Sequential Phase II clinical trials evaluating CRLX101 as monotherapy and in combination with bevacizumab in recurrent ovarian cancer.

BACKGROUND: Topoisomerase-1 inhibitors are an important class of cytotoxics associated with toxicity that limits their use. CRLX101 is a novel cyclodextrin-containing polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles to deliver sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. METHODS: We conducted sequential phase II, open label, single arm clinical trials to evaluate CRLX101 as a single agent (n = 29) and with bevacizumab (Bev) (n = 34). Patients (pts) had measurable recurrent epithelial ovarian, tubal or primary peritoneal cancer, that could be platinum refractory, resistant or sensitive. Cohort A (Single agent CRLX101) allowed up to 3 prior chemotherapy regimens, but no prior topo-1 inhibitors. Pts received CRLX101 15 mg/m2 IV every 14 days Q28 with response evaluation every 2 cycles. Cohort B also received Bev 10 mg/kg D1,15 Q28, and included only platinum resistant disease with up to 2 prior lines, and more rigorous eligibility criteria. RESULTS: CRLX101 was well tolerated other than nausea, fatigue and anemia. 29 pts. received a median of 3 (1-16) cycles with a clinical benefit rate (CBR) of 68% and overall response rate (ORR) of 11%. With the addition of Bev in Cohort B (n = 34), the CBR was increased to 95% and the ORR to 18%. PFS was 4.5 months (0.9 to 15.9 months) in Cohort A and 6.5 months (2.8 to 14.4 months) in Cohort B. Bev increased the incidence of hypertension and qualitatively increased bladder toxicities, but without SAEs. CONCLUSIONS: CRLX101 meets the clinical need for an effective and tolerable topoisomerase I inhibitor and can be safely combined with bevacizumab.

Phase I/II trial of nano-camptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treatment for locally advanced rectal cancer.

CRLX101 is a nanoparticle-drug conjugate with a camptothecin payload. We assessed the toxicity and pathologic complete response (pCR) rate of CRLX101 with standard neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. A single-arm study was conducted with a 3 + 3 dose escalation phase Ib followed by phase II at the maximum tolerated dose (MTD). Thirty-two patients were enrolled with 29 (91%) patients having T3/4 and 26 (81%) N1/2 disease. In phase Ib, no patient experienced a dose limiting toxicity (DLT) with every other week dosing, while 1/9 patients experienced a DLT with weekly dosing. The weekly MTD was identified as 15 mg/m2. The most common grade 3-4 toxicity was lymphopenia, with only 1 grade 4 event. pCR was achieved in 6/32 (19%) patients overall and 2/6 (33%) patients at the weekly MTD. CRLX101 at 15 mg/m2 weekly with neoadjuvant CRT is a feasible combination strategy with an excellent toxicity profile. Clinicaltrials.gov registration NCT02010567.

Potential Use of Cyclodextrins as Drug Carriers and Active Pharmaceutical Ingredients.

Cyclodextrins (CyDs) are extensively used in various fields, and especially have been widely utilized as pharmaceutical excipients and drug carriers in the pharmaceutical field. Owing to the multi-functional and biocompatible characteristics, CyDs can improve the undesirable properties of drug molecules. This review outlines the current application of CyDs in pharmaceutical formulations, focusing on their use as CyD-based drug carriers for several kinds of drugs. Additionally, CyDs have great potential as active pharmaceutical ingredients against various diseases with few side effects.

Efficacy of the nanoparticle-drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I-IIa clinical trial.

BACKGROUND: Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle-drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. PATIENTS AND METHODS: Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m(2)) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. RESULTS: Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. CONCLUSIONS: CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.

First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies.

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

Effect of a pre-freezing treatment with cholesterol-loaded cyclodextrins on boar sperm longevity, capacitation dynamics, ability to adhere to porcine oviductal epithelial cells in vitro and DNA fragmentation dynamics.

