In Vitro-In Vivo Correlation of Indomethacin Release from Prolonged Release W/O/W Multiple Emulsion System

A prolonged release oral w/o/w multiple emulsion was formulated using hydroxypropyl methyl cellulose as thickening agent. The polymer when used in different proportions, controlled indomethacin release from the biphasic emulsion system. Double emulsification technique was used for formulation of the biphasic emulsion system. The stability of the emulsion was found to be inversely proportional to the drug release characteristics. The in vitro release of indomethacin followed diffusional path through the oil layer and through the polymeric oil. The in vivo release studies were carried out using rabbits as animal models. A good linear correlation was obtained between in vivo-in vitro drug release from such multiple emulsion system.     

Prolonged Release of Tegafur from S/O/W Multiple Emulsion

Abstract

To develop a prolonged and sustained release preparation, we prepared an albumin microsphere-in-oil-in-water emulsion (S/O/W) and examined sustained release from it in comparison with other control preparations such as water-in-oil (W/O) emulsions and microspheres in vitro and in vivo, respectively. Tegafur was used as a model drug. A microsphere-in-oil emulsion was prepared by adding albumin microspheres to soybean oil containing 20% Span 80. To prepare an S/O/W emulsion, the microsphere-in-oil emulsion was added into an aqueous solution of hydroxypropyl methylcellulose containing Pluronic F68. The mean particle size of the albumin microspheres was 3 µm, and the ratio of entrapment of tegafur into albumin microspheres was about 25%. In an in vitro release test, the t₇₅ of the S/O/W emulsion was fourfold greater and in an in vivo release test the mean residence time of tegafur from the S/O/W emulsion was more than twofold that from a W/O emulsion or microsphere system. The mean residence time of 5-fluorouracil (5-FU) from an S/O/W emulsion was also greater than with other dosage forms. These results suggest the possible usefulness of an S/O/W emulsion for the sustained and prolonged release of tegafur.     

Effect of Oil Phase Lipophilicity on In Vitro Drug Release from O/W Microemulsions with Low Surfactant Content

ABSTRACT

In this work we investigated the effects of oil phase lipophilicity on in vitro drug release from topical o/w microemulsions (MEs) containing low percentages of emulsifiers. Three different lipids, isopropyl myristate (IPM), isopropyl palmitate (IPP), and isopropyl stearate (IPS), whose lipophilicity increased in the order IPM < IPP <IPS, were used as oil phase to prepare o/w MEs containing low amounts (7.7% w/w) of two surfactant/cosurfactant mixtures, isoceteth-20/glyceryl oleate (5:2) (MEs 1–3) and oleth-20/glyceryl oleate (5:2) (MEs 4–6). All the MEs were prepared using the phase inversion temperature (PIT) method.

Three active compounds (0.5% w/w), Naproxen (NAP), Idebenone (IDE), and Butylmethoxydibenzoylmethane (BMBM), were selected as model drugs and their release rates from PIT MEs were evaluated using Franz-type diffusion cells. All the MEs gave a mean droplet diameter ranging from 28 to 44 nm and showed a single peak in size distribution. The addition of IDE to MEs 1–6 did not significantly change ME droplet size. On the contrary, an increase of the droplet size beyond the ME limit (150 nm) was observed when isoceteth-20 was used as surfactant to prepare MEs containing NAP or MEs containing BMBM and IPS as oil phase. Pseudo-first order release rates were observed only for NAP from MEs 1–3, while MEs containing IDE showed an initial slow release followed by an increased release of the test compound. The release rate constants were found to be dependent on the ME composition and on the active compound incorporated. The highest release rate was observed from ME 1 containing IPM as oil phase and NAP as drug. As regards BMBM, its release rate was not calculated since no release was observed until 6 h from the beginning of the experiment. The cumulative amount of active compound released after 22 h was inversely related to drug lipophilicity (NAP Log P = 2,9; IDE Log P 3,5; BMBM Log P 4,8). These findings could be attributable to a reduced thermodynamic activity of the drugs in the vehicles containing the most lipophilic oil phase due to an increase of drug solubility which could lead to an unfavorable drug partition from the oil phase. The results of this study suggest that the choice of proper combinations of oil phase lipids and emulsifiers may allow achieving drug controlled delivery from topical o/w MEs with low emulsifier content.     

