Design and evaluation of a dry coated drug delivery system with floating-pulsatile release

The objective of this work was to develop and evaluate a floating-pulsatile drug delivery system intended for chronopharmacotherapy. Floating-pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, we generated the system which consisted of three different parts, a core tablet, containing the active ingredient, an erodible outer shell and a top cover buoyant layer. The dry coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer which is responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with Methocel K4M, Carbopol 934P and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their buoyancy, dissolution and pharmacokinetic, as well gamma-scintigraphically. The results showed that a certain lag time before the drug released generally due to the erosion of the dry coated layer. Floating time was controlled by the quantity and composition of the buoyant layer. Both pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time.     

Modulation of a pulsatile release drug delivery system using different swellable/rupturable materials

Diclofenac sodium tablets consisting of core coated with two layers of swelling and rupturable coatings were prepared and evaluated as a pulsatile drug delivery system. Cores containing the drug were prepared by direct compression using microcrystalline cellulose and Ludipress as hydrophilic excipients with the ratio of 1:1. Cores were then coated sequentially with an inner swelling layer of different swellable materials; either Explotab, Croscarmellose sodium, or Starch RX 1500, and an outer rupturable layer of different levels of ethylcellulose. The effect of the nature of the swelling layer and the level of the rupturable coating on the lag time and the water uptake were investigated. Drug release rate studies were performed using USP paddle method. Results showed the dependence of the lag time and water uptake prior to tablet rupture on the nature of the swelling layer and the coating levels. Explotab showed a significant decrease in the lag time, followed by Croscarmellose sodium and finally by Starch RX 1500. Increasing the level of ethylcellulose coating retarded the diffusion of the release medium to the swelling layer and the rupture of the coat, thus prolonging the lag time.     

Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin

Oral sustained release gastroretentive dosage forms offer many advantages for drugs having absorption from upper gastrointestinal tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new gastroretentive sustained release delivery system was developed with floating, swellable and bioadhesive properties. All these properties were optimized and evaluated. Various release retarding polymers like psyllium husk, HPMC K100M and a swelling agent, crosspovidone in combinations were tried and optimized to get the release profile for 24 h. Formulations were evaluated for in vitro drug release profile, swelling characteristics and in vitro bioadhesion property. The in vitro drug release followed Higuchi kinetics and the drug release mechanism was found to be of anomalous or non-Fickian type. For the developed formulation, the value of n was found to be 0.5766 while for the marketed formulation the value was 0.5718 indicating the anomalous transport. The high water uptake leading to higher swelling of the tablet supported the anomalous release mechanism of ofloxacin. The similarity factor f2 was found to be 91.12 for the developed formulation indicating the release was similar to that of the marketed formulation (Zanocin OD). The swelling properties were increased with increasing crosspovidone concentration and contributed significantly in drug release from the tablet matrix. The bioadhesive property of the developed formulation was found to be significant (P < 0.005) in combination as compared to HPMC K100M and psyllium husk alone.     

Development of pulsatile multiparticulate drug delivery system coated with aqueous dispersion Aquacoat ECD

The objective of this study was to develop and evaluate a pulsatile multiparticulate drug delivery system (DDS), coated with aqueous dispersion Aquacoat ECD. A rupturable pulsatile drug delivery system consists of (i) a drug core; (ii) a swelling layer, comprising a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating. Upon water ingress, the swellable layer expands, resulting in the rupturing of outer membrane with subsequent rapid drug release. Regarding the cores, the lag time was shorter, when 10% (w/w) theophylline was layered on sugar cores compared with cores consisting of 100% theophylline. Regarding swelling layer, the release after lag time was fast and complete, when cross-linked carboxymethyl cellulose (AcDiSol) was used as a swelling agent. In contrast, a sustained release was achieved after the lag time, when low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate (Explotab) were used as swelling agents. The optimal level of AcDiSol to achieve a fast and complete release after the lag time was 26% (w/w) (based on the weight of the coated pellets) for poorly soluble theophylline and 48% (w/w) for highly soluble propranolol HCl. The lag time can be controlled by the coating level of an outer membrane and increased with increasing coating level of the outer membrane. Outer membrane, formed using aqueous dispersion Aquacoat ECD was brittle and ruptured sufficiently to ensure fast drug release, compared to ethylcellulose membrane formed using organic solution. The addition of talc led to increase brittleness of membrane and was very advantageous because of (i) reduced sensitivity of lag time on variations in the coating level and (ii) fast and complete drug release. Drug release starts only after rupturing of outer membrane, which was illustrated by microscopical observation of pellet during release.     

