Medicament Release From Ointment Bases: V. Naproxen In-Vitro Release and In-Vivo Percutaneous Absorption In Rabbits

The in- vitro release of Naproxen from various ointment bases, including a water-washable base with the drug in the water phase (I) and the drug in the oil phase (II), a hydrophilic base with the drug in the water phase (III), and the drug in the oil phase (IV), and an anhydrous ointment (V), a gel (VI) and a modified University of California (U .C .H.) base (VII) were studied. In addition, the effects of various additives (urea, ethanol, dimethyl sulfoxide and polyethylene glycol-400) on the release of Naproxen from formulations (I) and (II) were determined. Low concentrations of urea and ethanol in the formulations increased the release of the drug from both these bases, however, higher concentrations adversely affected the release of the drug. While dimethyl sulfoxide (DMSO) had no significant effect on the drug release, the inclusion of polyethylene glycol-400 in both bases decreased the release of Naproxen.

The percutaneous absorption of Naproxen from the waterwashable base (drug in the oil phase) and hydrophilic base (drug in the oil phase) were studied by applying the ointments on rabbit's skin. It was observed that the bioavailability of Naproxen from the hydrophilic base was slightly greater than that from the water-washable base, and that DMSO had no effect in enhancing the in-vivo release of Naproxen from the ointments evaluated. Using the in-vivo data, the absorption and elimination rate constants, the half-life and AUC were calculated.     

Medicament Release From Ointment Bases: V. Naproxen In-Vitro Release and In-Vivo Percutaneous Absorption In Rabbits

Abstract

The in- vitro release of Naproxen from various ointment bases, including a water-washable base with the drug in the water phase (I) and the drug in the oil phase (II), a hydrophilic base with the drug in the water phase (III), and the drug in the oil phase (IV), and an anhydrous ointment (V), a gel (VI) and a modified University of California (U.C.H.) base (VII) were studied. In addition, the effects of various additives (urea, ethanol, dimethyl sulfoxide and polyethylene glycol-400) on the release of Naproxen from formulations (I) and (II) were determined. Low concentrations of urea and ethanol in the formulations increased the release of the drug from both these bases, however, higher concentrations adversely affected the release of the drug. While dimethyl sulfoxide (DMSO) had no significant effect on the drug release, the inclusion of polyethylene glycol-400 in both bases decreased the release of Naproxen.

The percutaneous absorption of Naproxen from the waterwashable base (drug in the oil phase) and hydrophilic base (drug in the oil phase) were studied by applying the ointments on rabbit's skin. It was observed that the bioavailability of Naproxen from the hydrophilic base was slightly greater than that from the water-washable base, and that DMSO had no effect in enhancing the in-vivo release of Naproxen from the ointments evaluated. Using the in-vivo data, the absorption and elimination rate constants, the half-life and AUC were calculated.     

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

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.     

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.     

In-Vivo Evaluation of Commercial and Formulated Conventional Aspirin Tablets

In-vivo evaluation of eight brands of conventional aspirin tablets (six commercial brands and two prepared formulae) was assessed in six healthy subjects. Measurements of urinary salicylate excretion were carried out using the method of Chiou and Onyemelukwe in which a proposed reagent was used instead of Trinder's reagent for the assay of total salicylate in urine. The bioava-ilability parameters of the studied brands were calculated. Out of all the studied commercial brands, brand A showed the best results while brand D showed the worst. A prepared formula (Y) was found to superior over all the commercial brands concerning their bioavailability. The inclusion of a surfactant in formula Y was found to be the main reason for absorption enhancement. The pharmacokinetic parameters of the six subjects for the different brands were also computed. A marked intersubject variation for bioavailability and pharmacokinetic parameters was observed.     

