Achievements in Thermosensitive Gelling Systems for Rectal Administration.

Rectal drug delivery is an effective alternative to oral and parenteral treatments. This route allows for both local and systemic drug therapy. Traditional rectal dosage formulations have historically been used for localised treatments, including laxatives, hemorrhoid therapy and antipyretics. However, this form of drug dosage often feels alien and uncomfortable to a patient, encouraging refusal. The limitations of conventional solid suppositories can be overcome by creating a thermosensitive liquid suppository. Unfortunately, there are currently only a few studies describing their use in therapy. However, recent trends indicate an increase in the development of this modern therapeutic system. This review introduces a novel rectal drug delivery system with the goal of summarising recent developments in thermosensitive liquid suppositories for analgesic, anticancer, antiemetic, antihypertensive, psychiatric, antiallergic, anaesthetic, antimalarial drugs and insulin. The report also presents the impact of various types of components and their concentration on the properties of this rectal dosage form. Further research into such formulations is certainly needed in order to meet the high demand for modern, efficient rectal gelling systems. Continued research and development in this field would undoubtedly further reveal the hidden potential of rectal drug delivery systems.

Risk Factors for Post-Endoscopic Retrograde Pancreatography Pancreatitis: A Retrospective Chart Review in a Regional Hospital in Japan.

BACKGROUND: Endoscopic retrograde pancreatography (ERCP) is sometimes complicated by post-ERCP pancreatitis (PEP), which is a severe adverse effect. OBJECTIVE: The present study was performed to (i) evaluate the risk factors for PEP and (ii) compare the risk of PEP after ERCP performed in the off hours versus regular hours. METHODS: This retrospective study included 374 patients who underwent ERCP from January 2013 to December 2017. Among these patients, 38 (10.2%) developed PEP. The potential risk factors for PEP were evaluated by multivariate regression analysis, and the risk of PEP was compared between ERCP performed during regular hours and off hours. RESULTS: The independent risk factors for PEP were a relatively younger age (<75 years; p = 0.024), female sex (p = 0.002), a history of pancreatitis (p = 0.044), and performance of pancreatography (p = 0.010). Use of a diclofenac suppository and performance of pancreatic stenting were not preventive for PEP after ERCP. The complication rate of PEP did not differ between ERCP performed during the off hours versus regular hours. CONCLUSIONS: A relatively younger age (<75 years), female sex, a history of pancreatitis, and performance of pancreatography were potential risk factors for PEP, whereas the risk of PEP was not different between ERCP performed during the off hours versus regular hours.

Analysis of the Pharmacokinetics of Suppository Forms of Bacteriophages.

Pharmacokinetics of suppository forms of bacteriophages was studied on male Chinchilla rabbits. Suppositories with various composition of bacteriophages were administered once per rectum to rabbits, and the presence of phage particles was estimated in the blood, urine, and feces over 24 h. Pharmacokinetic study showed that the phages were detected in the blood, urine, and feces at various terms of the experiment irrespective of the size of viral particles, which confirmed the possibility of their systemic effects after rectal administration. Thus, the use of suppository form of bacteriophages can ensure the presence of phage particles even in infection foci that cannot directly contact with the preparation.

Budesonide Suppositories Are Effective and Safe for Treating Acute Ulcerative Proctitis.

