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.     

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.     

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.     

Studies on Drug Release from a Carbomer Tablet Matrix

The purpose of this investigation was to study the drug release mechanisms for tablet matrices of carbomer. Carbomer is a polymer of acrylic acid which is cross-linked with polyalkenyl polyether. The drug and the carbomer were blended and directly compressed into tablets using a laboratory Carver press. The influence of the level of carbomer, the type of drug, and the pH of dissolution media were investigated by measuring drug release kinetics. In general, the release of a relatively neutral molecule (e.g. theophylline) in the pH 7.2 phosphate buffer solution appears to exhibit nearly zero-order kinetics via a diffusion-controlled mechanism for all polymer levels studied (10-85%).

The drug release process based on diffusion can be described by the general expression:

M_t = k₁t^1/2 + k₂t

where M, represents the amount of the drug released at time t, and k₁, k₂ are related to kinetic constants characteristic of the drug delivery systems. The release kinetics are modified when an ionic species, such as sodium salicylate, is incorporated into the tablet matrix.     

Solid Dispersion Controlled Release: Effect of Particle Size, Compression Force and Temperature

Solid dispersions are dynamic systems, a careful control of processing variables is required to produce desired physicochemical properties of these systems.

The influence of drug particle size, dispersion temperature and compression force on the release rate of theophylline from solid dispersed system tablets was studied. Theophylline base (micronized and granulate) were embedded into a polymeric mixture of PEG and acrylic/methacrylic esters at controlled temperature and shock cooled. Tablets were made at two compressional forces and drug release was measured spectrophotometrically over a period of fifteen hours.

The release rate of drug dispersed in these insoluble matrices was independent of particle size but not of hardness.

However, variations in ratios of polymeric mixture and dispersion temperature controls the drug release rate from inert matrix more effectively than such factors as drug particle size and lower range of tablet hardness. The fast cooling produced excellent reproducibility of drug content throughout the entire entrapment product. X-ray diffraction study demonstrated no changes in crystalline form of theophylline.     

Mathematical Simulation of Controlled Drug Release from Cylindrical Matrix Devices

The general mathematical model for controlled drug release from the cylindrical matrix device was developed. The system under consideration is composed of an active agent which is dissolved homogeneously in a cylindrical porous matrix device. The method of lines was employed to solve the partial differential equation in the present study.

The effects of hydrodynamic diffusion layer, the rate of spontaneous decay reaction in the device, the height to radius ratio of the device and the porosity distribution in the device on the rate of drug release were investigated by solving the two dimensional diffusion equation under non-steady state conditions.

The results indicated that the release rate may be significantly underevaluated if the data obtained in the in vitro studies under a poor mixing condition are analyzed mistakenly on the assumption of well mixing condition.

The findings in the present analysis are of practical significance to the design and development of matrix-diffusion type controlled release drug products.     

Dissolution OP Nalidixic Acid Solid Dispersions 1. Nal-Hydrotropic salts and NAL-Hyrj systems

The effect of solid dispersion techniques on the dissolution rate of nalidixic acid powder was investigated.

The thermodynanic parameters of all tested systems revealed a spontaneous reaction with no complex affinity to the drug.

Hexamine and sodium citrate showed very powerful solubilizing capacity towards NAL powder.

For piperazine citrate in spite of its low interaction with NAL in the aqueous phase, it proved to be efficient carrier in the solid dispersion system. Hyrj 59 caused the greatest enhancement in NAL dissolution rate of all carriers examined. After 5 minutes, the RDR of the four-fold NAL-HyrJ 59 co-precipitate system was 16.5 times the untreated drug.     

Miconazole and Miconazolenitrate Chewing Gun as Drug Delivery Systems - A Practical Application of Solid Dispersion Technique

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs - incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole - 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.     

Dissolution Study of Prolonged Release Morphine Tablets Using Hydrophilic Matrices

This study presents the results of “in vitro” dissolution of prolonged release morphine tablets using hydroxypropylmethylcellulose. Tablets with four different doses were elaborated and the liberation from these formulated tablets was compared with that of the only commercial pharmaceutical preparation of this type registered in the Spanish Pharmaceutical Market.

The results of the dissolution tests show that the drug was gradually released in all cases and tablets had released from 60 to 90% of its contents after 8 hours.

In the comparative study, the commercial tablets showed the fastest release. In both cases the release rate was lower when artificial intestinal fluids were used as the dissolution medium.     

