Sustained-release Suppositories Research Articles

Modern Aspects of Suppositories: A Review

Suppositories are an underutilized dosage form. Suppositories are such types of dosage forms used to provide medication via the vaginal and rectal routes. Vaginal suppositories are commonly referred to as pessaries. It was developed from a formulation called Liquid Enema. Enema has a great disadvantage in that, it used to leak out of the cavity in which they were put. So, this led to the discovery of suppositories as an alternative method of medication. Suppositories can be described as semi-solid dose forms utilized to provide medications for therapeutic action via rectal, vaginal, or urethral routes, where they will melt or dissolve and deliver localized or systemic impact. It is composed of cocoa butter, PEG, and fatty base (and a few others) as main ingredients, and it comes in different shapes and sizes. Although suppositories were formulated it was not that stable inside the orifices and also used to draw out of it. So, in order to overcome the problem of leaking, researchers added some mucoadhesive substance to improve its stability. From here onward improvement in the suppositories started as an alternative medication other than oral dosage form. The current article aimed to fabricate descriptive information about the advancement of suppositories. These advancements are Bi-layered Suppositories, Homogeneous Plain Suppositories, Hollow Suppositories, Effervescent Suppositories, Gel suppositories, Sustained Release Suppositories, etc.

Development and Characterization of Tramadol Hydrochloride Rectal Suppository

Tramadol is a centrally acting analgesic drug. Rectal administration of tramadol is useful in the treatment of post-operative pain or malignant pain in cases where it cannot be administered orally. Rectal suppositories of tramadol hydrochloride were prepared using different bases and polymers and the effect of different additives on in vitro release of tramadol hydrochloride was studied. The agar-based suppositories were non-disintegrating/non-dissolving. All the prepared suppositories were evaluated for various physical parameters like weight variation, drug content and hardness. In vitro release study was performed by USP type I apparatus. Addition of 10% w/w propylene glycol accelerates the release of tramadol hydrochloride significantly (P<0.05) as in A1, which may be due to decrease in the gel matrix of agar. In formulation A2, A3 Addition of HPMC (1%, 3% w/w) and in formulation A3 and A4 addition of PVP (1%, 3% w/w) retards the release significantly (P<0.05), which may be due to increase in the viscosity and gel strength of the polymer matrix. Hence, PVP, HPMC and similar polymers in higher concentration can be used to formulate sustained released suppositories. The sustained release suppositories can be prepared by addition of PVP, HPMC in agar-based suppositories. Keywords: Tramadol, Rectal suppositories, PVP, HPMC, Agar.

Hierarchical Bayesian approach applied to the formulation of sustained-release suppositories and dissolution profile modeling

In-Vitro Dissolution Study and Shelf Life Calculation of Developed Sol-To-Gel Ocular Drug Delivery System of Brimonidine for Conjunctivitis during Accelerated Stability StudyManu Babbar, Kanchan Kohli, Anil Bhandari

Sustained Release Bioadhesive Suppository Formulation for Systemic Delivery of Ornidazole: In-silico Docking Study

Abstract: Background and Objectives: Ornidazole is widely used as an antiprotozoal and antiamoebic drug and its onset of action is within 2 h. The major extent of the drug is metabolized in the liver and excreted in the urine and faeces. Hence, the present study of suppository formulation for sustained systemic delivery of ornidazole is significant which could minimize abdominal disturbances and nausea and delayed onset of action particularly after oral administration. Methods: Bioadhesive suppository formulations were prepared for systemic delivery of ornidazole via rectal and vaginal route. Results: The physical drug-excipient-interaction was confirmed by in-silico docking study. The affinity between drug-HPMC and drug-PEG was found to be -2 and -0.9 k cal/mol respectively. In vitro drug release of the suppositories varied depending on the viscosity grade of HPMC used and all have followed mostly diffusion controlled mechanism. The formulation containing HPMC K100 showed the most sustained release of ornidazole in both the dissolution fluid of pH 7.4 and 4.5 (54.53 and 41.89 % respectively after 360 min). Conclusion: In conclusion, present bio adhesive suppositories could be utilized for sustained systemic delivery of ornidazole via rectal and vaginal route. The findings of this work will contribute to the current knowledge and encourage future pre-clinical research. Key words: Ornidazole, Sustained release suppository, In-silico docking, Bioadhesive formulation, in-vitro dissolution.

