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.     

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.     

Preparation and Evaluation of Controlled Release Indomethacin Microspheres

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.     

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.     

Correlation of Urinary Excretion with in Vitro Dissolution Using Four Dissolution Methods for Aiipicillin Capsules

The in vitro release of ampicillin from 8 brands of ampicillin capsules, using four dissolution apparatus, was determined. These apparatus were the USP dissolution apparatus, the USP paddle stirrer apparatus, the USP disintegration apparatus and the spiral—stirrer apparatus. Significance of the differences in dissolution between brands and between methods were tested. Analysis of variance of the dissolution data showed statistically significant differences between brands and between methods at selected time. The paddle method showed superior discriminating capacity than the other methods. Correlation between the present in vitro data and the previously reported in vivo data, in order to find the apparatus capable to mimic in vivo release of ampicillin from capsules, was also determined.     

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.     

Controlled Transdermal Mucolytic Delivery System

Bromhexine a mucolytic agent was studied to explore for dermal route of administration. The formulations were based on commercial eudragit polymers and polyvinyl pyrrolidone.

Two systems i.e., Matrix and Pseudolatex were studied for their comparative performance evaluation in in vitro. The various combinations of hydrophobic (Eudragit RL-100) and hydrophilic (PVP 40,000) polymers were used to prepare the both matrix and pseudolatex topical systems. The prepared systems were studied for in vitro diffusion using a Franz diffusion cell. Study revealed that the relative concentration of hydrophobic to hydrophilic polymers determines the drug diffusion and across the skin permeation of the drug. Both the systems were noted to be stable, however, the drug release and across the skin permeability of drug from pseudolatex system recorded to be better and uniform. Preliminary studies on bromhexine are indicative of its potentiality for transdermal preparation and establish the need for in vivo evaluation.     

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

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.     

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     

Advances in Dissolution Technology: Design, Pros and Cons

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.     

Development and Validation of a Drug Release Rate Method for a Water Soluble Drug in a Liposome Preparation

An in vitro method was developed to determine the rate of drug release from a liposome preparation. Three batches of liposomes containing orciprenaline sulphate were evaluated for release of drug over a 24 hour period in an end-over-end tumbler device. Intra and inter day precision studies indicate good reproducibility for this test method. This method is easy to use in drug development and quality control laboratories to evaluate drug release from liposome formulations.     

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

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.     

Optimization of Slow-Release Tablet Formulations Containing Montmorillonite II. Factors Affecting Drug Release

The influence of electrolytes, surfactants in the dissolution medium, and particle size of drug and montmorillonite on the in vitro release of the soluble model drug sodium sulfathiazole from directly compressed slow-release tablets containing 20% drug and 30% magnesium aluminum silicate was investigated. The presence of electrolytes in the dissolution media decreased the release from the tablets. A decrease in release was also observed in deionized water when sodium chloride was included in the tablet formulation. The surface tension of the media appeared to have little influence on the dissolution rate of the drug. Varying the particle size of the drug had a greater effect on release rates than varying the particle size of the montmorillonite clay.     

Suppository Dissolution Testing: Apparatus Design and Release of Aspirin

Present methods of in vitro dissolution testing for suppositories were found to be lacking in universal acceptance, reproducibility, and difficult to perform. Initially a USP basket for tablet dissolution with one-hundred milliliters of phosphate buffer of pH 8 to approximate rectal pH was used. A slow constant stirring speed was maintained by means of a Hanson dissolution drive control and hollow spindle-stirrer apparatus as well as a constant temperature of 37.5±0.1° Aspirin in polyethylene glycol bases gave plausible, reproducible results with this apparatus. However, oil bases (i.e. cocoa butter) gave unacceptable, irreproducible results since the base blocked the openings of the basket mesh. This report describes a modified basket method where the basket is polyurethane of the same size and configuration as the USP basket. The basket described has twelve linear vertical slots of 0.25 mm width allowing for a porosity of 52%. Results of aspirin release from four PEG bases prepared in this laboratory are presented and discussed. The results were reproducible. Five commercially available suppositories were also tested in the above described manner.

Dissolution, or drug release has been extensively studied and reported for only a few selected tablets and other oral solid dosage forms. Dissolution has been shown to be the best in vitro parameter to correlate release of drug to bioavailability. Dissolution of drug from non-oral dose forms however, has not been extensively investigated. Past research into drug release from suppository bases has taken a number of approaches, some of which are not very scientifically sound or reproducible. Gibaldi and Gundhofer in 1975 studied bioavailability of aspirin from commercially available suppositories (1). These researchers reported “the rate of absorption of aspirin was sufficiently slow to raise considerable doubt as to whether efficaceous body levels of aspirin or salicylate are obtained after a single dose” (1). Other reports also question the absorption of aspirin from suppositories (2, 3).

Because present methods of in vitro dissolution testing appeared lacking in universal acceptance and reproducibility or were difficult to perform, this study was undertaken to develop an apparatus for suppository dissolution. To test the reproducibility of the devised method, four PEG base blends were used as vehicle for aspirin. Several commercially available products were also tested to determine their release patterns.     

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

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.     

Microencapsulation by Emulsion Non-Solvent Additicin Method

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.     

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

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.     

磁性载药微球的制备

合成了含有铁粉和抗癌药的明胶微球,这种微球在体外磁场的作用下具有定位作用。微球的粒径在０２～１３ｍｍ之间,粒径大小是由制备条件决定的。微球可用戊二醛进行固化。研究了微球体外药物的释放规律     

Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation

Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30°C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.     

明胶微球/磷酸镁基骨水泥复合药物缓释体系的构建

采用乳化交联法制备出粒径主要分布在100~300 μm的载药明胶微球, 分析了交联剂含量、药物含量和转速对载药率和包封率的影响及药物含量和转速对微球粒径的影响。对载药明胶微球与磷酸镁基骨水泥进行复合, 探讨微球降解过程中复合体系孔隙率的变化及其在体外药物释放的规律, 以期获得一种具有药物缓释性能的多孔磷酸镁基复合骨水泥。结果表明, 随着葡萄糖浓度增加, 载药率和包封率先上升再下降; 随着药物含量的增加, 载药率保持上升, 包封率先上升后下降; 随着转速增加, 载药率和包封率均下降。综合分析, 在转速为400 r/min、葡萄糖浓度为0.5 g/mL、药物与明胶质量比为1:2的条件下制备的载药明胶微球载药量较高, 且粒径合适。将复合不同比例该载药微球的磷酸镁基骨水泥浸泡在Tris-HCl缓冲溶液中进行体外药物释放研究, 结果表明: 在释放前期(0~10 h)药物释放速率较快, 之后药物释放明显减缓。7 d后, 微球几乎降解完全, 药物释放率达到60%~89%, 达到了一定的药物缓释效果。