Enhanced Release of Drugs from Silicone Elastomers (III): Subcutaneous Controlled Administration of Melatonin for Early Onset of Estrus Cycles in Ewes

Abstract

Implants were fabricated from swellable silicone elastomers to release hydrophilic melatonin at a controlled rate for the early induction of breeding season in ewes. Both the in vitro and in vitro release profiles of melatonin were observed to follow a linear Q vs. t^1/2 relationship. The in vitro/in vivo release flux ratio ranging from 0.415 to 1.452 was obtained depending upon the polyethylene glycol 400 concentration in the aqueous release medium used for in vitro studies. The release flux (Q/t^1/2) of melatonin from the implants was observed to increase as a function of the glycerol content in the silicone elastomers. When the ewes were treated with subdermal implants containing 25% w/w of melatonin for up to 49 days, blood melatonin levels above the target level of 450-900 pmole/1 were achieved and maintained for at least 35 days.     

Enhanced Release of Drugs from Silicone Elastomers (III): Subcutaneous Controlled Administration of Melatonin for Early Onset of Estrus Cycles in Ewes

Implants were fabricated from swellable silicone elastomers to release hydrophilic melatonin at a controlled rate for the early induction of breeding season in ewes. Both the in vitro and in vitro release profiles of melatonin were observed to follow a linear Q vs. t^1/2 relationship. The in vitro/in vivo release flux ratio ranging from 0.415 to 1.452 was obtained depending upon the polyethylene glycol 400 concentration in the aqueous release medium used for in vitro studies. The release flux (Q/t^1/2) of melatonin from the implants was observed to increase as a function of the glycerol content in the silicone elastomers. When the ewes were treated with subdermal implants containing 25% w/w of melatonin for up to 49 days, blood melatonin levels above the target level of 450-900 pmole/1 were achieved and maintained for at least 35 days.     

Enhanced Release of Drugs from Silicone Elastomers (I) Release Kinetics of Pineal and Steroidal Hormones

Abstract

The release of melatonin, estradiol, and flourogestone acetate from subdermal implants was enhanced when implants were fabricated from silicone elastomers containing co-solvents. This enhancement followed a Q vs. t relationship. As glycerol concentration increased, the increments in release rate were greater for hydrophilic drugs than for hydrophobic drugs. When drug loading in the implants was held constant, release rates were found to be a function of glycerol concentrations in the device. A synergistic enhancement of release rate was observed when both glycerol and sodium chloride were added to the silicone matrix. The fact that co-solvents enhance the rate of drug release from silicone elastomers indicates that a reduction in the activation energy required for drug release may occur.     

Enhanced Release of Drugs from Silicone Elastomers (I) Release Kinetics of Pineal and Steroidal Hormones

The release of melatonin, estradiol, and flourogestone acetate from subdermal implants was enhanced when implants were fabricated from silicone elastomers containing co-solvents. This enhancement followed a Q vs. t relationship. As glycerol concentration increased, the increments in release rate were greater for hydrophilic drugs than for hydrophobic drugs. When drug loading in the implants was held constant, release rates were found to be a function of glycerol concentrations in the device. A synergistic enhancement of release rate was observed when both glycerol and sodium chloride were added to the silicone matrix. The fact that co-solvents enhance the rate of drug release from silicone elastomers indicates that a reduction in the activation energy required for drug release may occur.     

Enhanced Release of Drugs from Silicone Elastomers (II): Induction of Swelling and Changes in Microstructure

Incorporation of glycerol into silicone elastomers was found to enhance the release of hydrophilic drugs as well as to cause the polymeric device to swell as a result of water uptake. There are similarities between the kinetics of drug release from the matrix of silicone elastomers and the kinetics of swelling, water uptake, and leaching of tritiated glycerol, in that they all follow a matrix diffusion-controlled mechanism. The results of absorption, desorption, and resorption kinetic studies suggest that the two processes of swelling and water uptake are reversible. The amount of glycerol which leached out from devices containing up to 20% glycerol was only 4 → 10^-4 to 6 → 10^-4% of the amount of glycerol that had been originally incorporated into the device. A scanning electron microscopic examination of a silicone device containing glycerol revealed a microstructure in which glycerol vesicles are dispersed. In contrast to this, the matrix of a silicone device containing no glycerol was shown to be a continuous network. The microstructure of a glycerol-containing silicone device became more “spongy” after leaching than it was before leaching.     

