Effects of Silicium Dioxide on Drug Release from Suppositories

Abstract

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.     

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.     

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.     

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.     

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.     

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.     

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 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.     

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     

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.     

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.     

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.     

Peculiar effect of polyethylene glycol in comparison with triethyl citrate or diethyl phthalate on properties of ethyl cellulose microcapsules containing propranolol hydrochloride in process of emulsion-solvent evaporation

Plasticizers play a crucial role in various process of microencapsulation. In this study, the effect of incorporation of plasticizer in process of emulsion solvent evaporation was investigated on properties of ethyl cellulose (EC) microcapsules containing propranolol hydrochloride. The effect of plasticizer type and concentration were investigated on characteristics of microcapsules prepared from different viscosity grades of EC. Product yield, encapsulation efficiency, mean particle size, shape, surface characteristics, solid state of drug, and drug release profiles were evaluated. Product yield and encapsulation efficiency were not dependent on plasticizer type and concentration. However, encapsulation efficiency decreased with increase in EC viscosity grade in the most of the cases. The mean particle size was in the range of 724–797?μm and was not dependent on plasticizer type. Microcapsules formed in the presence of PEG had a very smooth surface with few pores. XRD and DSC studies revealed a reduction of drug crystallinity after microencapsulation especially in presence of PEG. The results showed that the presence of TEC and DEP with different concentrations had no marked effect on drug release from microcapsules containing different viscosity grades of EC. This was not the case when PEG was used, and despite its water solubility it reduced the drug release rate noticeably. The reduction in the drug release in the presence of PEG was concentration-dependent. The use of PEG as a plasticizer in process of emulsion solvent evaporation highly improved the EC microcapsule structure and retarded the drug release rate and therefore is recommended.     

Influence of Physicochemical Interactions on the Properties of Suppositories. III. Reeological Behaviour of Fatty Supfository Bases and its Effect on Spreading in Rats

The viscosity and other rheological properties of the molten base at rectal temperature can markedly affect the rate of release and absorption of drugs' from fatty suppositories. The rheograms of pure mono-acid triglycerides, their mixtures and triglyceride suppository bases were determined at various temperatures using a rotational rheometer. Completely molten systems gave Newtonian behaviour, while incompletely molten mixtures, containing a suspension of higher melting triglyceride, exhibited plastic behaviour with thixotropy which reverted to Newtonian behaviour on removal, dissolution or melting of the higher melting component, The plastic yield values (67 Nm^-2) were less tnan the reported rectal pressure (300 Nm^-2), suggesting that they exert little effect on spreading in the rectum.     

Mucoadhesive delivery systems. II. Formulation and in-vitro/in-vivo evaluation of buccal mucoadhesive tablets containing water-soluble drugs

From the previous work (Part I), mucoadhesive formulae containing 5% CP/65% HPMC/30% lactose and 2% PC/68% HPMC/30% mannitol as well as formulae based on sodium carboxymethyl cellulose (SCMC) were selected. Medicated tablets were prepared using diltiazem hydrochloride (DZ) and metclopramide hydrochloride (MP) in two different doses (30 and 60 mg). The effect of drug and dose on the mucoadhesive properties and in-vitro drug release was evaluated. All formulae produced extended drug release (over 8 to 12 h). Polyacrylic acid based matrices (PAA) showed Fickian's diffusion release pattern for both drugs. SCMC ensured zero-order release for DZ, which deviated to anomalous behavior in case of MP. Doubling the dose significantly reduced the bioadhesion strength (p<0.05) with a slight improvement in drug release rate. The formulation of bilayer tablets containing drug-free layer and medicated layer enhanced the drug release without affecting the bioadhesive performance. The bilayer tablet formulated with 2% PC/68% HPMC/30% mannitol (PC2) was selected for studying the in-vivo metoclopramide release in four healthy volunteers. The tablet ensured controlled drug release for 12 h, in addition, good correlation (r=0.9398) was observed between in-vitro and in-vivo data. The effect of ageing on selected formulae containing DZ and MP, respectively, was studied. Storage at 40 degrees C and 75% relative humidity for 6 months didn't influence the mucoadhesive performance, however, an enhanced released rate was observed.     

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.     

Formulation development of allopurinol suppositories and injectables

Allopurinol was formulated into injectable and suppository dosage forms. The injectable formulation was prepared by dissolving allopurinol in a cosolvent system consisting of dimethyl sulfoxide (DMSO) and propylene glycol (v/v = 50/50). The stability of allopurinol in the cosolvent system was studied under accelerated storage conditions, and results indicate first-order degradation kinetics with an activation energy of 24.3 kcal/mol. The development of suppository dosage forms was performed by formulating allopurinol with polyethylene glycol (PEG) mixtures of different molecular weights. In vitro release profiles of suppositories formulated with different polyethylene bases were obtained in the pH 7.4 buffer solution using the USP 23 paddle method at 100 rpm. Results indicate that the release rate of the suppository formulations containing PEG 1500/PEG 4000 at the ratio (w/w) of 2.5/10 to 10/2.5 appeared to be similar. However, the addition of sodium lauryl sulfate in the suppository decreased the release rate of allopurinol significantly. A future study to establish in vitro/in vivo correlation (iv/ivc) is suggested.     

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.