Development and Evaluation of Vaginal Suppository Containing Althaea officinalis L. Polysaccharide Extract

Abstract Intrauterine adhesions cause several gynecological problems. Althaea officinalis L. roots known as marshmallows contain polysaccharides (M.P.) which possess anti-inflammatory and anti-ulcerogenic activities also can form a bio-adhesive layer on damaged epithelial membranes prompting healing processes. Vaginal formulations of herbal origin are commonly applied to relieve cervico-uterine inflammation. Herein, we aim to develop and evaluate vaginal suppositories containing polysaccharides isolated from the A. officinalis root. Six formulations (four P.E.G.-based and two lipid-based suppositories containing 25% and 50% M.P.) met standard requirements, which were then subjected to qualitative and quantitative evaluation. All suppositories exhibited acceptable weights, hardness, content uniformity, melting point, and disintegration time, which fall within the acceptable recommended limits. Higher concentrations of M.P. in PEG-bases moderately increased the hardness (p<0.05). PEG-formulations showed content uniformity>90% of the average content while it was 75-83% for suppocire formulations. All formulations disintegrated in<30minutes. In-vitro release test revealed that M.P. release from 25%-MP formulations was higher than that of 50%-M.P. suppositories. Overall, results revealed the feasibility of preparing P.E.G.-or lipid-based suppositories containing M.P., which met the B.P. quality requirement

Comparación del bloqueo periprostático con lidocaina y supositorio de diclofenac y placebo en la biopsia prostática / Comparison of periprostatic block with lidocaine and diclofenac suppository and placebo in prostate biopsy

El bloqueo del nervio peri prostático con lidocaína, proporciona un buen alivio del dolor en la realización de la biopsia prostática guiada por ultrasonido, pero el dolor post-procedimiento, puede llegar a ser significativo, la adición del supositorio de diclofenac, podría proporcionar alivio adicional. Se asignaron al azar pacientes en 2 grupos el grupo 1 bloqueo con lidocaína del plexo peri prostático + supositorio de diclofenac sódico y el grupo 2 bloqueo con lidocaína del plexo peri prostático + supositorio de placebo, realizando biopsia doble sextante, el dolor a varios intervalos después del procedimiento se registró en una escala visual análoga (EVA) de 0 a 10. Los 2 grupos fueron similares en cuanto a edad, volumen de próstata, antígeno prostático específico, diagnóstico histopatológico. Los pacientes que recibieron diclofenac tuvieron puntajes de dolor significativamente más bajos que los que recibieron placebo (2 frente a 3,35) p 0,02. La administración rectal de diclofenac antes de la realización de la biopsia de próstata es un procedimiento simple que alivia significativamente el dolor experimentado sin aumento en la morbilidad(AU)

The peri-prostatic nerve block with lidocaine, provides good pain relief in performing ultrasoundguided prostate biopsy, but the postprocedure pain can be significant, the addition of diclofenac suppository, could provide additional relief. Patients were randomly assigned in 2 groups to group 1 blockade with lidocaine of the prostatic peri plexus + suppository of diclofenac sodium and group 2 blockade with lidocaine of the prostatic peri plexus + placebo suppository, performing double sextant biopsy, pain at several intervals after the procedure was recorded on a visual analog scale (EVA) from 0 to 10. Thee 2 groups were similar in terms of age, prostate volume, prostate-specific antigen, histopathological diagnosis. Patients who received diclofenac had pain scores significantly lower than those who received placebo (2 vs. 3.35) p 0.02. Rectal administration of diclofenac before performing a prostate biopsy is a simple procedure that relieves significantly pain experienced without increased morbidity(AU)

Development of doxycycline hyclate suppositories and pharmacokinetic study in rabbits.

