The Effect of Bases and Formulation on the Release of Indomethacin from Suppositories

The in vitro release characteristics of indomethacin from different suppository formulations were investigated using a dialysis method. Suppositories containing 100 mg of indomethacin were prepared by the fusion method in a variety of Witepsol and Novata bases with different hydroxyl values. The rate of release of indomethacin was found to be unexpectedly higher from oily bases with low hydroxyl values.

Furthermore, the effect of surface active agents and some excipients commonly used in suppository formulations on the release properties of indomethacin was determined. Colloidal silicon dioxide, sodium lauryl sulphate and cetyl alcohol had a slight effect, on the release of indomethacin, whereas dioctyl sodium sulphosuccinate significantly increased the amount of indomethacin released. White beeswax and Tween-80, however, resulted in a marked decrease in the release of indomethacin.

The in vitro release of indomethacin from five commercially available preparations was also determined using the same method. Suppositories formulated in PEG bases gave better release properties than those in oily bases.     

Development and Validation of Method for Determination of In Vitro Release of Retinoic Acid from Creams

The objective of this study was to develop and validate an in vitro test method that can be used as a tool for accessing batch-to-batch uniformity of finished topical products. The studies were performed by utilizing topical creams containing the 13-cis isomer of retinoic acid. Various physicochemical factors which may affect drug release from topical cream formulations were evaluated including drug concentration, internal phase droplet size distribution, viscosity and the composition of the emulsion internal and external phases. Utilizing a modified Franz diffusion cell with a cellulose membrane, the in vitro drug release profile from various cream formulations was established

The effect of varying the concentrations of various key ingredients by 30% does affect the viscosities and release rates compared to a standard formulation. However, there is no correlation between the viscosities and the release rates. No significant differences in pH and droplet size distribution were observed in these cream formulations compared to a standard formulation. The oil phase volume ratio appears to have the largest influence on the in vitro release of the drug. Intra- and inter-batch comparisons of the finished cream products show reproducible release profiles. Based on the results obtained in this study, when used together, both in vitro release and viscosity measurements may be useful as tools to assess batch-to-batch uniformity and consistent manufacturing of the finished cream product     

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.     

Carbamazepine Modified Release Dosage Forms

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid - methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Evaluation of In Vitro/In Vivo Correlation Utilizing a Rotating Basket-Paddle Dissolution Apparatus

The desirability of good correlations of parameters derived from in vitro dissolution study with parameters derived from in vivo bioavailability study is well established in biopharmaceutics. Reports on several in vitro dissolution apparatus, including the two official USP/NF methods, have appeared in the literature over the years. However, none have been accepted as universal because each apparatus is useful only for the dissolution testing of a specific group of drugs or dosage forms. Comparative dissolution testing was performed using the rotating basket-paddle apparatus and the two official USP/NF apparatus.

A comparative bioavailability study was carried out on four batches of rapidly disintegrating tablets (Formulations A to D) of nitrofurantoin and perphenazine using rabbit as an animal model. Excellent rank order (qualitative) correlations were observed among all combinations of in vitro and in vivo parameters. With the drug nitrofurantoin, an excellent quantitative correlation was found between the dissolution halftime and Cmax or Tmax or AUC. Yet, a repeated run with perphenazine yielded excellent correlation between dissolution halftime and Cmax or Tmax, but poor correlation between dissolution halftime and AUC.     

Influence of Drug Loading and Gel Structure on in-Vitro Release Kinetics from Photopolymerized Gels

Precious work has shown that stabls and homogenous poly HEMA gels can be prepared using a visible light sensitive initiator system. Gels were prepared from solutions of water and poly-2-hydroxyethyl methacrylate monomer. At concentrations of water greater than 10% v/v, translucent gel resulted. However, polymerization solvents such as glycerol and tertiary butyl alcohol (T.B.T.A) gave transparent, flexible gels over a wider range of concentrations. Subsequent work showed that changes in polymerization solvent and monomer concentration brought about changes in the mechanical and structural properties of the gels.

In this work, the effects of drug loading and polymerization solvents on in vitro drug release rate from the photopolymerized polyHEMA gels were studied. Polymerization solvents used included glycerol and tertiary butyl alcohol. Results indicated that the release rate in vitro was a diffusion-controlled process except at high drug concentrations in poly HEMA - T.B.T.A. gels when a departure from root-time kinetics occurred. Poly HEMA T.B.T.A. gels presented greater hindeirance to the mobility of the drug than polyHEMA - glycerol gels. Higuch's model for release from incoluble homogenous matrices containing dispersed solute was found to be inappropriate for the analysis of the release of the drug from the gels. A simple equation based on the modelling of desorption in diffusion was found more appropriate. Estimates of drug release rates in vitro may be made from measurements of the physical crosslinking density of the polymer (if matrix-diffusion controlled release is operative). Quantitative drug loading was achieved in the gels as evidenced from variation in crosslinking density and in vitro release rate with drug loading.     

