Effects of Silicium Dioxide on Drug Release from Suppositories

Silica gel is frequently introduced into lipophilic excipients for suppositories as a viscosity agent, to prevent drug sedimentation in the melted mass, and to decrease release rate. The effect of silica gel (Aerosil 200) concentration on the availability of some drugs frequently used in suppositories in different unitary doses was studied. When silica gel concentration in the excipient was increased, a decrease in aminophylline and aminophenazone release rate was observed. Paracetamol in small unitary doses has shown a tendency to increase release rate at higher silica gel concentrations. This behavior was even more evident in suppositories containing promethazine hydrochloride, while for those containing benzydamine hydrochloride the increase in release rate with increasing silica gel concentration was evident for all drug doses. However, the behavior was a consequence of the trend of suppository viscosity during drug release. As a consequence of both the drug and silica gel being discharged, the viscosity progressively decreased with an increased silica gel concentration. The effect on drug availability was conditioned by silica gel concentration, as well as the type and dose of the drug, which could act on the shape of the suppository inner structure that is responsible for viscosity and mobility of drug particles.     

Suppository formulation of amodiaquine - In vitro release characteristics

In vitro release characteristics of amodiaquine hydrochloride from suppositories were studied. Results showed that water soluble bases (polyethylene glycol and glycero-gelatin) and water miscible synthetic fatty base (Witepsol W45) are superior to natural fatty bases (theobroma oil and shea butter) in terms of their ability to release amodiaquine hydrochloride.

The in vitro availability of amodiaquine from polyethylene glycol suppository (the suppository which gave the highest rate and extent of release) was compared with its in vitro availability from tablets (Camoquin^R) under the same experimental conditions. Polyethylene glycol suppository was found to be superior to the tablet.     

Sustained Release of Diclofenac from Polymer-Containing Suppository and the Mechanism Involved

Sustained release of diclofenac sodium (DcNa) from suppositories composed of triglycerides and polymer was investigated by dissolution testing through an artificial membrane. DcNa was slowly released from a suppository containing carboxyvinyl polymer (CVP), and the extent of the release decreased with the amount of CVP added. Little effect was noted with the addition of other water-soluble polymers, such as hydroxyethylcellulose (HEC), xanthan gum, and polyvinylalcohol (PVA). When sodium benzoate was used instead of DcNa, a similar result was obtained with the addition of CVP. The result of release rate analysis together with the viscosity and pH in these cases showed that the reduction of solubility and diffusion due to sodium exchange between DcNa and CVP played an important role in the sustained release from the suppository. Also, in comparison with the results when CVP was not used, the plasma concentration profile of diclofenac after the administration of CVP suppository displayed a twofold longer half-life time.     

Sustained release of diclofenac from polymer-containing suppository and the mechanism involved

Sustained release of diclofenac sodium (DcNa) from suppositories composed of triglycerides and polymer was investigated by dissolution testing through an artificial membrane. DcNa was slowly released from a suppository containing carboxyvinyl polymer (CVP), and the extent of the release decreased with the amount of CVP added. Little effect was noted with the addition of other water-soluble polymers, such as hydroxyethylcellulose (HEC), xanthan gum, and polyvinylalcohol (PVA). When sodium benzoate was used instead of DcNa, a similar result was obtained with the addition of CVP. The result of release rate analysis together with the viscosity and pH in these cases showed that the reduction of solubility and diffusion due to sodium exchange between DcNa and CVP played an important role in the sustained release from the suppository. Also, in comparison with the results when CVP was not used, the plasma concentration profile of diclofenac after the administration of CVP suppository displayed a twofold longer half-life time.     

Evaluation of Dika Fat as a Suppository Base II: Thermal and Release Characteristics of Blended Dika Fat Suppositories

Thermal parameters such as capillary melting temperature (CMT), softening temperature (ST) and liquefaction temperature (LT), as well as drug release parameters were used as bases for evaluating the suitability of dika fat as a suppository base. Mean values of the thermal parameters for pure dika fat were generally higher than the values normally required for an ideal suppository base. Blending the fat with a vegetable oil was found to be suitable in adjusting the thermal properties to acceptable values. Two vegetable oils -Avop oil and palm kernel oil-were used and were found to produce statistically non-significant effects on the physical properties of the suppositories. The release of diazepam from the suppositories presented varying mechanisms, but the rate of release was attributed to the oil-water partition coefficient of the drug.     

Release Characteristics and Bioavailability of Norfloxacin from Suppository Bases

Abstract

The in vitro release of norfloxacin (a new broad spectrum antimicrobial agent whose pharmacokinetics are characterised by varied gastrointestinal absorption and irregular plasma level) from different suppository bases was studied in order to obtain suitable formulation with good release and satisfactory drug concentrations in plasma. The bioavailability of suppositories containing 200 mg drug made from the bases that showed the best in vitro release was investigated. The release rate was in the order of PEG 400, 1540, 4000 mixture in ratio of 20: 33: 47 respectively > Witepsol H1S > Witepsol W 35 > Witepsol E 75. Addition of Tween 20, Tween 80 and Myrj 45 to the Witepsol members greatly increased the release rate especially at surfactant concentration of 5 × 10 mol.g. of the drug.     