Doxycycline hiclate is a broad spectrum antibiotic widely used in human and veterinary medicine. The inability to perform the parenteral administration of drugs and the lack of oral preparations can be mentioned as difficulties in the treatment of animals in the domestic environment. In this scenario, the aim of this study was to investigate the bioavailability of the drug by rectal route, to propose a potential suppository formulation containing 25 mg of doxycycline as an alternative to the available injectable formulations. Hydrophilic and lipophilic suppositories were prepared, in polyethylene glycol (S-PEG) or cocoa butter (S-CBT), respectively. The suppositories were prepared and evaluated concerning visual characteristics, content, average weight, melting range, content uniformity and in vitro release. A stability study was performed and the two most stable formulations were submitted to a pharmacokinetic study in rabbits. The bioavailability of the suppositories was compared to the data of the intravenous (i.v.) formulation. PEG suppository showed 49.13% bioavailability and CBT 51.43% with Cmax equal to 2.06 ±â€¯2.96 µg.mL-1 and 1.54 ±â€¯0.28 µg.mL-1, respectively. The data obtained suggest that rectal administration may become another method of administration of doxycycline in the treatment of bacterial infections.

Recombinant streptokinase vs hydrocortisone suppositories in acute hemorrhoids: A randomized controlled trial.

AIM: To compare the efficacy and safety of recombinant streptokinase (rSK) vs hydrocortisone acetate-based suppositories in acute hemorrhoidal disease. METHODS: A multicenter (11 sites), randomized (1:1:1), open, controlled trial with parallel groups was performed. All participating patients gave their written, informed consent. After inclusion, patients with acute symptoms of hemorrhoids were centrally randomized to receive, as outpatients, by the rectal route, suppositories of rSK 200000 IU of one unit every 8 h (first 3 units) and afterwards every 12 h until 8 administrations were completed (schedule A), one unit every 8 h until 6 units were completed (schedule B), or 25 mg hydrocortisone acetate once every 8 h up to a maximum of 24 administrations. Evaluations were performed at 3, 5, and 10 d post-inclusion. The main end-point was the 5(th)-day response (disappearance of pain and bleeding, and ≥ 70% reduction of the lesion size). Time to response and need for thrombectomy were secondary efficacy variables. Adverse events were also evaluated. RESULTS: Groups were homogeneous with regards to demographic and baseline characteristics. Fifth day complete response rates were 156/170 (91.8%; 95%CI: 87.3-96.2), 155/170 (91.2%; 95%CI: 86.6%-95.7%), and 46/170 (27.1%; 95%CI: 20.1%-34.0%) with rSK (schedule A and B) and hydrocortisone acetate suppositories, respectively. These 64.6% and 63.9% differences (95%CI: 56.7%-72.2% and 55.7%-72.0%) were highly significant (P < 0.001). This advantage was detected since the early 3(rd) day evaluation (68.8% and 64.1% vs 7.1% for the rSK and active control groups, respectively; P < 0.001) and was maintained even at the late 10(th) day assessment (97.1% and 93.5% vs 67.1% for rSK and hydrocortisone acetate, respectively; P < 0.001). Time to response was 3 d (95%CI: 2.9-3.1) for both rSK groups and 10 d (95%CI: 9.3-10.7) in the hydrocortisone acetate group. This difference was highly significant (P < 0.001). All subgroup stratified analyses (with or without thrombosis and hemorrhoid classification) showed a statistically significant advantage for the rSK groups. Thrombectomy was necessary in 4/251 and 14/133 patients with baseline thrombosis in the rSK and hydrocortisone acetate groups, respectively (P < 0.001). There were no adverse events attributable to the experimental treatment. CONCLUSION: rSK suppositories showed a significant advantage over a widely-used over-the-counter hydrocortisone acetate preparation for the treatment of acute hemorrhoidal illness, as well as having an adequate safety profile.

Recombinant streptokinase vs phenylephrine-based suppositories in acute hemorrhoids, randomized, controlled trial (THERESA-3).

