Brythromycihn Gel - a Topical Anti-Acne Preparation

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.     

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.     

Correlation of Dissolution-Dialysis Rates with Bioavailability of Nitrofurantoin Solid Dosage Forms

The correlation of in-vitro dissolution-dialysis rates of solid dosage forms with in-vivo bioavailability was investigated. Dissolution-dialysis measurements were made of 50mg and 100mg tablets and capsules of Nitrofurantoin commercial products. The samples used represented product lots whose bioavailability had been previously reported. The dissolution-dialysis medium used was pH 7.2 phosphate buffer. A cellulose dialysis membrane was used. A high degree of correlation was osbserved between apparent dialytic rate constant (K_app) of the drug and reported in-vivo bioavailability parameters for all 50mg tablets. But the 50mg capsule K_app value, measured under the same test conditions, was higher and did not correlate with the tablet data. However a value correlating with tablet data was obtained when the stirring speed was reduced from 100 RPM to 10 RPM. A satisfactory correlation was not obtained for the 100 mg dosage forms. This might be due to bladder drug saturation reported to occur at higher dose levels of Nitrofurantoin.     

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.     

Development of Controlled Release Formulations of Ketoprofen for Oral Use

Microencapsulated forms of ketoprofen were formulated using polymers and polymer combinations and their in-vitro release characteristics were evaluated against pure ketoprofen using Vanderkamp 600 dissolution test apparatus. Suspensions of cellulose acetate phthalate were prepared and various quantities of drug, glycerin, tween 80, span 80, methocel and avicel were added and the resulting solution was passed through a peristaltic pump into a hardening solution. Beads were formed, dried and the release of the drug was studied at various time intervals in a dissolution medium of simulated intestinal pH. The dissolution studies of the ketoprofen demonstrated differences in drug release properties depending on composition and method of preparation. A formulation of Methocel beads with equal proportions of the two surfactants released its drug content over a period of 12 hours in a zero-order fashion. Rapid drug dissolution was seen when the formulations contained Tween 80 as a surfactant. Varying the drug to CAP ratio in the suspension from 0.1 to 0.4 did not appear to alter dissolution. It is concluded that proper control of the formulation can give any desirable release from ketoprofen formulations.     

An In-Vivo Bioequivalence Study of a New Nifedipine Extended Release Dosage Form, 'Opticaps'

A single dose fasting cross over study was carried out in human volunteers comparing Nifedipin-Mepha 20 retard Opticaps® capsules to Adalat® retard tablets. Opticaps® is a newly developed release formulation containing an active ingredient in a “semi solid” matrix within a hard gelatin capsule. Pharmacokinetic variables were calculated from the nifedipine plasma concentration data and evaluated statistically. The results showed Nifedipin-Mepha 20 retard Opticaps® capsules to be bioequivalent to Adalat® retard in all respect. Primary parameters were calculated by fitting the mean plasma concentration data for a two compartment open first order absorption model with lagtime using the computer PCNONLIN program. The parameter's obtained were used to simulate blood levels for a multiple dose administration of 20 mg nifedipine every 12 hours.     

A Comparative Study of the In Vitro and In Vivo Release of Dexamethasone from a Spray-On Bandage and Timed Release Aerosol

The formulation of several dexamethasone topical delayed release aerosol preparations was studied. Ethylcellulose and tributyl citrate were the film-forming agent and plasticizer, respectively, for the spray-on bandage formulation. The aerosol timed release preparation contained dexamethasone microcapsules suspended in a fluorocarbon aerosol propellant by isopropyl myristate and fumed silica. Both preparations were evaluated using an in vitro method which measured the release of dexamethasone hourly for eight hours. In vitro studies showed that each of the formulations delayed the release of dexamethasone. In the in vivo tests aerosols were sprayed on the unabraded back area of rabbits and the increased 17 - hydroxycorticosteriod urine levels at 24, 48, and 72 hours indicated dexamethasone absorption. In vivo studies indicated that absorption did not occur with the timed release preparation containing dexamethasone microcapsules. However, dexamethasone from the spray-on bandage preparation was absorbed over 72 hours. A commercially marketed topical dexamethasone cream was used for comparison in evaluating the two experimental formulations; however, in vivo studies showed that no absorption occurred with this preparation.

In recent years, a great deal of work has been directed towards the application of medicated polymeric films or tissue adhesives onto the skin to treat minor dermatological problems or serious skin wounds. Among the factors to be considered are: incorporation of a specific active ingredient, the mode of application and the dosage form. Lange and Fang (1,2) developed spray-on bandages using water soluble resins and water as the solvent. Fischl (3) evaluated the effectiveness of a cyanoacrylate monomer in closing skin incisions without affecting wound healing. Bhaskar and Cutright (4) showed that butyl cyanoacrylate could be successfully used as a surface dressing while reducing the degree of inflammation. Sciarra and Gidwani (5,6) reported on the release of gentian violet from selected polymer and plasticizer combinations and established various polymer-plasticizer combinations which could be applied as an aerosol spray. Other studies (7,8) have shown that ethylcellulose and a thermoplastic polyamide resin have potential use in spray-on bandage formulations.

