Witepsol H15 Research Articles

Preparation and investigation of acetyl salicylic acid-caffeine complex for rectal administration

An acetyl salicylic acid-caffeine complex was prepared and evaluated for the potential use in rectal administration. The results revealed the formation of a complex between acetyl salicylic acid and caffeine in a 1:1 molar ratio by a charge transfer mechanism. The effects of acetyl salicylic acid and complex on the rectal tissues showed destruction in the mucosal epithelium in case of acetyl salicylic acid; however, no change in the rectal tissues was noticed upon the administration of the complex. The effect of suppository bases on the release of the complex was studied using Witepsol H15 as fatty base and polyethylene glycols (PEG) 1000 and 4000 as a water soluble suppository base. The release profiles of acetyl salicylic acid and the complex were faster from PEG than from that of Witepsol H15. The percent release for the complex and acetyl salicylic acid from PEG base were 45.8, and 34.9%, respectively. However, it was 8.7 and 7.8%, respectively, from Witepsol H15 fatty base. The release kinetic was found to follow the non-Fickian diffusion model for complex from the suppository bases. It was concluded that acetyl salicylic acid caffeine complex can be used safely for rectal administration.

Improvement of the in vitro release of omeprazole from suppository bases using Kollicoat IR

Solid dispersion of a slightly water soluble drug, omeprazole (OME), was prepared using different concentrations of Kollicoat IR by a spray drying technique. The physicochemical properties of the drug alone and its microparticles were investigated using differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD). The analyses showed that omeprazole transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the characteristic of the crystalline peaks. Solid dispersion of the drug with this hydrophilic polymer was used in suppository formulations to investigate their role in enhancement drug release. The bases used in this study include hydrophilic base, polyethylene glycol (PEG), and lipophilic bases such as Suppocire AM and Witepsol H15. The release of omeprazole from a hydrophilic base was higher than that of a lipohilic base. Also, the release of drug from Supocire AM was superior to Witepsol H15. Incorporation of solid dispersion of drug using Kollicoat IR prepared by spray drying technique increases the release of OME from its suppository bases. The Kinetic study of the release of drug and its solid dispersion was carried out and the results indicated that the release of drug from different suppository bases is diffusion model.

Preparation and investigation of acetyl salicylic acid-caffeine complex for rectal administration.

An acetyl salicylic acid-caffeine complex was prepared and evaluated for the potential use in rectal administration. The results revealed the formation of a complex between acetyl salicylic acid and caffeine in a 1:1 molar ratio by a charge transfer mechanism. The effects of acetyl salicylic acid and complex on the rectal tissues showed destruction in the mucosal epithelium in case of acetyl salicylic acid; however, no change in the rectal tissues was noticed upon the administration of the complex. The effect of suppository bases on the release of the complex was studied using Witepsol H15 as fatty base and polyethylene glycols (PEG) 1000 and 4000 as a water soluble suppository base. The release profiles of acetyl salicylic acid and the complex were faster from PEG than from that of Witepsol H15. The percent release for the complex and acetyl salicylic acid from PEG base were 45.8, and 34.9%, respectively. However, it was 8.7 and 7.8%, respectively, from Witepsol H15 fatty base. The release kinetic was found to follow the non-Fickian diffusion model for complex from the suppository bases. It was concluded that acetyl salicylic acid caffeine complex can be used safely for rectal administration.

