Controlled Transdermal Occlusive Delivery Device of Primaquine

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.     

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.     

Controlled Transdermal Mucolytic Delivery System: In Vivo Performance

Abstract

A multicomponent transdermal bromhexine delivering system was developed. The drug permeation across the human cadavar skin from either sexes was determined and found to be dependent on age, sex and site of skin. The system that could control the the delivery of the drug to allow it to permeate across the skin at a rate that is required to achieve the therapeutic concentration was selected and chosen for in vivo performance evaluation. Prior to in human volunteers availability testing the designed system was evaluated in rabbits and the system exhibiting desirable performance was redesigned for evaluation in human volunteers.T.P.S_o system delivering 1.991±0.116 mg bromhexine/cm² hr with a 453 μg/cm² priming dose was tested in human volunteers and found to maintain bromhexine blood level at or around peak plasma level for 20–24 hrs. The study reveals that bromhexine holds potential for transdermal delivery with a need of further clinical and pharmacodynamic studies.     

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.     

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: 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.     

Stratum Corneum Hydration; Consequences for Skin Permeation Experiments

Abstract

Experimental approaches to the study of drug diffusion in skin in vitro generally fail to take due account of the effects of hydration on the stratum corneum. Attention is therefore drawn to neglect of this aspect of the problem in a recent article which describes an otherwise very sophisticated apparatus for the study of diffusion phenomena.

Chien and Valia¹, have recently described a carefully designed experimental apparatus for long term permeation studies of skin. Most experimental problems are successfully controlled by this technique, which will undoubtedly prove valuable for membrane permeation experiments in general. However, the approach as described neglects an aspect so fundamental to the barrier property of skin in particular, that re-emphasis of the point at issue seems eminently desirable.

The major barrier to diffusion in intact skin is the stratum corneum. As a working hypothesis, the mechanism by which the stratum corneum exerts its barrier effect appears to consist of two components. Firstly, the movement of foreign molecules through the stratum corneum is slow; that is, the activation energy for the diffusion process is generally high. Secondly, for some molecules at least, a fraction of the diffusing material is bound within the stratum corneum, and is effectively immobilised. This seems to be true for steroids, as one example, and was first reported by Vickers². The phenomenon was discussed in terms of the existence of a reservoir for such molecules in the stratum corneum, and has subsequently been demonstrated by in vitro studies³.

The point at issue in the present discussion is that it has long been known that the overall barrier effect of the skin is markedly dependent on the degree of stratum corneum hydration⁴. It has also been shown that both components of the barrier mechanism are separately dependent on the hydration level. The reservoir effect, for example, can be reduced by occlusion of the skin in vivo. This was elegantly demonstrated by Vickers in human volunteers, by re-occluding sites previously treated with a corticosteroid, after the initial corticosteroid induced blanching response had disappeared². Skin blanching was again observed shortly thereafter, which suggests that a fraction of the applied steroid had been retained within the stratum corneum, and that the increase in stratum corneum hydration resulting from the occlusion had released this material from the reservoir, allowing it once again to exhibit its pharmacological effect. Using an in vitro technique, a preliminary attempt has recently been made to assess the change in enthalpy associated with displacement of a representative steroid from stratum corneum reservoir sites by water in this way. A value of -60+11 kJ mole^-1 was obtained⁵ which is consistent with a chemisorption process. Likewise it has been shown that the diffusion constant for the diffusing (non-reservoir bound) fraction is also appreciably increased by stratum corneum hydration⁶.

Any experimental design such as that described by Chien and Valia¹, in which the skin has both faces in contact with aqueous donor and receptor solutions, will inevitably cause the skin sample to become extensively hydrated. Further, the degree of hydration attained will almost certainly be in excess of that achievable in vivo by skin occlusion, and the measurements will therefore relate only to skin under unphysiologically high levels of hydration, where the barrier property is impaired. Such measurements must therefore be of very dubious value. What is clearly required is an experimental situation where the degree of stratum corneum hydration is controllable at least over physiologically realistic limits. Such a situation can, in fact, be established experimentally, and the appropriate mathematical analysis for diffusion under such circumstances has already been described⁷.     

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.     

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.     

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.     

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.     

