In vitro release of Tacrolimus from Tacrolimus ointment and its speculated mechanism.

The in vitro release profiles and the bleeding phenomenon of Tacrolimus and propylene carbonate (PC) as a dispersing solvent for Tacrolimus drug substance in Tacrolimus ointment were investigated when changing concentrations of Tacrolimus and PC in the ointment were used, respectively. The bleeding test result indicated that Tacrolimus was in equilibrium between inside and outside of PC droplets in intact ointment base. A cumulative release amount of Tacrolimus from ointment, plotted against the square root of time, showed a straight line initially with a slope of q1 followed to change a slope to be q2 at a certain time, where the relation of these slopes being q1

[Labial adhesion in a reproductive woman with difficulties of sexual intercourse and urination: a case report].

A 27-year-old female patient consulted us with chief complaints of difficulties of sexual intercourse and urination. On examination, the labia was found to be extensively fused at the midline, with a pinhole opening. We diagnosed it as labial adhesion. We operated on it under lumbar anesthesia. Four months after the operation, there were no symptoms of recurrence. Labial adhesion is thought to be caused by inflammation, lack of sexual activity and estrogen deficiency. It is not uncommon in children and post-menopausal women, but is extremely rare in reproductive women.

Effect of truncal vagotomy on gallbladder bile kinetics in conscious dogs.

Previous studies on the effects of vagotomy on gallbladder (GB) motility have yielded conflicting results. The aim of this study was to evaluate the effects of vagotomy on GB motility and bile kinetics using a new method. Twelve dogs were divided into two groups of six (control and pyloroplasty) and, 4 weeks later, underwent truncal vagotomy. A catheter secured in the GB fundus was used to monitor GB volume. After injecting polyethylene glycol (PEG) into the GB, combined measurements of GB volume and PEG concentration enabled GB emptying and bile kinetics to be estimated. Seven and five of the 12 vagotomized dogs were classified as having large and normal fasting GB volumes, respectively. Postprandial GB emptying was impaired when the fasting GB volume was enlarged. In the fasting state, bile kinetics of vagotomized dogs were significantly smaller than the control values. The emptying ability of the GB of vagotomized dogs with large fasting GB volumes was reduced considerably both in the postprandial and the fasting states. Such retention of bile in the GB after vagotomy may facilitate cholesterol crystal nucleation and stone growth.

Factors affecting membrane-controlled drug release for an osmotic pump tablet (OPT) utilizing (SBE)(7m)-beta-CD as both a solubilizer and osmotic agent.

PURPOSE: The purpose of this study was to define membrane controlling factors responsible for drug release from a controlled-porosity osmotic pump tablet (OPT) that utilizes a sulfobutyl ether-beta-cyclodextrin, (SBE)(7m)-beta-CD, as both a solubilizing and osmotic agent. METHOD: The OPT was spray coated with cellulose acetate solutions varying the amount and size of micronized lactose, the amount of triethyl citrate (TEC) and the composition ratio of dichlormethane to ethanol. Chlorpromazine (CLP) was used as a model drug. The release of CLP from the OPTs was studied using the Japanese Pharmacopoeia dissolution method. The membrane surface area of the OPTs were measured with multi-point analysis by the gas absorption method. RESULTS: The release rate of CLP from OPTs containing (SBE)(7m)-beta-CD increased with increasing amounts of micronized lactose and decreasing amounts of TEC and lactose particle size in the membrane. Also, the CLP release rates from the spray-coated OPTs using mixtures of varying ratios of dichlormethane to ethanol were almost identical. The membrane surface area of the OPTs following release of membrane components had a linear relationship to CLP release rates from the OPTs. CONCLUSION: The present results confirmed that the membrane controlling factors responsible for the drug release were the amount and size of micronized lactose and the amount of TEC in the membrane.

Design and evaluation of an osmotic pump tablet (OPT) for chlorpromazine using (SBE)7m-beta-CD.

PURPOSE: The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) which exhibits pH-independent release profiles for a basic drug using a sulfobutyl ether-beta-cyclodextrin, (SBE)7m-beta-CD, which acts as both a solubilizer and as an osmotic agent. METHODS: Chlorpromazine free base (CLP) was chosen as a model drug for this study. The release of CLP from osmotic pump tablets was studied in vitro. In vivo absorption of CLP from the OPT was evaluated in male beagle dogs. RESULTS: The CLP release profile from an OPT prepared from a core tablet composed of a 1:10 molar ratio of CLP to (SBE)7m-beta-CD was pH-independent, and was controlled by modulating the membrane thickness of the OPT. Another cyclodextrin, hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and a sugar mixture of lactose and fructose resulted in pH-dependent release at the same molar ratio. An in vivo absorption study in dogs with an OPT containing (SBE)7m-beta-CD correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. CONCLUSIONS: In addition to serving as a solubilizer and osmotic agent, (SBE)7m-beta-CD can also serve as the controlling agent for pH independent release of CLP from OPTs. This system successfully modified the in vivo input rate of CLP without compromising oral bioavailability.

