Evaluation of the Tablet Core Factors Influencing the Release Kinetics and the Loadability of Push–Pull Osmotic Systems

Push–pull osmotic systems have been developed to deliver poorly soluble drugs in a modified-release fashion. The aim of this study was to investigate the influence of the tablet core factors on the drug release kinetics and loadability. The release kinetics was efficiently modulated by varying either the proportion of osmotic agent or the drug layer polymer grade as an alternative to change the membrane characteristics. High osmotic agent proportions and viscous-grade polymers were recommended to formulate high drug loads up to 20%?without losing both the release completeness and the zero-order drug release kinetics.     

Influences of Osmotic Agents in Diffusion Layer on Drug Release from Multilayer Coated Pellets

Nonpareil beads were coated with three different functional layers, namely inner chlorpheniramine maleate‐loaded hydroxypropylmethylcellulose (HPMC, 4 mPa · s) deposition layer, middle HPMC (400 mPa · s) diffusion layer, and outer polyacrylic polymer (Eudragit RS30D) retention layer. The osmotic agents, including sodium chloride, glycine, citric acid, and disodium hydrogen phosphate, were incorporated in different amounts into the diffusion layer and the influences on drug release were studied. The osmotic agent competed with HPMC for imbibed water and subsequently caused more water influx owing to the osmotic pressure gradient. An appropriate amount of osmotic agent in the diffusion layer was necessary to exert its effect on retarding drug release. The osmotic effect on drug release was compromised with pellets at a higher coating level of the diffusion layer due to the extensive swelling and rupture of coat. The release parameters, including dissolution T_50% and mean dissolution time, showed linear relationship with osmolalities of osmotic agents studied. The effect of the osmotic agent in the diffusion layer played an important role in determining the unique multiphase drug release profiles, particularly in the initial phase of dissolution, and reduced with depletion of the osmotic agent in the later phase of dissolution.     

Influences of osmotic agents in diffusion layer on drug release from multilayer coated pellets

Nonpareil beads were coated with three different functional layers, namely inner chlorpheniramine maleate-loaded hydroxypropylmethylcellulose (HPMC, 4 mPa · s) deposition layer, middle HPMC (400 mPa · s) diffusion layer, and outer polyacrylic polymer (Eudragit RS30D) retention layer. The osmotic agents, including sodium chloride, glycine, citric acid, and disodium hydrogen phosphate, were incorporated in different amounts into the diffusion layer and the influences on drug release were studied. The osmotic agent competed with HPMC for imbibed water and subsequently caused more water influx owing to the osmotic pressure gradient. An appropriate amount of osmotic agent in the diffusion layer was necessary to exert its effect on retarding drug release. The osmotic effect on drug release was compromised with pellets at a higher coating level of the diffusion layer due to the extensive swelling and rupture of coat. The release parameters, including dissolution T_50% and mean dissolution time, showed linear relationship with osmolalities of osmotic agents studied. The effect of the osmotic agent in the diffusion layer played an important role in determining the unique multiphase drug release profiles, particularly in the initial phase of dissolution, and reduced with depletion of the osmotic agent in the later phase of dissolution.     

Salbutamol Delivering Transdermal Dosage Form Based on Osmo-Regulatory Principle

A transdermal drug delivery system of Salbutamol was developed which released the drug following zero order kinetics. The designed system essentially based on trilaminated matrix concept. The delivery of drug from the system affected by osmotic phenomenon where sodium chloride was used as an osmogent. To establish the desired release rate polyethylene glycol 4000 (PEG 4000) was used as channelising agent in rate controlling membrance of cellulose acetate. The designed systems exhibiting zero-order release rate, were studied for the in-vitro skin permeation. The product which was having skin permeability rate 115 mcg/hr/cm² was selected for the in-vivo evaluation. The forced expiratory volume (FEV₁) and drug plasma concentration were monitored periodically. The study revealed that designed osmoregulatory transdermal drug delivery system of Salbutamol could be used successfully with improved therapeutic response and holds promise for the clinical studies.     