Design and Evaluation of Sustained Release Suppositories of Carvedilol

Design and Evaluation of Sustained Release Suppositories of Carvedilol

Effect of bioadhesive agents on physico-chemical properties of suppositories

Dissolution rate of an active substance from suppositories may be altered by the qualitative and quantitative selection of suitable excipients. Thus, the accelerated-release or sustained-release suppositories can be manufactured. The objective of our study was to prepare the suppositories containing paracetamol in Novata BD and Novata BCF bases by the fusion method as well as to evaluate the influence of addition of the bioadhesive substances, namely: hydroxypropyl methyl cellulose (HPMC) and methylcellulose (MC) at concentrations of 5, 10, 15 and 20%, on the physico-chemical properties of suppositories. Assessment of the preparations were based on the outcomes of the following tests: uniformity of mass, uniformity of content of active substance, hardness of suppositories, softening time determination and the disintegration time of suppositories. Release of the active substance into the phosphate buffer at pH 7.2 was also performed. Content of the active substance was determined spectrophotometrically at 243 nm. On the basis of the obtained results it may be concluded that the addition of MC at concentrations of 15%, 20% and HPMC at concentrations of 5%, 10%,15%, 20% delays the release of active substance from suppositories. The physical properties of the prepared suppositories met the requirements of the Polish Pharmacopoeia, 9th edition.

Novel chronotherapeutic rectal aminophylline delivery system for therapy of asthma

The aim of this study was to develop a new chronotherapeutic pharmaceutical preparation as a sustained-release suppository for prevention and therapeutic use against bronchial asthma in the early morning. Sustained-release hollow-type (SR-HT) suppositories using sodium alginate (Alg-Na), sodium polyacrylate (PANa) or polyacrylate-PANa co-polymer (PA-PANa) as gelling polymers (gel agent) were prepared and pharmaceutical characteristics of these suppositories were investigated. Type A SR-HT suppositories comprised a suppository shell prepared with oleaginous base and containing aminophylline only or aminophylline with Alg-Na or PANa in the cavity (hollow space). Type B SR-HT suppositories comprised a suppository shell prepared with oleaginous base and gel agent (30%), with aminophylline in the hollow space. In drug-release studies, the acrylate polymer-containing suppositories showed linearity of delayed release rate, providing significantly decreased the highest concentration of theophylline in plasma ( C max) and delayed the time required to reach C max ( t max) and the mean residence time ( MRT) after rectal administrated in rabbits. In particular, suppositories containing PA-PANa maintained significantly higher theophylline concentrations than control suppositories at 12 h after rectal administration. Furthermore, histopathological examination indicated that these suppositories using acrylate polymers did not result in rectal lesions. The SR-HT suppository, particularly using PA-PANa as a gel agent, may thus be useful against nocturnal symptoms of asthma. In this study, we confirmed new formulation of sustained-release suppository for chronotherapy of theophylline using oily base material in combination with polymer such as PA-PANa. The hollow-type suppository containing oleaginous base and hydrophilic polymer in the shell could be useful device for rectal administration of various drugs with prolongation of plasma concentration.

Sustained-Release Progesterone Vaginal Suppositories 1-Development of Sustained-Release Granule-

Progesterone (P) is an important hormone for the establishment of pregnancy, and its administration is useful for luteal insufficiency. Considering the problems of commercially available oral and injection drugs, hospital-formulated vaginal suppositories are clinically used. However, since the half-life of P suppositories is short, it is difficult to maintain its constant blood concentration. To sustain drug efficacy and prevent side-effects, we are attempting to develop sustained-release suppositories by examining the degree of sustained-release of active ingredients. In this study, we examined the combinations of granulation methods and release systems for the preparation of sustained-release granules of P, and produced 13 types of sustained-release granules. We also examined the diameter, content, and dissolution of each type of granules, and confirmed that the sustained-release of all types of granules was satisfactory. Among the sustained-release granules, we selected granules with a content and a degree of sustained-release suitable for sustained-release suppositories.

徐放性プロゲステロン膣坐剤―第２報：開発と評価―

徐放性プロゲステロン膣坐剤―第２報：開発と評価―

Formulation and evaluation of tramadol hydrochloride rectal suppositories

Rectal suppositories of tramadol hydrochloride were prepared using different bases and polymers like PEG, cocoa butter, agar and the effect of different additives on in vitro release of tramadol hydrochloride was studied. The agar-based suppositories were non-disintegrating/non-dissolving, whereas PEGs were disintegrating/dissolving and cocoa butter were melting suppositories. All the prepared suppositories were evaluated for various physical parameters like weight variation, drug content and hardness. The PEG and cocoa butter suppositories were evaluated for macromelting range, disintegration and liquefaction time. In vitro release study was performed by USP type I apparatus. The prepared suppositories were within the permissible range of all physical parameters. In vitro drug release was in the order of PEG>Agar>cocoa butter. Addition of PVP, HPMC in agar suppositories retards the release. The mechanism of drug release was diffusion controlled and follows first order kinetics. The results suggested that blends of PEG of low molecular weight (1000) with high molecular weight (4000 and 6000) in different percentage and agar in 10% w/w as base used to formulate rapid release suppositories. The sustained release suppositories can be prepared by addition of PVP, HPMC in agar-based suppositories and by use of cocoa butter as base.

