Intravaginal Controlled Administration of Flurogestone Acetate: (III) Development of Rate-Control Vaginal Devices

A Rate-Control vaginal device was developed which overcomes the low bioavailability and unpredictable Q - t^1/2 type release and absorption rate profiles of flurogestone acetate delivered by the currently marketed Syncro-Mate pessary.

The in vitro release and vaginal absorption profiles from the Rate-Control vaginal device were run simultaneously, a linear Q - t relationship was obtained with a significant improvement in bioavailability. A mathematical model was developed to correlate the in vitro drug release and the vaginal absorption profiles of flurogestone acetate from the vaginal devices.

The design, development and the simultaneous release and absorption profiles of flurogestone acetate from this new vaginal device were outlined and discussed.     

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

Abstract

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.     

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.     

Mucosal Delivery of Progestational Steroids from a Controlled Release Device: In-Vitro/In-Vivo Relationships

Abstract

The mucosal delivery of progestational steroids from a model controlled release device was studied using female New Zealand White rabbits as the animal model. A controlled release device was developed which was suitable for nasal, rectal and vaginal application. The in-vitro permeation and in-vivo absorption of progesterone from the model controlled release device was investigated through the nasal, rectal and vaginal mucosa. The influence of penetrant hydrophilicity on the in-vitro permeation and in-vivo absorption from the controlled release device was also investigated using the mono-hydroxy, di-hydroxy and tri-hydroxy derivatives of progesterone. The results indicate that the nasal route demonstrates a significantly higher rate of in-vitro permeation and extent of in-vivo absorption than the rectal and vaginal mucosa. The in-vitro permeation rates and steady-state plasma concentrations achieved from the device tend to decrease with increasing penetrant hydrophilicity. A linear in-vitro/in-vivo correlation was obtained for all the mucosa studied. The slope of the relationship between the in-vitro and in-vivo data was similar for the rectal and vaginal mucosa. The results of this investigation agree with the results of a previous investigation with a solution formulation, and suggest that the hydrodynamic and/or membrane barrier properties of the nasal mucosa may from that of the rectal and vaginal mucosa.     

Testing of Drug Release from Bioadhesive Vaginal Tablets

Abstract

To establish en in vitro test method that can predict the drug release and dissolution behaviour of vaginal bioadhesive controlled release tablets, a system was developed and its appropriateness to the in situ conditions was examined. For this purpose, the dissolution rates of vaginal bioadhesive tablets were measured by three different methods. These were, USP dissolution apparatus two and a new vaginal dissolution tester (NVDT) which was developed by us with some modification of the vaginal tablet desentegration apparatus of BP 1988 and, testing in cow vaginas in situ. Four different bioadhesive tablet formulations were used being composed of the drug and the anionic polymer, polyacrylic acid (PAA) and the nonionic polymers, hydroxypropylmethyl cellulose (HPMC) and ethyIcellulose (EC). The release profiles of the in vitro and in situ methods were investigated and evaluated kinetically.

It was found that NVDT could be used to investigate the drug release from vaginal tablets.     

Subcutaneous Controlled Delivery of Estradiol by Compudose° Implants: in Vitro and in vivo Evaluations

Abstract

The in vitro and in vivo releases of estradiol from the recently marketed Compudose°-200 and -400 implants were evaluated. These subdermal implants are designed for subcutaneous controlled administration of estradiol in steers for 200- or 400-day growth promotion.

Analysis of the in vitro release profiles of estradiol from Compudose implants indicated that the release of estradiol is under a matrix diffusion-controlled process and follows a linear Q vs. t^1/2 relationship.

The release flux from both Compudose-200 and -400 implants was found to be dependent upon the volume fraction of polyethylene glycol 400, which acts as the solubilizer for estradiol, in the aqueous elution solution.

Subcutaneous release of estradiol from Compudose implants was also conducted in laboratory rats for a duration of up to 114 days. Results indicated that the Q vs. t^1/2 linearity is also followed. The subcutaneous rate of release was calculated to be 520 mcg/cm²/day^1/2 for Compudose-200 and 360 mcg/cm²/day^1/2 for Compudose-400.     

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 (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.     

Mucoadhesive tablets for the vaginal delivery of progesterone: in vitro evaluation and pharmacokinetics/pharmacodynamics in female rabbits

Objective: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism.

Methods: The tablets were prepared using mixtures of P4/Pluronic^® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively.

Results: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (～25%) during the first 2?h but sustained the drug release for ～48?h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ～2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection.

Conclusion: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.     

Long-Term Permeation Kinetics of Estradiol: (V) Development and Evaluation of Transdermal Bioactivated Hormone Delivery System

Abstract

Based on the results of simultaneous skin permeation and bioconversion profiles, a Transdermal Bioactivated Hormone Delivery (TBHD) System was developed from the microreservoir partition-controlled drug delivery technology for the transdermal controlled delivery of estradiol prodrugs.

Using the in vitro skin permeation apparatus developed earlier, the kinetics of release and skin permeation of estradiol prodrugs from the TBHD system and the regeneration of estradiol were simultaneously studied. Results indicated that all prodrugs are totally converted by the esterase to estradiol during the course of skin permeation.

