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PubMed1992

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.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Hemicrania continua: a case responsive to piroxicam-beta-cyclodextrin.

The case of a 53-year-old woman is described, who since the age of 38 years had been suffering from a unilateral headache that was at first remitting, but then evolved into an unremitting course. The headache was burning in quality, located in the left forehead and face, and was accompanied by mild ipsilateral autonomic symptoms. The clinical picture, as well as the absolute response to indomethacin, suggested a diagnosis of hemicrania continua. The presence of mild gastric discomfort on continuous indomethacin administration made us transfer the patient to another NSAID (piroxicam-beta-cyclodextrin). With this drug, complete relief and good tolerability was obtained.

Chronic Disease↗
PubMed1992

Inhibitory effect of 2-hydroxypropyl-beta-cyclodextrin on crystal-growth of nifedipine during storage: superior dissolution and oral bioavailability compared with polyvinylpyrrolidone K-30.

To prevent the crystal-growth of nifedipine during storage, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) was employed as a hydrophilic drug carrier and compared with polyvinylpyrrolidone K-30 (PVP). Amorphous nifedipine powders were prepared by spray-drying with HP-beta-CyD or PVP, and their crystal-growing behaviour at accelerated storage conditions were examined by X-ray diffraction analysis and microscopy. Although PVP initially retarded the crystallization of nifedipine, it failed to control the increase of crystal size after prolonged storage at 60 degrees C, 75% r.h., resulting in a remarkable decrease in dissolution rate in water. In sharp contrast, a relatively fine and uniform size of nifedipine crystals was maintained in the HP-beta-CyD system even after accelerated storage conditions. The enhanced dissolution observed for all the HP-beta-CyD systems in a dissolution medium containing 0.1% non-ionic surfactant HCO-60 were clearly reflected in the in-vivo absorption of nifedipine following oral administration to dogs. These results suggest that HP-beta-CyD is particularly useful in solving problems encountered on storage of amorphous nifedipine in solid dosage forms.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Improved transdermal delivery of prostaglandin E1 through hairless mouse skin: combined use of carboxymethyl-ethyl-beta-cyclodextrin and penetration enhancers.

The optimal prescription of transdermal preparations of prostaglandin E1 (PGE1) for treatment of peripheral vascular diseases has been investigated. The chemical stability of PGE1 in fatty alcohol/propylene glycol (FAPG) ointment was markedly improved by carboxymethyl-ethyl-beta-cyclodextrin (CME-beta-CyD). Application of a PGE1 ointment containing the penetration enhancer, 1-dodecylazacycloheptane-2-one (Azone) or 1-[2-(decylthio)ethyl]azacyclopentane-2-one (HPE-101), onto the skin of hairless mice showed the increase of blood flow in the skin due to the vasodilating action of PGE1. In particular, the ointment containing a PGE1-CME-beta-CyD complex supplemented with HPE-101 showed the most prominent increase of the blood flow. Compared with other ointments, this ointment was found to show significantly greater transfer of HPE-101 into in-vitro preparations of the skin of hairless mice. Transfer of PGE1 into the skin was thought to be facilitated by this increased transfer of HPE-101. These results suggest that a combination of CME-beta-CyD and HPE-101 is useful for designing PGE1 ointments for topical application with good chemical stability and percutaneous permeability.

Administration, Cutaneous↗
PubMed1992

Effect of cyclodextrin on the pharmacology of antifungal oral azoles.

Concentrations of oral azoles in serum were compared in a single-dose pharmacologic study in mice. When hydroxypropyl-beta-cyclodextrin was used as a carrier and compared with a standard carrier, polyethylene glycol, drug concentrations determined by bioassay showed that the peak concentration and area under the concentration-time curve were greatly enhanced for itraconazole and saperconazole; moderately enhanced for ketoconazole; but negligibly affected for fluconazole, miconazole, and SCH 42427.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

The effects of a brain-enhanced estradiol delivery system on testosterone and androgen-dependent tissues. I. Dose-response and time-course evaluation.

