Preparation and evaluation of double-phased mucoadhesive suppositories of lidocaine utilizing Carbopol and white beeswax.

In an attempt to restrict drug absorption from suppositories to only the lower rectum, mucoadhesive lidocaine (LID) suppositories were prepared using Witepsol H-15 as a base, and Carbopol 934P (CP) and white beeswax (WAX) as additives. CP has a mucoadhesive property and WAX gives the suppositories stiffness. The suppositories containing 10% CP and 20% WAX stayed in the lower recta of rats for at least 2 h. Double-phased suppositories consisting of a front layer containing 10% CP and 20% WAX and a terminal layer containing LID and various amounts of CP were prepared. In vitro release profiles of LID from double-phased suppositories were similar to conventional single-phased suppositories containing CP alone. Values of AUC(0-6 h) and MRT of LID after administration of double-phased suppositories to rabbits were larger than those for single-phased suppositories with or without CP. On the other hand, the initial plasma metabolites concentrations after administration of double-phased suppositories were significantly lower and tended to exhibit delayed T(max) compared to single-phased suppositories. These results suggest that the double-phased mucoadhesive suppositories suppress initial metabolism of LID, and may be useful for improving bioavailabilities of drugs, like LID, which accept first-pass effect considerably.     

Preparation,pharmacokinetics and pharmacodynamics of ophthalmic thermosensitive in situ hydrogel of betaxolol hydrochloride

Conventional ophthalmic formulations often eliminate rapidly after administration and cannot provide and maintain an adequate concentration of the drug in the precorneal area. To solve those problems, a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system was prepared and evaluated, the system was composed of poloxamer analogs and polycarbophil (PCP) and betaxolol hydrochloride (BH) was selected as model drug. The concentrations of poloxamer 407 (P407) (22% (w/v)) and poloxamer 188 (P188) (3.5% (w/v)) were identified through central composite design-response surface methodology (CCD-RSM). The BH in situ hydrogel (BH-HG) was liquid solution at low temperature and turned to semisolid at eye temperature. BH-HG showed good stability and biocompatibility, which fulfilled the requirements of ocular application. In vitro studies indicated that addition of PCP enhanced the viscosity of BH-HG and the release results of BH from BH-HG demonstrated a sustained release behavior of BH because of the gel dissolution. In vivo pharmacokinetics and pharmacodynamics studies indicated that the BH-HG formulation resulted in an improved bioavailability and a significantly lower intraocular pressure (IOP). The results suggested BH-HG could be potentially used as an in situ gelling system for ophthalmic delivery to enhance the bioavailability and efficacy.     

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.     

Use of adjuvants for enhancement of rectal absorption of cefoxitin in humans.

The biological availability of cefoxitin administered rectally in the form of suppositories was examined in six human subjects by a cross-over design. Four different suppository systems containing adjuvants expected to enhance the absorption of the drug were studied. The presence of sodium salicylate and a nonionic surface-active agent, Brij 35, gave increased bioavailability as high as 20% compared with 3% for a system without adjuvants. The quantity of sodium salicylate was found to have an influence on the quantity of cefoxitin absorbed, and the salicylate was absorbed over an extended period of time from the rectum. The suppositories were well tolerated, and there were no adverse effects on bowel flora.     

Oral sustained delivery of theophylline using in-situ gelation of sodium alginate.

Gels formed in situ following oral administration of aqueous solutions of sodium alginate (1.0-2.0%w/v) to rats were evaluated as sustained release vehicles for the delivery of theophylline. The liquid formulation contained calcium ions in complexed form, the release of which in the acidic environment of the stomach caused gelation of the alginate. Bioavailability of theophylline from alginate gels formed by in situ gelation in the rat stomach was increased by 1.3-2-fold in rats for alginate concentrations of 2.0 to 1.0%w/v respectively compared with that from a proprietary oral sustained release formulation containing an identical drug concentration. There was no significant difference in the mean residence times of theophylline when administered by these two vehicles.     

Development of mucoadhesive patches for buccal administration of ibuprofen.