In vivo and in vitro characterization of rifampicine suppositories

In this research, rifampicin suppositories were prepared due to the easy use of suppository administration in the elderly and the fact that plasma concentrations are higher than tablets. The suppositories were formulated with 100 mg of rifampicin using different bases, namely Witepsol H15, Witepsol S58, Witepsol E76, Polyethylene glycol PEG (two different formulations) and modified glycerogelatin (MGG) using the melting method. To optimize the drug release rate, different enhancers such as sodium lauryl sulfate (SLS) as an ionic surfactant, as well as Brij 92 as non-ionic surfactants, and Cetrimide as a cationic surfactant in different concentrations were chosen. The highest release of rifampicin was observed with formulations containing 0.4% SLS in Witepsol S58, 1.2% Cetrimide in Witepsol S58 and 0.4% Brij 92 in PEG2. The drug plasma levels after rectal administration were compared to those obtained after oral administration of the same dose. After 4 h, C max of rifampicin was 23.91 ± 2.74 μg/mL for the oral suspension vs. 43.03 ± 1.76 and 28.90 ± 1.37 μg/mL for PEG2 with 0.4% Brij 92 and Witepsol H15 with 1.2% Brij 92 suppositories. The comparative bioavailability of rifampicin from PEG2 with 0.4% Brij 92 and Witepsol H15 with 1.2% Brij 92 suppositories were 207.42 and 148.31% respectively, in relation to that after oral administration.

Physical and Release Properties of Metronidazole Suppositories

Purpose: A study was made of the effects of some bases and adjuvants on the physical and release properties of metronidazole suppositories with a view to providing more information for the optimization of the rectal formulation of metronidazole. Method: Suppositories (1g) containing 200mg of metronidazole each were prepared in witepsol (H15 and E75) and polyethylene glycol (PEG 2850 and 4650) bases, using different concentrations of Tween 80, sodium salicylate and methylcellulose as adjuvants. The setting time, solidification point and melting range of the suppositories were determined, along with their crushing strength, disintegration time and the time for 80% of metronidazole to be released from the suppositories (t80). Results: The ranking of setting time for the suppositories was witepsol H15 > PEG 2850 > witepsol E75 > PEG 4650, while the ranking of solidification point, melting range, crushing strength, disintegration time and the time for 80% of metronidazole to be released from the suppositories (t80) was the reverse of that for setting time. Optimal concentrations of Tween 80 and sodium salicylate were observed for the suppository formulations. Using Kitazawa plots, all formulations showed two dissolution rate constants, k1 and k2 intersecting at time t1, with formulations containing 5 to 20 % w /w of methylcellulose exhibiting a third dissolution rate constant, k3 intersecting with k2 at time t2. Conclusion: The physical and release properties of metronidazole suppositories are influenced considerably by the bases and adjuvants employed. Tween 80 and sodium salicylate can probably be used to formulate only immediate-release suppositories while methylcellulose can be useful for sustained-release metronidazole suppositories. Some insight into these inferences can be obtained from parameters derived from Kitazawa plots.

Development of Controlled Release Sildenafil Formulations for Vaginal Administration

Sildenafil is an active substance that has already been approved by FDA for human use. It is known to be an active compound for the treatment of sexual dysfunction in men. Some encouraging results have been published concerning the treatment of infertility with sildenafil in women, but there is no pharmaceutical preparation available. Therefore, various formulations were prepared and the most suitable sildenafil release was found to be with the sildenafil-containing suppositories prepared using Eudragit RS100 and Witepsol H15. The vaginal insert with EVAC 210 polymer containing sildenafil has also provided sildenafil release for a longer period.

Effects of interacting variables on the release properties of chloroquine and aminophylline suppositories

Purpose: The individual and interaction effects of formulation variables on the release of suppositories were investigated using a 23 factorial experimental design. The variables studied were nature of base (B), type of drug (D), and presence of surfactant (S). Method: Suppositories were formulated with theobroma oil and Witepsol H15 as bases at ‘low' and ‘high' levels respectively. Chloroquine and aminophylline, both water-soluble drugs, were incorporated as active constituents at ‘low' and ‘high' levels respectively while Tween 80 was incorporated as surfactant in some of the formulations. Disintegration time and time taken for 50% of the drug to dissolve were used as assessment parameters. Results: The inclusion of surfactant in the suppository formulation proved to be the most significant variable in the formulation. The ranking for the individual coefficient values for the formulations was S>>B>D for disintegration time DT and S>>>D>B for the dissolution parameter t50. While the ranking for the interaction effects was B-D>B-S>S-D on DT and on t50 S-D>B-S>B-D. Conclusion: The results suggest that in formulating water-soluble drugs such as chloroquine and aminophylline as suppositories in a hydrophobic base, the presence of a surfactant is the most influential variable. Keywords: Suppositories, chloroquine, aminophylline, surfactant, interacting variables. > Tropical Journal of Pharmaceutical Research Vol. 3 (1) 2004: pp. 285-290