The primary objective underlying hormone treatment of prostatic adenocarcinoma is to induce an effective androgen deprivation, and high dose estrogen therapy is as effective as surgical castration in abolishing the growth-promoting effects of androgens on prostatic tissue. An estradiol-chemical delivery system (E2-CDS), with sustained release of E2 in the brain, may be potentially useful in the treatment of prostatic cancer by virtue of the need for lower or less frequent doses of the estrogen. In this study we evaluated the dose- and time-dependent effects of the E2-CDS vs. 17 beta-E2 on serum testosterone (T) and weights of androgen-dependent tissues in male rats. Rats received a single iv injection of E2-CDS (0.1, 0.5, or 1.0 mg/kg), equimolar doses of 17 beta-E2, or the drug's vehicle. Sera and tissues were collected 1, 7, 14, or 21 days later for determination of hormone levels and tissue weights. The E2-CDS exhibited a dose- and time-dependent suppression of serum T and weights of the ventral prostate and seminal vesicles. In contrast, 17 beta-E2 had no significant effect on serum T or growth of these androgen-dependent tissues. Serum T levels were significantly reduced by 98%, 82%, and 59% at 1, 7, and 14 days, respectively, with the 1.0 mg/kg dose of E2-CDS. The E2-CDS significantly reduced prostate weight by 45% and 50% (1.0- and 0.5-mg/kg doses, respectively) 7 days and by 27% (0.5 mg/kg dose) 14 days after treatment. Similarly, seminal vesicle weights were reduced by 14-20% on day 1, maximally reduced by 39-48% on day 7, and still reduced by 24-36% on day 14 compared with the control levels. Weights of these tissues returned to control levels by day 21. Serum E2 was elevated through 7 days by E2-CDS or on day 1 only by 17 beta-E2. PRL secretion was stimulated for 1 week by both forms of estrogen. Anterior pituitary weights were increased by the E2-CDS through 14 days, while 17 beta-E2 had no significant effect. These data indicate that the E2-CDS causes chronic suppression of serum T, which subsequently results in regression of androgen-dependent tissue weight.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

Sublingual administration of testosterone-hydroxypropyl-beta-cyclodextrin inclusion complex simulates episodic androgen release in hypogonadal men.

In search of a more physiological testosterone (T) replacement therapy for hypogonadal states, we evaluated an inclusion complex of T with 2-hydroxypropyl-beta-cyclodextrin (HPBCD). HPBCD enhances T solubility and absorption, but HPBCD is not absorbed. Five hypogonadal men (mean age, 32.4 +/- 2.3 yr) with serum T levels below the normal range were treated in two separate experimental phases with either a 2.5- or 5.0-mg tablet of sublingual (SL) T-HPBCD three times daily for 7 days. Acute pharmacodynamic changes were monitored at baseline and 10, 20, and 40 min and 1, 1.5, 2, 3, 4, and 8 h after administration of the first dose. At the 5-mg dose, a maximal concentration (Cmax) of T (85.4 +/- 11.0 nmol/L) was achieved in 20 min (63 +/- 24-fold increase), followed by a rapid decline to below the normal range (less than 12 nmol/L) at 2 h, with an estimated half-life of decline of 1.87 +/- 0.19 h. The dihydrotestosterone (DHT) Cmax (4.1 +/- 0.5 nmol/L) occurred at 32 +/- 5 min (8.9 +/- 1.3-fold increase) and declined to below the normal range (less than 1.2 nmol/L) after 3 h. The integrated 8 h value for the ratio of T/DHT was 10.0 +/- 1.1, which fell within the normal range. The increment in androstenedione paralleled that in T, and the Cmax (6.8 +/- 0.9 nmol/L) was reached in 24 +/- 4 min (2.3 +/- 0.6-fold increase). Compared to baseline, the Cmax was significantly greater for T (P less than 0.005), DHT (P less than 0.0005), and androstenedione (P less than 0.005). Both estradiol (E2) and estrone (E1) remained in the normal range (less than 200 pmol/L), although the Cmax for E1 was significantly greater than baseline (P less than 0.05). Serum LH levels were suppressed (19.0 +/- 2.6%) at 2 h (P less than 0.05), without a significant change in FSH. During 7 days of treatment, there was no cumulative increase in basal T, DHT, and E2 levels or further decline in LH or FSH levels. There was no change in sex hormone-binding globulin levels. Similar results were observed with the 2.5-mg dose, suggesting that the capacity of SL absorption may be limited to a certain dose of T-HPBCD. The fluctuations in T after SL administration of T-HPBCD resemble endogenous episodic secretion. We conclude that T, complexed with HPBCD, is rapidly absorbed by the SL route and quickly metabolized without sustained elevations of DHT or E2.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

[Improvement of stability and bioavailability of 1-hexylcarbamoyl-5-fluorouracil (HCFU) by O-carboxymethyl-O-ethyl-beta- cyclodextrin].