The Preparation and Evaluation of Sustained Release Suppositories Containing Ketoprofen and Eudragit RL 100 by Using Factorial Design

The preparation of ketoprofen (KP) sustained release (SR) suppositories was designed according to the 32 × 21 factorial design as three different KP:Eudragit RL 100 ratios (1:0.5, 1:1, 1:2), three particle sizes of prepared granules (250–500, 500–710, and 710–1000 μm) and two different PEG 400:PEG 6000 ratios (40:60, 50:50). The conventional KP suppositories were also prepared by using Witepsol H 15, Massa Estarinum B, Cremao and the mixture of PEG 400:PEG 6000. The dissolution studies of suppositories prepared were carried out according to the USP XXIII basket method in the phosphate buffer (pH = 7.2) at 50 rpm, and it was shown that the dissolution time was sustained up to 8 hours. According to the results of the factorial design, the most important independent variable on t50 and t80 was drug:polymer ratios. The log of partition coefficient of KP was determined as 1.46, showing the high affinity to the oily phase. n exponent and kinetic studies were conducted to explain diffusion mechanism, and it is understood that if the inert KP:Eudragit RL 100 ratio is increased in the particles, the Fickian difusion dominates and the best kinetic turns to Higuchi from the Hixson-Crowell. There is neither crystalline form of KP nor degradation product in the suppositories detected with the differential scanning calorimetry (DSC) studies. In addition to these studies, antiinflammatory activity of SR suppositories also determined that it was significantly extended according to the conventional suppositories.

Bioequivalence of progesterone sustained release suppository in rabbits.

To study the bioequivalence of a kind of progesterone sustained release suppository, a randomized cross-over study was conducted in 12 rabbits. A single rectal dose of 2.75 mg/kg progesterone sustained released suppository (tested formulation, T) and progesterone suppository (reference formulation, R) was administered; a multiple dose of 2.75 mg/kg was given up to seven times with an interval of 8 h. Concentrations in serum were determined by a competitive enzyme immunoassay. The main parameters of T were: for single and multiple doses, Cmax was 48.8 +/- 11.8 ng/mL and 43.5 +/- 9.4 ng/mL, Tmax was 0.5 +/- 0.3 h and 0.4 +/- 0.3 h, AUC(0-24 h) was 362.4 +/- 143 ng x h x mL(-1) and 310.6 +/- 70.3 ng x h x mL(-1), respectively. The relative bioavailability of T to R were (104.2 +/- 13.4)% and (111.4 +/- 19.1)%, respectively. Statistical analysis showed that the two formulations were bioequivalent and T had sustained released feature.

中小病院における院内製剤の品質評価―プロゲステロンちつ坐剤―

Progesterone (P) is an important hormone for achieving pregnancy, and administering it is a useful therapy for luteal insufficiency. However, owing to problems with existing oral preparations and injections, P is increasingly administered by the transvaginal route in suppository form in medical institutions. Since vaginal suppositories are not commercially available, each institution has to prepare its own.For P-containing vaginal suppositories prepared in our hospital, we conducted hardness, weight variation, content uniformity, and elution tests as well as a 6-month stability test in cold storage and pharamacodynamics testing in vivo. The results confirmed that they were uniform in quality and stable, and valid for use as pharmaceutical preparations in clinical practice.Furthermore, the sustained-release suppositories prepared by us were found to maintain adequate blood levels of P.

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 Studies on Sustained Release Suppository Formulations of Tiaprofenic Acid with Sucrose Fattv Acid Ester

The objective of this study was to evaluate the performance of Sucro Ester 7 (sucrose distearate) as additive for preparing sustained release suppositories of tiaprofenic acid. Suppocire AIM (semi-synthetic glycerides) was used as suppository base and formulations were prepared containing different ratios of sugar ester: Suppocire AIM. Content uniformity, disintegration time and in vitro release characteristics of suppositories were investigated. Significant decrease in the extent of drug release was observed with the increase in the content of sugar ester, which was due to the longer disintegration time of suppositories.