Analysis and Simulation of Capsule Dissolution Problem Encountered During Prodkt Scale-Up

An in vitro capsule dissolution rate problem was encountered during scale-up of cofadroxil monohydrate, a water-soluble drug product. Initial formulation development had been carried out on a Zanasi LZ-64 with a blend containing 1.0% magnesium stearate lubricant. Scale-up capsules manufactured using a Hoflinger-Karg model GFK-1500 (H&K) showed a significantly slower dissolution rate when compared to those produced on a Zanasi LZ-64. Analysis of the problem indicated that during encepsulation on the H&K capsule machine, powder was being sheared resulting in slower in vitro capsule dissolution rate.

Shear simulation studies were conducted to select the level of magnesium stearate for encapsulation on the H&K which would maintain a satisfactory in capsule dissolution rate. A 0.3% level of magnesium stearate was selected on the basis of the simulation studies. At this lubricant level, capsules have been routinely produced on the H&K with satisfactory dissolution and encapsulation characteristics.     

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.     

THe Incorporation and in Vitro Release Profiles of Liquid, Deliquescent or Unstable Drugs with Fusible Excipients in Hard Gelatin Capsules

The in vitro release profiles of four liquid or deliquescent model drugs incorporated in various Gelucire^R excipients were examined. In every case, it was possible to obtain release of the active substance as rapidly as with the equivalent commercial soft gelatine capsules tested. Gelucire^R grades with high HLB values (despite having high melting points) were found to be the most favorable. Release patterns could be related to the behaviour of the Gelucire^R bases in the gastric fluid

Drug-excipient ratio played a prominent role, which differed when hydrophilic or hydrophobic Gelucire^R types were used. Storage of the capsule formulations for more than two years did not usually change the drug release profiles significantly, but chloral hydrate capsules could not be stocked for more than a few months     

Testing of “In Vitro” Dissolution Behaviour of Microparticulate Drug Delivery Systems

No official dissolution method exists concerning microparticulate drug delivery systems. The purpose of this work is the evaluation of different dissolution methods commonly used to test the in vitro release behaviour of microparticulate drug delivery systems. The influence of different environmental conditions, as stirring speed, ionic strength and presence of surfactant, on drug release is also evaluated.

Four dissolution methods, based on different equipments (USP dissolution test apparatus, rotating bottle apparatus, shaker incubator, recycling flow through cell), are performed on the same batch of indomethacin loaded poly-D, L-lactide (PDLLA) microspheres prepared by spray drying. The results obtained with the methods tested show the influence of in vitro dissolution method employed and of the environmental conditions on drug release profile.     

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.     

The Effect of Formulation on 1-131 Dissolution In Vitro from Sodium Iodide Capsules

Because of the importance of the bioavailability of 1-131 for thyroid uptake studies and thyroid therapy, the present investigation was conducted to determine the influence of diluents, type of lubricant and the concentration of lubricant on the in vitro release rate of 1-131 from 1-131 sodium iodide capsules. Formulations and 1-131 sodium iodide capsules were prepared in-house and dissolution profiles determined using the U.S.P. XXII Dissolution Test. Distilled water was employed as the solvent. Lactose only, calcium phosphate only, a mixture of dicalcium phosphate—Avicel PH 101 and a sodium phosphate formulation consisting of lactose, L-cysteine hydrochloride and sodium phosphate were chosen as diluents. Several concentrations of the lubricant magnesium stearate were employed. The influence of 3% or 5% talc as the lubricant was studied using the sodium phosphate formulation.

The results of the study demonstrated the influence of the formulation on the dissolution of 1-131 when the concentration of magnesium stearate was held constant. This was particularly noted at a 3% concentration and to a lesser degree at a 1% concentration of magnesium stearate. The dissolution rate for 1-131 from capsules prepared with the sodium phosphate—Avicel PH 101 formulation was slow and not influenced by varying the concentration of magnesium stearate. Using talc as the lubricant resulted in 1-131 dissolution rates that were rapid for the sodium phosphate formulation. Based upon the findings it is apparent that the diluent and the lubricant can influence the dissolution rate of 1-131 from sodium iodide labeled capsules. The relationship of in vitro dissolution profiles should be compared to the bioavailability of 1-131 in animals to ascertain the importance of formulation in thyroid function studies and treatment.     