Miconazole and Miconazolenitrate Chewing Gum as Drug Delivery Systems - A Practical Application of Solid Dispersion Technique

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs-incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole - 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.     

Cellulose Acetate Trimellitate Microspheres Containing NSAIDS

Indomethacin and ketoprofen (non-steroidal anti-inflammatory drugs) were incapsulated with cellulose acetate trimellitate, enteric polymer, using a spray drying technique.

Organic solutions of polymer and drug were prepared in different weight ratios and sprayed, achieving drug loaded microspheres.

The obtained spray dried microparticles were characterized in terms of yield of production, shape, size, morphological characteristics and drug content.

The in vitro drug release tests, carried out using a pH change method with a flow-through cell apparatus, show a typical delayed drug release due to the pH-dependent solubility of the polymer.     

Formulation of Silicone Matrix Systems for Long Term Constant Release of Peptides

Theoretically, release of drug through the water-filled pores of matrix systems is expected to show a square-root-of-time dependence, with time exponents of 0.5 and hence continuosly declining release rates. Yet there have been many research groups finding remarkable deviations.

The aim of this work was to investigate on factors which lead to deviations from the square-root-of-time law and may be helpful for the development of matrix systems with constant drug release for long time. Matrices of polydimethylsiloxane (PDMS) were prepared incorporating varying amounts of different pore-building, water soluble hydrogels. The hydrophilic model drug was Gly-Tyr.

The following essential factors influencing the long-term release profiles were found: (i) total matrix loading, (ii) its dissolution rate and (iii) the viscosity of the pore-building hydrogel. A proper choice of conditions lead to release profiles with time-exponents up to 0.8 for a time period of several weeks.     

Technological Evaluation of three Enteric Coating Polymers I. With an Insoluble Drug

The enteric properties of a recent cellulose polymer, cellulose acetate trimellitate (CAT, EASTMAN KODAK) were evaluated on an insoluble substract for comparison, included in this paper are the properties of two other cellulose esters: cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HP55).

The physical properties and disintegration time at pH 1.2 and 6.5 were influenced by the level of coating solution. The gastroresistance was obtained more fastly with CAT and CAP than for HP55.

The influence of coating solution on drug release from tablet was investigated. The dissolution studies were made allowing the variation of pH in the dissolution medium during the kinetics.

Drug release from coated tablets was found to be dependent upon the type of polymers used to form film: higher release rates were obtained with CAT compared to CAP and HP55.     

Dissolution Characteristics of Pharmaceutical Equivalents

The in-vitro release of diltiazem from pharmaceutical equivalents of sustained release tablets, commercially available in Italy, was studied.

The in-vitro release profiles were determined by means of different methods and apparatus. Paddle, basket, Poole, Diffutest and Stricker methods were compared.

The absorption rates in artificial gastric and enteric juices by means of lipid barriers were calculated.

Some preparations showed a diffusion mechanism, some a first-order release.

The differences among the dissolution profiles of the formulations were enhanced with the Strieker method.     

Polymeric Pseudolatices Dispersion Bearing Isosorbide Dinitrate for Transdermal Application

A pseudolatex based system for transdermal delivery (PL-ISDN-D) of isosorbide dinitrate (ISDN) was developed for its prolonged and controlled systemic availability. To achieve the desired and controlled release rate, different combinations of Eudragit RL-100 and polyvinylpyrrolidone were used in the preparation of pseudolatices polymeric dispersions. These preparations were evaluated for in-vitro release and permeation of the drug across human cadavar skin. The designed systems exhibited linear relationship between drug release (Q) Vs 0.80 function of time (t^0.80).

The product exhibiting required skin permeation (500 mcg/h/ 100 mg) calculated to achieve an effective plasma concentration was selected for the in-vivo performance evaluation. The drug plasma profile was compared with the plasma profile obtained following the administration of conventional oral dose of isosorbide dinitrate.

The study revealed that designed pseudolatex transdermal drug delivery system of isosorbide dinitrate could be used successfully with improved performance.     

Comparison of In VitroRelease Rates of Multisource Sustained-Release Papaverine Hydrochloride Products

The extent of differences in the In vitro release rate among 24 lots of 150 mg sustained-release papaverine hydrochloride products from six manufacturers was investigated.

The rotating bottle method for timed-release capsules, official in N.F. XIV, was used. Quantitation of papaverine hydrochloride in solution was done using ultra-violet spectrophotometry at two wavelengths to assure that there was no interference from other components of the formulation.