A new formulation for topical administration of drugs in the oral cavity has been developed using several film-forming and mucoadhesive polymers. The films have been evaluated in terms of swelling, mucoadhesion and organoleptic characteristics. The best film, containing polyvinylpyrrolidone (PVP) as film-forming polymer and carboxymethylcellulose sodium salt (NaCMC) as mucoadhesive polymer, was loaded with ibuprofen as a model compound and in vitro and in vivo release studies were performed. Statistical investigation of in vitro release revealed that the diffusion process was the main drug release mechanism and the Higuchi's model provided the best fit. In vivo studies showed the presence of ibuprofen in saliva (range 70-210 microg/ml) for 5 h and no irritation was observed. These mucoadhesive formulations offer many advantages in comparison to traditional treatments and can be proposed as a new therapeutic tool against dental and buccal diseases and disturbs.     

Pharmacokinetics of two novel rectal controlled-release morphine formulations.

Administration of morphine by the oral route is not possible in cancer patients who are unable to swallow or are intolerant of oral morphine. Thus, there is a need for reliable alternate routes of drug administration. We compared the bioavailability of two prototype 30-mg morphine sulfate controlled-release suppository formulations (high and low viscosity) with 30-mg oral controlled-release morphine sulfate tablets in a 14-subject single-dose randomized, three-way crossover study. Venous blood samples were obtained immediately prior to and for 24 hr following each dose. Morphine concentrations were determined by radioimmunoassay. Compared with oral controlled-release morphine, the high- and low-viscosity suppository formulations had significantly greater bioavailability (AUC0-24 72.7 +/- 13.2 for the oral preparation versus 98.6 +/- 35.7 and 105.8 +/- 37.3 ng.hr/mL for the suppositories, respectively, P < 0.05), later peak concentration (tmax 2.3 +/- 0.8 versus 3.1 +/- 2.3 and 5.0 +/- 1.5 hr, respectively, P < 0.05), and longer half-value duration (4.3 +/- 1.6 versus 10.4 +/- 5.5 and 9.5 +/- 4.3 hr, respectively, P < 0.05). Peak concentration for the high-viscosity suppository formulation (Cmax 7.75 +/- 2.66 ng/mL) was significantly lower than the low-viscosity suppository (Cmax 9.23 +/- 2.85 ng/mL) and the oral tablet (Cmax 10.4 +/- 2.78 ng/mL) formulations (P < 0.05). The increased bioavailability observed with the two controlled-release suppositories may be the result of partial avoidance of hepatic biotransformation with rectal administration.     

Propranolol: pooled Michaelis-Menten parameters and the effect of input rate on bioavailability

Average steady-state propranolol plasma concentration (Css) were calculated from published steady-state propranolol clearance data for dose rates (Ro) of 40, 80, 160, 240, and 320 mg/ day in divided doses every 6 hours. The Css-Ro data for each of four subjects were fit essentially perfectly by the equation: Css = KmRo/ (Vm-Ro). Very similar Vm and Km values were obtained with the Vmi and Kmi values for four parallel Michaelis-Menten pathways of propranolol metabolism. It is shown by use of the mean Vm and Km values that the propranolol input rate profoundly affects its bioavailability, which is expected for a first-pass drug that follows Michaelis-Menten elimination kinetics after oral dosing. This most likely explains the poor bioavailability of propranolol after a sustained-release formulation. The decreased bioavailability of propranolol when the number of subdivisions of the daily dose is increased is also explained.     

Development of controlled drug release systems based on thiolated polymers.

The purpose of the present study was to generate mucoadhesive matrix-tablets based on thiolated polymers. Mediated by a carbodiimide, L-cysteine was thereby covalently linked to polycarbophil (PCP) and sodium carboxymethylcellulose (CMC). The resulting thiolated polymers displayed 100+/-8 and 1280+/-84 micromol thiol groups per gram, respectively (means+/-S.D.; n=6-8). In aqueous solutions these modified polymers were capable of forming inter- and/or intramolecular disulfide bonds. The velocity of this process augmented with increase of the polymer- and decrease of the proton-concentration. The oxidation proceeded more rapidly within thiolated PCP than within thiolated CMC. Due to the formation of disulfide bonds within thiol-containing polymers, the stability of matrix-tablets based on such polymers could be strongly improved. Whereas tablets based on the corresponding unmodified polymer disintegrated within 2 h, the swollen carrier matrix of thiolated CMC and PCP remained stable for 6.2 h (mean, n=4) and more than 48 h, respectively. Release studies of the model drug rifampicin demonstrated that a controlled release can be provided by thiolated polymer tablets. The combination of high stability, controlled drug release and mucoadhesive properties renders matrix-tablets based on thiolated polymers useful as novel drug delivery systems.     

Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease.

This study describes the formulation, characterisation and preliminary clinical evaluation of mucoadhesive, semi-solid formulations containing hydroxyethylcellulose (HEC, 1-5%, w/w), polyvinylpyrrolidine (PVP, 2 or 3%, w/w), polycarbophil (PC, 1 or 3%, w/w) and tetracycline (5%, w/w, as the hydrochloride). Each formulation was characterised in terms of drug release, hardness, compressibility, adhesiveness (using a texture analyser in texture profile analysis mode), syringeability (using a texture analyser in compression mode) and adhesion to a mucin disc (measured as a detachment force using the texture analyser in tensile mode). The release exponent for the formulations ranged from 0.78+/-0.02 to 1. 27+/-0.07, indicating that drug release was non-diffusion controlled. Increasing the concentrations of each polymeric component significantly increased the time required for 10 and 30% release of the original mass of tetracycline, due to both increased viscosity and, additionally, the unique swelling properties of the formulations. Increasing concentrations of each polymeric component also increased the hardness, compressibility, adhesiveness, syringeability and mucoadhesion of the formulations. The effects on product hardness, compressibility and syringeability may be due to increased product viscosity and, hence, increased resistance to compression. Similarly, the effects of these polymers on adhesiveness/mucoadhesion highlight their mucoadhesive nature and, importantly, the effects of polymer state (particularly PC) on these properties. Thus, in formulations where the neutralisation of PC was maximally suppressed, adhesiveness and mucoadhesion were also maximal. Interestingly, statistical interactions were primarily observed between the effects of HEC and PC on drug release, mechanical and mucoadhesive properties. These were explained by the effects of HEC on the physical state of PC, namely swollen or unswollen. In the preliminary clinical evaluation, a formulation was selected that offered an appropriate balance of the above physical properties and contained 3% HEC, 3% PVP and 1% PC, in addition to tetracycline 5% (as the hydrochloride). The clinical efficacy of this (test) formulation was compared to an identical tetracycline-devoid (control) formulation in nine periodontal pockets (>/=5 mm depth). One week following administration of the test formulation, there was a significant improvement in periodontal health as identified by reduced numbers of sub-gingival microbial pathogens. Therefore, it can be concluded that, when used in combination with mechanical plaque removal, the tetracycline-containing semi-solid systems described in this study would augment such therapy by enhancing the removal of pathogens, thus improving periodontal health.     

Thermosetting gels with modulated gelation temperature for ophthalmic use: the rheological and gamma scintigraphic studies.

For ophthalmic drug delivery, Pluronic F127 solutions have a phase transition temperature too low for them to be instilled into the eye at room temperature. Refrigerator storage is usually required to make administration easier, whereas the potential irritation of cold to the sensitive ocular tissues may result in poor topical bioavailability. The purpose of this study is to develop a thermosetting gel with a suitable phase transition temperature by combining Pluronic analogs and to examine the influence of incorporating mucoadhesive polysaccharide, sodium hyaluronate (HA-Na), on the ocular retention of the gel. Dynamic rheological method and single photon emission computing tomography (SPECT) technique were used to ex/in vivo evaluate the thermosetting gels, respectively. An optimized formulation containing 21% F127 and 10% F68 increased the phase transition temperature by 9 degrees C as evaluated by elasticity modulus compared to that of individual 21% F127 solution. Rheological behaviors of the Pluronic solutions showed that the combined Pluronic formulation was free flowing liquid below 25 degrees C and converted to a firm gel under the physiological condition. Furthermore, this formulation possessed the highest viscosity both before and after tear dilution at 35 degrees C. Gamma scintigraphic data demonstrated that the clearance of the thermosetting gel labeled with 99mTc-DTPA was significantly delayed with respect to the phosphate buffered solution, and at least a threefold increase of the corneal residence time was achieved. However, no further improvement in the ocular retention was observed when adding HA-Na into the thermosetting gel due to the substantially decreased gel strength.     

