HP Beta CD Research Articles

Surface tension and wettability in transdermal delivery: a study on the in-vitro permeation of haloperidol with cyclodextrin across human epidermis

The aim of this work was to study the effect of surface tension and contact angle on the permeation of haloperidol across human skin using cyclodextrin derivatives. Surface tension and contact angle of randomly methylated beta-cyclodextrin (RM beta-CD) and hydroxypropyl beta-cyclodextrin (HP beta-CD) solutions were measured. Haloperidol solubility and molecular modelling were carried out using the two cyclodextrin derivatives. In-vitro skin permeation was carried out using human skin models. The highest increase in drug solubility was observed when the drug was in solution with pH 5 when compared to non-ionised solution, resulting in a 128-fold increase in the intrinsic solubility of the drug. Surface tension measurements indicate a surface-active effect for RM beta-CD and HP beta-CD. Contact angle measurements showed that vehicles with higher skin wettability increased the contact of the drug with the skin surface and therefore resulted in higher drug permeation across human epidermis. It is concluded that transdermal flux of a drug through the skin may be optimised by controlling surface tension, drug solubility and skin wettability.

The Solubility–Permeability Interplay in Using Cyclodextrins as Pharmaceutical Solubilizers: Mechanistic Modeling and Application to Progesterone

A quasi-equilibrium mass transport analysis has been developed to quantitatively explain the solubility-permeability interplay that exists when using cyclodextrins as pharmaceutical solubilizers. The model considers the effects of cyclodextrins on the membrane permeability (P(m)) as well as the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on cyclodextrin concentration (C(CD)). The analysis reveals that: (1) UWL permeability markedly increases with increasing C(CD) since the effective UWL thickness quickly decreases with increasing C(CD); (2) membrane permeability decreases with increasing C(CD), as a result of the decrease in the free fraction of drug; and (3) since P(aq) increases and P(m) decreases with increasing C(CD), the UWL is effectively eliminated and the overall P(eff) tends toward membrane control, that is, P(eff) approximately P(m) above a critical C(CD). Application of this transport model enabled excellent quantitative prediction of progesterone P(eff) as a function of HP beta CD concentrations in PAMPA assay, Caco-2 transepithelial studies, and in situ rat jejunal-perfusion model. This work demonstrates that when using cyclodextrins as pharmaceutical solubilizers, a trade-off exists between solubility increase and permeability decrease that must not be overlooked; the transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.

Characterization of Cyclodextrin Inclusion Complexes of the Anti-HIV Non-Nucleoside Reverse Transcriptase Inhibitor UC781

The highly potent anti-HIV agent UC781 is being evaluated for use in topical microbicides to prevent HIV transmission. However, UC781 is extremely hydrophobic with poor water solubility, a property that may complicate appropriate formulation of the drug. In this study, we examined the ability of several cyclodextrins, beta-cyclodextrin (beta CD), methyl-beta-cyclodextrin (M beta CD), and 2-hydroxylpropyl-beta-cyclodextrin (HP beta CD), to enhance the aqueous solubility of UC781. Each of the cyclodextrins provided dramatic increases in UC781 aqueous solubility, the order being M beta CD>HP beta CD>beta CD. The complexation constants (K (1:1)) of the inclusion complexes were determined via a phase solubility technique using high-performance liquid chromatography and showed that UC781 solubility increased linearly as a function of cyclodextrin concentration. Ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and 2D (1)H ROESY NMR spectroscopy were used to further characterize these UC781/cyclodextrin complexes. The inhibitory potency of UC781 and its HP beta CD inclusion complex were evaluated using an in vitro HIV-1 reverse transcriptase inhibition assay The inhibitory potency of the UC781/HP beta CD complex was 30-fold greater than that of UC781 alone, showing that the complexed drug is able to provide substantial inhibition of its target. The enhancement of UC781 aqueous solubility is essential for the development of a useful vaginal microbicide dosage form, and our data suggest that UC781/cyclodextrin inclusion complexes may be useful in this context.

Formation of natamycin:cyclodextrin inclusion complexes and their characterization.