While in vitro dissolution data by itself cannot predict in vivo performance, variations from one manufacturer to another and also for the same manufacturer were observed. These included variations in the amount released both in the first hour and also in the total amount released.

Of the six products tested, Pavabid and Cerespan demonstrated the most consistent release patterns with slightly better consistency observed for the former. Observed differences may or may not be of clinical significance.     

Investigation of Prolonged Drug Release from Matrix Formulations of Chitosan

A hydrocolloidal matrix system containing complexes of chitosan was investigated for preparation of sustained release tablets and examined in-vitro.

Theophylline tablets using chitosan as a sustained release base were evaluated. It was found that when chitosan is used in a concentration of more than 50% of tablet weight, an insoluble non-erosion type matrix was formed. Tablets prepared with a chitosan concentration of less than 33% were fast releasing.

Chitosan used in a concentration of about 10% acted as a disintegrant and the drug was dissolved within an hour.

Citric acid slowed down the release rates of chitosan based theophylline tablets. Theophylline tablets using carbomer-934P as a sustained release base were evaluated. Carbomer-934P in lower concentrations forms an erosion type matrix. In order to produce a twenty-four (24) hour sustained release tablet, more than 10% concentration of carbomer-934P is needed. Combination with chitosan and carbomer-934P produced slower releasing tablets.

A hydrocolloidal erosion type matrix was formulated using chitosan, carbomer-934Pand citric acid. Only 10% of chitosan was needed to prepare theophylline sustained release tablets in these mixtures.

The dose dumping potential of chitosan tablets due to rapid disintegration in alkaline media was eliminated by preparing hydrated erosion type matrix systems.     

Influence of extrusion-spheronization processing on the physical properties of d-Indobufen pellets containing pH adjusters

d-Indobufen pellets containing pH adjusters (acids, buffer, salt) were prepared by extrusion-spheronization technology.

The interaction effect between some processing variables (feeding/agitator speeds of extruder, plate speed and residence time of spheronizer) was evaluated by comparing the basic formulation pellets with the pellets in which the soluble filler (lactose) was substituted by fumaric, tartaric and citric acids and also sodium citrate.

The criteria of formulation and process evaluation were the reproducibility of the particle size distribution, the density, the hardness and morphological properties, in addition to the reproducibility of the drug dissolution rates.

In all cases, the physical/technological characteristics were not influenced very much by pH adjuster incorporation, but the drug dissolution profiles showed some significant variations in the first hour. As a logical extension of this work, wet granulations with aqueous ethylcellulose and acrylic resin dispersions instead of only water were tested to evaluate the wetting effect of the release modifier inclusion. The results confirmed the validity of polymeric systems in the preparation of pellets and their ability to produce a further delay of d-Indobufen release.     

Methods for the Determination of the Carbon Dioxide Evolved from Effervescent Systems

Different methods for determining the carbon dioxide evolved from effervescent systems are described. In addition, a comparison between some of them is carried out when a stoechiometric mixture of L-tartaric acid and sodium bicarbonate reacts.

The methods compared are: gravimetric, volumetric and gasometric.

The gravimetric methods can be direct or indirect. The direct ones are based on taking in the carbon dioxide by a sorbent substance. The increase of weight after the absorption represents the CO₂ evolved. In the indirect gravimetric methods the amount of carbon dioxide is determined by substraction of the weight of the sample after and before the effervescent reaction.

The volumetric methods are based on an acid-base titration. In the method used, the carbon dioxide released reacts with barium hydroxide. The excess of barium hydroxide is titrated with oxalic acid. It is possible to calculate then the carbon dioxide produced in the reaction from the volume of oxalic acid used.

In the gasometric methods the volume of gas is directly determined by the displacement of a solution when the gas is released.

The gasometric method seems to be the most efficient among the studied ones.     

Sustained release nifedipine formulations: Moment, Modelling and Simulation as pharmacokinetic analysis approach

The bioequivalence of three sustained release nifedipine formulations designed in this laboratory, was assayed in rabbits by comparing their plasma time profiles to a reference (Adalat^R retard).

The analysis of data was performed by using the statistical moments as a measure of drug release. Results show a slowler absorption rate in the experimental formulations than in Adalat^R retard, and not differences in the absorption extent.

The composed one-compartment model, described for humans, showed to be also succesfull for rabbits.