The aim of this work was to examine how a pre-freezing treatment with cholesterol-loaded cyclodextrins (CLC) affects boar sperm longevity, capacitation dynamics, ability to bind to a porcine telomerase-immortalised oviductal epithelial cell line (TERT-OPEC) in vitro and DNA integrity dynamics after freeze-thawing. Although the samples treated with CLC exhibited lower sperm quality than the control samples (P<0.05) immediately after thawing, these differences disappeared (P>0.05) after long-term incubation (26h at 37 or 16°C). Additionally, the CLC-treated spermatozoa underwent similar capacitation and DNA fragmentation dynamics as the control spermatozoa (P>0.05). However, CLC-treated spermatozoa were better able to bind to TERT-OPEC in vitro (P<0.0001). In conclusion, the pre-freezing treatment of boar spermatozoa with CLC enhanced the ability of the spermatozoa to bind to TERT-OPEC in vitro, which could have an effect on the establishment of the sperm reservoir in the ampullary--isthmic junction in vivo. Additionally, frozen-thawed spermatozoa can be stored at 16°C for at least 6h without a significant observable decline in sperm quality, which could be beneficial for the transport of thawed diluted doses of spermatozoa from the laboratory to the farm.

Recent advances in ocular drug delivery.

Amongst the various routes of drug delivery, the field of ocular drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. Recent research has focused on the characteristic advantages and limitations of the various drug delivery systems, and further research will be required before the ideal system can be developed. Administration of drugs to the ocular region with conventional delivery systems leads to short contact time of the formulations on the epithelium and fast elimination of drugs. This transient residence time involves poor bioavailability of drugs which can be explained by the tear production, non-productive absorption and impermeability of corneal epithelium. Anatomy of the eye is shortly presented and is connected with ophthalmic delivery and bioavailability of drugs. In the present update on ocular dosage forms, chemical delivery systems such as prodrugs, the use of cyclodextrins to increase solubility of various drugs, the concept of penetration enhancers and other ocular drug delivery systems such as polymeric gels, bioadhesive hydrogels, in-situ forming gels with temperature-, pH-, or osmotically induced gelation, combination of polymers and colloidal systems such as liposomes, niosomes, cubosomes, microemulsions, nanoemulsions and nanoparticles are discussed. Novel ophthalmic delivery systems propose the use of many excipients to increase the viscosity or the bioadhesion of the product. New formulations like gels or colloidal systems have been tested with numerous active substances by in vitro and in vivo studies. Sustained drug release and increase in drug bioavailability have been obtained, offering the promise of innovation in drug delivery systems for ocular administration. Combining different properties of pharmaceutical formulations appears to offer a genuine synergy in bioavailability and sustained release. Promising results are obtained with colloidal systems which present very comfortable conditions of use and prolonged action.

Cyclodextrins, Natural Compounds, and Plant Bioactives-A Nutritional Perspective.

Cyclodextrins (CDs) are a group of cyclic oligosaccharides produced from starch or starch derivatives. They contain six (αCD), seven (ßCD), eight (γCD), or more glucopyranose monomers linked via α-1,4-glycosidic bonds. CDs have a truncated cone shape with a hydrophilic outer wall and a less hydrophilic inner wall, the latter forming a more apolar internal cavity. Because of this special architecture, CDs are soluble in water and can simultaneously host lipophilic guest molecules. The major advantage of inclusion into CDs is increased aqueous solubility of such lipophilic substances. Accordingly, we present studies where the complexation of natural compounds such as propolis and dietary plant bioactives (e.g., tocotrienol, pentacyclic triterpenoids, curcumin) with γCD resulted in improved stability, bioavailability, and bioactivity in various laboratory model organisms and in humans. We also address safety aspects that may arise from increased bioavailability of plant extracts or natural compounds owing to CD complexation. When orally administered, α- and ßCD-which are inert to intestinal digestion-are fermented by the human intestinal flora, while γCD is almost completely degraded to glucose units by α-amylase. Hence, recent reports indicate that empty γCD supplementation exhibits metabolic activity on its own, which may provide opportunities for new applications.

Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-ß-Cyclodextrin.

BACKGROUND: Intrathecal 2-hydoxypropyl-ß-cyclodextrin has been found to mobilize cholesterol, extend life, reduce cerebellar pathology, and delay onset of ataxia in the mouse and cat models of Niemann-Pick disease, type C1, a clinically variable progressive and ultimately fatal neurodegenerative storage disorder characterized by endolysosomal accumulation of unesterified cholesterol. OBJECTIVE: In this study, the long-term effects of intrathecal 2-hydoxypropyl-ß-cyclodextrin treatment for 2.5 to three years in humans with Niemann-Pick disease, type C, were evaluated. METHODS: Three patients with Niemann-Pick disease, type C, in different stages of progression and displaying varying disease manifestations were treated with intrathecal 2-hydoxypropyl-ß-cyclodextrin (VTS-270) delivered by lumbar puncture infusion through an intermediate-size patient population investigational new drug application for expanded access. Disease progression was monitored with the Niemann-Pick disease, type C, Neurological Severity Scale and numerous objective measures of function in five neurological domains typically impacted by the disease: cognitive/language, gait/balance, fine motor, swallowing, and eye movement. RESULTS: No worsening in any domain except eye movements (vertical pursuit gain) was seen for any of the three patients, and in the other domains, improved scores on measures were seen over time for one or more patients. The Niemann-Pick disease type C (NPC) Neurological Severity Scale (NSS) showed stable to slightly improved ratings. CONCLUSIONS: These trajectories are not consistent with the typical trajectory of the disease and suggest that intrathecal 2-hydoxypropyl-ß-cyclodextrin has stabilized the disease over an extended period of time, supporting the current phase 2/3 controlled registration trial with VTS-270.

Acid-active supramolecular anticancer nanoparticles based on cyclodextrin polyrotaxanes damaging both mitochondria and nuclei of tumor cells.

As a supramolecular macrocyclic polymer, cyclodextrin (CD) polyrotaxanes (PRs) have many advantages for developing nanomedicines, such as stable chemical composition, abundant functionalized hydroxyl groups, moving across biological barriers, adjustable nanoparticle size and good biocompatibility. Herein, we synthesized a class of acid-active therapeutic nanoparticles comprising a α-CD-based PR polymeric prodrug of PRs-poly(doxorubicin)-co-poly[(ethylene glycol) methyl ether methacrylate] (PR-PDOX-co-POEGMA, denoted as PRMO@DOX) to reduce drug leakage and selectively deliver drugs into tumor cells, aiming to achieve maximal treatment efficacy of supramolecular therapeutics. The obtained PRMO@DOX showed desirable features of high drug loading rates (>25 wt%), fast cellular uptake, acid-active controlled release, effective anti-tumor activity and low systemic toxicity. Benefiting from its unique amphiphilic nanostructure, PRMO@DOX can form water-soluble prodrug nanoparticles in aqueous media. The acid-active hydrazone bond in the prodrug can break and thus release drug molecules precisely and in a timely manner under an acidic tumor microenvironment, damaging the nuclei and mitochondria of tumor cells. Both in vitro and in vivo experiments clearly demonstrated a remarkable antitumor efficacy of this therapeutic platform, which provided a new strategy for the development of polyrotaxane-based nanomedicine for enhanced cancer therapy.

Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent.

Because both HIV-1 virions and HIV-infected cells are present in the semen and cervical mucus of infected individuals, HIV-1 prevention strategies must consider both cell-free and cell-associated virus. Antibodies that target HIV-1 virions have been shown to prevent vaginal transmission of cell-free virus in macaques, but since cell-associated transmission has not been reliably demonstrated in this model system, no strategies to prevent such transmission have been tested. We have employed a mouse model in which SCID mice carry human peripheral blood leukocytes (HuPBLs). In these mice, vaginal transmission of cell-associated, but not cell-free, HIV-1 transmission occurs, mediated by transepithelial migration of HIV-infected cells. Topical application of beta-cyclodextrin (beta-CD), a cholesterol-sequestering agent that interferes with cell migration and budding of virus from lipid rafts, blocks transmission of cell-associated HIV-1. The HuPBL-SCID model of vaginal HIV-1 transmission should prove useful for investigating cell-associated HIV-1 transmucosal HIV-1 transmission, as well as for screening reagents for their potential efficacy in preventing sexual HIV-1 transmission.

