Ketoprofen sustained-release suppositories containing hydroxypropylmethylcellulose phthalate in polyethylene glycol bases

In this study, conventional and sustained-release suppositories of ketoprofen (KP) were prepared and the effects of suppository bases and the inert matrix material (hydroxypropylmethylcellulose phthalate, HP 55) on in vitro release of ketoprofen suppositories were investigated. Suppositories containing 100 mg ketoprofen were prepared by the fusion method. Witepsol H15, Massa Estarinum B, and polyethylene glycols (PEG) were used as examples of hydrophobic and hydrophilic bases, respectively. Sustained-release suppositories of KP were prepared by using HP 55. Weight variation, content uniformity, breaking (hardness) and melting range tests were then conducted on these formulations. In vitro release and diffusion rate tests were also carried out according to the USP XXII basket method and the Muranishi method, respectively. The results show that the rate of release of KP is very slow for Witepsol H15 and Massa Estarinum B bases. However, KP was released very rapidly from the PEG bases in the conventional suppositories. On the other hand, HP 55 might be useful as a vehicle for sustained release preparations of ketoprofen in suppository form. It was shown from the kinetic assessment of release data that the best fit was achieved with zero-order kinetics.     

Investigation of the relationship between melting-related parameters and in vitro drug release from vaginal suppositories

The effect of temperature on drug release from meteneprost potassium vaginal suppositories was investigated using a dissolution test based on the USP I apparatus. Comparison of the dissolution results with the DSC melting behaviour revealed that drug release was extremely slow until melting of the suppository was essentially complete. The melting behaviour of the meteneprost potassium suppositories was also varied by preparing suppositories from bases with higher and broader melting ranges. The observed dissolution behaviour (at 37 degrees C) confirmed that drug release increased as the melting temperature of a particular suppository decreased. Differential scanning calorimetry, viscosity and dilatometry methods were used to characterize the suppository melting process. The effects of suppository melting range, melt temperature and composition were investigated with respect to in vitro drug release. Methodology for the HPLC determination of meteneprost in suppositories and in dissolution media are also reported.     

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

Salbutamol is a selective beta(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.     

Preparation and In vitro Evaluation of Naproxen Suppositories

The aim of this work was to develop the best formulations for naproxen suppositories. The effects of different bases and surfactants on the physicochemical characteristics of the suppositories were determined by several tests such as weight variation, melting point, assay, hardness, and release rate. All formulations met the standard criteria for tested physicochemical parameters; weight variation (97-112%), content uniformity (97-105%), melting point (4.66-8.7 min) and hardness tests (>5400 g). Based on release rate studies, hydrophilic, and lipophilic bases without surfactants were not suitable bases for naproxen suppository. Amongst the formulations containing surfactants only Witepsol H15 with 0.5% w/w of Tween 80 and Witepsol W35 with 0.5% of cetylpyridinium chloride were suitable and released nearly complete drug during 30 and 60 min, respectively. This study demonstrates the effects of incorporation of known agents on the in vitro release characteristics of naproxen suppository.     

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°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.     

硫酸沙丁胺醇缓释胶囊的研制

以硬脂酸为主要辅料,采用熔融制粒法,制备了硫酸沙丁胺醇绥释胶囊,并对其溶出度进行了研究。     

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 (C_max). Bioavailabilities and C_max 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 (T_max), mean absorption time (MAT) and mean residence time in the plasma (MRT) than Witepsol suppository. The T_max 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 C_max, 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.     

Pharmacokinetics and anti-hypertensive effect of metoprolol tartrate rectal delivery system

The main aim of this work was to develop rectal suppositories for better delivery of metoprolol tartrate (MT). The various bases used were fatty, water soluble and emulsion bases. The physical properties of the prepared suppositories were characterized such as weight variation, hardness, disintegration time, melting range and the drug content uniformity. The in vitro release of MT from the prepared suppositories was carried out. The evaluation of the pharmacological effects of MT on the blood pressure and heart rate of the healthy rabbits after the rectal administration compared to the oral tablets was studied. Moreover, the formulation with the highest in vitro release and the highest pharmacological effects would be selected for a further pharmacokinetics study compared to the oral tablets. The results revealed that the emulsion bases gave the highest rate of the drug release than the other bases used. The reduction effect of the emulsion MT suppository base on the blood pressure and heart rate was found to be faster and greater than that administered orally. The selected emulsion suppository base (F11) showed a significant increase in the AUC (1.88-fold) in rabbits as compared to the oral tablets. From the above results we can conclude that rectal route can serve as an efficient alternative route to the oral one for systemic delivery of MT which may be due to the avoidance of first-pass effect in the liver.     