Enhanced Release of Drugs from Silicone Elastomers (II): Induction of Swelling and Changes in Microstructure

Abstract

Incorporation of glycerol into silicone elastomers was found to enhance the release of hydrophilic drugs as well as to cause the polymeric device to swell as a result of water uptake. There are similarities between the kinetics of drug release from the matrix of silicone elastomers and the kinetics of swelling, water uptake, and leaching of tritiated glycerol, in that they all follow a matrix diffusion-controlled mechanism. The results of absorption, desorption, and resorption kinetic studies suggest that the two processes of swelling and water uptake are reversible. The amount of glycerol which leached out from devices containing up to 20% glycerol was only 4 → 10^?4 to 6 → 10^?4% of the amount of glycerol that had been originally incorporated into the device. A scanning electron microscopic examination of a silicone device containing glycerol revealed a microstructure in which glycerol vesicles are dispersed. In contrast to this, the matrix of a silicone device containing no glycerol was shown to be a continuous network. The microstructure of a glycerol-containing silicone device became more “spongy” after leaching than it was before leaching.     

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

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.     

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.     

Development of a New Controlled Release Theophylline Tablet: In Vitro and in Vivo Studies

Five formulations of controlled release theophylline tablets, specially shaped to a multi scored approximately rectangular structure, manually dividable accurately and conveniently into bisectional or trisectional subdosage units were prepared, using ethyl cellulose/hydroxypropylcellulose and Eudragit RL. The influence of two parameters (fillers, granulation) on the dissolution rate of all tablets was studied. It was found that granulation yields greater retardation in dissolution rate, in comparison to direct compression. No significant differences were found among the fillers used, concerning the dissolution rate.     

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

Abstract

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.     

Development of a New Controlled Release Theophylline Tablet: In Vitro and in Vivo Studies

Abstract

Five formulations of controlled release theophylline tablets, specially shaped to a multi scored approximately rectangular structure, manually dividable accurately and conveniently into bisectional or trisectional subdosage units were prepared, using ethyl cellulose/hydroxypropylcellulose and Eudragit RL. The influence of two parameters (fillers, granulation) on the dissolution rate of all tablets was studied. It was found that granulation yields greater retardation in dissolution rate, in comparison to direct compression. No significant differences were found among the fillers used, concerning the dissolution rate.     

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.     

Intravaginal Controlled Administration of Flurogestone Acetate: (IV) In Vitro - In Vivo Correlation for Intravaginal Drug Delivery from Rate-Control Vaginal Pessary

One hundred fifty sheep received various types of Rate-Control vaginal pessaries for a period of up to 19 days at various geographic locations. As predicted from the in vitro studies, a constant (Q - t) absorption profile was also observed in in vivo. The effect of the loading dose of flurogestone acetate on the in vitro and in vivo absorption profiles were examined and minimum effective loading dose was determined. An excellent the prediction of the long-term (19-day) in vivo absorption profiles from a short-term (3-day) in vitro absorption study.     

Preparation and in Vitro Evaluation of Controlled Release Dosage form of Indomethacin

A controlled release oral drug delivery system of Indomethacin was developed using gelatin as the matrix system, which was rigidized with different concentrations of formalin, without using alcohol. The proportion of drug and gelatin as well as the concentration of formalin had the pronounced effect on the Indomethacin release rate and the patterns of which depicted that they correlated with Lang primary requirements for drug release from controlled release dosage forms. All the types of formulations showed release rate patterns that could best be described by First Order Kinetics, indicating that First Order release was mainly operative.     

Preparation and in Vitro Evaluation of Controlled Release Dosage form of Indomethacin

Abstract

A controlled release oral drug delivery system of Indomethacin was developed using gelatin as the matrix system, which was rigidized with different concentrations of formalin, without using alcohol. The proportion of drug and gelatin as well as the concentration of formalin had the pronounced effect on the Indomethacin release rate and the patterns of which depicted that they correlated with Lang primary requirements for drug release from controlled release dosage forms. All the types of formulations showed release rate patterns that could best be described by First Order Kinetics, indicating that First Order release was mainly operative.     

In Vitro and in Vivo Release of Salicylic Acid from Povidone/Polydimethylsiloxane Matrices

Povidone (PVP)/Polydimethylsiloxane (PDMS) matrices were evaluated as drug delivery devices. PVP was utilized as a hydrophilic component to alter drug release. Salicylic acid was employed as a model drug substance.

Discs were prepared by placing the blended ingredients into a mold and allowing PDMS to cross-link at room temperature. The experimental formulations were evaluated for salicylic release via in vitro and in vivo experiments. In vitro experiments were conducted by USP Method II. In vivo release was determined by monitoring salicylate depletion after subdermal implantation. In vitro and in vivo release rate of salicylic acid was found to be proportional to PVP concentration. All release rate curves displayed t^1/2relationships for at least 75% of the total release period. Mouse survival was related to salicylic acid release rate.     