Monolithic Osmotic Tablet Containing Solid Dispersion of 10-hydroxycamptothecin

A novel monolithic osmotic tablet composed of solid dispersion of water-insoluble 10-hydroxycamptothecin (HCPT) was prepared. The tablet core was made of a suspending agent, polyethylene oxide, an osmotic agent, sodium chloride, and a solid dispersion consisting of polyethylene glycol 6000 and HCPT. Optimized formulation was able to deliver HCPT at the constant rate of 1.21 mg/hour for 12 hours with cumulative release above 90% in vitro, independent of environmental media and stirring rate, and the release rate is co-controlled by osmotic pressure, suspending effect, and drug solubility in solid dispersion. The monolithic osmotic tablet containing solid dispersion has great potential in the controlled delivery of water-insoluble drugs.     

Cyclodextrin complex osmotic tablet for glipizide delivery

Poorly soluble glipizide was selected as the model drug to prepare osmotic pump tablets (OPT) with proper accessorial material after it was made an inclusion complex by kneading method in order to increase solubility. Polyethylene glycol 4000 (PEG4000) and cellulose acetate (CA) were selected as the coating materials, and acetone-water (95:5) co-solvent was employed as the coating medium. The effects of the osmotic promoting agent, diameter of the drug-releasing orifice, coating composition, and coat weight on the drug release profile were investigated. The drug release profile of the optimal formulation was compared with a commercialized push-pull osmotic tablet. The results indicated that glipizide-cyclodextrin inclusion complex OPT had excellent zero-order release characteristics in vitro.     

Cyclodextrin Complex Osmotic Tablet for Glipizide Delivery

ABSTRACT

Poorly soluble glipizide was selected as the model drug to prepare osmotic pump tablets (OPT) with proper accessorial material after it was made an inclusion complex by kneading method in order to increase solubility. Polyethylene glycol 4000 (PEG4000) and cellulose acetate (CA) were selected as the coating materials, and acetone–water (95:5) co-solvent was employed as the coating medium. The effects of the osmotic promoting agent, diameter of the drug-releasing orifice, coating composition, and coat weight on the drug release profile were investigated. The drug release profile of the optimal formulation was compared with a commercialized push–pull osmotic tablet. The results indicated that glipizide–cyclodextrin inclusion complex OPT had excellent zero-order release characteristics in vitro.     

Investigation of cyclobenzaprine hydrochloride release from oral osmotic delivery systems containing a water-swellable polymer

Oral osmotic delivery systems containing polyethylene oxide (PEO, a water-swellable polymer) were designed and the release of cyclobenzaprine hydrochloride (model drug) from the devices was investigated. The systems consisted of model drug, mannitol (osmotic agent), and increasing amounts of PEO surrounded by a semipermeable membrane drilled with a delivery orifice. There was a decrease in drug release rate with PEO in the core. This may be due to solubility-modulating properties of the polymer. Visual inspection of the devices with PEO showed significant swelling during dissolution testing. Swelling (internal pressure) may influence water imbibition rate into the core and subsequently drug release rate. The release rates were a function of membrane thickness. The release rates were independent of orifice size (range of 150-510 μm diameter) and hydrodynamic conditions for the devices. This would be advantageous in the delivery of drugs in man.     

Investigation of Cyclobenzaprine Hydrochloride Release from Oral Osmotic Delivery Systems Containing a Water-Swellable Polymer

ABSTRACT

Oral osmotic delivery systems containing polyethylene oxide (PEO, a water-swellable polymer) were designed and the release of cyclobenzaprine hydrochloride (model drug) from the devices was investigated. The systems consisted of model drug, mannitol (osmotic agent), and increasing amounts of PEO surrounded by a semipermeable membrane drilled with a delivery orifice. There was a decrease in drug release rate with PEO in the core. This may be due to solubility-modulating properties of the polymer. Visual inspection of the devices with PEO showed significant swelling during dissolution testing. Swelling (internal pressure) may influence water imbibition rate into the core and subsequently drug release rate. The release rates were a function of membrane thickness. The release rates were independent of orifice size (range of 150–510 μm diameter) and hydrodynamic conditions for the devices. This would be advantageous in the delivery of drugs in man.     