The release rate of estradiol was found to be first enhanced by the esterification of the OH groups at 3- and 17-position and then decreased as the alkyl chain length increased.

The rate of regeneration of estradiol from the prodrugs was found to follow the order of: diacetate > valerate > heptanoate > acetate > cypionate.     

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

Abstract

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     

Dissolution of Suppositories III: Effect of Insoluble Polyvinylpyrrolidone on Acetaminophen Release

Abstract

Previously reported studies from this laboratory have demonstrated the usefulness of a new apparatus for suppository dissolution study. Acetaminophen suppositories gave slow release and it was posited that addition of a disintegrating agent commonly used in tablet manufacture would increase this release rate. To test the hypothesis, four PEG blends were used as bases as in the previous studies. Each contained 320 mg acetaminophen and 1%, 5%, or 10% of insoluble polyvinylpyrrolidone (Polyplasdone XL^R). One thousand milliliters of phosphate buffer, pH 8.0 to approximate rectal pH was employed as the dissolution media and maintained at 37.5°. A constant agitation rate of 2 5 and 50 rpm was used. Acetaminophen was assayed spectrophotometrically at 243 nm. Comparative dissolution profiles at the various agitation rates and with the concentrations of polyvinylpyrrolidone were developed. Addition of insoluble polyvinylpyrrolidone increased the dissolution rate constant and dissolution half-times at the two agitation rates. While the disintegration aid increased release, this release was not linear with respect to disintegrating agent concentration.

Release of acetaminophen from suppositories and the bioavailability of acetaminophen Erom suppository bases have not received much study. Feldman reported that the rate of bioavailability of suppositories was extremely variable and might not produce a clinically noted response (1). Maron and Ickes, however, reported that acetaminophen suppositories were clinically as effective an antipyretic as were tablets (2).

Pagay, et al. studied the influence of the vehicle on the bioavailability of acetaminophen suppositories using a modified beaker method with a media of pH 7.0 and an agitation of 25 rpm (3). These researchers correlated the dielectric constant of the base to acetaminophen bioavailability. Commercial suppositories were not discussed.

A recent report by Palmieri (4) discussed release of acetaminophen from laboratory prepared PEG bases and commercially available suppositories. Dissolution half-times for laboratory prepared suppositories at 50 rpm ranged from 8 minutes for Base A to 22 minutes for Base D. The commercially available acetaminophen suppositories had a dissolution half-time of 90 minutes at 50 rpm. Because of these apparently slow release rates, it was posited that addition of a disintegrating agent would increase the release of acetaminophen from the polyethylene glycol base sup-positores. Polyplasdone XLR, (5) a crosslinked insoluble homopolymer of n-vinyl-2-pyrrolidone was used in an attempt to increase the release rate.     

Oral controlled drug delivery systems based on microporous polymers

Abstract

Microporous polypropylene (PP) powder shows excellent properties for tabletting. Oral controlled release delivery systems were made by simply blending with drug and compressing to make both matrix and coated tablets. To prevent wetting problems and food interactions, sodium lauryl sulphate (SLS) was adsorbed prior to tabletting on the surface of the microporous PP. In order to reveal possible dosage form-food interactions a new and simple food interaction model (slight modification of the USP XX paddle method) is proposed to standardize both in vitro and in vivo testing procedures. The PP coated oxprenolol tablets show no food interactions when tested in vitro in the food simulation mixture. The same liquid food was used in the in vivo study. The PP coated oxprenolol tablets were given to six male volunteers with and without the food. The absorption profiles, which were calculated by numerical deconvolution, showed hardly any food interactions in vivo. The absolute bioavailability at 12 hours was 38±19% on an empty stomach and 37±20 for the food experiment. The developed coated tablets are able to control the release of oxprenolol at least 12 hours both with and without concomitant food intake. Their bioavailability is comparable to different OROS formulations of oxprenolol controlled release systems based on microporous PP are not only highly effective ones but also low cost formulation products.     

Fast- and Slow-Release Tablets for Oral Administration of Flavonoids: Rutin and Quercetin

ABSTRACT

Many derivatives of rutin (Rt) and its metabolite quercetin (Q) are employed in clinics for cardiovascular chronic pathology, and are also known for their antiulcer behavior in vivo and antiproliferative and antimutagenic activity in vitro. Unfortunately, the absorption of quercetin and rutin from the gastrointestinal tract is slow and irregular, probably due to their very slight solubility in water and slow dissolution rate.

In this work the dissolution rate of the drugs from oral formulations has been improved using some enhancers such as cross-linked sodium carboxymethylcellulose (CMC-XL), sodium carboxymethylstarch (E), and cross-linked polyvinylpyrrolidone (P). The drugs were loaded on the hydrophilic carriers by different techniques such as mixing or co-milling. The in vitro dissolution profiles of the mixed or co-milled drug/polymer systems, obtained in various media with different pH, were compared. The results show that the drug dissolution rate from the co-milled drug/carrier systems is faster than that from mixed systems, and CMC-XL and sodium carboxymethylstarch systems are able to enhance the dissolution rate. For this reason, these co-milled drug/carrier systems were used for the production of both fast- and slow-release tablets. The co-milled drug/CMC-XL system was used for the preparation of fast-release tablets containing rutin, while three different fast-release tablets were formulated and tested using respectively Q/CMC-XL, Q/E, and Q/P co-milled systems.