Development and evaluation of pulsatile drug delivery system using novel polymer

The aim of the present investigation was to develop a pulsatile drug delivery system based on an insoluble capsule body filled with theophylline microspheres and sealed with a swellable novel polymer plug isolated from the endosperm of seeds of higher plant Delonix regia family-Fabaceae. Theophylline microspheres were prepared by solvent evaporation method using Eudragit S 100. The swellable plugs of varying thickness and hardness were prepared by direct compression, which were then placed in the capsule opening. The drug delivery system was designed to deliver the drug at such a time when it was needed most to offer convenience to the chronic patients of asthma. Formulated dosage forms were evaluated for an in vitro drug release study, which showed that the release might be consistent with a release time expected to deliver the drug to the colon depending on the thickness and hardness of the hydrogel plug. Thus, thickness and hardness of the novel polymeric plug plays an important role in controlling the drug release from the formulated drug delivery system.     

Development and in-vitro evaluation of a colon-specific controlled release drug delivery system

The major challenges in targeting drug to various parts of the gastrointestinal tract include control of drug release with respect to its environment and transit time. These two variables should be taken into consideration in designing a rational colonic drug delivery system. To this end, a swelling matrix core containing pectin, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose and 5-aminosalicylic acid was developed. This was subjected to a dual coating operation: an inner pH-sensitive enteric and an outer semi-permeable membrane coat with a pore former. In-vitro dissolution studies were carried out in USP apparatus-I using sequential pH media. The first 2 h of dissolution studies were done in HCl buffer at pH 1.5, the next 2 h in pH 5.5 and, finally, in phosphate buffer at pH 6.8 with and without pectinolytic enzyme present. Less than 2% drug was released in the first 6 h and about 90% released in the following 12 h in a controlled manner. The stability studies of the coated systems were performed for 90 days under various conditions and it was found that drug release was not adversely affected. Results indicate that this delivery system has potential for site-specific delivery of drugs to the colon irrespective of transit time and rapid changes in the proximal pH of the gastrointestinal tract.     

Design of a drug delivery system with bimodal pH dependent release of a poorly soluble drug

A delivery system which provides bimodal pH dependent release of poorly water soluble carvedilol in gastric and intestinal environment was designed. Preparation of solid dispersion with porous silica ensured a significantly higher dissolution rate of carvedilol in acidic and alkaline media in comparison to pure drug, while granulation of that solid dispersion with enteric polymer dispersion resulted in diminished immediate release in acidic media and fast release of the remaining drug in alkaline media. The ratio in quantities of first vs. second release was controlled with amount of enteric polymer dispersion used for granulation process. Desired 25 mg release of carvedilol at pH values 1.2 and 6.8 was achieved when 1.80 g of polymer per 1.0 g of solid dispersion (drug to silica ratio= 0.25 g : 2.0 g) was used.     

pH-independent pulsatile drug delivery system based on hard gelatin capsules and coated with aqueous dispersion Aquacoat ECD.