BACKGROUND & AIMS: Although proctitis is the most limited form of ulcerative colitis, it causes unpleasant symptoms. Topical mesalamine, the standard treatment, is not always effective. We conducted a randomized phase 2 trial to determine the efficacy and safety of 2 doses of a budesonide suppository vs mesalamine suppositories vs combined budesonide and mesalamine suppositories for proctitis. METHODS: We performed a prospective, double-blind, double-dummy, multicenter trial in 337 patients with active proctitis to compare the efficacies of 4 different suppository treatments. Patients were randomly assigned to groups given 2 mg budesonide suppositories (2 mg BUS; n = 89 patients), 4 mg BUS (n = 79), 1 g mesalamine suppositories (1 g MES; n = 81), or the combination of 2 mg BUS and 1 g MES (n = 88). The study was performed from November 2013 through July 2015 at 36 study sites in Europe and Russia. The primary end point was the time to resolution of clinical symptoms, defined as the first of 3 consecutive days with a score of 0 for rectal bleeding and stool frequency. RESULTS: The mean time to resolution of symptoms in the 4 mg BUS (29.8 days) and combination of 2 mg BUS and 1 g MES (29.3 days) groups resembled that of the standard 1 g MES treatment (29.2 days), but was significantly longer in the 2 mg BUS group (35.5 days). Furthermore, proportions of patients with deep, clinical, and endoscopic remission, as well as mucosal healing, were similar among the 1 g MES, 4 mg BUS, and combination therapy groups, but significantly lower in the group that received 2 mg BUS. No safety signals were observed, and the patients' treatment acceptance was high (67%-85% of patients). CONCLUSIONS: In a multicenter randomized trial, we found that the efficacy and safety of 4 mg BUS in treatment of active proctitis did not differ significantly from those of 1 g MES. Budesonide suppositories offer an alternative therapy to mesalamine for topical treatment of proctitis. Clinicaltrialsregister.eu no: 2012-003362-41.

Advances in rectal drug delivery systems.

Drug delivery via the rectum is a useful alternative route of administration to the oral route for patients who cannot swallow. Traditional rectal dosage forms have been historically used for localized treatments including delivery of laxatives, treatment of hemorrhoids and for delivery of antipyretics. However, the recent trend is showing an increase in the development of novel rectal delivery systems to deliver drug directly into the systemic circulation by taking advantage of porto-systemic shunting. The present review is based on research studies carried out between years 1969-2017. Data for this review have been derived from keyword searches using Scopus and Medline databases. Novel rectal drug delivery systems including hollow-type suppositories, thermo-responsive and muco-adhesive liquid suppositories, and nanoparticulate systems incorporated into an appropriate vehicle have offered more control over delivery of drug molecules for local or systemic actions. In addition, various methods for in vitro-in vivo evaluation of rectal drug delivery systems are covered which is as important as the formulation, and must be carried out using appropriate methodology. Continuous research and development in this field of drug delivery may unleash the hidden potential of the rectal drug delivery systems.

Observation on efficacy for rectal medication of methyl carprost suppository combined with oxytocin in preventing hemorrhage after cesarean section.

The efficacy for rectal medication of methyl carprost suppository combined with oxytocin in preventing and controlling hemorrhage after cesarean section is observed and analyzed. The 180 parturients who are conducted cesarean section in our hospital are selected as research subjects. All parturients are entitled to the right to know and randomly divided into research group and control group with 90 cases in each group. Among them, the parturients in control group are given oxytocin to prevent and control hemorrhage during the operation, while the research group combines with rectal medication of methyl carprost suppository to prevent and control postoperative hemorrhage base on the ways of control group. The condition of hemorrhage in two groups is observed and compared. By comparing with the time of the third stage of labor in two groups, the results don't demonstrate significant difference (p>0.05). Compared with the amount of hemorrhage during the operation, 2h and 24h after delivery, the amount of hemorrhage in research group is less than control group with obvious difference (p<0.05); through recording the change of blood pressure before and after medication in two groups, the result shows that there is no significant difference (p<0.05), which indicates higher safety. In preventing and controlling hemorrhage after cesarean section, rectal medication of methyl carprost suppository combining with oxytocin can achieve good efficacy, significantly reduce the amount of postpartum hemorrhage and will not affect the blood pressure index.

Development of the suppository form of human immunoglobulin preparation with high titers of antibodies to herpes simplex virus types 1 and 2 for the treatment of chronic forms of herpetic disease.