Natamycin is a broad spectrum antimycotic with very low water solubility, which is used to extend the shelf life of shredded cheese products. beta-Cyclodextrin (beta-CD), hydroxypropyl beta-cyclodextrin (HP beta-CD), and gamma-cyclodextrin (gamma-CD) were found to form inclusion complexes with natamycin in aqueous solution. The increase in solubility of natamycin with added beta-CD was observed to be linear (type A(L) phase solubility diagram). The 1:1 stability constant of natamycin:beta-CD complex was estimated from its phase solubility diagram to be 1010 M(-1). The phase solubility diagrams of both gamma-CD and HP beta-CD exhibited negative deviation from linearity (type A(N) diagram) and, therefore, did not allow the estimation of binding constants. The water solubility of natamycin was increased 16-fold, 73-fold, and 152-fold with beta-CD, gamma-CD, and HP beta-CD, respectively. The natamycin:CD inclusion complexes resulted in in vitro antifungal activity nearly equivalent to that of natamycin in its free state.

Inclusion complexes of nabumetone with beta-cyclodextrins: thermodynamics and molecular modelling studies. Influence of sodium perchlorate.

Fluorescence, (1)H-NMR and molecular mechanics have been used to study the inclusion complexes of nabumetone (4,6-methoxy-2-naphthyl-butan-2-one; NAB) with beta-cyclodextrin (beta-CD), randomly methylated-beta (M beta-CD) and hydroxypropyl-beta-cyclodextrins (HP beta-CD). The emission spectrum of NAB shows a maximum whose fluorescence intensity increases with the different beta-CDs growing concentrations. This phenomenon allows calculation of the stability constants at 15, 25, 37 and 45 degrees C. The thermodynamic parameters Delta H degrees and Delta S degrees for the inclusion process were obtained from the temperature dependence of the stability constants. Molecular mechanics calculations, together with proton NMR measurements, for the complex with beta-CD prove that the complex can be formed by penetration through any of the rims, with the naphthalene nucleus included and the substituents outside the cavity. The influence of NaClO(4) in the aforementioned complexes has been analysed by spectrofluorimetric measurements. It has been found that the stability constants for the complexes decrease with the salt concentration; the causes are discussed.

Development of a toxin-binding agent as a treatment for tunicaminyluracil toxicity: protection against tunicamycin poisoning of sheep.

To assess the ability of certain derivatives of beta-cyclodextrin to treat sheep affected by tunicaminyluracil toxicity, using tunicamycin poisoning as a model system. Controlled treatment trial. One hundred and sixty Merino wethers were used in the studies. Groups of sheep were experimentally poisoned with tunicamycin. Derivatives of beta-cyclodextrin, with or without magnesium sulphate and magnesium gluconate, were administered to treatment groups daily for 2 to 3 days. Treatment groups were compared with untreated groups in terms of survival. A significant increase in survival was observed following treatment of tunicamycin-affected sheep with hydroxypropyl-beta-cyclodextrin (HP beta-CD) and magnesium sulphate in solution (P < 0.05). In subsequent trials, formulation of the cyclodextrin in the form of a magnesium gluconate gel suspension demonstrated significant protection (P < 0.01) and was equally as effective as the cyclodextrin in solution, but required half the frequency of administration, even when the treatment was not commenced until 24 h after the final toxin dose. Beta-cyclodextrin-epichlorohydrin copolymer also improved the survival rate. After toxin administration, the sheep lost significantly less weight if treatment with HP beta-CD was commenced early (P < 0.001). Protection studies using these two beta-cyclodextrin derivatives suggest that they may be effective in increasing the survival of sheep poisoned by tunicamycin and warrant further testing in field outbreaks of annual ryegrass toxicity.

Intravenous carbamazepine: comparison of different parenteral formulations in a mouse model of convulsive status epilepticus.

A drawback of carbamazepine (CBZ), a major antiepileptic drug (AED) with clinical efficacy against partial and generalized convulsive seizures, is its isolubility in aqueous vehicles, which is generally considered a contraindication to parenteral administration in epileptic patients. However, CBZ can be dissolved in glycofurol, a solvent used clinically as a vehicle for parenteral preparations of drugs such as diazepam (DZP) and phenytoin (PHT). Furthermore, aqueous CBZ solutions can be prepared by complexing CBZ with 2-hydroxypropyl-beta-cyclodextrin (HP beta CD), an inert beta-cyclodextrin derivative believed to have acceptable tolerability for human use. Such solutions of CBZ have been proposed to be suitable for intravenous administration in treatment of convulsive (grand mal) status epilepticus (CSE). A series of five generalized tonic-clonic seizures (GTCS) in 30 min was induced by repeated transauricular electrical stimulation in mice. In this model of convulsive (grand mal) SE, the anticonvulsant potency of intravenous CBZ dissolved in aqueous dilutions of either HP beta CD or glycofurol was evaluated. In both solutions, CBZ rapidly suppressed seizures after intravenous bolus injection. Potent anticonvulsant activity was obtained as early as 30 s after injection, and peak effects were observed at approximately 3 min. ED50 for blockade of GTCS throughout the 30-min period of repeated electrical stimulation was approximately 7 mg/kg, similar to the potency of DZP in this model. Whereas the HP beta CD/CBZ solutions were tolerated by the animals, with no pronounced behavioral or motor adverse effects, the glycofurol/CBZ solutions induced marked sedation and motor impairment, indicating interactions between drug and solvent. Determination of CBZ in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue. An intravenous formulation of CBZ achieved through complexing with HP beta CD might be suitable for parenteral use in acute clinical conditions such as SE, particularly because CBZ has the advantage of being almost free of respiratory or cardiovascular adverse effects.