The possible utility of O-carboxymethyl-O-ethyl-beta-cyclodextrin (CME-beta-CyD) as a novel drug carrier was studied in vitro and in vivo, by using 1-hexylcarbamoyl-5-fluorouracil (HCFU) as a model drug. The chemical instability of HCFU in solution and solid state was improved by CME-beta-CyD complexation. The in vitro release of HCFU from the CME-beta-CyD complex was decelerated in acidic solution, while accelerated at neutral pH regions, showing a typical delayed-release pattern. This pattern was clearly reflected in the blood levels after the oral administration of the complex to dogs, increasing the bioavailability. The present results suggested that CME-beta-CyD is useful as a delayed-release-type carrier for the oral administration of chemically labile HCFU.

Administration, Oral↗
PubMedDate not supplied

Preparation and physical evaluation of microcapsules of hydrophilic drug-cyclodextrin complexes.

An emulsion-solvent evaporation method for preparation of microcapsules containing water-soluble 2-hydroxypropyl-beta-cyclodextrin complex of a lipophilic water-insoluble drug, hydrocortisone, is described. The release of the drug from the microcapsules was determined in simulated gastric fluid. The drug release rate from the microcapsules could be controlled by addition of a plasticizer and it was sustained over extended time. Addition of solubilizing compounds to the dissolution medium did not affect the drug release rate.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

[Studies and preparations of fufang danshen granules].

With the preparation of borneol-beta-cyclodextrin inclusion compound, the stability of the product was improved. In the studies on quality standards, TLC method was used in the identification of three medicinal ingredients and TLC-ultraviolet spectrophotometry was used in the content determination of the chemical constituent tanshinone II A in Salvia miltiorrhiza.

Abietanes↗
PubMed1992

Use of 2-hydroxypropyl-beta-cyclodextrin as an intrathecal drug vehicle with opioids.

2-Hydroxypropyl-beta-cyclodextrin (CDEX), a seven-membered glucose pyranose structure, forms reversible inclusion complexes with the lipophilic portion of a drug molecule by noncovalent bonding. This can increase the water solubility of lipid-soluble drugs and reduce the rate of clearance of such agents from the spinal cord into the vasculature after i.t. administration. In this study, opioids (morphine, lofentanil, alfentanil and sufentanil) with and without CDEX (20, 2, 0.2 and 0.02% w/v in sterile water) were administered spinally in rats prepared with chronic i.t. catheters. CDEX prolonged the duration of analgesia (52.5 degrees C hot plate) and reduced the incidence of catalepsy otherwise produced by a supermaximal i.t. dose of each of the opioids. The magnitude of the potentiating effect of CDEX on opioids was dependent upon concentration of the CDEX and varied with drug lipid partition coefficients. The highest concentration of CDEX alone (20%) had no effect upon the volume-evoked micturition reflex, blood pressure, heart rate, or spinal reflexes. Our data indicate that CDEX may be a useful i.t. vehicle for modifying the redistribution characteristics of highly diffusible molecules after their i.t. administration, and that for each drug there is an optimal CDEX concentration. In the present case, CDEX prolongs the spinal analgesic action and reduces the supraspinal actions of i.t. drugs.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Interactions between epidurally and intrathecally administered sufentanil and bupivacaine in hydroxypropyl-beta-cyclodextrin in the rat.

The interaction between inactive doses of the opioid sufentanil and the local anesthetic bupivacaine after complexation in various concentrations of hydroxypropyl-beta-cyclodextrin (HP-B-CD) were studied after epidural and intrathecal administration in the rat. Whereas 0.125 microgram sufentanil and 80 micrograms bupivacaine produced only limited effects, a combination of the two compounds resulted in a profound surgical analgesia in all rats tested after epidural administration. Also intrathecally, a clear potentiation was present. The complexation of the same doses of sufentanil plus bupivacaine in HP-B-CD increased the duration of analgesia. Epidurally, a maximal potentiation of analgesia was present at 0.125 microgram sufentanil plus 80 micrograms bupivacaine in 20% HP-B-CD. Intrathecally, maximal potentiation of the analgesic activity was present starting from a complexation of both drugs in 10% hydroxypropyl-beta-cyclodextrin. Higher concentrations of hydroxypropyl-beta-cyclodextrin did not significantly further increase the duration of analgesia. These results indicate that for both routes of spinal administration, the complexation of sufentanil plus bupivacaine in HP-B-CD can produce a longer analgesia than either plain sufentanil, sufentanil combined with bupivacaine or sufentanil alone in HP-B-CD. The complexation of sufentanil plus bupivacaine in HP-B-CD did not diminish the increased safety observed to occur after complexation of sufentanil in HP-B-CD and after combination of sufentanil plus bupivacaine.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Hydroxypropyl-beta-cyclodextrin can modulate the activity of spinally administered sufentanil.

