Development and evaluation of immediate release diclofenac sodium suppositories.

The objective of present study was to develop and evaluate polyethylene glycol (PEG) based diclofenac sodium suppositories. This study used water soluble PEG bases (1000, 4000 and 6000) in different combinations to formulate suppositories, which were further subjected for their physicochemical properties evaluation such as weight variation, average melting point, content uniformity and disintegration. Dissolution test was used to perform the in vitro release rate studies of the suppositories. The suppository (P3) containing PEG-6000 (50%) and PEG-4000 (50%) exhibited rapid in vitro release rate of diclofenac sodium. Moreover, homogeneous distribution of diclofenac sodium is found in all six formulations. The in vitro release patterns of diclofenac sodium from the marketed Voltral suppository (100mg) and formulated suppositories were also compared and found in standard limits.

Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository.

Astragalus polysaccharide (APS) (used for intestinal protection) was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which were assessed in New Zealand rabbits using an orthogonal experimental design. The single-agent Aceclofenac was taken as the control formulation. The concentration-time and drug release curves were drawn, and T max (min), C max (µg·mL(-1)), AUC0→∞ , and MRT were compared using a pharmacokinetic systems program. The formulated Tongshu suppository had moderate hardness, a smooth surface with uniform color, and theoretical drug-loading rate of 8%. Its release rate was in accordance with the drug preparation requirements. The concentration-time curves and drug release curves revealed that the maximum concentrations (C max) were 4.18 ± 1.03 µg·mL(-1) and 3.34 ± 0.41 µg·mL(-1) for the Tongshu and Aceclofenac suppositories, respectively, showing statistically insignificant difference, while the peak times were 34.87 ± 4.69 min and 34.76 ± 6.34 min, respectively, also showing statistically insignificant difference. Compared with the Aceclofenac suppository, the relative bioavailability of the Tongshu suppository was 104.4%, and the difference between them was statistically insignificant. In this experiment, the Tongshu suppository was prepared using the hot-melt method. In vivo pharmacokinetic studies confirmed it had higher bioavailability than the Aceclofenac suppository.

[Study on effect of pH on rectum permeability of active ingredients in Reduning suppositories in vitro].

OBJECTIVE: To investigate the effect of different pH on rectum permeability of chlorogenic acid and geniposide. METHOD: Four kinds of Reduning suppositories of different pH were separated and put into the rectum to study the suppositories in vitro and the content of chlorogenic acid and geniposide samples was determined by HPLC to calculate the permeation in 24 hours. RESULT: With increase of pH within 2.5-7.4, the steady state flux of chlorogenic acid was increased, but the steady state flux of geniposidesamples was steady. CONCLUSION: Adjusted the pH can increase the rectum permeability of active ingredients in Reduning auppositories.

Mucoadhesive and thermogelling systems for vaginal drug delivery.

This review focuses on two formulation approaches, mucoadhesion and thermogelling, intended for prolonging residence time on vaginal mucosa of medical devices or drug delivery systems, thus improving their efficacy. The review, after a brief description of the vaginal environment and, in particular, of the vaginal secretions that strongly affect in vivo performance of vaginal formulations, deals with the above delivery systems. As for mucoadhesive systems, conventional formulations (gels, tablets, suppositories and emulsions) and novel drug delivery systems (micro-, nano-particles) intended for vaginal administration to achieve either local or systemic effect are reviewed. As for thermogelling systems, poly(ethylene oxide-propylene oxide-ethylene oxide) copolymer-based and chitosan-based formulations are discussed as thermogelling systems. The methods employed for functional characterization of both mucoadhesive and thermogelling drug delivery systems are also briefly described.

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.

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.

Curcumin (diferuloylmethane) delivery methods: a review.

Curcumin interacts with a large number of extra- and intracellular targets in a biphasic dose-dependent manner. It controls inflammation, oxidative stress, cell survival, cell secretion, homeostasis, and proliferation. Its mechanisms of action are generally directed toward cells that exhibit disordered physiology or blatant mutation-based abnormal states. Optimizing preventative or therapeutic applications require delivering appropriate quantities of curcumin to lesioned cellular targets. Since diseased conditions anatomically are located from topical to systemic sites, efficient application of curcumin requires specific lesion-oriented delivery methods, representatives of which are here reviewed.

Solid dispersion in pharmaceutical technology. Part II. The methods of analysis of solid dispersions and examples of their application.

In the first part of the article solid dispersions were classified the properties and methods of their preparation were described. This section presents methods of analysis of solid dispersions i.e.: thermoanalytical methods, XRPD, FTIR, microscopic methods, dissolution studies and examples of drug forms where solid dispersions were used.

Boric acid for recurrent vulvovaginal candidiasis: the clinical evidence.