Release of cyclobenzaprine hydrochloride from osmotically rupturable tablets

Osmotically rupturable systems were developed and the release of cyclobenzaprine hydrochloride (model drug) from the systems was investigated. Systems were designed using mannitol (osmotic agent) and increasing amounts of polyethylene oxide (PEO, a water-swellable polymer) surrounded by a semipermeable membrane. When placed in an aqueous environment, osmotic water imbibition into the systems distended and swelled the systems until the membrane ruptured and released the active compound to the outside environment. Tablets with increasing amount of PEO exhibited longer rupture times. This may be due to osmotic pressure-modulating properties of the polymer, changing the rate of water imbibition into the systems.

The integrity of the membranes was investigated using high-pressure mercury intrusion porosimetry. Minimal mercury intrusion into the membrane structure and core tablet indicated membrane integrity and lack of defective areas or pinholes. The results were in agreement with the release profiles where no drug release was detected prior to membrane rupture. Mercury intrusion porosimetry appears to be a promising technique for evaluation of membrane integrity.

Once the systems ruptured, drug was released by osmotic pumping and diffusion mechanisms through the ruptured area. There was a decrease in drug release rate with inclusion of PEO in the core.

The effects of film thickness on rupture and release times were also investigated. Devices with thicker films produced longer rupture times. This is in agreement with the theoretical prediction.     

Release of Cyclobenzaprine Hydrochloride from Osmotically Rupturable Tablets

ABSTRACT

Osmotically rupturable systems were developed and the release of cyclobenzaprine hydrochloride (model drug) from the systems was investigated. Systems were designed using mannitol (osmotic agent) and increasing amounts of polyethylene oxide (PEO, a water-swellable polymer) surrounded by a semipermeable membrane. When placed in an aqueous environment, osmotic water imbibition into the systems distended and swelled the systems until the membrane ruptured and released the active compound to the outside environment. Tablets with increasing amount of PEO exhibited longer rupture times. This may be due to osmotic pressure-modulating properties of the polymer, changing the rate of water imbibition into the systems.

The integrity of the membranes was investigated using high-pressure mercury intrusion porosimetry. Minimal mercury intrusion into the membrane structure and core tablet indicated membrane integrity and lack of defective areas or pinholes. The results were in agreement with the release profiles where no drug release was detected prior to membrane rupture. Mercury intrusion porosimetry appears to be a promising technique for evaluation of membrane integrity.

Once the systems ruptured, drug was released by osmotic pumping and diffusion mechanisms through the ruptured area. There was a decrease in drug release rate with inclusion of PEO in the core.

The effects of film thickness on rupture and release times were also investigated. Devices with thicker films produced longer rupture times. This is in agreement with the theoretical prediction.     

Mucoadhesive elementary osmotic pump tablets of trimetazidine for controlled drug delivery and reduced variability in oral bioavailability

The objectives of this work was preparation and evaluation of the mucoadhesive elementary osmotic pump tablets of trimetazidine hydrochloride to achieve desired controlled release action and augmentation of oral drug absorption. The drug-loaded core tablets were prepared employing the suitable tableting excipients and coated with polymeric blend of ethyl cellulose and hydroxypropyl methylethylcellulose E5 (4:1). The prepared tablets were characterized for various quality control tests and in vitro drug release. Evaluation of drug release kinetics through model fitting suggested the Fickian mechanism of drug release, which was regulated by osmosis and diffusion as the predominant mechanism. Evaluation of mucoadhesion property using texture analyzer suggested good mucoadhesion potential of the developed osmotic systems. Solid state characterization using Fourier-transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectroscopy confirmed the absence of any physiochemical incompatibilities between drug and excipients. Scanning electron microscopy analysis showed the smooth surface appearance of the coated tablets with intact polymeric membrane without any fracture. In vivo pharmacokinetic studies in rabbits revealed 3.01-fold enhancement in the oral bioavailability vis-à-vis the marketed formulation (Vastarel MR®). These studies successfully demonstrate the bioavailability enhancement potential of the mucoadhesive elementary osmotic pumps as novel therapeutic systems for other drugs too.     