The effect of cyclodextrin modifiers on electrophoretic separation of aromatic hydrocarbons.

Cyclodextrin-modified capillary electrophoresis has been developed for separation and analysis of benzene and its derivatives. The procedure used a mixture of negatively charged sulfobutyl ether-beta-cyclodextrin (SB beta CD) and neutral hydroxypropyl-beta-cyclodextrin (HP beta CD) to effect differential distribution (partitioning) of the aromatic hydrocarbons between the buffer and CD phases. In 80 mM phosphate buffer, containing 15 mM SB beta CD and 5 mM HP beta CD, benzene, toluene, ethyl benzene and three xylene isomers (BTEXs) were well resolved with a number of theoretical plates well above 100,000, for 50 cm of effective length. Some halogenated benzenes were also observed to separate well from the BTEX components to indicate their suitability as an internal standard for BTEX analyses. Equilibrium complexation models were used for investigating the effect of the cyclodextrin(s) at different concentrations and temperature on the electrophoretic mobility.

The Effect of a Cyclodextrin Vehicle on the Cardiovascular Profile of Propofol in Rats

We studied the aqueous solution of propofol dissolved in hydroxypropyl-beta-cyclodextrin (HP beta CD) 20% to determine whether the cardiovascular profile differed from that measured for propofol prepared in Intralipid 10% (Diprivan). Conscious male rats were given an intravenous bolus of propofol, 5.0 mg/kg, the minimum dose that induces a loss of righting. Immediately severe bradycardia occurred which was the result of a combination of sinus arrest and atrioventricular block; a significant decrease of blood pressure resulted. A bolus of HP beta CD produced no significant changes in heart rate rhythm. The severe bradycardia produced by propofol in HP beta CD was blocked by both atropine and bilateral cervical vagotomy. Therefore, the effects of propofol in HP beta CD are cholinergic and neurally mediated. These results are consistent with the hypothesis that propofol reduces sympathetic tone prior to reduction in vagal tone, and thereby produces a period of time during which vagal tone is dominant.

The Effect of a Cyclodextrin Vehicle on the Cardiovascular Profile of Propofol in Rats

We studied an aqueous solution of propofol dissolved in hydroxypropyl-beta-cyclodextrin (HP beta CD) 20% to determine whether the cardiovascular profile differed from that measured for propofol prepared in Intralipid Registered Trademark 10% (Diprivan Registered Trademark). Conscious male rats were given an intravenous bolus of propofol, 5.0 mg/kg, the minimum dose that induces a loss of righting. Immediately severe bradycardia occurred which was the result of a combination of sinus arrest and atrioventricular block; a significant decrease of blood pressure resulted. A bolus of HP beta CD produced no significant changes in heart rate or rhythm. The severe bradycardia produced by propofol in HP beta CD was blocked by both atropine and bilateral cervical vagotomy. Therefore, the effects of propofol in HP beta CD are cholinergic and neurally mediated. These results are consistent with the hypothesis that propofol reduces sympathetic tone prior to reducing vagal tone, and thereby produces a period of time during which vagal tone is dominant. (Anesth Analg 1996;82:920-4)

New Injectable Aqueous Carbamazepine Solution Through Complexing with 2‐Hydroxypropyl‐β‐Cyclodextrin: Tolerability and Pharmacokinetics After Intravenous Injection in Comparison to a Glycofurol‐Based Formulation

