Preparation of Gelatin: Phenytoin Sodium Microsphers: An IN VITRO and IN VIVO Evaluation

Abstract

In this study phenytoin sodium microspheres were formulated with biodegradable acid-treated gelatin. The microspheres were subjected to in vitro and in vivo testing. The percent drug retained in the microspheres, as well as its release from the microspheres, was tested. In vitro data revealed a decrease in percent druq retained in the microspheres with an increase in addition of glutaraldehyde to the microsphere formulations. The statistically most consistent drug release was observed from formulations containing 10 g of gelatin and 2 g of phenytoin sodium. From this formulation the slowest release was observed when 5 ml of glutaraldehyde were added to the various formulations, whereas the fastest release was observed when no glutaraldehyde was added. In vivo studies consisted of administering phenytoin sodium in microsphere form and an aqueous solution v i a various routes of administration and determining phenytoin plasma concentration vs. time profiles in female Sprague Dawley Rats. Computer fitting of the in vivo data and subsequent statistical testing enabled comparison of the effect of microsphere formation and the effect of microsphere dose on selected pharmacokinetic parameters.     

Medicament Release from Ointment Bases: III. Ibuprofen: In Vitro Release and In-Vivo Absorption in Rabbits

Abstract

The in-vitro release of ibuprofen from various topical bases including: water-washable base, hydrophilic base, cream, Canadian formulary base, gel, emulsion, water-soluble base and University of California Hospital base were studied. Also, the effects of the additives (ethanol, polyethylene glycol—400, urea and dimethylsulfoxide) on the release rate of the drug from the water-washable base were evaluated.

In general, the in-vitro release rate rank order of the drug was observed to be: water-washable base > hydrophilic base > Canadian formulary base > gel > PEG water washable > emulsion > cream > University of California base. The additive ingredients had a Little or no effect in enhancing the release of drug from the samples studied.

The formulations with optimum in-vitro drug release were scaled up for in-vivo percutaneous absorption in rabbits. The blood samples were analyzed by a HPLC method. Among the candidates evaluated in-vivo, the bioavailability of the drug was significantly higher from the water-washable base when compared to the hydrophilic base and others. The addition of 10% dimethylsulfoxide to the hydrophilic enhanced the release of ibuprofen and adversely affected the release from the water-washable base.

In-vitro and in-vivo data were treated by various kinetic models and the values for diffusion coefficient, permeability coefficient and partition coefficient were calculated. Also, some pharmacokinetic parameters, such as, absorption rate constant, elimination rate constant and half-life of the drug were calculated for meaningful interpretations of the data for the release of drug from topical bases.     

The Tabletting Properties of Dika Fat Lubricant

Abstract

The lubricant property of dika fat, a solid vegetable oil extracted from the kernels of Irvingiaqabonensis var gabonensis and var excelsia was investigated. An instrumented tablet machine (ITM) was used to evaluate the effect of dika fat on the unit ejection force (EJF/A) of a model direct compression formulation. Dika fat, at equivalent concentration levels, performed better than magnesium stearate, stearic acid and a hydrogenated vegetable oil STEROTEX, in reducing EJF/A of tablets compressed from the model direct compression formulation. Dika fat imparted no adverse effect on the hardness, disintegration and dissolution of directly compressed hydrochlorothiazide tablets prepared in this study.     

Release Kinetics of Tobramycin Sulfate from Polymethylmethacrylate Implants

Abstract

The effects of various formulation factors on the in vitro release characteristics of spherical polymethylmethacrylate implants were studied. Physical and mathematical models were proposed to describe observed in vitro release profiles. The in vitro release data could be described by a biexponential equation of the type: fraction of tobramycin remaining in the implant at time t = Ae^?αt + Be^?βt, where α and β represent the rate constants for the initial rapid and subsequent slow phases of release. The influence of drug loading, volume of dissolution medium, implant size, type of commercial cement and the incorporation of water soluble additives on the release profiles as well as the α and β rate constants is described     