Use of sodium alginate in the preparation of gelatin-based hard capsule shells and their evaluation in vitro

Using only type B gelatin produces hard capsule shells which are too brittle. This study examines the blending of type B bovine gelatin with sodium alginate to produce hard capsule shells and through evaluation of their in vitro physicochemical properties provides a reflection on the role of gelatin and sodium alginate in the blend. The compositions and formulation of the capsule shells in this study comprised gelatin (10%, 20% and 30%), sodium alginate (1%, 2%, 3%, 4% and 5%), water, and opacifying agents (titanium dioxide; TiO₂) and polyethylene glycol (PEG) whose concentrations were kept constant. From the 15 films prepared, five were found to form hard capsule shells. Increased concentrations of sodium alginate increased the viscosity of the blends accompanied by capsule thickening. There was a good molecular compatibility between gelatin and sodium alginate. Increased gelatin and sodium alginate concentrations increased the water-holding capacity of the film, which decreased the redness (a*), lightness (L*), blueness (b*), variation in the color parameters (ΔE*) and the whiteness index (WI). The weight of the capsule shells ranged between 0.080 g and 0.25 g and the moisture content was between 5% and 11%. Ash contents for all the formulations were below 5% and the sensitivity of capsules at pH 7 was higher than that at acidic pH. Highest rupture times were observed with simulated gastric fluid (SGF, pH 1) for all formulations. Increased gelatin concentration decreased the resistance of the capsule to force while increased sodium alginate concentration had no effect on resistance to force.

Using only type B gelatin produces hard capsule shells which are too brittle.     

Bioavailability of metronidazole in rabbits after administration of a rectal suppository

The bioavailability of metronidazole in rabbits was studied using plasma concentration measurements after the administration of the drug in a hydrophilic (glycerogelatin) suppository form. The peak in the plasma concentration time curve occurred about 1 hour after administration, indicating that the rate of absorption is fast and equivalent to that observed in humans after oral administration. There was rapid elimination of the drug, as indicated by a relatively high elimination rate constant and low plasma half-life. The in vitro dissolution profile of the suppositories further confirms rapid absorption of the drug from the suppositories in the rectum. The presence of Tween 80 enhanced the in vitro release of metronidazole, but the presence of a hydrogenated vegetable oil lubricant (Lubritab) caused retardation in the drug release from the suppositories.     

利巴韦林眼用在体凝胶剂的制备及流变学性质

背景：利巴韦林易被泪液稀释,生物利用度低。在体凝胶剂可使药物在生理条件下由溶液向凝胶转化,延长药物在角膜前的滞留时间。目的：制备利巴韦林眼用在体凝胶剂,并评价其流变学性质。设计、时间及地点：体外对比观察实验,于2006-09/10在天津中医药大学现代中药发现与制剂技术教育部工程研究中心完成。材料：海藻酸钠、卡波姆、利巴韦林。方法：质量分数分别为0.01,0.02的海藻酸钠和质量分数为0.003,0.006,0.02的卡波姆进行不同的组合制备在体凝胶,凝胶中再加入利巴韦林。主要观察指标：用黏度计在不同角速度下测定不同质量浓度配比在体凝胶的黏度。结果：质量分数为0.01的海藻酸钠和质量分数为0.006的卡波姆制备的利巴韦林眼用在体凝胶剂黏度最大,其黏度变化不受加入利巴韦林的影响。海藻酸钠和卡波姆的混合溶液制备的在体凝胶剂接触泪液后发生相转变反应形成凝胶。结论：质量分数为0.01的海藻酸钠和质量分数为0.006的卡波姆制备的利巴韦林眼用在体凝胶剂流变学性质最佳,能显著延长药物在角膜前的滞留时间。     

Formulation and in vivo evaluation of omeprazole buccal adhesive tablet.

For the development of omeprazole buccal adhesive tablets, we studied the release and bioavailability of omeprazole delivered by buccal adhesive tablets composed of sodium alginate, hydroxypropylmethylcellulose (HPMC), magnesium oxide and croscarmellose sodium. Croscarmellose sodium enhanced the release of omeprazole from the tablets. The analysis of the release mechanism showed that croscarmellose sodium changed the release profile of omeprazole from first- to zero-order release kinetics by forming porous channels in the tablet matrix. However, it decreased the bioadhesive forces and stability of omeprazole tablets in human saliva. The tablet is composed of omeprazole-sodium alginate-HPMC-magnesium oxide-croscarmellose sodium (20:24:6:50:10 mg). It may be attached to the human cheek without collapse and it enhanced the stability of omeprazole in human saliva for at least 4 h, giving a fast release of omeprazole. The plasma concentration of omeprazole in hamsters increased to reach a maximum of 370 ng/ml at 45 min after buccal administration and remained at the high level of 146-366 ng/ml for 6 h. The buccal bioavailability of omeprazole in hamsters was 13.7+/-3.2%. These results demonstrate that the omeprazole buccal adhesive tablet would be useful to deliver omeprazole which degrades very rapidly in acidic aqueous medium and undergoes hepatic first-pass metabolism after oral administration.     