The poor water solubility of the antiepileptic drug (AED) carbamazepine (CBZ) is generally considered an absolute contraindication to parenteral administration in epileptic patients. However, the water solubility of CBZ can be largely enhanced through formation of an inclusion complex with an amorphous cyclodextrin derivative, 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). We studied tolerability and pharmacokinetics of an aqueous CBZ:HP beta CD solution after intravenous (i.v.) administration in dogs. For comparison, a conventional glycofurol-based solution of CBZ was used. We also administered a commercial liquid formulation of CBZ orally (p.o.). Infusion of CBZ:HP beta CD solutions or HP beta CD "placebo" formulations i.v. was well tolerated by the animals. In contrast, infusion of CBZ:glycofurol solutions and glycofurol placebo solutions induced marked behavioral and cardiovascular adverse effects. Pharmacokinetic studies indicated that glycofurol inhibited CBZ metabolism by decreasing formation of the major CBZ metabolite CBZ-10,11-epoxide (CBZ-E). With infusion of CBZ:HP beta CD 10 ml/min for 12-15 min, resulting in a CBZ dose of CBZ 5 mg/kg body weight, peak CBZ plasma levels of approximately 3.6 micrograms/ml were obtained. This relatively low peak concentration is primarily due to the rapid elimination of CBZ in dogs [half-life (t1/2) < 1 h]. Comparison of peak plasma levels determined after p.o. administration of CBZ to dogs with peak CBZ levels previously determined after p.o. administration in humans indicated that about four times higher doses are needed in dogs to attain the same peak plasma levels as in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of absorption enhancers on rat nasal epithelium in vivo: release of marker compounds in the nasal cavity.

The assessment of the effects of nasal absorption enhancers on the rat nasal epithelium and membrane permeability in vivo after a single nasal dose of the enhancers. The release of marker compounds (protein, cholesterol and acid phosphatase) from the nasal epithelium was measured using a lavage technique. The nasal membrane permeability was determined after intravenous administration of a systemic tracer (FITC-albumin). The effects of the absorption enhancers could be classified into four categories. The first consisted of HP beta CD (5%), DM beta CD (2%) and RAMEB (2%) and was not different from the control (physiological saline). For the second category, DM beta CD (5%), effects were significantly higher than for the control. The third category, SGC (1%), was more active than DM beta CD (5%) but less active than the last group. The fourth, most membrane damaging, category consisted of STDHF (1%), laureth-9 (1%) and LPC (1%). Administration of these three enhancers also resulted in release of acid phosphatase, indicating that severe membrane damage occurred. The release of cholesterol from nasal epithelium was largely dependent on the cholesterol solubilisation of the absorption enhancers. The amount of cholesterol released by laureth-9 and LPC was the largest. The results of this in vivo study are in agreement (i.e. similarity in rank order) with morphological and ciliotoxicity studies of nasal absorption enhancers, demonstrating that this in vivo model is a valuable tool to classify nasal absorption enhancers according to their effects on the rat nasal epithelium.

Cyclodextrins as mucosal absorption promoters of insulin. II. Effects of beta-cyclodextrin derivatives on alpha-chymotryptic degradation and enteral absorption of insulin in rats.

The relative effectiveness of two beta-cyclodextrin derivatives, i.e., dimethyl-beta-cyclodextrin (DM beta CD) and hydroxypropyl-beta-cyclodextrin (HP beta CD), in enhancing enteral absorption of insulin was evaluated in the lower jejunal/upper ileal segments of the rat by means of an in situ closed loop method. The incorporation of 10% (w/v) DM beta CD to a 0.5 mg/ml porcine-zinc insulin solution dramatically increased insulin bioavailability from a negligible value (approximately 0.06%) to 5.63%, when administered enterally at a dose of 20 U/kg. However, addition of 10% (w/v) HP beta CD did not improve enteral insulin uptake significantly with a bioavailability of only 0.07%. Similarly, the pharmacodynamic relative efficacy values obtained after the enteral administration of 20 U/kg insulin, 20 U/kg insulin with 10% HP beta CD, and 20 U/kg insulin with 10% DM beta CD were 0.24%, 0.26%, and 1.75%, respectively. Biodegradation studies of 0.5 mg/ml insulin hexamers by 0.5 microM alpha-chymotrypsin revealed no inhibitory effect on the enzymatic activity by the two cyclodextrins. On the contrary, the apparent first-order rate constant increased significantly in the presence of 10% DM beta CD, suggesting insulin oligomer dissociation by DM beta CD. Histopathological examination of the rat intestine was performed to detect tissue damage following enteral administration of the beta-cyclodextrin derivatives. Light microscopic inspection indicated no observable tissue damage, thereby arguing direct membrane fluidization as the primary mechanism for enhanced insulin uptake. This study indicates the feasibility of using cyclodextrins as mucosal absorption promoters of proteins and peptide drugs.

Effect of cyclodextrins on protein binding of drugs: the diflunisal/hydroxypropyl-beta-cyclodextrin model case.