Determination of ibuprofen solubility in wax: A comparison of microscopic, thermal and release rate techniques

The solubility of ibuprofen in Witepsol H15, a semi-solid wax matrix, was determined using microscopy, Higuchi release rates and HyperDSC (high speed differential scanning calorimetry); solubility values of 15–20%, 18.6% and 12.7% w/w resulted from the three techniques, respectively. Microscopy was useful in additionally examining crystal size, shape and homogeneity. Release rate experiments showed that release from these formulations followed Higuchi kinetics with an inflection in release rate constant at the drug loading corresponding to drug solubility. HyperDSC not only measured solubility but also determined the melting point of the formulation. The results from these three techniques correlated well, suggesting that the simpler techniques of microscopy or HyperDSC are appropriate to determine the solubility in semi-solid pharmaceutical formulations.

Determination of Flurbiprofen Solubility in a Wax-Based Matrix Using Hyperdsc, Higuchi Release Kinetics and Microscopy

The solubility of flurbiprofen in Witepsol H15, a semi-solid wax matrix, was determined using microscopy, Higuchi release rates and HyperDSC (high speed differential scanning calorimetry); solubility values of 20–30% w/w, 9.56% w/w and 20.13% w/w resulted from the three techniques, respectively. Microscopy was useful in additionally examining crystal size, shape and distribution. Release rate experiments showed that release from these formulations followed Higuchi kinetics with an inflection in release rate constant at the drug loading corresponding to drug solubility. HyperDSC not only measured solubility but also determined the melting point of the formulation. The results from microscopy and HyperDSC correlated well with release kinetics providing a much lower solubility value. Higuchi release kinetics are based on release from liquids and ointments whereas melting waxes provide a more complex system which may account for the variation in solubility estimation using this technique. This study further demonstrated the use of HyperDSC as a robust, high throughput technique to measure the solubility of a drug in a semi-solid.

Preparation and in vitro evaluation of suppositories of halofantrine hydrochloride

Halofantrine (HF) hydrochloride is commercially available only as oral dosage forms. Limitations of oral dosing of the drug coupled with non-availability of the safe parenteral preparations prompted the need to develop and evaluate suppository HF formulations, which may serve as a practical alternative. The effects of type of suppository base and incorporation of non ionic surfactants on in vitro release characteristics of HF from suppositories were investigated. The release rates were determined using a modification of the continuous flow bead-bed dissolution apparatus for suppositories. The results showed that the drug release from water-soluble base (polyethylene glycol) was significantly greater than that from lipophilic bases (Shea butter and Witepsol H15) (P surfactants (Tweens 20 and 80, Spans 20 and 60) at different concentrations did not improve the in vitro availability of the drug from composite polyethylene glycol base (1500:4000, 80:20, w/w) suppositories. The extent of drug release was very low (maximum of 2.3%) It is suggested that further studies are required for development of modalities to enhance the release of halofantrine from polyethylene glycol suppositories so as to optimize this dosage formulation of the drug.

In-vitro and in-vivo availability of mebeverine hydrochloride suppositories

Mebeverine hydrochloride suppositories were prepared using Witepsol H15 suppository base. The effect of different concentrations of various enhancers (surfactants, amino acids and osmotic modifiers) on the drug release form the prepared suppositories was studied. The results showed that mebeverine hydrochloride suppositories containing Brij 35 (2%) and urea (10%) were superior to the other formulations containing the tested enhancers. These formulae showed the highest release rates (K = 0.083 ± 0.004 min-1 and 0.111 ± 0.005 min-1 , respectively) that followed first-order kinetics with t50% of 8.35 ± 0.45 min and 6.24 ± 0.33 min, respectively. Therefore, these two formulae with the control suppositories were subjected to in vivo study in albino rabbits compared to the commercial Duspatalin® tablets and intravenous injection. Higher Cmax (1770.26 ± 165.46 ng.ml-1) within shorter Tmax (0.75 ± 0.20 h) was observed after rectal administration of the control suppositories compared to that of commercially available film-coated tablets (Duspatalin® – 135 mg). A significant difference (p≤0.05) between the absolute bioavailability of Duspatalin® tablets (27.09 ± 3.80%) and control suppositories (46.66 ± 1.72%) was detected. Statistically (p≤0.05), the mean residence time (MRT) after oral administration of Duspatalin® tablets (3.16 ± 0.30 h) was significantly longer than that after the rectal administration of control suppositories (2.73 ± 0.30 h). suppositories containing 2% Brij 35 showed higher plasma levels of the drug (2766.11± 339.50 ng.ml-1) with an absolute bioavailability of 70.50 ± 10.51% compared to 27.09 ± 3.80% for Duspatalin® tablets.

