Nasal delivery progesterone powder formulations comparison with oral administration.
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Administration, Intranasal↗
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Effect of dimethyl-beta-cyclodextrin on nitrazepam stability.
Nitrazepam was found to form an inclusion complex with heptakis; 2,6 di-O-methyl-beta-cyclodextrin (DM-beta-CD) in solution. The phase solubility diagram was found to be AL type with no precipitation of the inclusion complex formed. The kinetic studies of nitrazepam hydrolysis in DM-beta-CD solution at 30, 40 and 50 degrees C was followed spectrophotometrically, as the degradation products of the drug did not interfere with such assay. It was found that the degradation of nitrazepam in acidic media followed the first order reaction kinetics at the temperatures studied. Inclusion complexation of nitrazepam in DM-beta-CD resulted in a relatively improved stability of the drug in solution at 30 degrees C. On the other hand, no appreciable stabilization was achieved at higher temperatures (40 and 50 degrees C).
Cyclodextrins↗
Preparation and central action of propofol/hydroxypropyl-beta-cyclodextrin complexes in rabbits.
Inclusion complexes of propofol (CAS 2078-54-8) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were examined in aqueous solution and in the solid state by phase solubility technique, IR-spectroscopy and differential scanning calorimetry. Solid complexes obtained by kneading method were dissolved in artificial plasma leading to a colloidal solution which was suitable for intravenous administration. In the in vivo studies propofol (15 mg/kg) was given intravenously to rabbits in equimolar doses as cyclodextrin complexes and as Diprivan. The central action of the drug was verified by recording the bioelectrical activity of the precentral cortex. The statistical evaluation of the results do not indicate differences in onset, duration and maximum of action between the two dosage forms.
Animals↗
Science reporters hear wide range of recent data at 12th annual conference.
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AIDS Vaccines↗
Conditions of cyclodextrin complexation.
In the past 20 years, cyclodextrin (CD) research has achieved considerable results, as indicated by the large number of publications and patents, the six international symposia on CDs, the new dosage forms of medicines prepared with CDs, etc. Sufficient data have accumulated to permit a survey of the most important conditions of CD complexation. Further, an account is presented of the success of precipitation of the complex involving furosemide and beta-CD.
Calorimetry, Differential Scanning↗
2-Hydroxypropyl-beta-cyclodextrin enhances phorbol ester effects on glucose transport and/or protein kinase C-beta translocation to the plasma membrane in rat adipocytes and soleus muscles.
In rat adipocytes and soleus muscles, 2-hydroxypropyl-beta-cyclodextrin (CD) was found to have a relatively small or no effect on basal or insulin-stimulated hexose uptake, but markedly enhanced hexose uptake effects of phorbol esters and/or diacylglycerol. In rat adipocytes, the CD-induced enhancement of hexose uptake during concurrent phorbol ester treatment was not associated with an increase in GLUT4 glucose transporter translocation to the plasma membrane, which was stimulated comparably by insulin and phorbol esters. Moreover, CD appeared to activate or facilitate the activation of glucose transporters subsequent to their translocation to the plasma membrane during ongoing phorbol ester treatment. In rat adipocytes, CD also enhanced the translocation of protein kinase C (PKC)-beta to the plasma membrane during the action of phorbol esters, which alone had little or no effect on this specific PKC translocation. Although it is uncertain how CD alters the function of plasma membranes to enhance the translocation of PKC-beta to, and the activation of glucose transporters within, this subcellular fraction during phorbol ester treatment, our findings provide direct support for a two-step model in the activation of glucose transport. In addition, it seems clear that, at least in some cell types, simple phorbol ester treatment does not necessarily serve as a ubiquitous activator of all activable PKC pools and all potential PKC-mediated responses.
2-Hydroxypropyl-beta-cyclodextrin↗
Cholesterol and 27-hydroxycholesterol 7 alpha-hydroxylation: evidence for two different enzymes.
The use of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for solubilizing cholesterol and 27-hydroxycholesterol has led to a study of their rates of 7 alpha-hydroxylation in microsomal preparations from hamster liver and HepG2 cells. Addition of the vehicle alone to the cholesterol 7 alpha-hydroxylase assay always caused a several-fold increase in activity. Preloading the vehicle with cholesterol further augmented the rate of 7 alpha-hydroxycholesterol formation. Preloading the vehicle with 27-hydroxycholesterol or 27-hydroxycholestanol (molar ratio 1/1.2) minimally decreased cholesterol 7 alpha-hydroxylase activity (-12%), compared with preloading with cholestanol (-50%), a known competitive inhibitor of the enzyme. Microsomes from hamster liver yielded rates of 7 alpha,27-dihydroxcholesterol formation of 1.5 to 3.0 nmol/min per mg protein, compared with 0.3 nmol/min per mg protein for 7 alpha-hydroxycholesterol. Although cholesterol and cholestanol had minimal effects on the rate of 7 alpha-hydroxylation of 27-hydroxycholesterol, addition of an approximately equimolar amount of 27-hydroxycholestanol inhibited the rate of formation by 65%. Attempts to separate and identify the two C-27 sterol 7 alpha-hydroxylases chromatographically led to the finding that Emulgen 913 selectively inactivates 7 alpha-hydroxylation of 27-hydroxycholesterol. These results indicate that the metabolic pathway for bile acid synthesis from 27-hydroxycholesterol is not governed by cholesterol 7 alpha-hydroxylase.