Development and Evaluation of Transdermal Salbutamol Delivering Systems

Abstract

The transdermal drug delivery systems based on polymeric pseudolatex and matrix diffusion controlled systems for salbutamol were prepared and compared for in vitro skin permeation profile and in vivo performances. Poly (isobutylene) was used as release controlling polymer in both the systems. In vitro skin permeation was studied using the human cadavar skin in franz diffusion cell. Permeation rate constants for matrix diffusion controlled system and pseudolatices were 10.625 and 13.750 mcg/hr/cm² respectively. The prepared transdermal systems were tested on human volunteers having chronic reversible airways obstruction and compared with oral treatments (Asthaline). The in vivo drug plasma profiles following transdermal and oral treatments reveal that although peak plasma level by oral administration was higher in comparison with the transdermal treatments, troughs and peaks were discernible at dosing times. In the case of transdermal treatments, constant drug plasma and FEV₁ levels were recorded indicating controlled and systemic delivery of drug spaced over 30 hours. Among the prepared transdermal drug delivery systems, pseudolatices demonstrated better drug plasma profile, maintained at relatively higher level and flatter in appearance. The relative performance of the systems was noted to reflect in AUC and FEV₁.     

Further Considerations in Correlating in Vitro - In Vivo Data Employing Mean-Time Concept Based on Statistical Moments

Abstract

Dissolution of a dosage form in vivo is often the rate-limiting factor determining the bioavailability and subsequently the therapeutic response. If a good correlation exists between an in vitro dissolution parameter and some bioavailabilty parameter, then monitoring of dissolution profile should permit the prediction of bioavailability.

The concept of Mean Residence Time based on statistical moments provides one method for correlating in vitro - in vivo data. The exemplification of this approach involving urinary excretion data is relatively straight forward. For plasma drug concentration-time data, however, this may not be the case realistically. This paper sets forth the mechanics of correlating in vitro data with bioavailability data employing both urinary excretion data as well as plasma data.     

Preparation and Evaluation of Controlled Release Indomethacin Microspheres

Abstract

Microspheres containing indomethacin were prepared with various combinations of polymers Eudragit RS and Eudragit L. The effects of different ratios of polymers, solvent-polymer ratio, polymer-drug ratio and evaporation temperature on the physical characteristics of the microspheres as well as the in vitro release rate of the drug were investigated. All the factors studied had an influence on the physical characteristics of the microspheres. In vitro dissolution results showed that all formulations gave prolonged release of indomethacin and the release followed apparent zero order kinetics until 80% of drug had been released.     

The In Vitro and In Vivo Performance of Aqueous Bases Enteric Coats of Neutralised Hydroxypropyl Methyl Cellulose Phthalate

Abstract

Prednisolone tablets, enteric coated with neutralised hydroxypropyl methylcellulose phthalate (HPMCP) were compared with Deltacortril tablets (Pfizer) by compendial in vitro testing and a pharmacokinetic study in 12 volunteers. Despite satisfactory compliance for both products with the specifications for enteric products of the European Pharmacopoeia and the United States Pharmacopoeia a significant difference in lag time before prednisolone was detected in plasma was observed between the products and only the Deltracortril tablet was concluded to exhibit true enteric properties

The failure of the neutralised HPMCP coating probably results from incomplete gastric conversion to its acidic form due to the majority of subjects having gastric pH values in excess of those stipulated in the compendial in vitro tests. Alternative in vitro testing procedures are proposed     

Medicament Release from Suppository Bases: III. Ibuprofen - Physicochemical Characteristics and Bioavailability in Rabbits

Abstract

This investigation was designed to determine the invitro release of ibuprofen from suppository bases, and their invivo bioavailability in rabbits. Suppositories containing ibuprofen were made by the fusion method with Theobroma oil, Witepsol H-15 and PEG 1540. In order to produce an exact dosage form, the displacement value was determined. The suppository hardness was determined by utilizing the SBT (Erweka) apparatus and it was found that the Witepsol H-15 allows the formation of brittler suppositories. The release rates were determined with the USP dissolution apparatus and with cellophane membrane and it was found to be: PEG 1540 > Witepsol H-15 > Theobroma oil. The bioavail-ability of Indomethacin after rectal administration was: PEG 1540 > Witepsol H-15 > Theobroma oil which correlates with the invitro release.     