AIM: To compare the efficacy and safety of recombinant streptokinase (rSK) and phenylephrine-based suppositories in acute hemorrhoidal disease. METHODS: A multicenter (14 sites), randomized (1:1), open, parallel groups, active controlled trial was done. After inclusion, subjects with acute symptoms of hemorrhoids, who gave their written, informed consent to participate, were centrally randomized to receive, as outpatients, rSK (200000 IU) or 0.25% phenylephrine suppositories, which had different organoleptic characteristics. Treatment was administered by the rectal route, one unit every 6 h during 48 h for rSK, and up to a maximum of 5 d (20 suppositories) for phenylephrine. Evaluations were performed at 3, 5 and 10 d post-inclusion. The main end-point was the 5(th)-day complete clinical response (disappearance of pain and edema, and ≥ 70% reduction of the lesion size). Time to response and need for thrombectomy were secondary efficacy variables. Adverse events were evaluated too. RESULTS: 5(th) day complete response rates were 83/110 (75.5%) and 36/110 (32.7%) with rSK and phenylephrine suppositories, respectively. This 42.7% difference (95%CI: 30.5-54.2) was highly significant (P < 0.001). The advantage was detected since the early 3(rd) day evaluation (37.3% vs 6.4% for the rSK and active control groups, respectively; P < 0.001) and was kept even at the late 10(th) day assessment (83.6% vs 58.2% for rSK and phenylephrine, respectively; P < 0.001). Time for complete response was significantly shorter (P = 0.031; log-rank test) in the rSK group (median: 4.9 d; 95%CI: 4.8-5.0) with respect to the active control (median: 9.8 d; 95%CI: 9.8-10.0). Thrombectomy was necessary in 1/59 and 8/57 patients with baseline thrombosis in the rSK and phenylephrine groups, respectively (P = 0.016). There were no adverse events attributable to the experimental treatment. CONCLUSION: rSK suppositories showed a significant advantage over a widely used over-the-counter phenylephrine preparation for the treatment of acute hemorrhoidal illness, with an adequate safety profile.

A suppository-base-matrix tablet for time-dependent colon-specific delivery system

Our research has focused on the main design features and release performances of time-dependent colon-specific (TDCS) delivery tablets, which relies on the relative constancy that is observed in the small intestinal transit time of dosage forms. But inflammatory bowel disease（IBD）can affect the transit time, and usually results in watery stool. Compared to the TDCS and wax-matrix TDCS tablet, a promising time-dependent colon-specific delivery system was investigated. In our study, a suppository-base-matrix coated tablet was evaluated. Water soluble suppository-base helps the expansion of tablet, facilitates uniform film dissolution and achives high osmotic pressure. Combining the expansion of carboxymethyl starch sodium (CMS-Na) and the moisture absorption of NaCl, the coated TDCS tablet obtained a burst and targeted drug delivery system. A very good correlation between in vitro drug release and in vivo outcome was observed. This TDCS coated tablet provides a promising strategy to control drug release to the desired lower gastrointestinal region.

Nossa pesquisa focou-se nas principais características de planejamento e de desempenho de liberação cólon-específica tempo-dependente (TDCS) de comprimidos, que leva em conta a constância relativa observada no tempo de trânsito intestinal das formas de dosagem. A doença inflamatória do intestino (IBD) pode afetar o tempo de trânsito e, geralmente, resulta em fezes aquosas. Comparando ao TDCS e a comprimidos TDCS com matriz-cerosa, investigou-se sistema promissor de liberação cólon-específica tempo-dependente. Em nosso estudo, avaliou-se comprimido revestido com matriz base de supositório. A base de supositório solúvel em água auxilia a expansão do comprimido, facilita a dissolução uniforme do filme e atinge alta pressão osmótica. Associando a expansão do carboximetil amido sódico (CMS-Na) à absorção de umidade do NaCl, o comprimido revestido TDCS originou sistema de liberação direcionado e de erupção. Observou-se correlação muito boa entre a liberação in vitro e a in vivo do fármaco. Este comprimido revestido TDCS representa estratégia promissora para o controle da liberação do fármaco na região gastrintestinal mais baixa.

Recombinant streptokinase suppositories in the treatment of acute haemorrhoidal disease. Multicentre randomized double-blind placebo-controlled trial (THERESA-2).