Ketoprofen suppository dosage forms: in vitro release and in vivo absorption studies in rabbits

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c10-c18) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c10-c18) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.     

Ketoprofen Suppository Dosage Forms: In Vitro Release and in Vivo Absorption Studies in Rabbits

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c₁₀–c₁₈) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c₁₀–c₁₈) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.     

Inter-Laboratory Reproducibility of Release Tests for Suppositories

Inter-laboratory reproducibility of representative release tests, namely paddle, Muranishi and dialysis tubing methods for suppositories were investigated using two kinds of suppositories of indomethacin, oily and water-soluble types. The inter-laboratory differences for the water-soluble suppository determined by paddle and modified Muranishi methods were small whereas the differences for the oily suppository determined by Muranishi and dialysis tubing methods were large. The release rate of oily suppository by Muranishi method was significantly reduced when the cylindrical cell containing suppository was placed slightly lower. The release rate by dialysis tubing method was decreased by addition of a small volume of test fluid into the dialysis tube. These variables probably contributed to the inter-laboratory differences for the oily suppository. Neither Muranishi or dialysis tubing method should be employed for quality control of oily suppositories unless their reproducibility is significantly improved.     

Dissolution of Suppositories III: Effect of Insoluble Polyvinylpyrrolidone on Acetaminophen Release

Abstract

Previously reported studies from this laboratory have demonstrated the usefulness of a new apparatus for suppository dissolution study. Acetaminophen suppositories gave slow release and it was posited that addition of a disintegrating agent commonly used in tablet manufacture would increase this release rate. To test the hypothesis, four PEG blends were used as bases as in the previous studies. Each contained 320 mg acetaminophen and 1%, 5%, or 10% of insoluble polyvinylpyrrolidone (Polyplasdone XL^R). One thousand milliliters of phosphate buffer, pH 8.0 to approximate rectal pH was employed as the dissolution media and maintained at 37.5°. A constant agitation rate of 2 5 and 50 rpm was used. Acetaminophen was assayed spectrophotometrically at 243 nm. Comparative dissolution profiles at the various agitation rates and with the concentrations of polyvinylpyrrolidone were developed. Addition of insoluble polyvinylpyrrolidone increased the dissolution rate constant and dissolution half-times at the two agitation rates. While the disintegration aid increased release, this release was not linear with respect to disintegrating agent concentration.

Release of acetaminophen from suppositories and the bioavailability of acetaminophen Erom suppository bases have not received much study. Feldman reported that the rate of bioavailability of suppositories was extremely variable and might not produce a clinically noted response (1). Maron and Ickes, however, reported that acetaminophen suppositories were clinically as effective an antipyretic as were tablets (2).

Pagay, et al. studied the influence of the vehicle on the bioavailability of acetaminophen suppositories using a modified beaker method with a media of pH 7.0 and an agitation of 25 rpm (3). These researchers correlated the dielectric constant of the base to acetaminophen bioavailability. Commercial suppositories were not discussed.

A recent report by Palmieri (4) discussed release of acetaminophen from laboratory prepared PEG bases and commercially available suppositories. Dissolution half-times for laboratory prepared suppositories at 50 rpm ranged from 8 minutes for Base A to 22 minutes for Base D. The commercially available acetaminophen suppositories had a dissolution half-time of 90 minutes at 50 rpm. Because of these apparently slow release rates, it was posited that addition of a disintegrating agent would increase the release of acetaminophen from the polyethylene glycol base sup-positores. Polyplasdone XLR, (5) a crosslinked insoluble homopolymer of n-vinyl-2-pyrrolidone was used in an attempt to increase the release rate.     

Dissolution of Suppositories III: Effect of Insoluble Polyvinylpyrrolidone on Acetaminophen Release

Previously reported studies from this laboratory have demonstrated the usefulness of a new apparatus for suppository dissolution study. Acetaminophen suppositories gave slow release and it was posited that addition of a disintegrating agent commonly used in tablet manufacture would increase this release rate. To test the hypothesis, four PEG blends were used as bases as in the previous studies. Each contained 320 mg acetaminophen and 1%, 5%, or 10% of insoluble polyvinylpyrrolidone (Polyplasdone XL^R). One thousand milliliters of phosphate buffer, pH 8.0 to approximate rectal pH was employed as the dissolution media and maintained at 37.5°. A constant agitation rate of 2 5 and 50 rpm was used. Acetaminophen was assayed spectrophotometrically at 243 nm. Comparative dissolution profiles at the various agitation rates and with the concentrations of polyvinylpyrrolidone were developed. Addition of insoluble polyvinylpyrrolidone increased the dissolution rate constant and dissolution half-times at the two agitation rates. While the disintegration aid increased release, this release was not linear with respect to disintegrating agent concentration.