In vitro and in vivo evaluation of bone morphogenetic protein-2 (BMP-2) immobilized collagen-coated polyetheretherketone (PEEK)

Polyetheretherketone (PEEK) is regarded as one of the most potential candidates of biomaterials in spinal implant applications. However, as a bioinert material, PEEK plays a limited role in osteoconduction and osseointegration. In this study, recombinant human bone morphogenetic protein-2 (rhBMP-2) was immobilized onto the surface of collagen-coated PEEK in order to prepare a multi-functional material. After adsorbed onto the PEEK surface by hydrophobic interaction, collagen was cross-linked with N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). EDC/NHS system also contributed to the immobilization of rhBMP-2. Water contact angle tests, XPS and SEM clearly demonstrated the surface changes. ELISA tests quantified the amount of rhBMP-2 immobilized and the release over a period of 30 d. In vitro evaluation proved that the osteogenesis differentiation rate was higher when cells were cultured on modified PEEK discs than on regular ones. In vivo tests were conducted and positive changes of major parameters were presented. This report demonstrates that the rhBMP-2 immobilized method for PEEK modification increase bioactivity in vitro and in vivo, suggesting its practicability in orthopedic and spinal clinical applications.     

In Vitro Dissolution Versus In Vivo Evaluation of Four Different Aspirin Products

The single dose pharmacokinetic characteristics of four aspirin formulations in humans were compared with their in vitro dissolution properties. The pharmacokinetic parameters were determined by measuring salicylate concentrations in the plasma. Dissolution was measured by using the USP XX single time point dissolution test. The four aspirin products were a commercial tablet, a commercial capsule, a capsule filled with a commercial granulation, and a slow dissolving capsule formulation that failed the USP dissolution specification. It was found that there was a poor correlation between the in vitro dissolution results and the in vivo computed pharmacokinetic parameter statistics. In vivo testing in humans showed that all of the formulations were bioequivalent in terms of half-life and AUC, and the capsule that failed to pass the dissolution specification was bioequivalent to two of the three products that did pass the specification with respect to the maximum plasma concentration. None of the products could be demonstrated to be bioequivalent with regard to the time to maximum plasma concentration. However, none of the in vivo differences between the four aspirin formulations were judged to be clinically significant. Therefore, while there was a poor relationship between the in vitro USP XX dissolution test results and the bioequivalence test results, from a practical viewpoint the dissolution test is a satisfactory manufacturing quality control test, since it can detect differences in in vitro dissolution prior to their having a significant clinical impact.     

A Comparative Study of the In Vitro and In Vivo Release of Dexamethasone from a Spray-On Bandage and Timed Release Aerosol

The formulation of several dexamethasone topical delayed release aerosol preparations was studied. Ethylcellulose and tributyl citrate were the film-forming agent and plasticizer, respectively, for the spray-on bandage formulation. The aerosol timed release preparation contained dexamethasone microcapsules suspended in a fluorocarbon aerosol propellant by isopropyl myristate and fumed silica. Both preparations were evaluated using an in vitro method which measured the release of dexamethasone hourly for eight hours. In vitro studies showed that each of the formulations delayed the release of dexamethasone. In the in vivo tests aerosols were sprayed on the unabraded back area of rabbits and the increased 17 - hydroxycorticosteriod urine levels at 24, 48, and 72 hours indicated dexamethasone absorption. In vivo studies indicated that absorption did not occur with the timed release preparation containing dexamethasone microcapsules. However, dexamethasone from the spray-on bandage preparation was absorbed over 72 hours. A commercially marketed topical dexamethasone cream was used for comparison in evaluating the two experimental formulations; however, in vivo studies showed that no absorption occurred with this preparation.

In recent years, a great deal of work has been directed towards the application of medicated polymeric films or tissue adhesives onto the skin to treat minor dermatological problems or serious skin wounds. Among the factors to be considered are: incorporation of a specific active ingredient, the mode of application and the dosage form. Lange and Fang (1,2) developed spray-on bandages using water soluble resins and water as the solvent. Fischl (3) evaluated the effectiveness of a cyanoacrylate monomer in closing skin incisions without affecting wound healing. Bhaskar and Cutright (4) showed that butyl cyanoacrylate could be successfully used as a surface dressing while reducing the degree of inflammation. Sciarra and Gidwani (5,6) reported on the release of gentian violet from selected polymer and plasticizer combinations and established various polymer-plasticizer combinations which could be applied as an aerosol spray. Other studies (7,8) have shown that ethylcellulose and a thermoplastic polyamide resin have potential use in spray-on bandage formulations.