Release of Methotrexate from Microsphere-In-Oil-In-Water Emulsions

Abstract

The in vivo and in vitro release characteristics of methotrexate from the microsphere-in-oil-in-water emulsions were studied. The results demonstrated a rapid and slow biphasic release profiles for the emulsions. This may be due to the release of methotrexate from the external aqueous phase of the emulsion for the rapid release phase and from the internal microsphere for the slow release phase. The addition of phosphatidylcholine in the emulsions resulted in a slower release of the methotrexate which may be caused by the formation of phospholipid layers on the surface of the emulsion particles to hinder the release of the drug from the emulsions.     

Dissolution Controlled Drug Release from Agarose Beads

Abstract

A simple method was used for loading ibuprofen or indomethacin into agarose beads to obtain sustained release. Placebo beads were prepared by a dropwise addition of a hot aqueous agarose solution into a beaker of chilled mineral oil and water. Prior to loading, the aqueous component in the beads was replaced by repeated soakings in ethanol. Loading was accomplished at room temperature using ethanolic drug solutions. Upon drying, the beads shrank to about a third of their original size. The surface morphology of dried placebo and loaded beads was studied using electron microscopy. The release time at 37° C and pH 7.5 increased with drug loading and at 50% loading the release time was 4 hours for indomethacin and 6 hours for ibuprofen. Release of chlorpheniramine from dried and swollen beads was examined to elucidate the release mechanism. From dissolution studies it was concluded that the delay due to swelling is less than 10 minutes, chlorpheniramine release from swollen beads was primarily diffusion controlled, and the release mechanism for indomethacin and ibuprofen has three components: i) swelling of the beads, ii) dissolution of crystallized drug, and iii) diffusion of dissolved drug from the beads.     

Enhanced Release of Drugs from Silicone Elastomers: (IV) Subcutaneous Controlled Release of Indomethacin and in Vivo/In Vitro Correlations

Abstract

The subcutaneous controlled release of indomethacin from implants was studied. The subderraal implants were prepared from silicone elastomers containing various levels of glycerol. The in vitro and in vivo releases of indomethacin were observed to follow a matrix diffusion-control mechanism. The release flux of indomethacin was enhanced when glycerol was incorporated into the silicone elastomers. An in vivo/in vivo correlation coefficient of 0.85 (< 0.05) was obtained for implants containing up to 20% (w/w) of glycerol. The survival rates on the ninth day post-implantation were determined to be 20, 65, and 100%, respectively, for the mice receiving implants containing 20, 10, and 0% glycerol. An LD₅₀ dose of 34 mg/kg was assessed for the subcutaneous controlled administration of indomethacin in CD-1 mice, which is not significantly different from the intraperitoneal LD₅₀ of 28 mg/kg and the intravenous LD₅₀ of 40 mg/kg.     

Medicament Release from Ointment Bases: I. Indomethacin. In Vitro and in Vivo Release Studies

Abstract

The in vitro release of indomethacin from 1%, 3%, and 5% indomethacin ointments and its in vivo absorption through the skin of rabbits was investigated. The in vitro release of indomethacin followed zero-order kinetics and was better from an absorption base ointment. No significant differences (F=3.047 and P=0.079 for the absorption base) and (F=2.15 and P=0.14 for the hydrophilic base) in the release rate of indomethacin in 1%, 3%, and 5% indomethacin ointments were observed. Indomethacin was most effectively absorbed from absorption ointment bases. A correlation between the in vitro release and the in vivo absorption was found; also, a correlation between the in vivo release pattern of the bases used and the in vivo data reported in the literature was observed.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

Abstract

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.     

Prolonged Tissue Levels of Pentazocine from Multiple W/O/W EMULSIONS IN MICE

Abstract

Multiple W/O/W emulsions containing pentazocine were prepared and tested in virto and in viro. The in viro results indicated a well controlled and higher drug release from teh W/O/W emulsions than the W/O emulsion. The in vivo data showed prolonged tissue levels of pentazocine after oral administration of W/O/W emulsions than the W/O emulsion to mice in comparison to acquenous drug solution and W/O emulsion.     