Ibuprofen Release from Beads Coated with an Experimental Latex: Effect of Certain Variables

The objective of this study was to evaluate the effect of factors such as drug loading, particle size, plasticizer type, antiadherent type, and annealing method on the release of ibuprofen from controlled-release beads coated with an experimental latex. Further, the in vitro release kinetics and mechanism of drug transport across the polymeric membrane have been investigated. Ibuprofen-loaded beads were coated with the experimental latex using a fluidized-bed coating machine (Uniglatt). The drug release from these spherical membrane reservoir systems appeared to be diffusion controlled. Evaluation of the effect of osmotic pressure by using dissolution media of various osmolal concentrations indicated that it has no significant effect on the drug release. To further elucidate the mechanism of release from these polymeric membranes, the permeation of drug through free films was studied.     

Osmotic delivery of flurbiprofen through controlled porosity asymmetric membrane capsule

The release of poorly water-soluble drug, flurbiprofen, through asymmetric membrane capsule of cellulose acetate containing different pore forming agents like glycerol, polyethylene glycol 400, and dibutyl phthalate, in presence of sodium lauryl sulfate was investigated. The asymmetric membrane was fabricated in the shape of capsule body and cap by phase inversion technique. The type of pore forming agent incorporated had a marked influence on the porosity of the asymmetric membrane. However flurbiprofen due to its poor solubility was unable to create enough osmotic pressure and hence less than 10% of drug was released from all the systems with out SLS. However when the study was conducted with SLS, a maximum release of 72% was observed from the capsule with 70% glycerol. The release rates were found to increase with the increase in the concentration of pore forming agent and the amount of SLS encapsulated.     

Evaluation of monolithic osmotic tablet system for nifedipine delivery in vitro and in vivo

The aim of this study was to evaluate the monolithic osmotic tablet system (MOTS) containing a solid dispersion with the practically water-insoluble drug nifedipine in vitro and in vivo. In the drug release study in vitro, the release profiles of this system had almost zero-order kinetics. The influences of tablet formulation variables, sizes of the delivery orifice, membrane variables, and values of pH in the dissolution medium on nifedipine release from MOTS have been investigated. The results provided evidence that the tablet core played an important role in MOTS. While orifice sizes and membrane variables affected the nifedipine release rate, MOTS was independent of the dissolution medium. The appropriate orifice size was found to be in the range of 0.5-1.0 mm. The coating membrane incorporating hydrophilic polyethylene glycol (PEG) formed a porous structure. The human pharmacokinetics and relative bioavailability of MOTS containing nifedipine were compared with a commercial Adalat® osmotic tablet system containing an equivalent dose of nifedipine following an oral single dose of 30 mg given to each of 11 healthy volunteers in an open, randomized crossover study in vivo. The relative bioavailability for MOTS was 112%. There was no statistically significant difference in the pharmacokinetic parameters between two dosage forms. It is concluded that the monolithic osmotic tablet controlled release system is feasible for a long-acting preparation as a once-daily treatment.     

Evaluation of Monolithic Osmotic Tablet System for Nifedipine Delivery In Vitro and In Vivo

Abstract

The aim of this study was to evaluate the monolithic osmotic tablet system (MOTS) containing a solid dispersion with the practically water-insoluble drug nifedipine in vitro and in vivo. In the drug release study in vitro, the release profiles of this system had almost zero-order kinetics. The influences of tablet formulation variables, sizes of the delivery orifice, membrane variables, and values of pH in the dissolution medium on nifedipine release from MOTS have been investigated. The results provided evidence that the tablet core played an important role in MOTS. While orifice sizes and membrane variables affected the nifedipine release rate, MOTS was independent of the dissolution medium. The appropriate orifice size was found to be in the range of 0.5–1.0 mm. The coating membrane incorporating hydrophilic polyethylene glycol (PEG) formed a porous structure. The human pharmacokinetics and relative bioavailability of MOTS containing nifedipine were compared with a commercial Adalat® osmotic tablet system containing an equivalent dose of nifedipine following an oral single dose of 30 mg given to each of 11 healthy volunteers in an open, randomized crossover study in vivo. The relative bioavailability for MOTS was 112%. There was no statistically significant difference in the pharmacokinetic parameters between two dosage forms. It is concluded that the monolithic osmotic tablet controlled release system is feasible for a long-acting preparation as a once-daily treatment.     