In spite of the vast arsenal of therapeutic agents, therapy of herpes virus infection (HVI) is very difficult, particularly in pregnant women, newborns and children in the first years of life, as well as in patients with immune deficiency. In this regard, possibility of using immunoglobulins for the treatment of HVI is currently attracting the attention of doctors. The aim of this work was to develop a suppository form of the drug containing donor immunoglobulins with high levels of neutralizing antibodies to herpes simplex virus types 1 and 2 for the treatment of chronic forms of herpetic disease. The study included the following steps: 1) selection of gamma-globulins with high antibody titer for HSV-1 and HSV-2 ELISA test; 2) determination of the level of neutralizing antibodies in the selected series of gamma-globulins in tests in tissue cultures and animals; 3) lyophilization of immunoglobulins; 4) development of the suppository form of the preparation containing gamma-globulin donors with high levels of neutralizing antibodies to HSV-1 and HSV-2; 5) study of the safety of the activity of neutralizing antibodies to HSV-1 and HSV-2 in the suppository form of the drug with hyaluronic acid used as immunomodulator. As the result of this work, immunoglobulin preparation in the suppository form was developed. The developed preparation meets the requirements for safety and efficacy. It is not toxic or pyrogenic. The problems of clinical use of this drug as a method of HVI therapy are discussed.

Impact of Probiotic SYNBIO(®) Administered by Vaginal Suppositories in Promoting Vaginal Health of Apparently Healthy Women.

The purpose of this study was to investigate whether vaginal administration of probiotic Lactobacillus results in their colonization and persistence in the vagina and whether it promotes normalization and maintenance of pH and Nugent score. A single-arm, open-label controlled towards the baseline (pre-post) study including 35 apparently healthy women was conducted. Each woman was examined three times during the study. Women were instructed to receive daily for 7 days, the probiotic suppositories SYNBIO(®) gin (Lactobacillus rhamnosus IMC 501(®) and Lactobacillus paracasei IMC 502(®)). Vaginal swabs were collected during visit 1, 2, and 3 to determine the total lactobacilli count, the presence of the two administered bacteria, the measure of the pH, and the estimation of Nugent score. Evaluation of treatment tolerability was based on analysis of the type and occurrence of adverse events. The probiotic vaginal suppository was well tolerated and no side effects were reported. Intermediate Nugent score was registered in 40 % of women at visit 1 and these intermediate scores reverted to normal at day 7 (end of treatment) in 20 % of subjects. Administration of SYNBIO(®) gin contributed to a significant increase in the lactobacilli level at visit 2. Molecular typing revealed the presence of the two strains originating from SYNBIO(®) gin in 100 % of women at visit 2 and 34 % at visit 3. No significant changes were registered for pH between visits. The SYNBIO(®) gin product is safe for daily use in healthy women and it could be useful to restore and maintain a normal vaginal microbiota.

Evaluation of Hydrogel Suppositories for Delivery of 5-Aminolevulinic Acid and Hematoporphyrin Monomethyl Ether to Rectal Tumors.

We evaluated the potential utility of hydrogels for delivery of the photosensitizing agents 5-aminolevulinic acid (ALA) and hematoporphyrin monomethyl ether (HMME) to rectal tumors. Hydrogel suppositories containing ALA or HMME were administered to the rectal cavity of BALB/c mice bearing subcutaneous tumors of SW837 rectal carcinoma cells. For comparison, ALA and HMME were also administered by three common photosensitizer delivery routes; local administration to the skin and intratumoral or intravenous injection. The concentration of ALA-induced protoporphyrin IX or HMME in the rectal wall, skin, and subcutaneous tumor was measured by fluorescence spectrophotometry, and their distribution in vertical sections of the tumor was measured using a fluorescence spectroscopy system. The concentration of ALA-induced protoporphyrin IX in the rectal wall after local administration of suppositories to the rectal cavity was 9.76-fold (1 h) and 5.8-fold (3 h) higher than in the skin after cutaneous administration. The maximal depth of ALA penetration in the tumor was ~3-6 mm at 2 h after cutaneous administration. Much lower levels of HMME were observed in the rectal wall after administration as a hydrogel suppository, and the maximal depth of tumor penetration was <2 mm after cutaneous administration. These data show that ALA more readily penetrates the mucosal barrier than the skin. Administration of ALA as an intrarectal hydrogel suppository is thus a potential delivery route for photodynamic therapy of rectal cancer.