Entrapment of Phenytoin into Microspheres of Oleaginous Materials: Process Development and in Vitro Evaluation of Drug Release

Abstract

A novel multiparticulate preparation of the antiepileptic agent phenytoin (1) was developed and evaluated in vitro. The preparation consists of gastroresistant microparticulate drug delivery system formulated with oleaginous material (lipospheres) to minimize unwanted effects of l on gastric apparatus. The drug was dispersed in a spherical micromatrix consisting of a mixture of stearyl alcohol and glycerol esters of various fatty acids. The best mixture to obtain discrete, reproducible, free-flowing lipospheres consisted of glyceryl monostearate dilaurate and stearyl alcohol (ratio 3: 17). The lipospheres were obtained by a technique involving melting and dispersion of drug-containing oleaginous material in aqueous medium. The oily droplets of the resulting emulsion after cooling under rapid stirring were transformed into solid. About 99% of the lipospheres were of particle size range 100–800 pm. The lipospheres were analyzed to determine the drug content in various particle sizes and to characterize the in vitro release profile. The average drug content was 23.8% w/w. Drug encapsulation efficiency was about 93.6% and the yield of production ranged from 94 to 98%. The drug discharge pattern from the microparticulate system in the intestinal environment was evaluated. Kinetic results were analyzed to distinguish between various release models. The matrix diffusion-controlled equation was the most appropriate one in describing drug release.     

In-Vitro Release of Acetaminophen from Sodium Alginate Controlled Release Pellets

Abstract

The production of spheres loaded with acetaminophen by the cross linking technique was achieved. The hydrophilic polymer sodium alginate which gels in presence of a cross linking ion was used as a matrix for the spheres production. Two processing variables were studied. The drug load in the formula which varied from 5% w/v to 20% w/v, and the cross linking agents used; calcium chloride, calcium acetate, and aluminum sulfate. Also the effects of the dissolution medium and the rotational speed of the dissolution apparatus on drug release were investigated. Spheres were compacted into 450 mg tablets without the aid of excipients. The drug release from spheres containing 20% w/v drug was 90% after 6 hours, while the drug release from compacts of these spheres was 90% after 12 hours. The mechanism of drug release from spheres and compacts containing 20% w/v drug and prepared with 5% w/v cross linking material     

Effect of Different Binders on Release Characteristics of Theophylline from Compressed Microspheres

Abstract

Microspheres with 60% w/w drug loading were prepared by the solvent-evaporation method using cellulose acetate butyrate as the encapsulating polymer and micronized anhydrous theophylline as the core material. Four different binders - microcrystalline cellulose, glyceryl palmito-stearate, glyceryl stearate and glyceryl behenate were used to compress three different particle sizes of microspheres. Comparison of the in vitro drug dissolution profiles revealed that drug release was fastest from all the microspheres compressed with microcrystalline cellulose as the binder followed by those compressed with glyceryl palmitostearate, glyceryl stearate and glyceryl behenate.     

Carnauba Wax Microspheres Loaded with Valproic Acid: Preparation and Evaluation of Drug Release

Abstract

To minimize unwanted toxic effects of valproic acid (1) by the kinetic control of drug release, gastroresistant carnauba wax microspheres loaded with the antiepileptic agent were prepared. The preparation was based on a technique involving melting and dispersion of drug-containing wax in an aqueous medium. The resulting emulsion after cooling under rapid stirring produced solid, discrete, reproducible free flowing microspheres which converted the liquid drug droplets into solid material. About 94% of the isolated microspheres were of particle size range 200-425 μm. The microspheres were analyzed to determine the drug content in various particle size range and to characterize the in vitro release profile. The average drug content was 26% w/w. The intestinal drug discharge of 1 from the carnauba wax microspheres was studied and compared with the release patterns observed for white beeswax and hexadecanol microspheres previously described. The drug release performance was greatly affected by the material used in the microencapsulation process. In the intestinal environment carnauba wax microspheres exhibited more rapid initial rate of release and about 80% of the entrapped drug was discharged in 120 min while complete release occurred in about 8 h.     