In-Vivo Evaluation of Commercial and Formulated Conventional Aspirin Tablets

Abstract

In-vivo evaluation of eight brands of conventional aspirin tablets (six commercial brands and two prepared formulae) was assessed in six healthy subjects. Measurements of urinary salicylate excretion were carried out using the method of Chiou and Onyemelukwe in which a proposed reagent was used instead of Trinder's reagent for the assay of total salicylate in urine. The bioava-ilability parameters of the studied brands were calculated. Out of all the studied commercial brands, brand A showed the best results while brand D showed the worst. A prepared formula (Y) was found to superior over all the commercial brands concerning their bioavailability. The inclusion of a surfactant in formula Y was found to be the main reason for absorption enhancement. The pharmacokinetic parameters of the six subjects for the different brands were also computed. A marked intersubject variation for bioavailability and pharmacokinetic parameters was observed.     

Development of An Oral Sustained-Release Antibiotic Matrix Tablet Using In-Vitro/In-Vivo Correlations

A sustained release (SR) cephalexin tablet formulation containing xanthan gum and sodium alginate as matrix formers was evaluated in human volunteers. The formulation was optimized based on response surface analysis and computer simulation of cephalexin plasma levels versus time curves. The optimized formulation was tested in-vivo in human volunteers along with a fast release (FR) capsule formulation. The SR matrix formulation prolonged the cephalexin blood levels up to 8 hours in humans. The matrix formulation reduced variations in cephalexin plasma levels in individual subjects without any dose dumping as compared to the FR formulation. The plasma levels predicted by the computer program using in-vitro release data and the drug's pharmacokinetic parameters showed excellent correlation with in-vivo data. Using the Wagner-Nelson method, there was good correlation between in-vitro dissolution and in-vivo absorption in individual subjects. The relative bioavailability of cephalexin was reduced by about thirty percent. Very little absorption was seen after six to eight hours. The SR matrix formulation is an alternative delivery method to produce prolonged concentrations.     

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

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     

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     

Inter-Laboratory Reproducibility of Release Tests for Suppositories

Inter-laboratory reproducibility of representative release tests, namely paddle, Muranishi and dialysis tubing methods for suppositories were investigated using two kinds of suppositories of indomethacin, oily and water-soluble types. The inter-laboratory differences for the water-soluble suppository determined by paddle and modified Muranishi methods were small whereas the differences for the oily suppository determined by Muranishi and dialysis tubing methods were large. The release rate of oily suppository by Muranishi method was significantly reduced when the cylindrical cell containing suppository was placed slightly lower. The release rate by dialysis tubing method was decreased by addition of a small volume of test fluid into the dialysis tube. These variables probably contributed to the inter-laboratory differences for the oily suppository. Neither Muranishi or dialysis tubing method should be employed for quality control of oily suppositories unless their reproducibility is significantly improved.     

Pharmacokinetic and In-Vitro Characteristics of Sustained Release Verapamil Products

The in-vitro dissolution and in-vivo pharmacokinetics of two marketed sustained release formulations, Verelan (V) and Isoptin SR (ISR), were compared. The effect of food on V was also examined in a separate study with conventional Isoptin (I) as a reference. Both sustained release preparations had extended dissolution profiles with 50% release times (T50%) of 4 hours for ISR and 8 hours for V. The extended in-vitro profile of V versus ISR was confirmed in-vivo with a Tmax of 7.3 hours compared to 5.0 hours, a Cmax of 114.3 compared to 171.0 and a peak to trough ratio of 3.8 compared to 10.1 for V and ISR respectively. In a second pharmacokinetic study the rate and extent of absorption of verapamil from V was shown to be unaffected by food.     

Pharmacokinetic and In-Vitro Characteristics of Sustained Release Verapamil Products

Abstract

The in-vitro dissolution and in-vivo pharmacokinetics of two marketed sustained release formulations, Verelan (V) and Isoptin SR (ISR), were compared. The effect of food on V was also examined in a separate study with conventional Isoptin (I) as a reference. Both sustained release preparations had extended dissolution profiles with 50% release times (T50%) of 4 hours for ISR and 8 hours for V. The extended in-vitro profile of V versus ISR was confirmed in-vivo with a Tmax of 7.3 hours compared to 5.0 hours, a Cmax of 114.3 compared to 171.0 and a peak to trough ratio of 3.8 compared to 10.1 for V and ISR respectively. In a second pharmacokinetic study the rate and extent of absorption of verapamil from V was shown to be unaffected by food.     