The objective of this study was to develop a rupturable, capsule-based pulsatile drug delivery system with pH-independent properties prepared using aqueous coating. The drug release is induced by rupturing of the top-coating, resulting by expanding of swellable layer upon water penetration through the top-coating. Croscarmellose sodium (AcDiSol) is a preferable superdisintegrant compared to low substituted hydroxypropylcellulose (L-HPC) and sodium starch glycolate (Explotab), because of controlled lag time, followed by a quick and complete drug release. However, due to its anionic character, AcDiSol showed pH-dependent swelling characteristics (pH 7.4 > 0.1N HCl) resulting in a pH-dependent lag time. The pH dependency could be eliminated by the addition of fumaric acid to the swelling layer, which allowed to keep an acidic micro-environment. Formation of the rupturable top-coating was successfully performed using an aqueous dispersion of ethylcellulose (Aquacoat) ECD), whereby sufficient drying during the coating was needed to avoid swelling of the AcDiSol layer. A higher coating level was required, when aqueous dispersion was used, compared to organic coatings. However, an advantageous aspect of the aqueous coating was the lower sensitivity of the lag time to a deviation in the coating level.     

Pharmacokinetic evaluation of a selegiline pulsatile oral delivery system

Selegiline is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. The sole recommended dosing regimen is 5 mg given in the morning and at noon with breakfast and lunch. A pulsatile oral dosage form was developed to mimic the conventional tablet release from two oral administrations separated by 4 h, to permit once-daily dosing and increase compliance. The pharmacokinetics of the pulsatile delivery system was studied in six healthy male volunteers. The plasma concentration–time profile from the pulsatile system of selegiline and metabolites is dissimilar to that obtained from the 5 mg bid administration of the conventional tablet and cannot be considered to be bioequivalent. The initial pulse of the delivery system is rapidly absorbed but to a lesser extent than the conventional regimen; the second pulse exhibits absorption which is delayed and prolonged. The decrease in the selegiline concentration may be due to the less absorptive surface of the lower GI tract which is available to the second pulse. Another reason could be the disparity between the in vitro and in vivo release profiles from the second pulse. Compartmental analysis indicates that the ratio of formation–absorption rate constant for the selegiline to N-desmethylselegiline pathway decreases from 1·57±1·04 for the first pulse to 0·61±0·54 for the second pulse of the pulsatile delivery system, suggesting that the upper portion of the GI tract has a greater capacity to convert selegiline to N-desmethylselegiline than the lower GI tract. The lack of in vivo and in vitro correlation is most likely due to site specific absorption/metabolism. Regimen has been previously shown to be a significant factor in estimating the extent of selegiline and metabolite exposure following oral administration. The inequivalence of dosing regimens of the same total daily dose may ultimately be linked to the saturability of gut wall metabolism. This phenomenon may preclude the development of novel delivery systems designed to mimic the recommended dosing regimen of the conventional Eldepryl^™ tablet. © 1997 John Wiley & Sons, Ltd.     

Polyacrylamide microbeads,a sustained release drug delivery system

Using tetracycline-HCl and theophylline as model drugs, polyacrylamide microbeads were prepared by w/o emulsion polymerization technique. Furthermore, drug-loaded polymer microbeads were prepared in the presence of different concentrations of gelatin, which were further cross-linked for different time intervals. The prepared microbeads were characterized through particle size analysis, electron microscopy, and in vitro dissolution. Relatively spherical free-flowing populations of microbeads were obtained. The presence of gelatin during the polymerization processes led to larger particles proportional to its concentration in the aqueous phase. The dried microbeads showed smooth pored or fissured surfaces. In aqueous media, they attained equilibrium hydration within 10 min, with 73.5% v/v water uptake forming spongy spheres. The products showed slower dissolution rates with higher gelatin concentrations and extended cross-linking.     

Evaluation of the swelling, hydration and rupturing properties of the swelling layer of a rupturable pulsatile drug delivery system.

The objective of this study was to investigate the swelling characteristics of various swellable polymers in swelling layers that induce the rupturing of an outer polymer coating in pulsatile drug delivery systems (DDS). An apparatus was designed to measure simultaneously the swelling energy/force and water uptake of discs, made of polymers. The swelling energy of several excipients decreased in the following order: croscarmellose sodium (Ac-Di-Sol) > low-substituted hydroxypropyl cellulose (L-HPC) > sodium starch glycolate (Explotab) > crospovidone (Kollidon CL) > hydroxypropyl methylcellulose (Methocel K100M). A linear correlation existed between the swelling energy and the water uptake. The swelling behavior of Ac-Di-Sol depended on the ionic strength and the pH of the medium due to a competition for free water and the acidic nature of this polymer. Analysis of the time-dependent swelling force data with a previously developed exponential equation confirmed a diffusion-controlled swelling force development, predominantly controlled by the penetration rate of the medium. The swelling behavior and the rupture of the outer polymeric coating of a pulsatile DDS were demonstrated in simulation tests.     