BACKGROUND: Recurrent vulvovaginal candidiasis (VVC) remains a challenge to manage in clinical practice. Recent epidemiologic studies indicate that non-albicans Candida spp. are more resistant to conventional antifungal treatment with azoles and are considered as causative pathogens of vulvovaginal candidiasis. METHODS: We searched PubMed and Scopus for studies that reported clinical evidence on the intravaginal use of boric acid for vulvovaginal candidiasis. RESULTS: We identified 14 studies (2 randomized clinical trials [RCTs], 9 case series, and 4 case reports) as eligible for inclusion in this review. Boric acid was compared with nystatin, terconazole, flucytosine, itraconazole, clotrimazole, ketoconazole, fluconazole, buconazole, and miconazole; as monotherapy, boric acid was studied in 7 studies. The mycologic cure rates varied from 40% to 100% in patients treated with boric acid; 4 of the 9 included case series reported statistically significant outcomes regarding cure (both mycologic and clinical) rates. None of the included studies reported statistically significant differences in recurrence rates. Regarding the adverse effects caused by boric acid use, vaginal burning sensation (<10% of cases), water discharge during treatment, and vaginal erythema were identified in 7 studies. CONCLUSIONS: Our findings suggest that boric acid is a safe, alternative, economic option for women with recurrent and chronic symptoms of vaginitis when conventional treatment fails because of the involvement of non-albicans Candida spp. or azole-resistant strains.

Population pharmacokinetic investigation of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants.

The population pharmacokinetics of phenobarbital was evaluated using 69 serum concentration measurements obtained from the routine phenobarbital monitoring of 35 neonates and infants. The data were analysed using the nonlinear mixed effects model. A one-compartment open pharmacokinetic model with first-order elimination was used. Covariates screened were current bodyweight (TBW), gestational age, postnatal age (PNA), postconceptional age and gender. The final pharmacokinetic parameters were CL/F (mL/h) = 3.41.TBW (kg) + 1.64. PNA (weeks), Vd/F(L) = 1.09.TBW.(kg) [corrected] and F = 0.406 for oral administration and F = 1 for suppository. Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target phenobarbital concentrations, thus enabling the clinician to achieve the desired therapeutic effect in neonates and infants.

Investigation of product quality between extemporaneously compounded progesterone vaginal suppositories and an approved progesterone vaginal gel.

The purpose of this investigation was to compare quality parameters, including product appearance, content uniformity, pH, weight uniformity, microbial limit testing and preservative effectiveness testing on extemporaneously compounded progesterone vaginal suppositories obtained from 10 randomly chosen compounding pharmacies (90 suppositories each) across the United States, to the Food and Drug Administration (FDA) approved prescription progesterone gel product (Prochieve/Crinone) which is manufactured in a cGMP regulated facility. The content uniformity and pH were determined using qualified methods. The microbial limits testing and preservative effectiveness testing were conducted according to compendial methods. Only one pharmacy provided suppositories that were all within the potency limits required for the prescription progesterone gel product. The other pharmacies provided at least some suppositories where progesterone content was either subpotent or superpotent for progesterone. The pH of most of the compounded suppository products was in the range of 4.22 to 7.68 with a median of 6.30 (normal vaginal pH is <5), whereas the gel product was 2.80. For compounded product from one of the pharmacies, microbial limits testing indicated CDC group IVC-2 and Comamonas acidovorans were detected. This data indicates that pharmacy compounded delivery systems for progesterone should be used with caution.

Development of suppository formulation safely improving rectal absorption of rebamipide, a poorly absorbable drug, by utilizing sodium laurate and taurine.

To develop the safe formulation that can safely improve bioavailability of poorly absorbable drugs and that is practically available, we prepared the suppositories of rebamipide, a poorly soluble and poorly absorbable antiulcer drug, by employing the combinatorial use of sodium laurate (C12), an absorption enhancer, with taurine (Tau) or L-glutamine (L-Gln), an adjuvant exerting the cytoprotective action. Although the dissolution of rebamipide from fatty base (FB) suppository prepared using Witepsol H-15 was very slow, it was remarkably improved by the addition of C12 and L-Gln or Tau into the suppository. On the other hand, the dissolution of rebamipide from water-soluble base (WB) suppository prepared using polyethylene glycol was very rapid and the addition of adjuvants did not influence its dissolution so much. Rectal absorption of rebamipide examined in rats was remarkably improved by FB suppository containing C12 or both C12 and Tau, while the enhancing effect of C12 was relatively small in the case of WB suppositories. Biochemical and histopathological studies have confirmed that FB suppository containing both C12 and Tau or L-Gln did not cause any serious local damage, while FB suppository containing C12 only caused the erosion and shrinkage for a lot of rectal epithelial cells. In conclusion, FB suppository employing the combinatorial use of C12 with Tau could be a promising formulation that is effective and safe enough for poorly absorbable drugs to be practically administered.

Rectal hydrocortisone during vomiting in children with adrenal insufficiency.