The Effect of Particle Size on Some In-Vitro and In-Vivo Properties of Indomethacin-Polyethylene Glycol 6000 Solid Dispersions

Abstract

Drug release from indomethacin-polyethylene glycol solid dispersions has been examined using three different size fractions. Release rates at a stirring rate of 100 rpm were generally higher from the 250-375 micron fraction than from particles in the ranges 125-188 and 500-750 microns. Release rates were highest from dispersions containing 5% indomethacin and showed a 240-fold increase at 100 rpm and a 1200-fold increase at 50 rpm over those at the same stirring rate of indomethacin alone (125-188 microns). As the percentage of indomethacin in the dispersions increased (5 to 40%) the dissolution rates decreased and for dispersions containing .15% indomethacin, complete solution of the drug was not achieved within 2 hours. The 500-750 micron fraction of the dispersion containing 10% indomethacin was significantly more gastro-toxic than particles of 125-188 microns.     

Preparation and In-Vitro Evaluation of Prolonged Release Tablets of Pheniramine Aminosalicylate

Prolonged release tablets of pheniramine aminosalicylate were prepared from co-precipitates of the drug in different types of Eudragit. The hardness of the tablet had a pronounced effect on the release rate of the drug. Tablets (500 mg, hardness 13 kg) and 375 mg tablets (hardness 6.5 kg) prepared from the co-precipitates containing 15% of the drug in Eudragit L 100, and 20% of the drug in Eudragit S 100 respectively, showed release rate patterns that were in agreement with Lang primary requirements for drug release from sustained release tablets.

Tablets (500 mg) prepared from the co-precipitates containing 15% of the drug in Eudragit L 100 or Eudragit S 100 and 375 mg tablets containing 20% of the drug in Eudragit S 100 showed release rate patterns that were best described by Higuchi equation, indicating that a diffusion controlled mechanism was mainly operative.     

Effects of Silicium Dioxide on Drug Release from Suppositories

Abstract

Silica gel is frequently introduced into lipophilic excipients for suppositories as a viscosity agent, to prevent drug sedimentation in the melted mass, and to decrease release rate. The effect of silica gel (Aerosil 200) concentration on the availability of some drugs frequently used in suppositories in different unitary doses was studied. When silica gel concentration in the excipient was increased, a decrease in aminophylline and aminophenazone release rate was observed. Paracetamol in small unitary doses has shown a tendency to increase release rate at higher silica gel concentrations. This behavior was even more evident in suppositories containing promethazine hydrochloride, while for those containing benzydamine hydrochloride the increase in release rate with increasing silica gel concentration was evident for all drug doses. However, the behavior was a consequence of the trend of suppository viscosity during drug release. As a consequence of both the drug and silica gel being discharged, the viscosity progressively decreased with an increased silica gel concentration. The effect on drug availability was conditioned by silica gel concentration, as well as the type and dose of the drug, which could act on the shape of the suppository inner structure that is responsible for viscosity and mobility of drug particles.     

Effects of Silicium Dioxide on Drug Release from Suppositories

Silica gel is frequently introduced into lipophilic excipients for suppositories as a viscosity agent, to prevent drug sedimentation in the melted mass, and to decrease release rate. The effect of silica gel (Aerosil 200) concentration on the availability of some drugs frequently used in suppositories in different unitary doses was studied. When silica gel concentration in the excipient was increased, a decrease in aminophylline and aminophenazone release rate was observed. Paracetamol in small unitary doses has shown a tendency to increase release rate at higher silica gel concentrations. This behavior was even more evident in suppositories containing promethazine hydrochloride, while for those containing benzydamine hydrochloride the increase in release rate with increasing silica gel concentration was evident for all drug doses. However, the behavior was a consequence of the trend of suppository viscosity during drug release. As a consequence of both the drug and silica gel being discharged, the viscosity progressively decreased with an increased silica gel concentration. The effect on drug availability was conditioned by silica gel concentration, as well as the type and dose of the drug, which could act on the shape of the suppository inner structure that is responsible for viscosity and mobility of drug particles.     