地奥司明栓剂的制备及质量控制研究

目的 制备地奥司明栓剂,建立其质量控制方法。方法 以地奥司明为原料药,以聚乙二醇6000、聚乙二醇400和甘油为基质,用热熔法制备含药栓剂,并对其外观、含量均匀度、融变时限、质量差异进行评价。结果 地奥司明栓剂外观呈棕色,室温下能保持较好的硬度,含量均匀度、质量差异、融变时限、溶出度均符合栓剂要求。结论 本方法制备的地奥司明栓剂符合栓剂的质量要求,适合作为地奥司明的新剂型进行开发。     

硫酸沙丁胺醇延迟释药片的制备及质量控制

目的:制备硫酸沙丁胺醇延迟释药片,并建立其质量控制方法。方法:用硫酸沙丁胺醇、乳糖、羧甲基淀粉钠、羟丙基甲基纤维素、乙基纤维素、微晶纤维素制备成缓释片,再用肠溶型丙烯酸树脂包衣,制备成延迟释药片;采用高效液相色谱法测定该延迟释药片中硫酸沙丁胺醇的含量,同时对其体外释放度进行测试,并考察其稳定性。结果:硫酸沙丁胺醇检测浓度在1.25～20.00μg/ml范围内与吸收峰面积积分值线性关系良好;平均回收率为98.60%(RSD=0.66%);制备的延迟释药片在服用后约5h定时释药,且在各项稳定性试验中,释放度均无明显变化。结论:本制剂组方合理,制备工艺简便可行,质量稳定可控。     

羟基喜树碱纳米脂质载体的制备及体外释放

采用“熔融乳化-高压均质法”制备以PEG40硬脂酸酯、PEG100硬脂酸酯修饰的纳米脂质载体PEG40-NLC和PEG100-NLC，并考察释放装置、NLC中脂质材料用量及释放介质流速对体外释放的影响。结果表明，PEG40-NLC和PEG100-NLC在桨-反向动态透析法和流通池-动态透析法中的释放曲线相似，而在转篮-动态透析法中的释放曲线与前二种装置的释放曲线均有显著性差异。随着NLC脂质材料用量增大，释放过程中药物扩散作用增强。对流通池法，释放介质流速增大，药物的释放加快。     

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.     

生物粘附性达那唑缓释栓剂的处方筛选与体外释放度考察

目的 :生物粘附性达那唑栓剂的处方筛选 ,并考察其体外释放规律。方法 :以羟丙甲基纤维素 (HPMC)为缓释材料 ,将等量聚乙二醇6000(PEG6000)和聚乙二醇600(PEG600)以熔融法制备含不同HPMC量的缓释栓剂 ,考察释放度与HPMC用量之间的关系。结果 :随着HPMC用量增加 ,栓剂释药减慢 ,当HPMC与PEG的比例为1∶6 5时 ,栓剂中药物在体外12h内缓慢释放 ,符合一级释放规律。结论 :生物粘附性骨架材料HPMC能延缓达那唑从栓剂中释放 ,当HPMC与PEG的比例为1∶6 5时栓剂能达到设计要求。     

Influence of cellulose ether mixtures on ibuprofen release: MC25, HPC and HPMC K100M

The influence of cellulose ether derivatives on ibuprofen release from matrix tablets was investigated. Raman spectroscopy and differential scanning calorimetry (DSC) experiments were used, in order to examine the compatibility between the matrix components: both excipients and ibuprofen. While both the DSC and Raman results did not detect any incompatibilities, DSC revealed the existence of some drug:excipient interactions, reflected by variations in the hydration/dehydration processes. Formulations containing mixtures of polymers with both low and high viscosity grades-methylcellulose (MC25) or hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K100M), respectively--were prepared by a direct compression method (using 20, 25, and 30% of either MC25 or HPC). The tablets were evaluated for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, surface area, and volume. Parameters such as the mean dissolution time (MDT) and the dissolution efficiency (DE) were calculated in all cases. The solid formulations presently studied demonstrated a predominantly Fickian diffusion release mechanism.     

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.     