AIM: To evaluate rectal hydrocortisone as an emergency glucocorticoid replacement therapy in adrenal insufficient children. METHODS: A parental questionnaire evaluated preferred treatment, problems or benefits of i.m. and rectal hydrocortisone, frequency and indications for administration and who administered treatment. Admissions of children with adrenal insufficiency were monitored. RESULTS: There were 39/52 families who responded to the questionnaire. 93% (26/28) preferred rectal hydrocortisone. Parents or children who previously received emergency treatment from a doctor now self-administered rectal hydrocortisone. The cost of suppositories and i.m. hydrocortisone is similar; however, storage of suppositories was inconvenient. One girl presented with pneumonia and collapse despite rectal hydrocortisone and a hydrocortisone level at admission of >2000 nmol/l with normal electrolytes. CONCLUSIONS: Rectal hydrocortisone is an acceptable and safe emergency therapy. We still advise i.m. hydrocortisone if rectal administration is not possible or with suppository extrusion.

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 characteristics, 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.

Investigation of physical and hypoglycaemic properties of rectal suppositories with chosen insulin.

Rectal suppositories with insulin Humulin M3 (30/70) were prepared. Witepsol H15 and a polyoxyethyleneglycol mixture, composed of PEG 400, PEG 1000 and PEG 6000, were used as bases. Tween 60 and sodium salicylate were used as auxiliary substances. Hypoglycaemic properties of the prepared suppositories were tested on rabbits. The obtained results were compared with the data acquired after intravenous administration of insulin and subcutaneous injection of insulin.

Relative hypoglycemia of rectal insulin suppositories containing deoxycholic acid, sodium taurocholate, polycarbophil, and their combinations in diabetic rabbits.

In this study, insulin suppositories containing 50 U insulin incorporated with 50 mg of deoxycholic acid, sodium taurocholate, or both were placed in the rectum of alloxan-induced hyperglycemic rabbits. A large decrease in plasma glucose concentrations was observed, and the relative hypoglycemias were calculated to be 38.0%, 34.9%, and 44.4%, respectively, compared with insulin subcutaneous (s.c.) injection (40 U). Insulin suppositories containing 50 mg polycarbophil alone or mixed with 50 mg deoxycholic acid produced relative hypoglycemia of 43.1% and 42.2%, respectively. The most pronounced effect was observed with the addition of polycarbophil to the suppository formulation containing a combination of deoxycholic acid and sodium taurocholate, which produced a 56% relative hypoglycemia compared with subcutaneous injection. These suppository formulations could be very promising alternatives to the current insulin injections, being roughly half as efficacious as subcutaneous injection.

Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum.

Mucoadhesive liquid suppositories were prepared by adding mucoadhesive polymers (0.6%) to a formulation of thermally gelling suppositories that contained poloxamer 407 (15%), poloxamer 188 (15%) and propranolol HCl (2%). Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carbopol, polycarbophil and sodium alginate were examined as mucoadhesive polymers. The characteristics of the suppositories differed depending on the choice of mucoadhesive polymer. For example, the gelation temperature was between 30 and 36 degrees C, the mucoadhesive force was between 430 and 5800 dyne/cm2, the apparent first-order release rate constant in phosphate buffer, pH 6.8, was between 0.399 and 0.271 h-1, the migration distance of the suppository in the rectum 4 h after administration was between 1 and 5 cm, and the bioavailability of propranolol was between 60.9 and 84.7%. Rectal bioavailability increased as the mucoadhesive force increased (r=0.984, p<0.0005), and the migration distance decreased (r=-0.951, p<0.005). No relationship was found between the bioavailability and the gelation temperature, drug release or irritation of the rectal mucosal membrane by the suppository. Therefore, retaining propranolol at the dosed site in the rectum by the addition of appropriate mucoadhesives to the formulation of liquid suppositories appears to be a very important factor in avoiding first-pass hepatic elimination and thereby increasing the bioavailability of the drug. Among the mucoadhesive polymers examined, sodium alginate and polycarbophil exhibited the largest mucoadhesive force and the smallest intrarectal migration resulting in the largest bioavailability of propranolol (84.7 and 82.3%, respectively). In contrast to other polymers, sodium alginate alone caused no irritation of the rectal mucosal membrane. Thus, poloxamer liquid suppositories containing sodium alginate appears to be a preferred formulation for drugs that are sensitive to extensive first-pass metabolism.

The suppository form of antibiotic administration: pharmacokinetics and clinical application.

The rectal route of antibiotic administration might be used effectively when other routes of administration are inadequate or unsuitable. With the use of various adjuvants, the rectal route can provide satisfactory pharmacokinetics and acceptable local tolerance. Experiments in animals have demonstrated the influence of the pharmaceutical formulation of suppositories on the rectal absorption and systemic distribution of beta-lactams and aminoglycosides. In healthy volunteers and in children under treatment, similar adjuvants--mainly glyceride mixtures or non-ionic surface agents--have increased the rectal absorption of aminopenicillins, cephalosporins and macrolides. Other antibiotics, including metronidazole and cotrimoxazole, have been investigated in respect of their potential rectal administration.