Rapidly disintegrating vagina retentive cream suppositories of progesterone: development, patient satisfaction and in vitro/in vivo studies.

Our objective was to develop novel vagina retentive cream suppositories (VRCS) of progesterone having rapid disintegration and good vaginal retention. VRCS of progesterone were prepared using oil in water (o/w) emulsion of mineral oil or theobroma oil in hard fat and compared with conventional vaginal suppositories (CVS) prepared by hard fat. VRCS formulations were tested for content uniformity, disintegration, melting range, in vitro release and stability studies. The most stable formulation (VRCS I) was subjected to scaling-up manufacturing and patients' satisfaction test. The rapid disintegration, good retentive properties are applicable through the inclusion of emulsified theobroma oil rather than hydrophilic surfactant into the hard fat bases. The release profile of progesterone from VRCS I showed a biphasic pattern due to the formation of progesterone reservoir in the emulsified theobroma oil. All volunteers involved in patients' satisfaction test showed high satisfactory response to the tested formulation (VRCS). The in vivo pharmacokinetic study suggests that VRCS of progesterone provided higher rate and extent of absorption compared to hard fat based suppositories. Our results proposed that emulsified theobroma oil could be promising to solve the problems of poor patients' satisfaction and variability of drug absorption associated with hard fat suppositories.

Rectal drug administration in adults: how, when, why.

Administering medication per rectum can be the most appropriate route for some patients may not always be considered by health professionals. Cultural sensitivities, as well as misinformation regarding insertion methods, may be barriers to the practice. This article explains how the rectal route functions in drug absorption, clarifies when this route is appropriate to use and outlines the steps nurses should follow to prepare patients adequately and safely to carry out the procedure.

A randomized clinical trial of the efficacy and safety of terconazole vaginal suppository versus oral fluconazole for treating severe vulvovaginal candidiasis.

Terconazole is a new, broad-spectrum, triazole antifungal agent. The aim of this study was to compare the efficacy and safety of a 6-day course of a terconazole vaginal suppository (80 mg) with two doses of oral fluconazole (150 mg) for the treatment of severe vulvovaginal candidiasis (SVVC). In this prospective, randomized case-control study, 140 consecutive patients with SVVC were enrolled at the Department of Obstetrics and Gynecology of Peking University Shenzhen Hospital from July 1, 2013, through June 31, 2014. Patients with SVVC, initially at a 1:1 ratio, were randomly assigned to receive treatment with either the terconazole vaginal suppository or oral fluconazole. The patients had follow-up visits at 7-14 days and 30-35 days following the last dose of therapy. The clinical cure rates in the terconazole group and the fluconazole group were, respectively, 81.0% (47/58) and 75.8% (50/66) at follow-up day 7-14 and 60.3% (35/58) and 56.1% (37/66) at day 30-35. The mycological cure rates in the two groups were, respectively, 79.3% (46/58) and 71.2% (47/66) at follow-up day 7-14 and 62.1% (36/58) and 53.0% (35/66) at day 30-35 (P > .05 for all). Local irritation was the primary adverse event associated with terconazole, whereas systemic side effects were associated with fluconazole; however, these effects were minimal. This study demonstrated that a terconazole vaginal suppository (80 mg daily for 6 days) was as effective as two dose of oral fluconazole (150 mg) in the treatment of patients with SVVC; as such, terconazole could be a choice for therapy of this disorder.

Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights.