Design and development of a novel controlled release PLGA alginate-pectinate polyspheric drug delivery system

A 23 full factorial design was employed to evaluate and optimize the drug entrapment efficiency and in vitro drug release from PLGA microparticles encapsulated in a complex crosslinked alginate-pectinate matrix (polysphere). The independent formulation variables included the volume of internal and external phases, and concentration of PLGA. Surface morphology and internal structure of PLGA microparticles and polyspheres were examined by scanning electron microscopy which revealed spherical PLGA microparticles with highly porous surfaces that accounted for the rapid burst effect of this system. Texture analysis was used to profile the matrix resilience, tolerance, and energy absorbed. In vitro drug release was assessed in buffer media on PLGA microparticles and polyspheres. Polyspheres exhibited ideal zero-order release while PLGA microparticles had a burst effect followed by lag phase. Kinetic modeling of in vitro drug release data indicated that formulations were not highly dependent on polymeric erosion as a mechanism for drug release but rather diffusion. A close correlation existed between the matrix tolerance and energy absorbed. Formulations with decreased tolerance absorbed less energy, thus led to rapid surface erosion, lower matrix integrity and hence a burst effect. The converse was true for an increased matrix tolerance, which led to zero-order release supported by superior matrix integrity and a significantly reduced burst effect. The rat subcutaneous model validated in vitro release data and demonstrated that the polyspheres provided flexible yet superior rate-modulated drug delivery.     

Design and evaluation of an oral controlled release delivery system for melatonin in human subjects

Six human subjects were given an oral formulation designed to provide an immediate and controlled release of melatonin (MT). The controlled release formulation consisted of MT-loaded sugar beads coated with 20% Aquacoat^®. A computer simulation program (MAXSIM^®) was used to estimate the MT dose and ratio of immediate and controlled release MT based on average population pharmacokinetics of MT. When 0.5 mg of MT (immediate release portion of MT, 0.1 mg) was administered to four subjects, average peak plasma MT concentration was reached at about 600 pg/ml and maintained at about 100 pg/ml over 8 h. Observed peak plasma MT concentrations were 3-times greater than predicted by simulation. These results suggest that the MT dose, ratio of immediate release MT to controlled release MT, and the controlled release dosage form must all be considered in order to closely mimic the endogenous plasma MT concentration-time curve. Deconvolution and pharmacokinetic analysis suggested that less than 20% of the orally administered controlled release MT dose reached the systemic circulation from time 0 to 8 h. A good correlation was observed between plasma MT concentration and urinary excretion rate of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT. As plasma MT concentration increased, the urinary excretion rate of 6-STMT increased concomitantly. This suggests that the urinary excretion rate of 6-STMT may be used as an index of human plasma MT concentration.     

Design and evaluation of an early stage drug release apparatus

This paper describes the design and evaluation of an early stage drug release apparatus (ERA) to determine drug release from pellets at times less than 1 min. The apparatus comprises a stirred sample chamber in which the sample is retained by a BS150 mesh screen (0.106 mm), and a series of jacketed cups containing the medium (80 ml) which are raised and lowered in turn over the fixed sample chamber for specified periods. Three types of early release studies were used: single 60s study (single cup), 10s followed by 50s (two cups) and 10, 20, 30...60s multiple changeover differential release (six cups). The effects of stirrer speed, stirrer position and multiple changeover on drug release from standard paracetamol-alginate pellets were investigated. Drug release rates from non-disintegrating pellets were reproducibly determined. The three types of early release study schemes yielded reproducible drug release data over sampling times less than 1 min. Stirrer speed, and depth, and changeover motion of release cups affected drug release but yielded reproducible results. Release from the standard pellets used to study the apparatus took 3 days to stabilize and remained stable thereafter. The apparatus can be used for screening of pellet formulations of sparingly soluble drugs during their developmental stage and regular quality assurance studies of pellets (>150 mesh size). Along with early release studies of pellets, it could be easily modified to study other types of formulations and for automation.     