Design of Controlled-Release Morphine Suppositories Containing Polyglycerol Ester of Fatty Acid

Controlled-release morphine suppositories were prepared by utilizing polyglycerol ester of fatty acid (PGEF). The addition of PGEF to fatty suppository base Witepsol H15 resulted in a decrease of morphine release rate from suppositories. Among PGEFs examined, decaglycerol heptabehenate (HB750) was the most effective additive for the controlled-release of morphine from fatty suppositories. The apparent viscosity of suppository bases increased with the increase in HB750 content, and good correlation was observed between the apparent viscosity of suppository bases at 37 degrees C and the amount of HB750 added in the mixed base. The in vitro release rate of morphine was decreased by the addition of HB750 and the release rate constant (Higuchi's rate constant) for morphine release was significantly correlated with the HB750 content in the mixed bases as well as the apparent viscosity of mixed bases, indicating that the release of morphine from the mixed bases could be regulated by the HB750 content in the mixed bases. After rectal administration of Witepsol H-15-HB750 mixed suppositories to dogs, plasma concentrations of morphine did not increase rapidly at early time periods, but relatively high levels of morphine in plasma were sustained for longer time periods. Mean residence time of morphine was considerably prolonged without changing relative bioavailability in the case of the mixed base suppositories containing 15-17% HB750, compared with the Witepsol H15 suppository, clearly indicating that the mixed bases containing HB750 are expected to be useful for the design of controlled-release morphine suppositories.

The role of various surfactants on the release of salbutamol from suppositories

Salbutamol is a selective β 2-adrenoreceptor agonist with different pharmacological effects. In this research because of the simplicity of suppository application in elderly and its higher plasma concentration than tablets as well as its particular indication in premature labour, salbutamol suppositories were prepared. The suppositories were formulated containing 10 mg of the drug and Witepsol H15, the oleaginous soluble base using melting method. To optimize the release rate of drug, different surfactants namely, sodium lauryl sulphate (SLS) as an ionic surfactant and Tween 80 as well as Arlacel 60 as non-ionic surfactants with different HLBs were chosen. The effect of surfactant concentration on the release rate of salbutamol from suppositories were also investigated. All prepared formulations fulfilled the specifications set down in British Pharmacopoeia. The results showed that Tween 80 (2%w/w) and SLS (0.75%w/w) caused an increase in dissolution rate of salbutamol from suppositories. As anionic surfactants, such as SLS, cause greater damage on mucosa than non-ionic surfactant, such as Tween 80, this study recommended that Tween 80 could be added in suppository formulation in order to increase the dissolution rate of salbutamol. It was also shown that the release rate of salbutamol altered linearly with the amount of Tween 80 in suppository formulations.

Evaluation of sustained release suppositories prepared with fatty base including solid fats with high melting points