AIM: A four-arm multicentre randomized double-blind placebo-controlled trial was undertaken to assess the effect and safety of suppositories containing recombinant streptokinase (rSK) at two dose levels (100,000 IU and 200,000 IU) with sodium salicylate (SS) compared with placebo and SS for the treatment of acute haemorrhoidal disease. METHOD: Patients with acute symptoms of haemorrhoids were randomized to four treatment groups: (I) placebo, (II) SS, (III) SS + rSK 100,000 IU and (IV) SS + rSK 200,000 IU per suppository. Inpatient treatment was by four suppositories given every 6 h to discharge at 24 h. Evaluations were made at the time of discharge (24 h) and at 3, 5 and 20 days later. The main end-point was the degree of relief of pain, oedema and reduction in the size of the lesion by 90% on day 5. Adverse events and the occurrence of anti-SK antibodies were also determined. RESULTS: Eighty patients were included. Respective response rates in the four groups were 16%, 30%, 25% and 52%. In the last group there was a significant difference (36.8%) compared with control (95% CI 7.0-58.4%). The time to response was significantly shorter (median 5 days) in the 200,000 IU rSK group with respect to the others. There were no adverse events attributable to the treatment. No increase in anti-SK antibodies was detected 20 days after treatment. CONCLUSION: Suppositories with 200,000 IU rSK showed a significant improvement in symptoms of acute haemorrhoids, with an adequate safety profile.

Comparative study on intermittent versus continuous use of a contraceptive pill administered by vaginal route.

A multicenter, international, randomized, comparative trial was conducted to assess the acceptability, efficacy and safety of two different schedules of a contraceptive pill, containing 250 micrograms levonorgestrel and 50 micrograms ethinyl estradiol, administered by the vaginal route. One schedule of daily administration for 21 days with a seven-day interruption to allow withdrawal bleeding was compared to daily administration without interruption for bleeding. A total of 900 women were recruited in three countries, Brazil, Egypt and China; 7,090 women-months of vaginal pill use were recorded (3,364 using the pills intermittently and 3,726 continuously). Four undesired pregnancies occurred, one in Egypt and three in China, all four in women using the pills intermittently. There was a statistically significant difference (p = 0.486) in pregnancy rate between the two groups. There were no other significant differences in discontinuation rates despite marked differences in bleeding patterns, amenorrhea predominating in the continuous use group. Hemoglobin levels increased significantly in the two groups but hematocrit was significantly higher in the continuous use group.

PIP: 900 healthy women 16-42 years old were recruited in Brazil, China, and Egypt for a multicenter, randomized, comparative clinical trial to determine the acceptability, efficacy, and safety of two different schedules of a contraceptive pill with 250 mcg levonorgestrel and 50 mcg ethinyl estradiol administered vaginally. The two schedules were: 1) daily vaginal use of the pill for 21 days, followed by withdrawal for regular bleeding, and restarted 7 days later, and 2) use of the pill by the vaginal route nonstop for one year. There were no significant difference in cumulative discontinuation rates between the two groups (total, 15.5 for intermittent group and 14.64 for continuous group), except for unwanted pregnancy. The only unwanted pregnancies occurred to 4 women in the intermittent group (1.04%) (p = 0.0486). Women in the continuous use group were more likely than those in the intermittent group to have spotting at least once (20.6% vs. 4.4%; p 0.001). Women in the continuous group were more likely than those in the intermittent group to have amenorrhea. For example, the mean number of bleeding/spotting days during all time intervals was lower for the continuous group than for the intermittent group (p 0.001; last interval, 0.97 vs. 12.83). Hemoglobin levels increased considerably in both groups between baseline and one year of use (11.61 vs. 11.9 g/dl for intermittent group and 11.54 vs. 11.81 g/dl for continuous use; p 0.001). The mean value of hematocrit at 12 months for the continuous group was higher than that at baseline (38.8% vs. 38.2%; p = 0.011). It did not increase in the intermittent group, however. Women in both groups gained weight during the 12 months of pill use. The weight gain was significant for the continuous group only. These findings suggest that continuous use of vaginal contraceptive pills may be more advantageous than intermittent use oral contraceptives and may benefit anemic women and those who bleed heavily during menstruation.

A dosing study of nonoxynol-9 and genital irritation.

The objective of the study was to assess the symptoms and signs of genital irritation produced by different frequencies of nonoxynol-9 (N-9) use. Thirty-five women were randomized to each of 5 groups and used a vaginal suppository for 2 weeks. Group 1: N-9 once every other day; Group 2: N-9 once a day; Group 3: N-9 twice a day; Group 4: N-9 4 times a day; and Group 5: placebo 4 times a day. Study women were examined at admission, one week and 2 weeks with a colposcope for erythema and epithelial disruption, and were interviewed about vaginal itching and burning. The rates of reported symptoms for N-9 users were not significantly different from that of placebo users. The rate of epithelial disruption for women using N-9 every other day was essentially the same as that of women using placebo. The rates of epithelial disruption for women using N-9 1/day and 2/day were 2.5 times greater than that of placebo users. The rate of epithelial disruption for women using N-9 4/day was five times greater than that of placebo users. Genital irritation was located primarily on the vagina or cervix, and vulvitis was not a significant problem. Women who infrequently use N-9 products may not experience an increase in genital irritation. Women who choose to use N-9 frequently may experience an increase in epithelial disruption.