AIMS: The application of α-adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of NRL001 administered as different strengths in 1 or 2 g suppositories. METHODS: This randomised, double-blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 5, 7.5 or 10 mg NRL001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 10, 12.5 or 15 mg NRL001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence. RESULTS: Tmax was at ~4.5 h post-dose for all NRL001 doses. Median AUC0-tz , AUC0-∞ and Cmax increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2 g with 1 g suppository, and regression analysis for dose proportionality, was close to 1 for the variables AUC0-tz , AUC0-∞ and Cmax (P > 0.05). For both suppository sizes, 20-min mean pulse rate was significantly decreased compared with placebo with all doses (P < 0.05). Blood pressure decreased overall. There were 144 adverse events (AEs) and no serious AEs reported during the study. All AEs were mild in severity. CONCLUSIONS: The regression analysis concluded that the doses were dose proportional.

In vitro-in vivo evaluation of in situ gelling and thermosensitive ketoprofen liquid suppositories.

The main objective of this study was to investigate the release and pharmacokinetic profiles of ketoprofen (KP) from developed thermosensitive and mucoadhesive liquid suppositories. Thermosensitive liquid suppositories were prepared using KP, poloxamer 407 (P 407), poloxamer 188 (P 188) and various amounts of different mucoadhesive polymers. In vitro release studies was monitored by the USP XXVI paddle method. The results thus obtained were evaluated kinetically and mechanism of release was analyzed. Identification of poloxamer gel localization in vivo was conducted using white male rabbits by adding 1 % methylene blue. For in vivo studies, twenty-four white male rabbits were randomly divided into three groups. The rabbits in each group were administered with liquid suppository F1 [P407/P188/KP (4/20/2.5 %)], F5 [P407/P188/KP/C (4/20/2.5/0.8 %)] or conventional suppository (F-C) into the rectum. The plasma concentration of KP was analyzed by high performance liquid chromatography (HPLC). C max, AUC, MRT and T max were evaluated. The release of KP was variously affected by the mucoadhesive polymers. In vitro release studies showed that Carbopol 934 P(C) has significant effect on release rate among the mucoadhesive polymers. When the formulations were evaluated kinetically, different kinetic models were obtained. Formulation F6 [P407/P188/KP/C (4/20/2.5/1.6 %)] which contains the highest C concentration and very high viscosity, shows a significantly better fit with Higuchi kinetic model. n value of this formulation was also found approximately 0.5. n exponent results of the other formulations showed that KP might be released from the suppositories by non-Fickian diffusion. Identification of poloxamer gel localization in vivo showed that the suppositories remain in the rectum without leakage after administration. With regard to the results of in vivo studies, the AUC6→14 values of KP in liquid suppository containing C are significantly higher than those in liquid suppository without C. MRT0→24 and MRT0→∞ values of liquid suppository containing C are significantly higher than those in liquid suppository without C and conventional suppository. Conventional suppository and liquid suppository without C significantly gave faster time to reach the maximum plasma concentrations of KP. With regard to the in vitro and in vivo experiments, liquid suppository formulation F5 might be a promising formulation for the development of an effective rectal dosage form.

Effects of jianpi herbal suppository on hemorheology and CD62p in patients with ulcerative colitis.

OBJECTIVE: To compare the effects of a Chinese herbal suppository (Jianpi suppository) and Western Medicine (mesalazine) on hemorheology and CD62p in patients with ulcerative colitis (UC). METHODS: In a randomized trial, 120 mild to moderate UC patients were randomly divided into two equal groups. The Jianpi suppository group used Chinese herbal suppository rectally, while the mesalazine group was treated with mesalazine tablets orally. Two 15-day courses of treatment were carried out in both groups. Changes in the hemorheology and CD62p indices in patients were observed. RESULTS: The hemorheology and CD62p indices in the Jianpi suppository group decreased significantly more than those of the mesalazine group. CONCLUSION: Jianpi suppository is effective in improving the hypercoagulability of UC patients, and therefore may be worth using in clinical practice.