To prepare the sustained release suppositories, solid fats such as polyglycerol ester of fatty acids (PGEFs) or beeswax were utilized with a fatty suppository base, Witepsol H15. PGEFs such as decaglycerol heptabehenate (HB750) and hexaglycerol pentastearate (PS500), and beeswax have relatively high melting points. The addition of PGEFs or beeswax to Witepsol H15 increased the apparent viscosity of suppository bases at 37 °C without any large change in the melting point of Witepsol H15. Moreover, the apparent viscosity of a mixed base with HB750, PS500 or beeswax at 37 °C was significantly correlated with the amount of each solid fat in a mixed base. The release of acetaminophen (AAP), a model drug, from suppositories was delayed by HB750, PS500 or beeswax, and an excellent correlation was observed between the apparent viscosity of these mixed bases and Higuchi’s rate constants in each mixed base suppository, suggesting that these solid fats could regulate the drug release from the mixed base suppositories by changing their viscosity. In the in vivo absorption study in rats, several suppositories made from Witepsol H15–HB750 or Witepsol H15–beeswax mixed bases prolonged the rectal absorption of AAP without reducing AUC. In conclusion, by using solid fats such as HB750 and beeswax with relatively high melting points, it is possible to control the rate of drug release from fatty base suppositories for maintaining the plasma concentration of drugs for longer time periods.

In vitro drug liberation and kinetics of sustained release indomethacin suppository

The aim of this study was to formulate sustained release (SR) suppositories containing indomethacin (IND) microspheres. In the first part of the study, IND microspheres were prepared by solvent evaporation method. Ethyl cellulose was used as polymer. Shape and surface charactheristics, particle size and size distribution of microspheres were determined. The effect of drug: polymer ratio and stirring rate on microsphere formation, average particle size, drug loading capacity and in vitro IND release were investigated. The highest drug loading capacity was found with 1:1 drug–polymer ratio. Stirring rate caused insignificant effect on drug loading capacity but particle size. Increase in stirring rate resulted in a decrease in particle size. In the second part, SR suppositories were formulated by incorporating IND microspheres having the highest drug loaded. The bases used were PEG mixtures (400:1500:4000) and Witepsol H15. Qualitative controls and IND assay on the suppositories were carried out. The drugs released were evaluated by in vitro dissolution tests. Comparative results of SR suppositories containing IND microspheres with that of conventional ones showed that the former has sustained effect up to 480 min in vitro. Release results were evaluated kinetically and the data was fitted (Bt) a kinetics.

In-vitro Evaluation and Vaginal Absorption of Metronidazole Suppositories in Rabbits

Vaginal suppository formulations of metronidazole were prepared using six different bases as Witepsol H15, Cremao, Ovucire WL2944, Ovucire WL3264, PEG 1500, PEG 6000. Three different dissolution methods were used to evaluate the in vitro drug release from the suppositories. The diffusion studies were performed through synthetic (cellophane) and natural membrane (rabbit vagina), but the drug did not show good permeation characteristics from natural membrane. Ovucire WL3264 suppositories of metronidazole labeled with 99mTc (Tecnetium-99m) were used for the vaginal absorption and biodistribution studies in the rabbits. Scintigraphic images were collected after vaginal administration of the labeled suppositories using SPECT gamma fitted with a low energy, high-resolution parallel hole collimator. The labeled drug showed high biodistribution in urine beside vaginal site.The results of this study suggested that the Ovucire WL3264 suppository of metronidazole prepared for vaginal infections could also be effective in the urinary infections.

PREPARATION AND IN VITRO EVALUATION OF SUSTAINED RELEASE SUPPOSITORIES OF INDOMETHACINE : İNDOMETAZİNİN SÜREKLİ ETKİLİ SUPPOZİTUVARLARININ HAZIRLANMASI VE İNVİTRO DEĞERLENDİRİLMESİ

Indomethacin (IM) sustained release suppositories were prepared by using a solid matrix of cellulose acetate phythalate (CAP) and trimethylamonium methacrylate chloride's (Eudragit RL and RS) as poorly soluble cariers. Witepsol H15 and polyethylene glycol (PEG) mixtures were used as examples of hydrophobic and hydrophilic bases, respectively. Disintegration time, fracture point and release experiments were conducted on the formulations. The results indicate that Eudragit RL/RS (1:1) combination was found more suitable than CAP as a matrix material. From the kinetic assesment of release data, the best fit was achieved with Q t kinetic

The release of isoconazole nitrate from different suppository bases: in-vitro dissolution, physicochemical and microbiological studies.