2-Hydroxypropyl-beta-cyclodextrin↗
In vitro and in vivo evaluation of o-carboranylalanine as a potential boron delivery agent for neutron capture therapy.
o-Carboranylalanine (B10H10C2CH2CHNH2COOH) is a carborane-containing amino acid, which has been synthesized as a potential capture agent for boron neutron capture therapy (BNCT) of cancer. The purpose of the present study was to develop a rational approach for the in vitro and in vivo evaluation of boron containing compounds that possibly might be used for BNCT. The in vitro uptake of carboranylalanine (CBA) was evaluated using two cell lines, the human melanoma MRA 27, and the murine Harding-Passey melanoma. Uptake of CBA by MRA 27 cells ranged from 135-551 micrograms B/10(9) cells following 3 hrs incubation with medium containing 100-113 micrograms B/ml and was not reduced by exposing the tumor cells to either rotenone, an inhibitor of electron transport, or by culturing them at ambient temperature (approximately 22 degrees C). Cellular uptake and elution of CBA occurred rapidly under in vitro conditions. Uptake of CBA was slightly greater than that of boronophenylalanine (BPA). Following a 3 hr incubation with CBA at a concentration of 106 micrograms B/ml, cell boron content was 255 micrograms B/10(9) MRA 27 cells, compared to 192 micrograms B/10(9) cells when cells were incubated with BPA at a concentration of 95 micrograms B/ml. In vivo studies initially were carried out using the Harding-Passey melanoma, which had been implanted intramuscularly (i.m.) into the right flank of BALB/c mice. Tumors were allowed to grow for 14 days at which time mice were injected intraperitoneally (i.p.) with either CBA or BPA (1.25 mgB/mouse), and were killed 3, 6 and 8 hrs later. CBA attained a low tumor to blood ratio(1.0-1.4), and the tumor boron levels ranged from 15.7-26.2 micrograms B/g at 3 hrs and 3.3-19.9 micrograms B/g at 6 hrs. Higher blood and lower tumor boron levels were observed at all time points with CBA compared to BPA, suggesting that CBA was not taken up selectively by the melanoma. Similar studies, carried out in rats bearing intra-cerebral gliomas, failed to reveal detectable amounts of boron in the tumor. From the present study, it can be concluded that CBA does not appear to possess the requisite properties to be useful as a boron delivery agent for BNCT.
Animals↗
Evaluation of in vitro cytotoxicity of carboranyl amino acids, their chemical precursors and nido carboranyl amino acids for boron neutron capture therapy.
The purpose of the present study was to define the in vitro cellular toxicity of three carborane-containing amino acids: p-(o-carboran-yl)-phenylalanine (CBPA), O-(o-carboran-1-ylmethyl)-tyrosine (CBT), and o-carboranylalanine (CBA), which are analogues of phenylalanine, tyrosine, and alanine respectively. In addition, two of their chemical precursors: CBACN (B10H11C2-CH2CHNH2CN) and CBTCN (B10H11C2-CH2OC6H4CH2CHNH2CN) and nido CBA were evaluated for their toxicity on human MRA 27 melanoma cells. Hydroxypropyl-beta-cyclodextrin (beta-CD) initially was used to solubilize all the compounds except nido CBA in the toxicity assays Cells were incubated with the test compounds at varying concentrations for 24 hrs, following which the proliferative activity of surviving cells was determined by pulsing with tritiated thymidine ([3H]-TdR) for an additional 18 hrs. CBT at a concentration of 280 micrograms/ml was non-toxic when solubilized with beta-CD. CBA at a concentration of 350 micrograms/ml was non-toxic when solubilized with beta-CD, but when solubilized with DMSO produced a 50% reduction in uptake of [3H]-TdR at a concentration of 75 micrograms/ml. CBPA, solubilized with beta-CD, was nontoxic at a concentration of 400 micrograms/ml, while CBTCN and CBACN at concentrations of 50 micrograms/ml and 40 micrograms/ml, respectively, were both toxic, even when solubilized with beta-CD. Nido CBA at a concentration of 400 micrograms/ml in medium was non-toxic. Although the toxicity of these boron compounds precludes their use as capture agents for Neutron Capture Therapy, they may have some potential for cytoreductive chemotherapy of cancer, and further evaluation may be warranted.