The results indicated that the anti-infectives were released from the films and the spray-on bandages reduced the degree of infection about the wound.

The process of microencapsulation has been applied to various industrial and medical uses. Microcapsules can be prepared so that the encapsulated material will be released slowly. There are various methods of microencapsulation including coacervation, phase separation, interfacial polymerization, an electrostatic method, and vacuum metalization and they have been successfully used with selected drugs (9-13).

The purpose of this study was to develop and evaluate different aerosol formulations containing a therapeutic agent which can be slowly released. In vitro and in Vivo systems were used to evaluate the release and absorption of the drug in the test animals.     

Sustained-Release Dosage Form of Nicardipine Hydrochloride: Application of Factorial Design and Effect of Surfactant on Release Kinetics

Microcapsules of nicardipine hydrochloride with core:wall ratios of 1:1, 2:1, and 1:2 were prepared by the coacervation-phase separation method, using ethyl-cellulose as the coating material. Two batches of nicardipine hydrochloride microscapsules were divided into size fraction by using standard sieves ranging from 840 μm to 476 pn. Dissolution rate studies from microcapsules were performed using the USP XXII basket method. The kinetic model according to the Rosin-Rammler-Sperling-Bennet-Weibull (RRSBW) distribution was applied for the parametric representation of the dissolution curves. Preparation and dissolution rate studies on the nicardipine hydrochloride microcapsules were pellformed and the influence of particle size, core:wall ratio, and the amount of nicardipine hydrochloride on the release rate was examined by 2³ factorial design. The sign@cance of the observed effects was tested with the F test. A surface active substance was added in the dissolution medium to understand how this substance effects the release of drug from ideal microcapsule form which is found by the findings of the 2³ factorial design. Dissolution studies were repeated with this ideal formulation using different ratio of Tween 20.

The results of this study suggested that the solubility and bioavailability of the sustained-release dosage forms of nicardipine hydrochloride using sullface active substances could be increased.     

A Comparison of Dissolution from Commercial Tablets and from Capsules Containing a Powdered Tablet

In clinical trials it may be necessary to convert a commercial tablet to a capsule so that the identity of each drug being tested remains unknown until the trial is completed. This study shows that for six commercial tablets, after pulverization and encapsulation of the powder, the in vitro dissolution was faster for one product, slower for two products and essentially unchanged for three products.     

Development and Optimization of a Methotrexate Topical Formulation

A topical methotrexate (MTX) formulation that would achieve optimal drug buildup in the epidermis and diminish potential systemic toxicity could be of great utility in the treatment of a variety of hyperproliferative skin disorders. In an attempt to develop an optimized MTX topical formulation containing pharmaceutically acceptable excipients, a 2³ factorial design was used to investigate the effects of a fatty alcohol, propylene glycol, and ethanol on the in vitro skin permeation and uptake of MTX. In vitro skin permeation studies were performed using excised human epidermis mounted in flow-through diffusion cells. The results of steady-state flux and skin uptake of MTX from these formulations ranged from 0.035 to 0.315 μg/cm²/hr and 1.146 to 7.929 μg/cm², respectively. Response surface analysis was used to determine the optimum formulation in terms of skin permeation and uptake of MTX.

An optimized cream formulation was developed and compared to a gel formulation containing 3% Azone in hairless mice to evaluate the uptake of MTX in the treated and untreated skin sites as well as the distribution of MTX in the blood and liver following topical application. The results of the in vivo study demonstrated the localization of MTX at the treated site for both formulations without significant uptake of MTX in the distant untreated epidermis and dermis. The levels of MTX in the blood and liver following topical application of the optimized cream were significantly less than those of the gel formulation with 3% Azone.     

The In Vitro and In Vivo Performance of Aqueous Bases Enteric Coats of Neutralised Hydroxypropyl Methyl Cellulose Phthalate

Prednisolone tablets, enteric coated with neutralised hydroxypropyl methylcellulose phthalate (HPMCP) were compared with Deltacortril tablets (Pfizer) by compendial in vitro testing and a pharmacokinetic study in 12 volunteers. Despite satisfactory compliance for both products with the specifications for enteric products of the European Pharmacopoeia and the United States Pharmacopoeia a significant difference in lag time before prednisolone was detected in plasma was observed between the products and only the Deltracortril tablet was concluded to exhibit true enteric properties

The failure of the neutralised HPMCP coating probably results from incomplete gastric conversion to its acidic form due to the majority of subjects having gastric pH values in excess of those stipulated in the compendial in vitro tests. Alternative in vitro testing procedures are proposed