The effect of the presence of sodium lauryl sulfate in the aqueous medium on the dissolution profile of flavonoids alone was also studied.

The prolonged-release formulations have been developed using hydroxypropylmethylcellulose (HPMC) of different viscosity grades as retarding polymer. An extended release of the drugs for times ranging from 6 to 14 hr could be obtained, depending on the type and viscosity of the HPMC used.     

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state

Objective: The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs).

Methods: The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control.

Results: The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5?min. Pharmacokinetic study showed that the AUC_(0–∞) and C_max for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption.

Conclusion: It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.     

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

Abstract

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%.     

The influence of tablet density on the human oral absorption of sustained release acetaminophen matrix tablets

Abstract

Low density bilayer compressed matrix tablets of acetaminophen were tested for in vitro dissolution and in vivo oral absorption. The upper layer contained a carbon dioxide-generating blend and the lower layer contained hydroxypropyl methylcellulose (HPMC) and acetaminophen. Carbon dioxide liberated by the action of the acidic dissolution medium on the upper layer is entrapped in the gelled hydrocolloid, providing buoyancy of the tablet and sustained release of the drug. For comparative purposes, similar but non-gas generating bilayer compressed matrix tablets were formulated and tested in vitro under the same conditions. These high density tablets were found to yield similar dissolution profiles as the low density tablets. The absorption characteristics of the bilayer compressed matrix tablets were compared with those of rapidly disintegrating acetaminophen tablets (TYLENOL® tablets, 500 mg) under fasted and fed conditions in six healthy subjects. Under fasted conditions, saliva profiles showed a rapid absorption for TYLENOL tablets but slower absorption for both compressed matrix tablets. Saliva profiles of TYLENOL® tablets under fed conditions were similar to those for the fasted case. In contrast, the peak saliva levels of acetaminophen for both compressed matrix tablets were significantly increased under fed conditions. The time to maximum saliva concentrations (Tmax) of all three dosage forms was not significantly affected by food intake. The relative bioavailability of the low density tablets under fasted and fed conditions was not significantly different from those of TYLENOL tablets, but vas significantly greater than that of high density tablets under fasted and fed conditions. A possibility exists that the buoyancy mechanism enabled the tablet to maintain more prolonged residence time in the gastrointestinal tract.     

Release Characteristics and Bioavailability of Norfloxacin from Suppository Bases

Abstract

The in vitro release of norfloxacin (a new broad spectrum antimicrobial agent whose pharmacokinetics are characterised by varied gastrointestinal absorption and irregular plasma level) from different suppository bases was studied in order to obtain suitable formulation with good release and satisfactory drug concentrations in plasma. The bioavailability of suppositories containing 200 mg drug made from the bases that showed the best in vitro release was investigated. The release rate was in the order of PEG 400, 1540, 4000 mixture in ratio of 20: 33: 47 respectively > Witepsol H1S > Witepsol W 35 > Witepsol E 75. Addition of Tween 20, Tween 80 and Myrj 45 to the Witepsol members greatly increased the release rate especially at surfactant concentration of 5 × 10 mol.g. of the drug.     

Development of a Transdermal Delivery Device for Melatonin In Vitro Study

Abstract

The present study was undertaken to develop a transdermal delivery device for melatonin and to determine the effects of system design on the release of melatonin. Melatonin(MT) diffusion characteristics from 2 solvents through a series of ethylene vinyl acetate membranes with 4.5%, 9%, 19%, 28% vinyl acetate were characterized using vertical Franz® diffusion cells. The solvent used were 40% (v/v) propylene glycol (PG) and 40%(v/v) propylene glycol with 30%(w/v) 2-hydroxypropyl-β-cytrodextrin. The best release rate (Jss = 0.795 μg/h/cm²) was obtained from the 40% PG vehicle through the 28% vinyl acetate membrane. Melatonin diffusion through this membrane with an acrylate pressure sensitive adhesive (PSA) with and without MT loading was also studied. The data revealed an interaction between MT and the PSA in the systems with MT-loaded adhesive. A MT transdermal delivery device was constructed based on the above data. Effect of storage time (1 day, 2 days, and 3 days) on the developed device was also investigated. Steady state flux values of MT did not vary significantly with storage time (p-value = 0.14). The steady state flux was 1.88 ± 0.6 μg/hr/cm²(n = 9). However, storage time did affect the burst effect of MT. Total amount of MT released in the first hour was 137.4 ± 25.7 μg after 3 days, 61.5 ± 8.9 μg after 2 days, and 43.8 ± 20.9 μg after 1 day.     

Development of Sustained-Release Tablets Containing Sodium Valproate: In Vitro and In Vivo Correlation

ABSTRACT

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.