Amino Acids↗
Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops. Aqueous humor pharmacokinetics in humans.
PURPOSE: To test an aqueous eye drop solution containing a high concentration of dexamethasone in a cyclodextrin-based drug delivery system. This system increases both drug solubility in aqueous eye drops and drug permeability into the eye, through drug cyclodextrin-polymer co-complexes. METHODS: 2-hydroxypropyl-beta-cyclodextrin is a water-soluble oligosaccharide that can be used to dissolve lipophilic drugs, such as dexamethasone, in aqueous solutions. Co-complexation with a polymer further increases the solubility and increases drug permeability through biologic membranes. Eye drops containing dexamethasone (0.32% and 0.67%), 2-hydroxypropyl-beta-cyclodextrin, and polymer were given to patients before cataract surgery, and the resultant dexamethasone concentration was measured from aqueous humor samples. RESULTS: The dexamethasone-cyclodextrin drops give a significantly higher concentration of dexamethasone in aqueous humor than dexamethasone alcohol 0.1% (Maxidex). Heating of the dexamethasone-cyclodextrin-polymer co-complexes appears to enhance the permeability of the drug into the eye. CONCLUSIONS: The cyclodextrin-based drug delivery system enhances both the solubility of dexamethasone in aqueous eye drops and the permeability of the drug into the human eye. Dexamethasone concentration levels in the human aqueous humor exceed those reported with currently available steroid eye drops.
2-Hydroxypropyl-beta-cyclodextrin↗
[Technological studies of effects of inclusion on pericarpium Citri reticulatae volatile oil-beta-cyclodextrin].
The effects of inclusion on Pericarpium Citri Reticulatae volatile oil-beta-cyclodextrin were studied by comparing four methods saturation, grinding, liquid to liquid and liquid to gas. The utilization ratio of oil, the ratio of oil in inclusion complex and the recovery of inclusion complex were used as the criteria in evaluating the inclusion effectiveness. The results showed that the saturation method was the best.
Citrus↗
A freeze-dried injectable form of ibuprofen: development and optimisation using response surface methodology.
In this study a complex of Ibuprofen and b-Hydroxypropylcyclodextrin was prepared employing a freeze drying method. The production parameters and the final specifications of this product were optimized by using response surface methodology. The results show that the freeze dried complex meets the requirements for solubility to be considered as a possible injectable form.
2-Hydroxypropyl-beta-cyclodextrin↗
Design and in vivo testing of 17 beta-estradiol-HP beta CD sublingual tablets.
17 beta-Estradiol is almost insoluble in water. The effect of various cyclodextrins and two different polymers, polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC), on the aqueous solubility of 17 beta-estradiol was investigated. 17 beta-Estradiol was dissolved in aqueous 50% w/v 2-hydroxypropyl-beta- cyclodextrin (HP beta CD) solution containing 0.25% (w/v) CMC and the dry 17 beta-estradiol-HP beta CD complex formed by lyophilisation of the solution. Sublingual tablets from the dry complex were produced by direct compression. The dissolution of 17 beta-estradiol from tablets containing the drug in a lyophilised HP beta CD complex was determined. For reference the dissolution of 17 beta-estradiol was determined from tablets containing physical mixture of 17 beta-estradiol and HP beta CD or tablets containing 17 beta-estradiol without HP beta CD. Sublingual tablets containing 17 beta-estradiol-HP beta CD in the lyophilised complex demonstrated the fastest dissolution profile and those tablets were selected for further studies in humans. Six postmenopausal women received a sublingual tablet containing 17 beta-estradiol-HP beta CD complex equivalent to 100 micrograms 17 beta-estradiol. Blood samples were collected over a 12 h period and the 17 beta-estradiol plasma concentration was determined. 17 beta-Estradiol was rapidly absorbed from the sublingual tablets, resulting in a peak 17 beta-estradiol plasma concentration of 568 +/- 97 pmol/l 15 min after administration of the tablets, followed by a biphasic elimination.
Administration, Sublingual↗
Reduced toxicity and enhanced antitumor efficacy of betacyclodextrin plumbagin inclusion complex in mice bearing Ehrlich ascites carcinoma.
Inclusion complex of plumbagin was prepared with betacyclodextrin employing neutralization method. The toxicity of the drug was reduced and the antitumor efficacy was enhanced on complexation with betacyclodextrin.