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.

Preparation and evaluation of tolmetin sodium conventional and sustained-release suppositories

Conventional suppositories of tolmetin sodium were prepared by using two different types of Witepsol as an oily base and two different ratios of polyethylene glycol 400: polyethylene glycol 4000 as an water-soluble base. In addition, sustained- release suppositories were prepared by adding Eudragit L-100 ta the suppositories. The effects of the suppository base and the ratios of the polyethylene glycol 400: polyethylene glycols 4000 on the in vitro release characteristics were investigated. The release rate of tolmetin sodium from the conventional suppositories prepared with polyethylene glycol was slower than the other suppositories prepared with Witepsol. All of the suppositories with Eudragit L-100 showed slow-release profiles and the drug release rates clearly depended on the Eudragit L-100 content. When dissolution results were evaluated kinetically, zero order kinetic was observed with the sustained- release suppositories of tolmetin sodium prepared with polyethyleneglycol 400: polyethyleneglycol 4000 by adding Eudragit L-100.

Topical treatment of vaginal candidosis with sertaconazole and econazole sustained-release suppositories

Objective: To compare the efficacy and safety of sertaconazole and econazole sustained-release suppositories in the treatment of vulvovaginal candidosis. Study design: 369 women with symptoms and signs of vulvovaginitis were enrolled in this multicenter, randomized, double-blind study. After clinical examination and vaginal sampling, 183 women were treated with a 300-mg sertaconazole suppository and the other 186 with a 150-mg econazole suppository. They were evaluated 1 week after treatment and those who were clinically uncured received a second suppository and were re-assessed 1 week later. All women were evaluated 1 month after the last administration. At each follow-up visit, clinical efficacy was assessed and a vaginal sampling was performed for microscopic examination and culture. Results: Of the 369 women included, only the 310 who had a positive culture for a strain of Candida were taken into account for efficacy analysis: 150 in the sertaconazole group and 160 in the econazole group. One hundred and five women (49 in the sertaconazole group and 56 in the econazole group) were not clinically cured after 1 week and received a second suppository. There were no differences between the two groups for the rates of clinical recovery (disappearance of signs and symptoms) and mycological recovery (negative culture), 1 week after the first application (62.1 and 67.7%, respectively), 1 week after the second application for women treated twice (72.3 and 80.6%, respectively) and for all patients 1 month after the last application (65.3 and 62.0%, respectively). Among the patients cured 1 week after the last application, the mycological recurrence rate after 1 month was significantly higher in the econazole group (32.7 vs. 19.8%, P=0.035). There was a trend towards better efficacy of sertaconazole after the first application, whereas the two treatments had similar efficacy in women treated twice. There were no serious adverse events and only local irritation was reported, without any statistically significant difference between the two groups. Conclusion: Single topical administration of sertaconazole and econazole had similar efficacy and safety but the former is associated with a lower rate of mycological recurrence one month after achieving a negative culture.

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

Sustained release double-layered progesterone suppository for luteal support therapy

A sustained release suppository containing progesterone with a double-layered structure was prepared for the treatment of the luteal phase defect. Hydroxypropylcellulose-H (HPC) and Carbopol-934P (CP) were used as bases of the inner layer and Witepsol W35 was used as a base of the outer layer. The strength of the inner layer (stick) decreased with the increase of the rate of content of HPC component. The strength of the stick which was prepared from a mixture of HPC and CP in a ratio of 1:1, was inverse by proportional to the rate of the addition of crystalline cellulose (CC) and the amount of released drug was proportional to the rate of the addition of CC. The area under the drug release curve of the stick containing 60% of CC in the base was about 12 times of the stick containing no CC (control stick). Furthermore, the mean release time of the stick containing 60% of CC became about a half of the control stick. It was suggested that the drug release of progesterone from the stick could be controlled by changing the rate of the addition of CC. Two types of suppository which containing progesterone in both phases (suppository A) and in the stick alone (suppository B) were prepared. Both suppositories showed a sustained release property and suppository B had a lag time of two hours. When the suppositories were administered in to the vagina of rabbits, they showed a sustained release property and a rapid rise in the serum concentration was more suppressed than an ordinary Witepsol suppository. One hour after the administration of the two layered suppository, some parts of the suppository was identified macroscopically to be remained in the vagina. The usefulness of the double-layered suppository as a hospital preparation should be suggested after the attainment of the optimization of the formulation.