The results indicated that the anti-infectives were released from the films and the spray-on bandages reduced the degree of infection about the wound.

The process of microencapsulation has been applied to various industrial and medical uses. Microcapsules can be prepared so that the encapsulated material will be released slowly. There are various methods of microencapsulation including coacervation, phase separation, interfacial polymerization, an electrostatic method, and vacuum metalization and they have been successfully used with selected drugs (9-13).

The purpose of this study was to develop and evaluate different aerosol formulations containing a therapeutic agent which can be slowly released. In vitro and in Vivo systems were used to evaluate the release and absorption of the drug in the test animals.     

An In-Vivo Bioequivalence Study of a New Nifedipine Extended Release Dosage Form, ‘Opticaps’

Abstract

A single dose fasting cross over study was carried out in human volunteers comparing Nifedipin-Mepha 20 retard Opticaps® capsules to Adalat® retard tablets. Opticaps® is a newly developed release formulation containing an active ingredient in a “semi solid” matrix within a hard gelatin capsule. Pharmacokinetic variables were calculated from the nifedipine plasma concentration data and evaluated statistically. The results showed Nifedipin-Mepha 20 retard Opticaps® capsules to be bioequivalent to Adalat® retard in all respect. Primary parameters were calculated by fitting the mean plasma concentration data for a two compartment open first order absorption model with lagtime using the computer PCNONLIN program. The parameter's obtained were used to simulate blood levels for a multiple dose administration of 20 mg nifedipine every 12 hours.     

Medicament Release from Ointment Bases: I. Indomethacin. In Vitro and in Vivo Release Studies

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.     

Investigation of Prolonged Drug Release from Matrix Formulations of Chitosan

A hydrocolloidal matrix system containing complexes of chitosan was investigated for preparation of sustained release tablets and examined in-vitro.

Theophylline tablets using chitosan as a sustained release base were evaluated. It was found that when chitosan is used in a concentration of more than 50% of tablet weight, an insoluble non-erosion type matrix was formed. Tablets prepared with a chitosan concentration of less than 33% were fast releasing.

Chitosan used in a concentration of about 10% acted as a disintegrant and the drug was dissolved within an hour.

Citric acid slowed down the release rates of chitosan based theophylline tablets. Theophylline tablets using carbomer-934P as a sustained release base were evaluated. Carbomer-934P in lower concentrations forms an erosion type matrix. In order to produce a twenty-four (24) hour sustained release tablet, more than 10% concentration of carbomer-934P is needed. Combination with chitosan and carbomer-934P produced slower releasing tablets.

A hydrocolloidal erosion type matrix was formulated using chitosan, carbomer-934Pand citric acid. Only 10% of chitosan was needed to prepare theophylline sustained release tablets in these mixtures.

The dose dumping potential of chitosan tablets due to rapid disintegration in alkaline media was eliminated by preparing hydrated erosion type matrix systems.     

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

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.     

Formulation design of an HPMC-based sustained release tablet for pyridostigmine bromide as a highly hygroscopic model drug and its in vivo/in vitro dissolution properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0-t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

Solid lipid nanoparticles incorporating melatonin as new model for sustained oral and transdermal delivery systems

melatonin (MT) is a hormone produced by the pineal gland at night, involved in the regulation of circadian rhythms. For clinical purposes, exogenous MT administration should mimic the typical nocturnal endogenous MT levels, but its pharmacokinetics is not favourable due to short half-life of elimination. Aim of this study is to examine pharmacokinetics of MT incorporated in solid lipid nanoparticles (SLN), administered by oral and transdermal route. SLN peculiarity consists in the possibility of acting as a reservoir, permitting a constant and prolonged release of the drugs included. In 7 healthy subjects SLN incorporating MT 3 mg (MT-SLN-O) were orally administered at 8.30 a.m. MT 3 mg in standard formulation (MT-S) was then administered to the same subjects after one week at 8.30 a.m. as controls. In 10 healthy subjects SLN incorporating MT were administered transdermally (MT-SLN-TD) by the application of a patch at 8.30 a.m. for 24 hours. Compared to MT-S, Tmax after MT-SLN-O administration resulted delayed of about 20 minutes, while mean AUC and mean half life of elimination was significantly higher (respectively 169944.7 +/- 64954.4 pg/ml x hour vs. 85148.4 +/- 50642.6 pg/ml x hour, p = 0.018 and 93.1 +/- 37.1 min vs. 48.2 +/- 8.9 min, p = 0.009). MT absorption and elimination after MT-SLN-TD demonstrated to be slow (mean half life of absorption: 5.3 +/- 1.3 hours; mean half life of elimination: 24.6 +/- 12.0 hours), so MT plasma levels above 50 pg/ml were maintained for at least 24 hours. This study demonstrates a significant absorption of MT incorporated in SLN, with detectable plasma level achieved for several hours in particular after transdermal administration. As dosages and concentrations of drugs included in SLN can be varied, different plasma level profile could be obtained, so disclosing new possibilities for sustained delivery systems.     