Design and evaluation of oral nanoemulsion drug delivery system of mebudipine

Abstract

A nanoemulsion drug delivery system was developed to increase the oral bioavailability of mebudipine as a calcium channel blocker with very low bioavailability profile. The impact of nano-formulation on the pharmacokinetic parameters of mebudipine in rats was investigated. Nanoemulsion formulations containing ethyl oleate, Tween 80, Span 80, polyethylene glycol 400, ethanol and deionized water were prepared using probe sonicator. The optimum formulation was evaluated for physicochemical properties, such as particle size, morphology and stability. The particle size of optimum formulation was 22.8?±?4.0?nm. Based on the results of this study, the relative bioavailability of mebudipine nanoemulsion was enhanced by about 2.6-, 2.0- and 1.9-fold, respectively, compared with suspension, ethyl oleate solution and micellar solution. In conclusion, nanoemulsion is an interesting option for the delivery of poorly water soluble molecules, such as mebudipine.     

Formulation and evaluation of metformin hydrochloride-loaded niosomes as controlled release drug delivery system

Abstract

Lactic acidosis is a serious, metabolic complication that may occur due to metformin hydrochloride (MH) accumulation during the treatment of diabetes mellitus. The aim of this study is to enhance the bioavailability of MH by oral route. Span 40 and cholesterol were used for the preparation of MH-loaded niosomes by the reverse phase evaporation technique. Dicetyl phosphate (DCP) and 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) were used to obtain negatively and positively charged vesicles, respectively. The mean particle size ranged from 223.5 to 384.6?nm and the MH-loaded niosomes’ surface was negatively charged in the absence of charge inducing agents (?16.6?±?1.4?mV) and also with DCP (?26.9?±?1.0?mV), while it was positively charged (+8.7?±?1.2?mV) with DOTAP. High entrapment efficiency was observed in all the formulations. MH-loaded niosomes were found to effectively sustain the release of drug, particularly with positively charged niosomes. The bioavailability of MH-loaded niosomes was assessed by measuring the serum values of glucose and metformin in the different studied Wistar rats groups. The pharmacokinetic data of MH-loaded niosomal preparation showed a significant prolongation and increased intensity of hypoglycemic effect more than that observed for free MH solution. Area above the blood glucose levels–time curve (AAC), maximum hypoglycemic response and time of maximum response (T_max) were significantly higher (p?<?0.001) when MH was administered in niosomal form compared to free drug solution. It could be concluded that MH-loaded niosome is promising extended-release preparation with better hypoglycemic efficiency.     

Preparation and drug release mechanism of CTS-TAX-NP-MSCs drug delivery system

Targeting delivery of anticancer agents is a promising field in anticancer therapy. Inherent tumor-tropic and migratory properties of mesenchymal stem cells (MSCs) make them potential vehicles for targeting drug delivery systems for tumors. Although, MSCs have been successfully studied and discussed as a vehicle for cancer gene therapy, they have not yet been studied adequately as a potential vehicle for traditional chemical anticancer drugs. In this study, we have engineered MSCs as a potential targeting delivery vehicle for paclitaxel (TAX)-loaded nanoparticles (NPs). The size, surface charge, starving time of MSCs, incubating time and concentration of NPs could influence the efficiency of NPs uptake. In vitro release of TAX from CTS (chitosan)-TAX-NP-MSCs and the expression of P-glycoprotein demonstrated that release of TAX from MSCs might involve both passive diffusion and active transport. In vitro migration assays indicated that MSCs at passage number 3 have the highest migrating ability. Although, the migration ability of CTS-TAX-NP-MSCs could be inhibited by uptake of CTS-TAX-NPs, this ability could recover 6 days after the internalization.     