Dissolution of Suppositories V: Influence of Aging on Aspirin Release from Polyethyleneglycol Suppositories with and Without Crospovidone

Abstract

This report details the effect of aging on release of aspirin from four PEG blends containing crospovidone as a disintegrant in concentrations of 0, 0.5, 1 and 5%. It has been reported in the literature that release from suppository formulations is often altered upon aging. In this experiment, suppositories containing 350 mg aspirin were dissolved in 1,000 mls of pH 8.0 dissolution fluid, at 37.5° with an agitation rate of 50 rpm. Suppositories were designated as fresh (less than 10 days old), 4 months old and 6 months old. Aspirin was assayed at 265 nm. Dissolution profiles as well as dissolution half-times were reported. Aging had little effect on Base A and Base B. However, Ease C exhibited an ambiguous effect in that the dissolution half-times were inconsistent. Base D exhibited a dramatic change in release upon aging in that the dissolution half-times increased from 23 minutes to 55 minutes with 1/22 crospovidone. It is hypothesized that Base D stabilized when larger amounts of crospovidone are used although the exact mechanism of this stabilization is unknown     

Dissolution of Suppositories V: Influence of Aging on Aspirin Release from Polyethyleneglycol Suppositories with and Without Crospovidone

This report details the effect of aging on release of aspirin from four PEG blends containing crospovidone as a disintegrant in concentrations of 0, 0.5, 1 and 5%. It has been reported in the literature that release from suppository formulations is often altered upon aging. In this experiment, suppositories containing 350 mg aspirin were dissolved in 1,000 mls of pH 8.0 dissolution fluid, at 37.5° with an agitation rate of 50 rpm. Suppositories were designated as fresh (less than 10 days old), 4 months old and 6 months old. Aspirin was assayed at 265 nm. Dissolution profiles as well as dissolution half-times were reported. Aging had little effect on Base A and Base B. However, Ease C exhibited an ambiguous effect in that the dissolution half-times were inconsistent. Base D exhibited a dramatic change in release upon aging in that the dissolution half-times increased from 23 minutes to 55 minutes with 1/22 crospovidone. It is hypothesized that Base D stabilized when larger amounts of crospovidone are used although the exact mechanism of this stabilization is unknown     

Development and In-Vitro Evaluation of a Multiparticulate Sustained Release Theophylline Formulation

A multiparticulate sustained release formulation of theophylline was developed and evaluated in-vitro. The formulation comprised spherical pellets of high drug loading, coated with a rate controlling membrane. The pellets were prepared using an extrusion spheronisation method, whilst coating was performed with an aqueous dispersion of ethylcellulose using a fluidized bed coating technique. When ethylcellulose was used alone as the coating polymer, the drug release profile was unsatisfactory, but could be improved by incorporating a coating additive. Several additives were evaluated and methylcellulose of high Viscosity grade was found most satisfactory. The in-vitro theophylline release was relatively linear and pH independent, and could be varied in a predictable manner by manipulating the coat thickness. In addition, when the coated pellets were subjected to additional thermal treatment, the drug release was stable after storage for one year.     

Degradation of Bisoprolol Fumarate in Tablets Formulated with Dicalcium Phosphate

Degradation of Bisoprolol Fumarate in tablet dosage forms was accelerated when granular Dicalcium Phosphate Anhydrous USP was substituted for milled Dicalcium Phosphate Anhydrous USP. Studies demonstrate that instability with the granular material is due to an acidic microenvironment created by this material in the presence of moisture. Bisoprolol is less stable at this low pH compared to a neutral microenvironmental pH which is created with milled Dicalcium Phosphate Anhydrous.