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

Abstract

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

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

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.     

Dissolution Characteristics of Pharmaceutical Equivalents

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

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

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

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

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

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

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.     

Fast- and slow-release tablets for oral administration of flavonoids: rutin and quercetin

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.     

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.     

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Polymeric Pseudolatices Dispersion Bearing Isosorbide Dinitrate for Transdermal Application

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

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

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

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

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

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

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

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

Cellulose Acetate Trimellitate Microspheres Containing NSAIDS

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

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

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

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

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

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

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

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

In Vitro and in vivo Availability of Spironolactone from Various Oral Preparations

The dissolution rates in vitro and the bioavailability in humans were determined for 6 preparations containing 25 mg spironolactone and 5 preparations containing 100 mg spironolactone. Linear relationships were obtained by pairwise correlation of in vitro parameters with in vivo parameters. The following parameters were used.

In vitro parameters of dissolution:

1. The area under the dissolution-time-curve up to 1 h

2. The fraction of active ingredient dissolved within 20 min.

3. The slope of the dissolution-time-curve at 50 % dissolution

4. The dissolution rate constant

5. The time up to 50 % dissolution of the substance

6. The maximum slope of the dissolution-time-curve

In vivo parameters of bioavailability:

1. The time of maximum plasmaconcentration

2. The area under the plasmaconcentration-time-curve up to 1 h and 2 h after application

3. The quantities of active ingredient excreted in the urine up to 2 h after application

The highest correlation coefficient was found between the areas beneath the dissolution-time-curve and the plasmaconcentration-time-curve up to 1 h each.

No significant correlations were found between the within 1 h dissolved substance and maximum plasma-concentration, the area under the plasmaconcentration-time-curve up to 4 h and 24 h and quantities of active ingredient excreted in the urine up to 4 h after application.     

In Vitro Adsorption of Propranolol Hydrochloride by Various Antacids

The purpose of this study was to investigate by in vitro methods whether an interaction takes place between propranolol hydro-chloride and adsorbents when antacids are taken concomitantly with the beta-blocker or when excipients having adsorbent properties are present in formulations of the drug products containing propranolol hydrochloride.

Specific surface areas of magnesium trisilicate, magnesium oxide, magnesium hydroxide, dihydroxy aluminum sodium carbonate, magnesium carbonate and kaolin were calculated from nitrogen adsorption isotherm using single pint method and it was found. that magnesium trisilicate has the largest specific surface area.

The adsorption of propranolol hydrochloride to these adsorbents was investigated by in vitro methods. The adsorption isotherms were drawn and the adsorptive capacities of the adsorbents were calculated from the slopes. It was found that magnesium tri-silicate, magnesium hydroxide arid dihydroxy aluminum sodium carbonate possess the highest adsorptive capacities while kaolin and magnesium carbonate possess the lowest.

The results of the adsorption studies indicate that the concomitant use of propranolol hydrochloride and the above mentioned adsorbents could affect the bioavailability of the beta-blocker adversely.     

Disposition of 14C-Quinelorane in Dogs Following Oral or Intravenous Dosing and Transdermal Patch Application

A transdermal patch was developed to circumvent the emesis associated with the oral and intravenous administration of a dopamine agonist, quinelorane, to dogs.

Approximate steady-state plasma concentrations were achieved following the daily application of a transdermal patch for 7 days. Each dog received between 0.1 and 0.2 mg/kg per day from the transdermal patch.

At steady-state conditions, dogs received either a single oral dose of ¹⁴C-quinelorane at 0.1 mg/kg, a bolus intravenous dose of 0.03 mg/kg or had a transdermal patch containing the radioactive free base, ¹⁴C-quinelorane, applied to their abdomens for 24 hours; the approximate dose was 0.18 mg/kg.

The plasma pharmacokinetics were measured by liquid scintillation counting and ELISA.

The systemic bioavailability of quinelorane, as measured by the ELISA, was 30%, indicative of first-pass metabolism.

The radioactive urinary metabolite profile was similar for all three routes of administration. Principal entities in the urine were quinelorane, the N-despropyl- and the hydroxy-lactam- metabolites, accounting for 29, 25 and 3% of the dose, respectively. The major route of excretion of radioactivity was via. the urine, irrespective of the route by which the drug was administered.     

Testing of Drug Release from Bioadhesive Vaginal Tablets

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.     

Medicament Release from Suppository Bases: II. Naproxen Physicochemical Characteristics and Bioavailability in Rabbits

Suppositories containing 25mg naproxen were prepared by the fusion method with tehobroma oil, PEG 1000, and witepsol 11-15. The liguefaction point and the time for complete liquefaction at temperatures from 37°C to 47°C were determined. By utilizing the SBT (Erwka) apparatus it was determined that the witepsol 11-15 formed supposltories which were more brittle.

The In vitro release rates were determined by using the USP method and by a modified one with dialyzing cellophane tubing. Samples withdrawn at definite time interval for up to 6 hours, and were analyzed by the spectrofluorometric method. The in vivo drug release was studied in rabbits. Ten blood samples were collected over a 24 hour period following administration of a 25mg dose of each suppository and of oral suspension. Plasma samples were assayed by spectrofluorometric method. A student “t” test was conducted on all date from the four different formulations and indicated significant difference between theobroma oil and oral suspension.

Significant correlation was obtained between the in vivo absorption and in vitro release when the suppository was placed In a dialyzing cellophane membrane.     

Habit Modifications of Nitrofurantion Crystallized from Formic Acid Mixtures

The crystal size and the length to width ratio of Nitrofurantoin, an anti-bacterial urinary tract drug, can be controlled using an appropriate mixture of solvents and suitable crystallization conditions.

Some solvents will form undesirable complexes with the drug (INF) while with others no crystal structure modification or complexation was detected (HCO₂H).

The length (y) to width (x) ratio of the Nitrofurantoin varies from 2.5 to 1.5 when crystallized from pure formic acid or in a mixture with water or ethanol.

The y/x values correspond to the solvent interactions and super saturation (S).

The crystal growth regularity is ascribed to the solvent power and thus when more regular crystals will precipitate bioavailability and solubilization of the drug will increase. Best results were obtained when mixture of formic acid-ethanol solution was used as crystallization media yielding large tabular crystals.