In Vitro and In Vivo Release of Naltrexone from Biodegradable Depot Systems

ABSTRACT

The aim of this study was to prepare poly(d, l-lactide) (PLA) microspheres containing naltrexone (NTX) by a solvent evaporation method, and to evaluate both in vitro and in vivo release characteristics and histopathological findings of tissue surrounding an implant formulation in rats.

This method enabled the preparation of microspheres of regular shape and relatively narrow particle size distribution. The in vitro release profiles of NTX from PLA microspheres showed the release of NTX did not follow zero-order kinetics. An initial burst release was observed, subsequently followed by a nearly constant rate of 0.4% per day after ten days. The cumulative amount of NTX released at the end of 60 days was 80%. Compressed microspheres showed near zero-order sustained release of NTX for 360 days. The plasma NTX levels in rats showed that for compressed microspheres NTX concentrations were constant and exceeded 2 ng/mL for 28 days. Throughout the 28 days of study, the implantations cause a minor inflammatory response, which can be regarded as a normal defence mechanism. The sustained release performance of NTX from the biodegradable depot systems may provide a reliable, convenient, and safe mechanism for the administration of NTX for the long-term treatment of opioid dependence.     

A Flow-Through Dissolution Approach to In Vivo/In Vitro Correlation of Adinazolam Release from Sustained Release Formulations

Abstract

A Copley? fraction collector and a Disotest? flow-through system were coupled to provide an automatic discrete sampling flow-through dissolution system for use both in the “open-loop” and “closed-loop” mode. The system was used to investigate the release characteristics of adinazolam in sustained release formulations using a pH 1.2 simulated gastric fluid (without enzymes) dissolution medium (USP XXI). These experimental formulations are designed to provide relatively slow to rapid drug release. The dissolution effluent was analysed off-line by reverse phase HPLC to determine the adinazolam concentration at programmed timed intervals. The differential dissolution profiles produced when the system is used in the “open-loop” configuration are more discriminating in describing the release characteristics of the formulations according to the relative release rates than the “closed-loop” cumulative profiles. Using the characteristic dissolution time parameter from the Weibull function, a better correlation with in vivo bioavailability data was achieved for the data from the system in the “open-loop” mode than when it was used in the “closed-loop” mode. In the “open-loop” mode the Weibull function characteristic dissolution time parameter yielded the best quantitative correlation with a correlation coefficient of 0.92 compared to a value of 0.85 for the “closed-loop” configuration     

A Flow-Through Dissolution Approach to In Vivo/In Vitro Correlation of Adinazolam Release from Sustained Release Formulations

A Copley^TM fraction collector and a Disotest^TM flow-through system were coupled to provide an automatic discrete sampling flow-through dissolution system for use both in the “open-loop” and “closed-loop” mode. The system was used to investigate the release characteristics of adinazolam in sustained release formulations using a pH 1.2 simulated gastric fluid (without enzymes) dissolution medium (USP XXI). These experimental formulations are designed to provide relatively slow to rapid drug release. The dissolution effluent was analysed off-line by reverse phase HPLC to determine the adinazolam concentration at programmed timed intervals. The differential dissolution profiles produced when the system is used in the “open-loop” configuration are more discriminating in describing the release characteristics of the formulations according to the relative release rates than the “closed-loop” cumulative profiles. Using the characteristic dissolution time parameter from the Weibull function, a better correlation with in vivo bioavailability data was achieved for the data from the system in the “open-loop” mode than when it was used in the “closed-loop” mode. In the “open-loop” mode the Weibull function characteristic dissolution time parameter yielded the best quantitative correlation with a correlation coefficient of 0.92 compared to a value of 0.85 for the “closed-loop” configuration     

In Vitro Topographical Characterization as a Predictor of in Vivo Controlled Release Quinidine Gluconate Bioavailability

The pH dissolution profiles and bioavailability data of six quinidine gluconate controlled release products were obtained, and attempts were made to identify a dissolution condition that is most indicative of in vivo bioavailability. This was achieved by graphically displaying the pH dissolution profiles of the six products in multi-dimensional graphs utilizing a topographical plotting technique. These graphs were found to be quite effective in illustrating: a) the effects of pH and buffer composition on the dissolution rate of the test products, and b) the in vitro condition that best correlates with in vivo data. It was found that for the quinidine gluconate controlled release dosage forms studied, dissolution carried out in pH 5.4 phosphate buffer was most meaningful in showing the differences among dosage forms and for predicting in vivo bioavailability