Osmotically Controlled Oral Drug Delivery*

It is advantageous to deliver some drugs with short half-life, and which are to be given frequently for chronic ailments, in the form of controlled-release (CR) formulations. The orally administered drugs, in the form of conventional matrix or reservoir type formulations, pose problems of bioavailability fluctuations due to gastric pH variations. Moreover, the release of drug(s) from these systems is affected by the hydrodynamic conditions of the body. Osmotically controlled drug delivery systems utilize the principles of osmotic pressure for the controlled delivery of active agent(s). The release rate of drug(s) from these systems is independent of the physiological factors of the gastrointestinal (GI) tract to a large extent. In the present review, theory underlying the delivery of drugs from osmotic systems is presented. Different types of oral osmotic systems, their advantages over conventional matrix and reservoir types of systems, and their applications are also discussed. Finally, some of the limitations, adverse effects, and patent and market status of these systems are reviewed. These systems form a major segment of drug delivery products. Because of their advantages and strong market potential, it appears that the future of osmotic systems in rate-controlled oral drug delivery is promising.     

Osmotically controlled oral drug delivery

It is advantageous to deliver some drugs with short half-life, and which are to be given frequently for chronic ailments, in the form of controlled-release (CR) formulations. The orally administered drugs, in the form of conventional matrix or reservoir type formulations, pose problems of bioavailability fluctuations due to gastric pH variations. Moreover, the release of drug(s) from these systems is affected by the hydrodynamic conditions of the body. Osmotically controlled drug delivery systems utilize the principles of osmotic pressure for the controlled delivery of active agent(s). The release rate of drug(s) from these systems is independent of the physiological factors of the gastrointestinal (GI) tract to a large extent. In the present review, theory underlying the delivery of drugs from osmotic systems is presented. Different types of oral osmotic systems, their advantages over conventional matrix and reservoir types of systems, and their applications are also discussed. Finally, some of the limitations, adverse effects, and patent and market status of these systems are reviewed. These systems form a major segment of drug delivery products. Because of their advantages and strong market potential, it appears that the future of osmotic systems in rate-controlled oral drug delivery is promising.     

Preparation and In Vitro Evaluation of Chitosan Matrices Cross-Linked by Formaldehyde Vapors

Rifampicin-chitosan matrices were prepared by a chemical cross-linking method to develop a sustained-release form. The effects of cross-linking agent (formaldehyde) on the drug release rate and release kinetics were investigated in this study. Moreover, the kinetics of rifampicin released from chitosan matrices exposed to formaldehyde vapors for predetermined time intervals were analyzed using Ritger and Peppas exponential equation. The in vitro release kinetics exhibited a non-Fickian transport model. Increasing the exposure time to formaldehyde vapors decreased the release rate of rifampicin from chitosan matrices as a result of formation of greater structural strength and tighter texture.     

Preparation and in vitro evaluation of chitosan matrices cross-linked by formaldehyde vapors

Rifampicin-chitosan matrices were prepared by a chemical cross-linking method to develop a sustained-release form. The effects of cross-linking agent (formaldehyde) on the drug release rate and release kinetics were investigated in this study. Moreover, the kinetics of rifampicin released from chitosan matrices exposed to formaldehyde vapors for predetermined time intervals were analyzed using Ritger and Peppas exponential equation. The in vitro release kinetics exhibited a non-Fickian transport model. Increasing the exposure time to formaldehyde vapors decreased the release rate of rifampicin from chitosan matrices as a result of formation of greater structural strength and tighter texture.