Release of acetaminophen from suppositories and the bioavailability of acetaminophen Erom suppository bases have not received much study. Feldman reported that the rate of bioavailability of suppositories was extremely variable and might not produce a clinically noted response (1). Maron and Ickes, however, reported that acetaminophen suppositories were clinically as effective an antipyretic as were tablets (2).

Pagay, et al. studied the influence of the vehicle on the bioavailability of acetaminophen suppositories using a modified beaker method with a media of pH 7.0 and an agitation of 25 rpm (3). These researchers correlated the dielectric constant of the base to acetaminophen bioavailability. Commercial suppositories were not discussed.

A recent report by Palmieri (4) discussed release of acetaminophen from laboratory prepared PEG bases and commercially available suppositories. Dissolution half-times for laboratory prepared suppositories at 50 rpm ranged from 8 minutes for Base A to 22 minutes for Base D. The commercially available acetaminophen suppositories had a dissolution half-time of 90 minutes at 50 rpm. Because of these apparently slow release rates, it was posited that addition of a disintegrating agent would increase the release of acetaminophen from the polyethylene glycol base sup-positores. Polyplasdone XLR, (5) a crosslinked insoluble homopolymer of n-vinyl-2-pyrrolidone was used in an attempt to increase the release rate.     

In-Vitro Release and In-Vivo Availability of Chloro-Quine Phosphate Formulated Suppositories

Abstract

Chloroquine phosphate suppositories were formulated using witepsol H15 as a model base. The physicomechanical properties of the prepared suppositories were studied. In-vitro drug release as well as in-vivo availability were determined and compared with those from commercial tablets containing the same dose of the drug (250 mg). In addition, the effect of pH of the different segments of GIT on the partition coefficient of the drug was tested

Results revealed that formulated suppositories exhibit good mechanical properties as well as high release characteristics. Volunteers received suppositories showed urine peak level after 2 hrs while with those administered the tablets the peak was reached after 3 hrs. The total amounts released were 60% and 48% from the administered dose in case of suppositories and tablets respectively. The higher bioavailability of the medicament after rectal therapy is explained on the basis of the partition coefficient data. The obtained values were 0.667, 0.941 and 5.333 at pH 1.2, 6.8 and 7.4 respectively. Volunteers used the formulated suppositories did not suffer from any GI irritation which is accompanying the oral administration of the drug. The proposed formula had no irritating effect on the rectum     

Release Property of Progesterone from a Mixed-Base Suppository Consisting of Witepsol® W35 and Witepsol® E85

The mechanism of drug release from progesterone suppositories that consist of two types of hard fat (Witepsol® W35 and Witepsol® E85) was investigated. The strength, the thermodynamic characteristics, the surface structures, the drug release property, methylene blue penetration into suppositories, and change of surface structure after the dissolution test were employed for detecting characteristics of progesterone suppositories. The formulation with a mixing ratio of Witepsol W35 and Witepsol E85 at a 1:1 ratio showed the maximum strength value. The peak temperature of the suppositories showed a tendency to increase with increases in the ratio of Witepsol E85. The maximum height of the profiles measured with laser microscopy, from 20.8 μm to 29.2 μm, reached a maximum after 3 h of the dissolution test. When the suppositories were immersed in pH 7.4 phosphate buffer containing 0.5% methylene blue at 37°C, the penetrating area increased with time. The weight of the suppositories also increased with time. According to these findings, it was suggested that the release of drug from a mixed type of suppository containing progesterone was via the matrix and pores.     

Non-destructive prediction of the drug content of an acetaminophen suppository by near-infrared spectroscopy and X-ray computed tomography

The purpose of this study is to develop non-destructive methods to determine the drug content of suppositories using near-infrared (NIR) spectrometry and X-ray computed tomography (XCT). The suppository samples (acetaminophen content: 0, 100, 200, 300, 400 and 500?mg/suppository) consisted of acetaminophen powder and hard fat. NIR spectra of 18 standard suppository samples were recorded, and the data were divided into two wave number ranges, 4000–10?000?cm^?1 (LR), and 4280–6650?cm^?1 (SR). The best calibration model was determined to minimize the standard error of cross-validation (SECV) by the leave-one-out method in the partial least squares regression (PLS). Sliced XCT images of the suppositories were measured, and apparent density (AD) was evaluated using the image of the sample. The NIR models gave the best correlation coefficient constant (R) values, since the results for LR and SR gave straight lines with R of 0.9274 and 0.9707, respectively. The AD of the suppositories by XCT increased with increasing drug content, and the relationship between the AD and drug content had a straight line with R of 0.9958. Both NIR and X-ray CT performed accurate measurements of suppository samples through plastic packaging.     