Acceptability of potential rectal microbicide delivery systems for HIV prevention: a randomized crossover trial.

We assessed the acceptability of three of over-the-counter products representative of potential rectal microbicide (RM) delivery systems. From 2009 to 2010, 117 HIV-uninfected males (79 %) and females (21 %) who engage in receptive anal intercourse participated in a 6-week randomized crossover acceptability trial. Participants received each of three products (enema, lubricant-filled applicator, suppository) every 2 weeks in a randomized sequence. CASI and T-ACASI scales assessed product acceptability via Likert responses. Factor analysis was used to identify underlying factors measured by each scale. Random effects models were fit to examine age and gender effects on product acceptability. Three underlying factors were identified: Satisfaction with Product Use, Sexual Pleasure, and Ease of Product Use. For acceptability, the applicator ranked highest; however, differences between product acceptability scores were greatest among females and younger participants. These findings indicate that RM delivery systems impact their acceptability and should be considered early in RM development to enhance potential use.

Clinical trial: marine lipid suppositories as laxatives.

UNLABELLED: Cod-liver oil and other marine products containing polyunsaturated fatty acids have anti-inflammatory, anti-bacterial and anti-viral effects and may be useful in the treatment of various inflammatory and infectious diseases. We developed suppositories and ointment with 30% free fatty acid (FFA) extract from omega-3 fish oil. Our purpose was to evaluate the safety of marine lipid suppositories and ointment in healthy volunteers and to explore the laxative effect of the suppositories. Thirty healthy volunteers were randomized either to a study group administrating 30% FFA suppositories and applying 30% FFA ointment to the perianal region twice per day for two weeks, or to a control group using placebo suppositories and ointment in a double blinded manner. RESULTS: No serious toxic effects or irritation were observed. In the study group 93% felt the urge to defecate after administration of the suppositories as compared to 37% in the control group (P = 0.001). Subsequently 90% in the study group defecated, compared to 33% in the control group (P = 0.001). CONCLUSION: The marine lipid suppositories and ointment were well tolerated with no significant toxic side effects observed during the study period. The suppositories have a distinct laxative effect and we aim to explore this effect in further clinical trials.

[Compound ciprofloxacin suppository combined with ningbitai and yunnan baiyao for histological prostatitis with PSA elevation].

OBJECTIVE: To explore the efficacy of compound ciprofloxacin suppository (CCS) combined with Ningbitai (NBT) and Yunnan Baiyao (YB) capsules in the treatment of histological prostatitis with elevated levels of PSA. METHODS: This study included 150 cases of type IIIA histological prostatitis, with PSA levels ranging from 4 to 50 microg/L. After 1 month's treatment with oral Levofloxacin tablets at 0.5 g qd, the PSA levels remained high in 86 patients. Prostate cancer was excluded by transrectal ultrasound-guided prostatic biopsy, and histological prostatitis was confirmed in 65 patients, who were assigned to an experimental group (n=45) and a control group (n=20) to receive CCS combined with NBT and YB capsules and CCS with NBT only, respectively, both for 4 weeks. We determined the PSA levels, obtained NIH-CPSI scores before and after medication, and compared them between the two groups. RESULTS: The two groups were well balanced in demographics and baseline characteristics. After treatment, both showed significant differences in the PSA level, PSA density (PSAD) and CPSI scores from the baseline (P<0.05), and there were also statistically significant differences between the two groups in the changes of the PSA level and CPSI scores after medication (P = 0.029 and 0.001). CONCLUSION: Compound ciprofloxacin suppository combined with Ningbitai and Yunnan Baiyao capsules can significantly decrease the level of serum PSA and relieve related symptoms in III A histological prostatitis with PSA elevation, and Yunnan Baiyao capsules can significantly enhance the therapeutic effect.