Use of Buffers in Matrix Capsule Formulations

Abstract

Relatively few reports have appeared in the literature on the formulation of the hydrophilic matrix capsule as compared to the matrix tablet. This study was concerned with the development of a matrix capsule formulation to control the release rate of the drug specifically through the incorporation of buffers. One of the characteristics of hydrophylic matrix drug delivery systems is that the initial rate of release is high. The release rate is gradually brought under control as the diffusional barrier of hydrating polymers is established. Many weak bases are more soluble at a gastric pH than at neutrality. Such drugs are generally unsuitable for matrix systems since constant rates of drug release under the dynamic conditions of increasing pH make release rate control difficult. However, by using an appropriate buffer system it was possible to suppress the initial release in acid by decreasing the solubility of the drug within the environment of the capsule matrix thereby controlling the rate of drug release. A buffered matrix capsule of an investigational drug was administered to normal healthy subjects in order to examine if a sustained plasma profile could be achieved. The absorption rate of the drug was calculated according to the Wagner-Nelson method. A dissolution test method was developed which correlated well with the in vivo data by selecting appropriate buffers and agitation rates. Capsule formulations exhibiting several different release rates between 6 and 24 hours were then prepared. The dissolution test conditions used for the drug release study were based upon the in vivo - in vitro correlation.     

Formulation Design of an HPMC-Based Sustained Release Tablet for Pyridostigmine Bromide as a Highly Hygroscopic Model Drug and its In Vivo/In Vitro Dissolution Properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0–t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

Design and in Vitro Evaluation of a Controlled Release Drug Delivery System of Sulfasomidine

A controlled release oral drug delivery system of Sulfasomidine was developed by spray congealing micropelleting technique using gelatin as the embedding matrix. The pellets were hardened by treating with Formalin-Isopropanol mixture. The in vitro release rate studies of Sulfasomidine from the micropelleted dosage form, revealed that the drug release can be prolonged upto eight hours and not more than 39% of the embedded drug released in the first hour of the in vitro dissolution study. The in vitro release patterns correlated with the reported in vivo studies. The method of formulation was optimized.     

Studies of floating dosage forms of furosemide: in vitro and in vivo evaluations of bilayer tablet formulations

For the purpose of enhancement the bioavailability of furosemide (FR), a floating dosage form with controlled release of FR was designed in this study. Because of the lower solubility of active material in the gastric medium, it was first enhanced by preparing an inclusion complex of FR with beta-cyclodextrin (beta-CD) in a 1:1 proportion using the kneading method. Following the design of dosage form, bilayer floating tablets were prepared. After dissolution rate studies were performed using the continuous flow-through cell method, the formulation that provided delivery of active material near the target profile was given to six healthy male volunteer subjects, and in vivo tests were performed. It was determined by radiographs that floating tablets prepared by adding BaSO4 stayed in the stomach for 6 hr. Further, values of the area under the plasma concentration-time curve (AUC) obtained with the floating dosage form were about 1.8 times those of the conventional FR tablet in blood analyses; maximum and minimum plasma concentrations were also found to be between the desired limits. In urine analyses, the peak diuretic effect seen in classical preparations was decreased and prolonged in floating dosage forms. Also, a considerably significant correlation was detected between in vivo results and in vitro data of the dissolution rate, and it was concluded that the modified continuous flow-through cell method is usable for in vitro dissolution rate tests of floating dosage forms.     

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

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     

Inclusion Complexation of Lorazepam with β — Cyclodextrin

The preparation of an inclusion complex of Lorazepam, a benzodiazepine antianxiety agent with β -cyclodextrin is described. The inclusion compound was prepared by the homogeneous coprecipitation method in the molar ratio of 1:2 of the drug and β -cyclodextrin respectively. The formation of inclusion complex was evaluated by UV spectral studies, IR studies, X-ray diffractometry, and Differential Thermal Analysis. The solubility and in-vitro drug release studies indicated that the complex form of the drug significantly increase the solubility and the dissolution rate compared to the free form. Tablets prepared with Lorazepam- β -cyclodextrin complex also showed a significant increase in dissolution of the drug indicating that P-cyclodextrin plays an important role in the solubilization of the drug.