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.     

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.     

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.     

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.     

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.     

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     

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.     

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 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.     

Book Reviews

Abstract

Physical Pharmacy Fourth Edition Alfred Martin 622 pages, hard cover, $59.50 published by Lea and Febiger, Philadelphia

UNDERSTANDING BIOTECHNOLOGY LAW Edited by Gale R. Peterson 488 pages, hard cover, $135, published by Marcel Dekker, Inc.

Drug Toxicokinetics Edited by Welling and Inglesia Published by Marcel Dekker, Inc. 1993 432 pages, hard cover $150

Colonic Drug Absorption and Metabolism Peter R. Bieck (Editor) Published by Marcel Dekker, Inc., June 1993 240 pages, hard cover, $110.00

Recent Advances in Pharmaceutical and Industrial Biotechnology 6th International Pharmaceutical Technology Symposium Hacettepe University, Ankara, 7–10 September 1992 Published by: Editions de Sante, Paris, 277 pages, soft cover     

Advances in Dissolution Technology: Design,Pros and Cons

Abstract

To date dissolution tests are considered to be the most reliable predictors of bioavailability of drugs. Dissolution tests are critical and difficult to carry out properly. A review of different dissolution apparatii currently in use or employed in the past is present along with the advantages and disadvantages offered by each. Criteria as to design, operation, sensitivity, etc. of an in vitro dissolution system are outlined which would assist in fabrication of a more efficient and reliable apparatus. If one is to obtain meaningful results, care and attention must be given to those aspects that have been identified as crucial. To date no universal dissolutiuon test has yet been devised that in every instance gives the same rank order for in vitro dissolution and in vivo availability for different formulation and batches.     

Brythromycihn Gel - a Topical Anti-Acne Preparation

Abstract

Carbopol gel bases containing Erythromycin (2%w/w) were formulated and screened for its anti-acne activity. Both in-vitro and in-vivo studies were carried out on laboratory models, animals and human volunteers. Drug release was evaluated using cellophane membrane. Primary skin irritation study was performed on albino rabbits using Draize patch technique. Reduction in the number of acne and its basal diameter was observed in human volunteers.     

The effect of water vapor in increasing growth stresses in the oxide scale on martensitic steam plant alloys

Abstract

Investigation of the oxidation behavior of 9% Cr steels at 650°C in dry air and air + 10% H₂O have shown that oxide scale growth stresses may play a significant role in breakaway. For this reason, preliminary studies on the development and characteristics of growth stresses in oxides on these materials have begun. These studies include in situ acoustic emission (AE) for monitoring scale cracking, deflection testing in monofacial oxidation (DTMO) and in situ X–ray measurements. The measurements were complemented by detailed post-experimental metallographic investigations.

From the DTMO measurements the stresses in the oxide on the specimens tested in humid environment are increased by about a factor of 5 compared to dry air at the beginning of oxidation for P91. In a humid environment the stresses decrease with oxidation time while in dry air they remain almost constant. Significant acoustic emission (AE) occurs in humid air for oxidation coupons while virtually no AE is observed for thin foils in a humid environment and for coupons in dry air. These first results seem to be in good agreement with weight gain data characterizing the breakaway behavior in these environments, indicating that, indeed, oxide growth stresses play a key role for oxidation resistance and, thus, component lifetimes of such steels.

The first X–ray results indicate that for E911 the scale structure and composition changes completely between the two environments. Furthermore, in humid air, a breakaway effect is observed with a change from protective spinel type oxide to locally non-protective Fe–rich oxide.     

Validation of Optimal Ampicillin/Sulbactam Ratio in Dosage Forms Using In-Vitro Dynamic Model

Abstract

To validate the optimal ampicillin/sulbactam ratio in dosage forms the antimicrobial action kinetics of the combinations against ampicillin-resistant strain of E. coli (MIC = 250 μg/ml) under simulated clinical conditions in an in-yitro dynamic model was studied. The in-yitro dynamic model simulating the drug kinetic profiles described by the two-compartment pharmacokinetic model (serum drug kinetics after intravenous injection) and the one-compartment pharmacokinetic model (drug profiles in serum and tissue fluid after oral and intravenous administration respectively) was used. The profiles realized after receiving of 0.5 g of ampicillin and 0.125, 0.25, 0.5, 1.0 g of sulbactam were reproduced. Changes in the viable count in the dynamic model were estimated microcalorimetrically with BioActivity Monitor LKB 2277-202. The use of the recently developed parameter of antimicrobial effect duration T_E (the time from the moment of drug administration till the moment when the bacterial count reaches again its initial level) provided determination of relationship between effect and ampicillin/sulbactam ratios. It is demonstrated that the variation of ampicillin/sulbactam ratio from 4:1 to 1:1 was accompanied by marked enhancement in the antimicrobial effect. Further increase of sulbactam content in the formulation not resulted in more pronounced effect. We conclude that validation of optimal ratio in chemotherapeutic combinations using in-vitro dynamic models is a promising approach to development of modern drug formulations.     

High temperature oxidation of hot-pressed aluminium nitride by water vapour

Hot pressed AIN without additives was oxidized et 1100 to 1400°C in dry air, wet air and wet nitrogen gas atmospheres with 1.5 to 20 kPa of water vapour pressure. AIN was oxidized by both air and water vapour, and formed -Al₂O₃ film on the surface above 1150°C. The oxidation kinetics in air were parabolic end were promoted by water vapour. On the other hand, the oxidation kinetics in wet nitrogen were linear below 1250°C and parabolic above 1350°C. The oxidation rate in wet nitrogen was much greater than that in wet air. The rate of oxidation increased with increasing temperature until 1350°C, and then decreased. The parabolic rate constant decreased with increasing temperature and increased linearly with increasing water vapour pressure. The linear rate constant at 1150 to 1250° C increased with increasing the temperature with the apparent activation energy of 250 kJ mol^–1. The relation between the linear rate constant and water vapour pressure was of the Langmuir type.     

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.     

Regulatory Considerations in Transdermal Controlled Medication

Abstract

The in vitro release of indomethacin from different suppository bases was inverstigated using the USP rotating basket dissolution method. Suppositories containing 100 mg of indomethacin were prepared by the fusion method using theobroma oil, Witepsol, polyethylene glycols, and glycerinated gelatic. The percent released was found to be in the order PEG 3 = PEG 4 - PEG 5 = glycerinated gelatin > theobroma oil = Witepsol. The addition of polysorbate 80 resulted in a significant increase in the percent indomethacin released in the case of fatty bases and a small increase in the case of water-soluble bases.