The binding of diflunisal to hydroxypropyl-beta-cyclodextrin (HP beta CD), bovine serum albumin (BSA), human serum albumin (HSA), normal human plasma, and mixed solutions of HP beta CD/protein was studied at 25 degrees C, pH 7.4, by potentiometry using an electrode selective to diflunisal. The experimental data for diflunisal/HP beta CD fit well to the 1:1 binding model. The binding of diflunisal with each of the studied proteins was compatible with a model having two independent classes of binding sites. The binding of diflunisal in mixed solutions HP beta CD/BSA, HP beta CD/HSA, and HP beta CD/plasma increased considerably when the HP beta CD concentration was increased. The binding behavior of the two biomolecules in the mixed solutions of HP beta CD/BSA or HP beta CD/HSA was described with an "additive" model formulated on the basis of the estimates of the binding parameters of diflunisal derived from the separate experiments with each one of the binders tested. The lower than theoretical binding observed in HP beta CD/plasma solutions was ascribed to the competitive displacement of diflunisal from the HP beta CD cavity by plasma cholesterol.

The influence of sucrose, dextran, and hydroxypropyl-beta-cyclodextrin as lyoprotectants for a freeze-dried mouse IgG2a monoclonal antibody (MN12).

The influence of lyophilization on the stability of a monoclonal antibody (MN12) was investigated. MN12 was freeze-dried in different formulations [without lyoprotectant or in the presence of sucrose, dextran, or hydroxypropyl-beta-cyclodextrin (HP beta CD)] and under varying conditions (with or without secondary drying). Subsequently, the monoclonal antibody was stored for 18 or 32 days at various temperatures (4, 37, or 56 degrees C). For comparison, solutions of MN12 were stored under the same conditions. Regardless of the lyoprotectant used, precipitation and a concomitant reduction of the antigen-binding capacity by about 10% were observed upon reconstitution of lyophilized MN12. HP beta CD proved to be the most effective stabilizer to prevent degradation of lyophilized MN12 during storage. Compared with MN12 solutions, HP beta CD-containing lyophilized MN12 cakes were more resistant to heat-induced charge alterations and loss of antigen-binding capacity.

Improved delivery through biological membranes. XLV. Synthesis, physical-chemical evaluation, and brain uptake studies of 2-chloroethyl nitrosourea delivery systems.

The dihydropyridine in equilibrium with pyridinium redox chemical delivery system (CDS) was supplied to two 2-chloroethylnitrosoureas, i.e., HECNU and CCNUOH, and the physicochemical properties of the delivery systems were studied to assess their potential as improved delivery forms to the CNS. Detailed physicochemical evaluation and brain uptake studies were performed on one of the delivery systems (CCNUOH-CDS) derived from trans-4-hydroxy-CCNU, an active metabolite of CCNU. Two aqueous-based formulations derived from hydroxypropyl-beta-cyclodextrin (HP beta CD) and Tween 80:ethanol:water system were developed for CCNUOH-CDS to overcome the poor aqueous solubility conferred upon it by its high lipophilicity. The formulations enabled a 200- to 400-fold improvement in the water solubility of CCNUOH-CDS. Dose- and vehicle-dependent comparative tissue distribution studies in rats indicated improved brain-to-organ ratios of the delivery system at lower doses.

Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats.

The absorption enhancing effect of alpha-, beta-, and gamma-cyclodextrin (CD), dimethyl-beta-cyclodextrin (DM beta CD), and hydroxypropyl-beta-cyclodextrin (HP beta CD) on intranasally administered insulin was investigated in rats. Coadministration of 5% (w/v) DM beta CD to the insulin solution resulted in a high bioavailability, 108.9 +/- 36.4% (mean +/- SD, n = 6), compared to i.v. administration, and a strong decrease in blood glucose levels, to 25% of their initial values. Coadministration of 5% alpha-CD gave rise to an insulin bioavailability of 27.7 +/- 11.5% (mean +/- SD, n = 6) and a decrease in blood glucose to 50% of its initial value. The rate of insulin absorption and the concomitant hypoglycemic response were delayed for the alpha-CD-containing solution as compared to the DM beta CD preparation. The other CDs, HP beta CD (5%), beta-CD (1.8%), and gamma-CD (5%), did not have significant effects on nasal insulin absorption. DM beta CD at a concentration of 5% (w/v) induces ciliostasis as measured on chicken embryo tracheal tissue in vitro, but this effect is reversible. In conclusion, DM beta CD is a potent enhancer of nasal insulin absorption in rats.