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.     

Evaluation of Dika Fat as a Suppository Base

Abstract

Dika fat, a solid vegetable fat, derived from the seeds of Irvingia qabonensis was evaluated as a suppository base for aspirin, aminophylline and chloroquine phosphate. The result show that the suppositories formulated with dika fat blends satisfied the pharmaceutical requirements of drug release and stability. A change in colour observed with aminophylline preparations may be due to a physical interaction between the drug and base. The observed change in colour did not however change the in vitro release of the drug.     

Evaluation of Dika Fat as a Suppository Base

Dika fat, a solid vegetable fat, derived from the seeds of Irvingia qabonensis was evaluated as a suppository base for aspirin, aminophylline and chloroquine phosphate. The result show that the suppositories formulated with dika fat blends satisfied the pharmaceutical requirements of drug release and stability. A change in colour observed with aminophylline preparations may be due to a physical interaction between the drug and base. The observed change in colour did not however change the in vitro release of the drug.     

Evaluation of Cefmetazole Rectal Suppository Formulation(s)

The objective of this study was to determine formulation parameters necessary to develop a cefmetazole suppository. Three 1 gram cefmetazole rectal suppository formulations were compared using in-vitro testing of melting behavior, dissolution times and fracture weight; and in-vivo dog studies of the three suppository formulations compared to IM single dose. The in-vivo study compared the dosage forms in four dogs by a cross-over design. The formulation containing one gram of sodium 5-methoxysalicylate as adjuvant gave a relative bioavailability of 29.4%, while the suppository containing sodium salicylate as adjuvant gave 17.5% relative bioavailability. The formulation which did not contain adjuvant neither dissolved properly in-vitro nor produced observable plasma levels during the in-vivo dog study. Despite the relatively large size (4.9 grams), the suppositories were easily inserted and no leakage occurred from medium-sized dogs. Proctoscopic examinations were performed following blood collection for each dose period. The suppositories were well tolerated as administered in this study. No clinical signs or symptoms of inflammation or irritation of the colon of the dogs dosed once weekly for four weeks with the suppository were noted. Blood levels obtained from the 1 g cefmetazole rectal suppositories are sufficient to be effective against many infectious diseases caused by certain pathogens. The data from the present investigation warrants further studies of the tolerance and pharmacokinetics of the 1 gram cefmetazole rectal suppository in man.     

In-vitro release of diazepam from conventional and double-layer polyethylene glycol suppositories

Abstract

A dissolution cell of simple design has been devised specifically for the assessment of hydrophilic suppositories. The measured total percentage release of three conventional diazepam formulations has been measured and interpreted in terms of appropriate kinetic microconstants. The desirability of assessing such tests in terms of a dissolution half-life is discussed.

A novel hydrophilic double-layer suppository has been formulated and its measured dissolution profile is described both mechanistically and in terms of suitably derived kinetic equations. The initial total percentage release of this formulation was significantly greater than that of the conventional suppositories which were tested. It is suggested that a double-layer suppository of this type could be therapeutically advantageous in the treatment of epilepsy.     

Evaluation of the percutaneous absorption of chlorpromazine from PLO gels across porcine ear and human abdominal skin

Objective: The overall objective of this work is to determine the percutaneous absorption of chlorpromazine hydrochloride from pluronic lecithin organogels (PLO gels) and verify the suitability of topically applied chlorpromazine hydrochloride PLO gels for use in hospice patients for relieving symptoms such as vomiting and nausea during the end stages of life.

Methods: PLO gels of chlorpromazine hydrochloride were prepared using isopropyl palmitate (IPP) or ricinoleic acid (RA) as oil phase. In vitro percutaneous absorption of chlorpromazine hydrochloride was assessed through porcine ear and human abdominal skin. Further, the theoretical steady state plasma concentration (C_ss) of chlorpromazine was calculated from the flux values.

Results: The pH, viscosity, and stability of both PLO gels prepared with IPP and RA were comparable. The thixotropic property of RA PLO gel was found to be better than that of IPP PLO gel. The permeation of chlorpromazine hydrochloride was higher from RA PLO gel than from IPP PLO gel and pure drug solution. Theoretical C_ss of chlorpromazine from pure drug solution, IPP PLO gel and RA PLO gel were found to be 1.05, 1.20, and 1.50?ng/ml, respectively. PLO gels only marginally increased the flux and theoretical C_ss of chlorpromazine.

Conclusion: From this study, it is clearly evident that PLO gels fail to achieve required systemic levels of chlorpromazine following topical application. Chlorpromazine PLO gel may not be effective in treating nausea and vomiting for hospice patients with swallowing difficulties.