Synthesis and Chemical Transformations of the Diels-Alder Adduct of [60] Fullerene and 4-Amino-O-quinodimethane

Abstract

Diels-Alder reaction of 4-amino-o-quinodimethane (6) with [60]fullerene (1) affords the thermally stable and chemically reactive adduct 7(n). The nucleophilic amino group of 7(n) is well suited for the covalent attachment of different molecules to the [60]fullerene core by further chemical reactions.     

In vitro and in vivo evaluation of sustained-release and enteric-coated microcapsules of diclofenac sodium

Abstract

This work examines the release of diclofenac sodium from ethylcellulose (EC) microcapsules made up of different drug to polymer ratios. The release process was found to follow the Higuchi square root equation and not the zero-order or first order equations. However, for drug to polymer ratio of 1:1, a critical time (θ) was reached beyond which the release rate was lower than that predicted on the basis of the Higuchi square root equation. Dissolution experiments in 0.1N HCL revealed that less than 1.5% of the encapsulated drug was released in 6 h. This finding indicates the suitability of the EC microcapsules for enteric-coated preparations. The in vitro release of diclofenac sodium from microcapsules of different drug to polymer ratios was compared with that from a commercial sustained-release product. A distinct similarity between the release profile of the commercial product with that obtained for the 1:2 drug to polymer microcapsules was noted. The in vivo work included determination of the serum drug profile following oral administration of the microcapsules and the commercial product to rabbits. The obtained serum concentration time profile of the EC microcapsules exhibited a sustained-release pattern similar to the commercial product and consistent with the in vitro results.     

Chemical-mechanical failure of oxide scales on 9% Cr steels in air with H2O

Abstract

The oxidation behaviour of 9% Cr steels P91 and Nf616 has been investigated at 650°C in dry air and in air with water vapour, where particular attention was given to breakaway failure. Additional emphasis was given to the quantitative characterisation of the kinetics of chromium depletion in the metal subsurface zone resulting from scale growth, CrO₂H₄ evaporation, and scale cracking and healing, with scale cracking being monitored by acoustic emission measurements. While in dry air the steels show protective oxidation behaviour up to 10000 h, breakaway oxidation may occur already after 100 h in humid environments, which was correlated with the stronger Cr-depletion and the development of intrinsic oxide scale growth stresses exceeding a critical value, in the case of water vapour containing air. In the paper the different parameters that are responsible for breakaway oxidation were identified and discussed with regard to the role of water vapour in the environment. As a conclusion it turns out that breakaway is not a consequence of Intrinsic Chemical Failure (InCF) but of a Mechanically Induced Chemical Failure (MICF).     

Spheronization II: Drug Release from Drug-Diluent Mixtures

Abstract

Pellets were prepared from wet granulations using an extruder and spheronizer. Binary mixtures of active ingredient and different types of Avicel micro-crystalline cellulose products have been processed and evaluated to determine the effect of varying the drug, the diluent, and the drug-diluent ratio. Physical properties including in-vitro drug release profiles were evaluated for the uncoated pellets. Anhydrous Theophylline, USP and Quinidine Sulfate, USP were evaluated at drug-diluent ratios from 10:90 to 80:20. Chlorpheniramine Maleate, USP and Hydrochlorothiazide, USP were incorporated into one system to study the influence of more extreme values of aqueous solubility on drug release. Drug release was found to vary with the drug, diluent, and the drug-diluent ratio.     