Hydroxypropyl-beta-cyclodextrin increased the effectiveness of sufentanil after epidural and intrathecal administration in rats, both in terms of a longer duration of analgesia after a fixed dose of sufentanil, and in a reduction of the lowest ED50s to produce analgesia. There was also an increase in specificity, as indicated by the greater dissociation between the ED50s for analgesia and for supra-spinal side-effects. Maximal activity was measured after inclusion complexation of sufentanil in 10% hydroxypropyl-beta-cyclodextrin. At higher concentrations of hydroxypropyl-beta-cyclodextrin, both the activity and the specificity were attenuated. The increased safety of sufentanil in 10% hydroxypropyl-beta-cyclodextrin after spinal administration was also confirmed in terms of opioid-induced deviations in arterial PO2, PCO2 and oxygen saturation. At a dose of twice the ED50 for deep surgical analgesia, the sufentanil/hydroxypropyl-beta-cyclodextrin complex produced no changes in these parameters. With sufentanil alone at comparable analgesic doses, significant shifts in all three parameters were present immediately after drug administration. At higher concentrations of sufentanil in hydroxypropyl-beta-cyclodextrin changes in the three blood gases were present but the deviations were always smaller than those observed with comparable doses of plain sufentanil. These results support the notion that after complexation sufentanil is present longer at the spinal level after spinal administration. As a consequence, there is less free sufentanil available for redistribution into lipid tissue and into the circulatory system, producing less systemic side-effects.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Bile acid and sterol solubilization in 2-hydroxypropyl-beta-cyclodextrin.

The use of 2-hydroxypropyl-beta-cyclodextrin has made it possible to prepare stable aqueous solutions of cholesterol, 26-hydroxycholesterol, 7 alpha-hydroxycholesterol, and monohydroxy bile acids such as lithocholic and 3 beta-hydroxy-5-cholenoic acids. These solutions are suitable for cell culture studies and for parenteral administration to animals.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Development of a lyophilized formulation of interleukin-2.

Native human interleukin-2 (IL-2) comprises a group of glycoproteins of MW 13,000-17,500. Recombinant human IL-2 (rhIL-2) (Cetus) is derived from E. coli and is not glycosylated. We have evaluated several processes for manufacturing rhIL-2, based on different chaotropic agents for solubilization of insoluble protein pastes. Formulation work carried out with material purified by one of these processes is reported here. Our studies have indicated that the presence of a stabilizer in the form of an amorphous excipient, such as amino acids, a non-ionic surfactant (polysorbate 80), hydroxypropyl-beta-cyclodextrin or human serum albumin was essential for preservation of rhIL-2 during lyophilization. Each of these formulations exhibited its own unique problems. We have overcome these problems through a systematic formulation development program and have been successful in developing several lyophilized formulations of rhIL-2 with optimum properties and performance.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMedDate not supplied

Solubilization of ovine growth hormone with 2-hydroxypropyl-beta-cyclodextrin.

Studies were undertaken to determine the effects of 2-hydroxypropyl-beta-cyclodextrin (HPCD) on the solubility of ovine-Growth Hormone (o-GH) in aqueous solution. HPCD, which is believed to form inclusion complexes with hydrophobic amino acid residues of peptides, markedly increased o-GH solubility at all o-GH and all HPCD concentrations tested. In HPCD solutions, o-GH was completely solubilized between pH 7.5 and 8.5, while in water, o-GH was not solubilized until a pH of 11.5 was reached. Temperature and repeated freeze-thaw cycles had little effect on o-GH solubility in HPCD. Vigorous shaking of solution of o-GH in HPCD did not result in precipitation of the peptide. These studies document that HPCD enhances o-GH solubility in aqueous solutions. Preparations of GH in HPCD may eliminate solubility problems observed in current human GH preparations intended for parenteral use.

2-Hydroxypropyl-beta-cyclodextrin↗