Comparative trial between two soft jelly capsules containing nonoxynol as spermicidal contraceptives.

The rupture time of two types of soft jelly capsules (treated and non-treated) containing Nonoxynol-9 after its vaginal insertion was investigated in 96 women. Subjects were allocated in four study groups: Group I (n = 24), women with clinical vaginal infection; Group II (n = 24), subjects without vaginal infection; Group III (n = 24), patients with vaginal infection; and Group IV (n = 24), women without vaginal infection. Groups I and II received the treated capsules, and Groups III and IV the non-treated capsules. The capsules remained in the vagina for 2.5 to 5 minutes. The weight of the capsules was measured before insertion and after their extraction. Additionally, vaginal pH and distribution of the compound were assessed. The results disclosed that in Groups I, III and IV, the capsules ruptured within 2.5 minutes, whereas in Group II the rupture did not occur until 3 minutes. The largest number of non-ruptured capsules was observed in Group II. The major capsule weight loss occurred at minute 5 in most of the groups. The conditions currently observed in cases of non-ruptured capsules were: alkaline pH, multiparity and vaginal dryness. The vaginal distribution of the compound was observed at its upper portion. In women with vaginal infections, there were more cases of rupture and a significant weight loss between the treated capsules than the non-treated capsules. Further postcoital tests are required to assess its effectiveness.

PIP: The rupture time of 2 types of soft jelly capsules (treated and non-treated) containing Nonoxynol-9 after its vaginal insertion was investigated in 96 women in Mexico. Subjects were allocated in 4 study groups: Group I (n=24), women with clinical vaginal infection; Group II (n=24), subjects without vaginal infection; Group III (n=24), patients with vaginal infection; and Group IV (n=24), women without vaginal infection. Groups I and II received the treated capsules, and Groups III and IV the non-treated capsules. The capsules remained in the vagina for 2.5 to 5 minutes. The weight of the capsules was measured before insertion and after their extraction. Additionally, vaginal ph and distribution of the compound were assessed. The results disclosed that in Groups I, III and IV, the capsules ruptured within 2.5 minutes, whereas in Group II the rupture did not occur until 3 minutes. The largest number of non-ruptured capsules was observed in Group II. The major capsule weight loss occurred at minute 5 in most of the groups. The conditions currently observed in cases of non-ruptured capsules were: alkaline ph, multiparity and vaginal dryness. The vaginal distribution of the compound was observed at its upper portion. In women with vaginal infections, there were more cases of rupture and a significant weight loss between the treated capsules than the non-treated capsules. Further postcoital tests are required to assess its effectiveness.

The social marketing of contraceptives in Mexico.

PIP: The success in social marketing of the PROFAM brand of subsidized contraceptives, by a nonprofit private institution that supports the Mexican government program, is related here. PROFAM began in 1978, when half of contraceptives were purchased commercially from drugstores: they were neither economical, consistently distributed, nor advertised. Comprehensive market research revealed that a great demand existed. It generated information for choice of items to market, package design, and instructions. In 1979, pills, condoms, foam, cream and vaginal suppositories, all locally produced were distributed. A serious problem initially was the impropriety of using the word "contraceptive" in the media. The first phase of advertising targeted newspapers. After 3 months, 40% of Mexico's drugstores carried PROFAM. The second phase of advertising, in radio, magazines and newspapers, approached consumers with information tailored to the specific socioeconomic group involved. The third phase, geared to rural areas and general stores, concentrates on advantages of each method. Other aggressive aspects of the campaign include house to house sampling and a mail-in question and answer service. Evidence of success in broadcasting the PROFAM message is the frequent reference to PROFAM in jokes in the media and even in graffiti. The government's goal is to reduce the growth rate form 2.9 percent annually to 1 percent by 2000.^ieng