双氯芬酸钠栓在会阴侧切缝合术中的研究

目的探讨双氯芬酸钠栓用于会阴侧切缝合术中及术后镇痛的疗效观察。方法随机将183例会阴侧切产妇分为观察组89例与对照组94例。两组用2％利多卡因会阴侧切局部麻醉,观察组在胎儿娩出结束第二产程及产后6h分别双氯芬酸钠栓直肠给药,观察会阴侧切缝合术中及产后会阴侧切伤口疼痛的镇痛效果、缝合时间、第三产程时间、产后出血量等。结果两组术中、术后镇痛效果、缝合时间比较,差异有统计学意义（P〈0．05或P〈0．01）;两组第三产程时间、产后出血量比较,差异无统计学意义（P〉0．05）。结论双氯芬酸钠栓用于会阴侧切缝合术中术后镇痛效果显著,并能缩短缝合时间,值得临床推广使用。     

Administering a suppository

A suppository is a medicated solid formulation prepared for insertion into the rectum to dissolve at body temperature (Moppet and Parker, 1999). The administration of a suppository requires skill and competence on behalf of the practitioner, as well as compliance with the NMC (2004a) guidelines on the administration of medicines and local drug administration policy.     

Symptom control in cancer patients: the clinical pharmacology and therapeutic role of suppositories and rectal suspensions

Rectally administered medications are essential in palliative medicine, particularly in the last days of life. They are underutilized. The pharmacology of rectally administered medications relates not only to the medication but also to the suppository base, additives, drug ionization, p K(a), absorptive surface of the rectum, and rectal health. The pharmacokinetics may differ from those of orally administered medications owing to reduced hepatic first-pass clearance. In this review the pharmacology of rectally administered palliative medications is reviewed and the use of individual drugs is outlined.     

Bioavailability of sodium cyanate in patients with sickle cell disease and the lack of inhibition in vitro of globin synthesis at in vivo concentrations of cyanate.

Studies have been made on the bioavailability in blood of sodium cyantate administered orally in gelatin capsules, in gelatin capsules plus antacid, in enteric-coated capsules and in cocoa butter suppositories administered rectally to patients with sickle cell disease. Maximal blood concentrations of cyanate did not exceed 0.4 mM. Sodium cyanate taken orally in gelatin capsules yielded the highest blood concentrations of the drug, but the peak concentrations and curve areas were not necessarily dose-related. The duration of the drug in the circulation was about 210 minutes. Administration of sodium cyanate in the gelatin capsules, taken with an antacid, improved the dose-response relationship within a given patient. Enteric-coated capsules and suppositories were found to show variable and low bioavailability profiles, respectively. Variability in bioavailability between patients with a given dosage form requires further study. Since the concentration of cyanate attainable in vivo does not inhibit synthesis of either the alpha- or beta-chain of hemoglobin in vitro, previous reports on the inhibitory effects of 10 to 100 mM cyanate on globin synthesis in vitro do not appear to be relevant.     

克林霉素磷酸酯栓治疗细菌性阴道病的疗效和安全性

目的评价克林霉素磷酸酯栓治疗细菌性阴道病的疗效和安全性。方法采用随机双盲对照的研究方法,共观察110例细菌性阴道病的患者。试验组（n=54）用克林霉素磷酸酯检,每次100mg;对照组（n=56）用甲硝唑栓,每次500mg。均为每日1次,塞入阴道深处,疗程7d。结果治疗后停药3～5d复查,试验组和对照组的有效率分别为87．0％和75．0％。月经后复查,试验组和对照组的有效率分别为74．1％和78．6％。2组间比较均无统计学差异（P〉0．05）。试验组和对照组药物不良反应发生率分别为5．6％和3．6％（P〉0．05）。结论克林霉索磷酸酯栓治疗细菌性阴道病能明显改善症状,疗效和安全性与甲硝唑栓相近。