Stability and Bioavailability of Five Brands of Ampicillin Suspensions Following Reconstitution

Abstract

The stability of the active ingredient of four generically equivalent brands of ampicillin for oral suspension were studied at three controlled conditions 5,25 and 40°C. All ampicillin suspensions tested, except one brand, did not meet the official compendial stability requirements when stored at the recommended conditions. However the different brands studied were not completely equivalent with respect to stability. In vitro release of ampicillin from 5 brands of ampicillin suspension was studied by using dialysis method. Slight differences in dissolution profiles among the studied brands were observed. The bioavailability of 5 brands of ampicillin suspensions was examined in 5 subjects using cross-over experimental design. Based upon the urinary excretion method, the extent and rate of ampicillin bioavailability were determined. Statistically significant differences were found between the brands examined. An insignificant intersubject variation was found between the volunteers participated in the present study.     

Influence of Hydroxypropyl Methylcellulose and of Manufacturing Technique on in Vitro Performance of Selected Antacids

Abstract

Factors affecting the performance of antacids F-MA 11, dihydroxy aluminum aminoacetate, magaldrate and magnesium hydroxide were studied in vitro using Schaub's acid neutralization test, a modified Reheis reaction velocity test and the USP test. From the results obtained it was evident that type and combination of antacid, the adjuvants and formulation techniques used in preparation of antacids affect their performance. The USP preliminary antacid test and acid neutralization test are not optimal in vitro tests to evaluate in vitro onset and duration of action of antacids.     

Controlled Transdermal Occlusive Delivery Device of Primaquine

Abstract

Primaquine an antimalarial drug was studied for its permeation behavior across the human cadaver skin. Ethylene vinyl acetate copolymer (E.V.A. cop) was used for the preparation of drug reservoir. To optimize the drug delivery from the drug reservoir E.V.A. cop of different vinyl acetate mole content (40%, 25%, 18%) was used. To achieve an enhanced skin permeation an occlusive face adhesive type delivery system was fabricated. The prepared systems were characterized for in-vitro studies. The system that delivered the drug in accordance with the theortically calculated required delivery rate was selected for in-vivo performance evaluation. The prepared system functions over an predicted definite time period in an uniform and defined fashion. The drug transdermal application has therapeutic potential.     

Bioavailability of Eight Brands of Ampicillin Capsules

Abstract

An in vivo absorption study was performed in a crossover fashion on 6 healthy volunteers (4 males and 2 females) to compare the bioavailability of 8 brands of ampicillin capsules. Absorption was assessed by a urinary excretion method in which the drug was assayed chemically. Statistical analysis of the results was carried out to evaluate the significance of differences between brands and between subjects. Results of the analysis of variance indicated no significant differences between the tested brands of ampicillin capsules. However, significant differences between brand A and brand B were found on using the student t-test. A significant intersubject variation was also found between the volunteers participated in the present study.     

Microencapsulation by Emulsion Non-Solvent Additicin Method

Abstract

Cellulose acetate butyrate microcapsules containing propranolol were prepared by emulsion non-solvent addition method. The effects on drug release of different polyethylene glycols (PEG), various concentrations of PEG 4000, and particle size of the drug to be encapsulated were investigated. In vitro dissolution of microcapsules in simulated intestinal fluid and buffers at different pH was also studied. PEGs were found to increase drug release for this system. The pH dissolution profiles of the microcapsules indicated that dissolution was slightly pH dependent during the first 8 hours of dissolution.     

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.     

“In-Vitro” Testing of an Antacid Formulation with Prolonged Gastric Residence Time (Almagate Flot-Coat®)

Abstract

Dynamic in vitro tests were used to study sensitivity to environmental acidity, buffering profile and residence time under simulated gastric conditions of pharmaceutical formulations incorporating the concept of prolonged gastric residence time (Almagate Flot-Coat^rG). In comparison with classical antacid products the new formulation was shown to have a high antacid potency together with a prolonged in vitro gastric residence time.