Transdermal Nicotine Delivery Systems: Multi-institutional Cooperative Bioequivalence Studies

Abstract

Nicotine transdermal delivery systems (nicotine-TDSs) have been evaluated clinically and found to provide effective assistance to smokers in smoking cessation with minimal occurrence of withdrawal symptoms. However, substantial skin reactions have been reported with the four nicotine-TDSs marketed recently. To reduce the skin reactions, a new type of nicotine-TDS has been recently developed. In vitro skin permeation studies demonstrated that this nicotine-TDS yields a constant skin permeation profile with a rate of permeation across the human cadaver skin comparable to the steady-state permeation rates attained by Habitrol? and Nicoderm® systems. Clinical studies completed in two ethnic groups have demonstrated that this newly-developed nicotine-TDS is clinically effective and has yielded minimal skin irritation. As part of technical transfer program, a clinical study was initiated in 18 non-obese non-smoking Taiwanese, using Latin-square design, to compare the systemic bioavailability and pharmacokinetic profile of nicotine delivered transdermally from the nicotine-TDSs fabricated at technology licensee (Sintong nicotine-TDS) in comparison with that from the technology developer (TBS nicotine-TDS), using one marketed nicotine-TDS (Habitrol? system) as the reference product. In vitro release and skin permeation studies of nicotine from the nicotine-TDSs manufactured at both licensor and licensee were found similar in kinetic profiles and comparable in rates. Since the patch size of these nicotine-TDSs studied was smaller than the marketed product used (10 cm² for both Sintong and TBS nicotine-TDSs, versus 20 cm² for Habitrol? system), the daily doses of nicotine delivered to the volunteers are equivalent between Sintong and TBS nicotine-TDSs [9.58 (± 2.23) vs. 8.76 (± 1.88) mg/day/patch] but are lower than that from Habitrol? system [15.13 (± 4.05) mg/day/patch]. Thus, for the statistical analysis of the pharmacokinetic parameters obtained need to be corrected for the difference in patch size and daily nicotine dose delivered. The results of statistical analysis suggested that Sintong and TBS nicotine-TDSs are bioequivalent to Habitrol? system.     

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.     

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.     

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.     

Aqueous-Lipid Transdermal Formulation of Anti-Inflammatory Agents,Prepared with Hydrogenated Soya Phospholipid

Abstract

The in vitro transport of various anti-inflammatory agents were examined using rat dorsal skin and shed snake skin as models of the stratum corneum for the evaluation of transdermal formulation. The aqueous-lipid vehicle formulations prepared with hydrogenated soya phospholipid increased the transport of ketoprofen and sodium diclofenac, and an addition of tetradecanol to the formulation increased the transport of both drugs more markedly. The amounts of drug (%) transported during 12 h with rat dorsal skin and during 24 h with shed snake skin was about 50% for ketoprofen and about 30 % for sodium diclofenac. The aqueous-lipid formulation including tetradecanol also increased the transport of indomethacin, but only about 10 %. It is suggested that the small effect of the aqueous-lipid vehicle formulation on indomethacin transport is due to the low solubility of indomethacin in the vehicle.     

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).     

Comparative In Vitro evaluation of cumulative release of the urinary antiseptics Nalidixic acid,Pipemidic acid,Cinoxacin, and norfloxacin from white beeswax Microspheres

Abstract

The in vitro diffusion of nalidixic acid (1), pipemidic acid (2), cinoxacin (3), and norfloxacin (4) was studied. The transfer rate constants (k_d) from simulated gastro-intestinal juices to simulated plasma, throughout artificial wall lipid membranes, were defined. The k_d values suggested that the four drugs are absorbed both in gastric and intestinal environments in similar amounts. To obtain lack of gastric unwanted effects white beeswax microspheres containing 1, 2, 3, and 4 were investigated as a vehicle for the drug intestinal release; they were prepared by the meltable dispersion process using wetting agents. Discrete, reproducible free flowing microspheres were obtained. The drug content increased when the particle size growed; it ranged from 4% to 18%. More than 95% of the isolated microspheres were of particle size range 100–500 μm. The drug release was evaluated in vitro. Dissolution of entrapped active ingredients was greatly retarded allowing absorption only in the intestinal tract as result of microsphere formation.     

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.