Absorption↗
Use of subambient differential scanning calorimetry to monitor the frozen-state behavior of blends of excipients for freeze-drying.
The purpose of this study was evaluation of mannitol and its blends with other excipients commonly used as freeze-drying cryoprotectants or bulking agents in simulated lyophilization conditions. Subambient differential scanning calorimetry (DSC) has been used as an analytical tool to evaluate the phenomena from both a qualitative and a quantitative point of view. The DSC scans were performed at rates comparable to those generally practicable in industrial lyophilizators. During a simulated freeze-drying process, three crystallization events have been observed on mannitol solutions: the first two on freezing, and the last one on heating. The phenomena are dependent on each other. The addition of other excipients can significantly influence this behavior by specifying the crystallization of mannitol in freezing or by inhibiting it fully. This means that the final physical state of the freeze-dried product (amorphous, crystalline, or partially amorphous/partially crystalline) can be tailored by accurately choosing not only the freeze-drying conditions but also the composition of the solution to be lyophilized. The results point out how the physical state of freeze-dried products can be controlled by an accurate choice of both excipients and their relative ratios, with the possibility of reducing the number of preformulation activities required to design the most appropriate formulation for each new drug candidate.
2-Hydroxypropyl-beta-cyclodextrin↗
Cyclodextrins as co-enhancers in dermal and transdermal drug delivery.
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2-Hydroxypropyl-beta-cyclodextrin↗
Quality of life assessment during six months of NSAID treatment [Gonarthrosis and Quality of Life (GOAL) Study].
OBJECTIVE: To identify the time point of the greatest degree of improvement in daily living activities, pain and depression in patients with osteoarthritis (OA) of the knee during 6 months of treatment with NSAIDs, in order to define compliance and drop-out rate. METHODS: 107 patients were recruited into a multicentre, prospective, randomized, controlled trial comparing two treatments, piroxicam-beta-cyclodextrin (PBCD) and slow release diclofenac (DCL). RESULTS: The greatest improvement in quality of life occurred in both groups after 3 months, with a slight further gain observed by the end of treatment. The Stanford Health Assessment Questionnaire score improved (p < 0.05 vs baseline) at 3 and 6 months with PBCD and at 6 months with DCL. The Arthritis Impact Measurement Scale score improved (p < 0.05 vs baseline) after 6 months in both groups. Significant (p < 0.05 vs baseline) improvement in other psychological and pain scores were recorded in both groups after 3 and 6 months. Compliance with treatment at 3 months was 73% for PBCD and 72% for DCL, and was 60% in both groups at 6 months. CONCLUSIONS: The results of this study indicate that the optimal length of time for an NSAID trial in OA patients is 3 months, when assessment of daily living activities is considered as the main outcome criterion.
Activities of Daily Living↗
Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers.
STUDY OBJECTIVES: To evaluate the effect of food on the bioavailability of itraconazole (ITR) hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solution under multiple-dose to steady-state conditions, and to determine the pharmacokinetics of ITR solution at steady state. DESIGN: Open-label, randomized, multiple-dose, crossover study SETTING: University-affiliated health center. PATIENTS: Thirty healthy men randomized to one of two treatment sequences (fasted-fed, fed-fasted). INTERVENTIONS: Subjects were either fasted or fed a standard breakfast before receiving ITR oral solution 200 mg once/day for 15 days. Crossover phases were separated by a 4-week washout period. MEASUREMENTS AND MAIN RESULTS: On day 1, blood samples were collected before the dose (time zero) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after the dose. Trough samples were obtained before the dose on days 4, 7, 12, 13, and 14. On day 15, samples were obtained at the same times as day 1, and at 36, 48, 72, 96, 168, 240, and 360 hours. Samples were analyzed by high-performance liquid chromatography for ITR and its major metabolite hydroxyitraconazole (OH-ITR). Urine was collected on days 1 and 15 before and 0-8 and 8-24 hours after the dose; HP-beta-CD was measured by size-exclusion chromatography. Mean bioavailabilities of ITR and OH-ITR were 43% and 38% higher, respectively, when ITR solution was taken as a single dose under fasted conditions. With multiple dosing, steady state was achieved by day 14. At steady state, mean bioavailabilities were 29% and 17% higher, respectively, in the fasted state; terminal half-life was similar under fasted and fed conditions (mean 39.8 and 37.5 hrs for ITR, respectively; 27.3 and 26.2 hrs for OH-ITR, respectively). HP-beta-CD was eliminated almost exclusively in urine. CONCLUSION: The bioavailability of ITR and OH-ITR is enhanced when ITR oral solution is given in the fasted state; this was true for both single and multiple dosing to steady state.
2-Hydroxypropyl-beta-cyclodextrin↗