复方甲硝唑缓释栓的制备及体外释放度考察

目的:制备适合老年人用的复方甲硝唑缓释栓,并考察其体外释放度。方法:以甲硝唑和硝酸咪康唑为主药,羟丙基甲基纤维素为骨架材料,利用热熔法制备缓释栓剂;同时采用篮法,以0.5%十二烷基硫酸钠溶液为介质,硝酸咪康唑为对象,进行体外释放度评价。结果:所制制剂外观、性状良好,可持续12h释药,体外释放行为符合Higuchi方程。结论:该制剂制备工艺合理、简单易行,并具有良好的体外释药特性,符合缓释制剂的要求。     

Influence of Cellulose Ether Mixtures on Ibuprofen Release: MC25, HPC and HPMC K100M

The influence of cellulose ether derivatives on ibuprofen release from matrix tablets was investigated. Raman spectroscopy and differential scanning calorimetry (DSC) experiments were used, in order to examine the compatibility between the matrix components: both excipients and ibuprofen. While both the DSC and Raman results did not detect any incompatibilities, DSC revealed the existence of some drug:excipient interactions, reflected by variations in the hydration/dehydration processes. Formulations containing mixtures of polymers with both low and high viscosity grades—methylcellulose (MC25) or hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K100M), respectively—were prepared by a direct compression method (using 20, 25, and 30% of either MC25 or HPC). The tablets were evaluated for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, surface area, and volume. Parameters such as the mean dissolution time (MDT) and the dissolution efficiency (DE) were calculated in all cases. The solid formulations presently studied demonstrated a predominantly Fickian diffusion release mechanism.     

Enhanced release of solid dispersions of etodolac in polyethylene glycol

This work examines the release of etodolac from various molecular weight fractions of polyethylene glycol (PEG) solid dispersions. Solid dispersions of etodolac were prepared in different molar ratios of drug/carrier by using solvent and melting methods. The release rate of etodolac from the resulting complexes was determined from dissolution studies by use of USP dissolution apparatus 2 (paddle method). The physical state and drug:PEG interaction of solid dispersions and physical mixtures were characterized by X-ray diffraction (XRD), infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The dissolution rate of etodolac is increased in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. The solid dispersion compound prepared in the molar ratio of 1:5 by the solvent method was found to have the fastest dissolution profile. The physical properties did not change after 9 months storage in normal conditions.     

茶碱脉冲栓剂的制备及体外释药性考察

目的:制备茶碱脉冲栓剂并评价其体外释药性质。方法:以处方基质中泊洛沙姆、羧甲基纤维素钠(CMC-Na)、聚乙二醇6000(PEG6000)、PEG400的不同用量为因素,以释药时滞及累积释药率为指标采用单因素法筛选栓剂处方组成,并考察填充不同内容物(茶碱原料、茶碱-PVP物理混合物和茶碱-PVP固体分散体)的栓剂的累积释药率。结果:较优基质处方组成为70%泊洛沙姆、6%CMC-Na、12%PEG6000、12%PEG400,其体外释药时滞为4h,90min累积释药率为85%以上;3种填充不同内容物的栓剂累积释药率分别为58.8%、65.8%、91%。结论:所制茶碱脉冲栓剂具有较好的脉冲释药作用。     

Improvement of availability of allopurinol from pharmaceutical dosage forms I - suppositories.

Solid dispersion and crystallization of a very slightly water-soluble drug, allopurinol, were prepared using urea, sodium salicylate and beta-cyclodextrin (beta-CD) as carriers. The spectroscopic infra-red (IR), differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) data indicate a role of these carriers in decreasing the crystallinity of allopurinol and complexing abilities. Solid dispersion and crystallization of the drug with these carriers were used in suppository formulations to investigate their role in enhancement of drug release through the membrane barrier. The bases used included Suppocire AM and the mixture of polyethylene glycols (PEGs). The release rates of allopurinol from lipophilic and hydrophilic suppository bases were examined and compared with those obtained for their inclusion compounds incorporated in the same bases. The prepared suppositories were evaluated for in-vitro drug release, when fresh and on storage. The release of pure allopurinol from the lipophilic base was remarkably higher than that from the hydrophilic one. The release of allopurinol from lipophilic as well as hydrophilic bases was significantly enhanced by crystallization of the drug from 5% w/v of sodium salicylate. Allopurinol crystallized from sodium salicylate, showed enhanced release reaching about 100% in 1 h from the Suppocire AM base. The obtained data from these experiments proved the superiority of the PEG formulations containing coevaporates of the drug to sodium salicylate, ratio 1:1, or of the drug to beta-CD, ratio 1:2; T(90%),12 and 36 min, respectively. A significant decrease of uric acid excretion in rabbits was observed after rectal administration of suppositories containing allopurinol crystallized from sodium salicylate.