Effect of curing conditions and plasticizer level on the release of highly lipophilic drug from coated multiparticulate drug delivery system

The study aimed to investigate the effect of triethyl citrate (TEC) plasticizer level (10, 15, and 20%), curing temperature (40, 50, and 60 degrees C) and time (0 to 168 h) on the release of a highly lipophilic drug bumetanide from pellets coated with methacrylate ester copolymer (Eudragit RS). Bumetanide was layered onto sugar pellets followed by coating with 6% Eudragit RS with and without hydroxypropyl methyl cellulose (HPMC) seal coat using Wurster Fluid Bed equipment. Coated pellets were stored for 3 months at room temperature and the release was tested in USP purified water. At 10% TEC level, increasing curing time and temperature lead to slower drug release. At 15 and 20% TEC levels, curing initially decreased drug release followed by increase in the release at longer curing time and higher temperature. Drug release from coated pellets plasticized with 15% TEC and completely cured followed zero order kinetic models. At plasticizer level of 20%, bumetanide release from the completely cured pellets was better modeled using the Higuchi's equation reflecting possible drug migration during curing. Storage led to an increase in drug release. The use of HPMC seal coat stabilized drug release after storage. It was concluded that bumetanide migration into Eudragit RS film coat was the main cause of the accelerated release after curing and storage. The drug migration during storage at room temperature was prevented by seal coating the pellets with HPMC.     

Enteric coated insulin pellets: development, drug release and in vivo evaluation

Pellets with human insulin as a model drug were prepared by an extrusion and spheronization process to investigate the oral application of peptides. The described process proved suitable for preparing small batches of about 50 g in laboratory scale. The developed formulation was completed by the addition of aprotinin as protease inhibitor and sodium cholate as an intestinal absorption promoter to enhance oral bioavailability of insulin. In order to protect the peptide against the gastric juice the pellets were coated with shellac in a fluid-bed ball coater. Pharmaceutical properties of the produced batches were examined by analysis of contents and dissolution tests. Dissolution of insulin in simulated gastric juice of pH 1.2 was prevented by shellac. On the other hand, a rapid and complete release of the molecular-dispersed insulin from the pellets was found in simulated intestinal fluid (pH 7.5) with simultaneous efficiency of the protease inhibitor against added enzyme activity. Despite promising in vitro results no significant absorption of insulin was detected in vivo after oral application of the pellets to streptozotocin diabetic rats. High sensitivity to enzymatic degradation and low ability to cross the intestinal wall are discussed as limiting factors for the insufficient absorption of insulin in vivo.     

Design,optimization and evaluation of mesalamine matrix tablet for colon drug delivery system

The aim of the present investigation was to develop and evaluate matrix tablet of mesalamine for colonic delivery by using Eudragit RSPO, RLPO and combination of both. The tablets were further coated with different concentration of pH-dependent methacrylic acid copolymers (Eudragit S100), by dip immerse method. The physicochemical parameters of all the formulations were found to be in compliance with the pharmacopoeial standards. The in vitro drug release study was conducted using sequential dissolution technique at pH 1.2 (0.1N) HCl, phosphate buffers pH 6.8 and 7.4, with or without rat cecal content mimicking different regions of gastro intestinal tract. The result demonstrated that the tablet containing Eudragit RLPO coated with Eudragit S100 (1 %) showed a release of 94.91 % for 24 h whereas in the presence of rat cecal content the drug release increases to about 98.55 % for 24 h. The uncoated tablets released the drug within 6 h. The in vitro release of selected formulation was compared with marketed formulation (Octasa MR). In vitro dissolution kinetics followed the Higuchi model via non-Fickian diffusion controlled release mechanism. The stability studies of tablets showed less degradation during accelerated and room temperature storage conditions. The enteric coated Eudragit S100 coated matrix of mesalamine showing promising site specific drug delivery in the colon region.