Albumin Microspheres: effect of process Variables on size Distribution and in Vitro Release

Abstract

Albumin microspheres used as target drug delivery systems were prepared from egg albumin by polymerization technique using glutaral dehyde as the cross linking agent. The present study was designed to evaluate the effect of process variables on the nicrosphere size distribution and in vitro drug release. Phase volume ratio and speed of agitation exerted greater influence on the microsphere size distribution whereas the albumin concentration and cross linking time effected only the yield and surface characteristics of the microspheres respectively. Lower phase volume ratios resulted in small and uniform microspheres with smooth surfaces in narrow size range. Speed of agitation exhibited an inverse relationship with size. In vitro release pattern of drug from the microspheres showed a biphasic profile and the release rates were prolonged upon increase in the concentration of cross linking agent and cross linking time.     

Design and Evaluation In Vitro of Controlled Release Mucoadhesive Tablets Containing Chlorhexidine

ABSTRACT

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

A New Ibuprofen Pulsed Release Oral Dosage Form

Abstract

Drug constant release is not always the desired solution for controlled drug administration; some therapeutic situations require consecutive pulses of active principle

A biphasic oral delivery system able to release an immediate dose of therapeutic agent as well as a further pulse of drug after some hours could be interesting

In order to obtain such desired releasing performances, a new system (three layer tablet) has been designed with the following characteristics

- an energy source, able to deliver the two divided doses of drug

- a control element, between the drug layers, able to delay the release of the second dose of drug. This control element acts as a barrier and is made with a mixture of water swellable polymers

- an outer film, which is made of water impermeable polymer, that covers the second dose of drug and the barrier

The new system works through subsequent interactions with aqueous fluids of the three different layers of material in the following order

1 - rapid interaction of the uncoated part of the system, and immediate disintegration of the first dose;

2 - slow interaction of the barrier and its gelation;

3 - interaction of the second drug layer and development of a force able to break the barrier thus promoting the release of the second dose of drug. Preliminary in vivo experiments carried out on this biphasic pulsed release device containing Ibuprofen as a model drug, show two distinct peaks in plasma profiles thus indicating that the in vitro results are in good agreement with the in vivo blood levels     

Design and in Vitro Evaluation of a Controlled Release Drug Delivery System of Sulfasomidine

Abstract

A controlled release oral drug delivery system of Sulfasomidine was developed by spray congealing micropelleting technique using gelatin as the embedding matrix. The pellets were hardened by treating with Formalin-Isopropanol mixture. The in vitro release rate studies of Sulfasomidine from the micropelleted dosage form, revealed that the drug release can be prolonged upto eight hours and not more than 39% of the embedded drug released in the first hour of the in vitro dissolution study. The in vitro release patterns correlated with the reported in vivo studies. The method of formulation was optimized.     

Release of Tolmetin from Carbomw Gel Systems

Abstract

Gel-formulations containing a nonsteroidal anti-inflammatory drug, tolmetin, were prepared using three different carbomers namely, Carbopol? 934, 940 and 941. Effects of cosolvent composition, carbomer type, carbomer concentration and drug concentration on drug release from the gels were analyzed by factorial design. Gels with high aqueous content yielded significantly higher tolmetin release rates than gels with lower aqueous content. Although no significant differences in drug release characteristics were observed between the three carbomer gels, there was a trend in the release profiles; fastest drug release was observed from Carbopol? 941 gels and the slowest drug release was observed from Carbopol? 940 gels. Increasing the carbomer concentration from 1% w/w to 2% w/w had no significant effect on drug release from gel formulations prepared with all the three different types of carbomers. However, increasing the tolmetin concentration in the gels from 1% w/w to 4% w/w resulted in a dramatic increase in drug release. An investigation of the mechanism of drug release from the gels revealed that tolmetin release was diffusion controlled, except at the outset.     

Stability,in-Vitro and in-Vivo Release Studies from Metronidazole Ointments

Abstract

The influence of ointment formulation on the stability, the in-vitro release and the in-vivo absorption through the skin of rabbits was investigated. The choice of the selected ointments has no influence on the drug stability with the exception of an acidified emulsion base. A good correlation between in-vitro release and in-vivo absorption was found revealing that metronidazole was quickly released and effectively absorbed from a polyethylene glycol base.