Microencapsulation of the renin inhibitor FK906 by phase separation of ethylcellulose in cyclohexane.

Microencapsulation of the renin inhibitor FK906 (tripeptide) by phase separation of ethylcellulose in cyclohexane was performed to obtain sustained release of the drug for a once-a-day application. Owing to the binding characteristics and to the very low solubility of FK906 in cyclohexane, microencapsulation can be performed after granulation of the drug with an inert filler, and no additional binder is required. Microcapsules with a particle size of 180-590 microns are obtained in a yield of 70%. Drug content determinations and SEM-micrographs reveal the almost complete incorporation of the polymer for the coating and the high quality of the microcapsule wall. Despite the strongly pH-dependent solubility of FK906 (.HCl) in water, the microcapsules show almost identical sustained-release curves at pH 1.2 and 6.0 (0.05 M phosphate buffer). This is explained by an acidic microenvironment inside the microcapsules at both pHs investigated and was attributed to the intrinsic physico-chemical properties of FK906 which help to overcome the buffer capacity of the phosphate buffer, pH 6.0, inside the microcapsules. This theory was confirmed by solubility experiments at pH 6.0 using excess amounts of FK906 as well as by dissolution tests as a function of the buffer capacity and the osmolality of the dissolution medium. The buffer capacity was found to be the parameter with greater influence on the release rate.

Long-term observations of uterine contractions in nonpregnant dogs.

Uterine contractile activity in nonpregnant conscious dogs was investigated based on 2- to 6-mo-long continuous recording by means of a chronically implanted force transducer. We found that nonpregnant uterine contractile activity could be classified into six major patterns: sporadic contractions, weak and strong tonic contractions, weak and strong phasic contractions, and phasic contraction bursts. The contractile patterns during proestrus and estrus were the most active, with strong phasic and tonic contractions and phasic contraction bursts. The phasic and tonic contractions were inhibited dose-dependently by a beta 2 adrenergic agonist, ritodrine, and reproduced by an alpha 2 adrenergic agonist, clonidine. In contrast, the cholinergic inhibitors atropine and hexamethonium did not affect the spontaneous occurrence of these contractions, although bethanechol evoked uterine contractions. Oxytocin and prostaglandin F2 alpha-induced contractions were phasic during estrus, whereas they showed tonic increases with phasic contractions during proestrus, diestrus, and anestrus, and these contractions did not resemble the spontaneous contractions. In conclusion, the nonpregnant uterus contracts continuously in harmony with the estrous cycle phases, and its contractile activity is enhanced by alpha adrenergic receptors and inhibited by beta 2 adrenergic receptors.

Development of a novel drug delivery system, time-controlled explosion system (TES). IV. In vivo drug release behavior.

Time-Controlled Explosion System (TES) has the time-controlled drug release property with a pre-designed lag time. The drug release from the system is initiated by destruction of the membrane. In this study, metoprolol tartrate was used as a model drug. After five types of TES with different in vitro lag times were orally administrated to dogs, plasma metoprolol concentration was monitored. There existed a good correlation between in vitro and in vivo lag time, while the extent of absorbed metoprolol decreased with prolongation of lag time. Next, the in vivo drug release behavior was directly investigated using five different colored TES with a lag time of two hours. Each TES was consecutively administrated to the fasted dogs at predetermined intervals. The amount of metoprolol released was monitored by recovering the administered TES from the gastrointestinal trace. The in vivo release profile corresponded with the in vitro one. It is demonstrated that TES can release the drug in in vivo conditions similarly to in vitro. Based on these results, the decrease of the absorption is suggested to be caused by increased hepatic first-pass metabolism of the drug due to the retarded release rate with longer lag time.

Nuclear factor I stimulates transcription of the adenovirus 12 E1A gene in a cell-free system.

Binding to the cis-acting region of NF-I-like protein and/or NF-III-like protein was previously suggested to be responsible for the preferential stimulation of transcription from distal start-site of the adenovirus 12 E1A gene in a cell-free system. In this study, nuclear extracts of Ehrlich ascites tumor cells depleted of NF-I-like protein were found to lose activity to stimulate the E1A gene transcription. This activity was recovered when NF-I purified from HeLa cells with no contamination of NF-III was supplemented. It is thus evident that NF-I is involved in stimulating distal transcription of the adenovirus 12 E1A gene. Moreover, activities for both stimulating the E1A gene transcription and binding to a region recognized by NF-I did not apparently exist in nuclear extracts of a cell line expressing the adenovirus 12 E1A gene. These results suggest that transcription of the adenovirus 12 E1A gene may possibly be autoregulated at least in part through modulation of the activity of NF-I.