative description for the release of the multi active agents from Traditional Chinese Medicines. The application of xCELLigence RTCA system for evaluating the release kinetics of Chinese compound medicine is feasible.

Preparation and evaluation of 1-deoxynojirimycin sustained-release pellets vs conventional immediate-release tablets

1-Deoxynojirimycin sustained-release pellets, which exhibit known release and absorption profiles, are used for the treatment of diabetes mellitus. In this study, a fluidised bed coater was employed to prepare new, drug-loaded pellets. In the dissolution test, it was found that 1-DNJ pellets exhibited a sustained release effect after being coated with hydroxypropyl methyl cellulose phthalate-55 S. For sustained-release pellets and immediate-release pellets, there was significant difference in the mean cumulative drug concentration profile in different media evaluation. In the bioavailability study, the ratio of mean relative bioavailability of the SR pellets to the IR tablets was calculated by the DAS from the AUC0-24 h of 1-DNJ and was found to be 117.3%. This suggested that the behaviour in vivo of the 1-DNJ SR pellets was superior to the IR tablets, which indicated the designed preparation method of the 1-DNJ SR pellets was acceptable for achieving sustained release of 1-DNJ with enhanced bioavailability.

Tanshinol sustained-release pellets with absorption enhancer: optimization, characterization, pharmacokinetics and pharmacodynamics

The objective of this study was to develop tanshinol sustained-release pellets (TS–SRPs) for the treatment of angina. Considering the poor intestinal absorption of TS, sodium caprate (SC) was used as an absorption enhancer for bioavailability improvement. Single-pass intestinal perfusion in rats demonstrated that the permeability of TS was remarkably enhanced, when the weight ratio of TS to SC was 1:3. Then, the cores were prepared with TS, SC and MCC at a weight ratio of 1:3:16 via extrusion–spheronization, followed by coating with Eudragit® RS30D/RL30D dispersion (9:1, w/w). In vitro release studies revealed that release methods and rotation rates had no significant effects on the drug release of optimized TS–SC–SRPs except for the dissolution media. The release behavior was characterized as non-Fick diffusion mechanism. The pellets possessed a dispersion-layered spherical structure and were stable during three months of storage at 40 °C/75% RH. Compared with TS immediate-release pellets, the AUC0–24 in healthy rabbits was increased by 1.97-fold with prolonged MRT (p < .05). Pharmacodynamic studies in rabbits with angina showed that the optimized TS–SC–SRPs had a steady and improved efficacy with synchronous drug concentration–efficacy. Consequently, preparation of sustained-release pellets with absorption enhancer provides a potential strategy to prolong the release and enhance the efficacy for hydrophilic drugs with poor intestinal absorption.

Preparation and evaluation of metoprolol tartrate sustained-release pellets using hot melt extrusion combined with hot melt coating

The objective of this study was to prepare and evaluate metoprolol tartrate sustained-release pellets. Cores were prepared by hot melt extrusion and coated pellets were prepared by hot melt coating. Cores were found to exist in a single-phase state and drug in amorphous form. Plasticizers had a significant effect on torque and drug content, while release modifiers and coating level significantly affected the drug-release behavior. The mechanisms of drug release from cores and coated pellets were Fickian diffusion and diffusion–erosion. The coated pellets exhibited sustained-release properties in vitro and in vivo.

Self-microemulsifying sustained-release pellet of Ginkgo biloba extract: Preparation, in vitro drug release and pharmacokinetics study in beagle dogs

Ginkgo biloba extract (GBE50), the fifth generation extract of Ginkgo biloba, has been widely used in clinical treatment. This study was aimed at developing self-microemulsifying drug delivery system sustained-release pellets (SMEDDS-SR pellets) to achieve sustained release and increased the oral bioavailability of GBE50. Solubility studies and Pseudo-ternary phase diagrams were investigated to optimize the suitable compositions of SMEDDS-SR pellets. The optimal formulation of GBE50-SMEDDS consisting of oil (16.7% MCT), surfactant (33.4% Cremophor EL35), cosurfactant (33.4% PEG 400) and drug (16.7% GBE50) was obtained. The GBE50-SMEDDS-SR pellets were prepared by mixing GBE50-SMEDDS with diluent agent (MCC), disintegration agent (PVPP) and coating material of ethyl cellulose (EC) using extrusion spheronization method. The Morphology study of GBE50-SMEDDS-SR pellets after dispersion in water revealed a spherical and homogeneous structure of droplets (51.6 ± 1.8) nm. The in vitro release data revealed the sustained-release effect of GBE50-SMEDDS-SR pellets. Pharmacokinetics study in beagle dogs after oral administration yielded relative bioavailability (Fr) of 160.24% and 236.18% for GBE50-SMEDDS and GBE50-SMEDDS-SR pellets, respectively. Collectively, these results indicated that the SMEDDS-SR pellets could be an effective delivery system to achieve sustained release and improved oral bioavailability of GBE50.