The influence of the suppository base on the in-vitro release of isoconazole nitrate was studied by dissolution, physicochemical diffusion and microbiological disk-diffusion methods. Vaginal suppository formulations containing 25 mg isoconazole nitrate for local treatment of vaginitis were prepared by a fusion method, using different hydrophilic and lypophilic suppository bases (PEG 6000, PEG 4000, PEG 1500, Witepsol H15, Novata BD and Cremao). In-vitro release rates were examined by dissolution, physicochemical diffusion and microbiological disk-diffusion methods. In the physicochemical investigations the pH indicators (pH 1-14) erythrosin B, thymol blue, bromocresol green, chlorophenol red, phenol red, and alkali blue were added to agar gels. The discs were placed onto the agar gels and 21 h later, the coloured zone diameters were measured. In the microbiological investigations, the discs were put on the inoculated plates with the suspension of Candida albicans (Institute Pasteur 628). The inoculated plates were incubated at 37 degrees C for 3 days, then the diameters of inhibition zones were measured. In the dissolution investigations release rates were in the order PEG 6000 > PEG 4000 > PEG 1500 > > Witepsol H15 > Cremao > Novata BD. The diffusion distance of isoconazole nitrate in the physicochemical investigation was in the order polyethylene glycols > Witepsol H15 > Novata BD. In the microbiological studies release rates were found with polyethylene glycols > Witepsol H15 > Novata BD > Cremao. The findings in the in-vitro studies suggested that polyethylene glycols are suitable bases for vaginal suppositories.

The release of isoconazole nitrate from different suppository bases: in-vivo release of drug labelled with 99mTc in rabbits.

The influence of the suppository bases on the in-vivo release of 99mTc-labelled isoconazole nitrate was investigated. The single-dose vaginal suppository formulations for local treatment of vaginitis were prepared by a fusion method using polyethylene glycols, Witepsol H15, Novata BD and Cremao. Prepared vaginal suppositories containing solid-labelled substance were applied to the vagina of rabbits and at 0, 2 and 24 h after administration, the amounts of radioactivity in the vagina were detected by the SPECT Gamma Camera and the release rates of the drug were calculated. The percent released was found to be in the following order; polyethylene glycol (PEG) 6000 > PEG 4000 > Witepsol > PEG 1500 > Novata BD > Cremao. The results obtained in both in-vitro and in-vivo studies indicated that the vaginal suppository of isoconazole nitrate prepared with polyethylene glycols could confidently be used in therapy.

Rectal absorption of omeprazole from suppositories in rabbits

Rectal absorption of omeprazole, a proton pump inhibitor, from suppositories was studied in rabbits. The suppositories were prepared by the conventional melting method with two types of bases, water-soluble polyethylene glycol (PEG) 4000 and oil-soluble Witepsol H15 bases, and administered intrarectally (ir) to rabbits at a dose of 10 mg omeprazole/kg. The plasma omeprazole concentration-time profiles of the two suppositories were compared with those following intravenous (iv) administration of the same dose. There were no significant differences between the two suppositories in bioavailabilities and peak plasma concentrations (Cmax). Bioavailabilities and Cmax of PEG- and Witepsol suppositories were 30.3 and 33.9%, and 7.0 and 5.6 μg/ml, respectively. However, PEG suppository showed significantly (P<0.05) shorter time to reach peak plasma concentration (Tmax), mean absorption time (MAT) and mean residence time in the plasma (MRT) than Witepsol suppository. The Tmax MRT and MAT were 25.0, 83.0 and 38.5 min for PEG suppository, but were 90.0, 122.5 and 78.0 min for Witepsol suppository, respectively. These differences between the two suppositories could be explained by the difference in the in vitro dissolution rates between the suppositories. The dissolution of omeprazole from PEG suppository was reportedly much faster than that from Witepsol suppository. It suggests that plasma profiles of omeprazole, especially Cmax, MAT and MRT, could be controlled by modifying thein vitro dissolution rate of the drug from the suppositories. Above results suggest that rectal suppository is worth developing as an alternative dosage form of omeprazole to the conventional oral preparations which need sophisticated treatments, such as enteric coating, to prevent acid degradation of the drug in the stomach fluid.