Surface modification of polymeric biomaterials: utilization of cyclodextrins for blood compatibility improvement.

A novel modified polymeric biomaterial surface using cyclodextrins (CDs) for improved blood compatibility was studied. Plasticized poly(vinyl chloride) (PVC-P) was selected for modification and polyethylene was used as a reference material. The modification was achieved by polymer blending. Fibrinogen and albumin adsorption were utilized as indices for the assessment of the blood compatibility. Surface characterization confirmed that CDs were able to accumulate at the PVC surface and alter the surface properties. The combination of other hydrophilic polymers such as poly(ethylene oxide) (PEO) and PEO/poly(propylene oxide) (PPO) copolymers, such as Pluronic F68 (F68), with CDs were also investigated. These modified materials have a remarkable protein-resistant surface. The combination of B-cyclodextrin (B-CD)/PEO and B-CD/F68 in certain feeding ratio are synergistic in producing enhanced blood compatibility.

Translational impact of nanoparticle-drug conjugate CRLX101 with or without bevacizumab in advanced ovarian cancer.

PURPOSE: Increased tumor hypoxia and hence elevated hypoxia-inducible factor-1α (HIF1α) is thought to limit the efficacy of vascular endothelial growth factor (VEGF) pathway-targeting drugs by upregulating adaptive resistance genes. One strategy to counteract this is to combine antiangiogenic drugs with agents able to suppress HIF1α. One such possibility is the investigational drug CRLX101, a nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a known topoisomerase-I poison. EXPERIMENTAL DESIGN: CRLX101 was evaluated both as a monotherapy and combination with bevacizumab in a preclinical mouse model of advanced metastatic ovarian cancer. These preclinical studies contributed to the rationale for undertaking a phase II clinical study to evaluate CRLX101 monotherapy in patients with advanced platinum-resistant ovarian cancer. RESULTS: Preclinically, CRLX101 is highly efficacious as a monotherapy when administered at maximum-tolerated doses. Furthermore, chronic low-dose CRLX101 with bevacizumab reduced bevacizumab-induced HIF1α upregulation and resulted in synergistic efficacy, with minimal toxicity in mice. In parallel, initial data reported here from an ongoing phase II clinical study of CRLX101 monotherapy shows measurable tumor reductions in 74% of patients and a 16% RECIST response rate to date. CONCLUSIONS: Given these preclinical and initial clinical results, further clinical studies are currently evaluating CRLX101 in combination with bevacizumab in ovarian cancer and warrant the evaluation of this therapy combination in other cancer types where HIF1α is implicated in pathogenesis, as it may potentially be able to improve the efficacy of antiangiogenic drugs.

Piroxicam-beta-cyclodextrin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in rheumatic diseases and pain states.

Piroxicam-beta-cyclodextrin is a complex of the established nonsteroidal antiinflammatory drug (NSAID) piroxicam and an inert cyclic macromolecule, beta-cyclodextrin. In clinical trials in patients with rheumatic diseases or pain arising from other conditions, it was as effective an analgesic as standard piroxicam, and showed a faster onset of action on the first day of treatment. In short term pharmacodynamic studies in healthy volunteers, piroxicam-beta-cyclodextrin was equivalent to or tended to show less gastrointestinal mucosal toxicity than standard piroxicam, as assessed by endoscopy and faecal blood loss. However, no data are available on its comparative gastrointestinal mucosal effects from long term clinical trials using similar measures. Preliminary findings from a clinical study suggest piroxicam-beta-cyclodextrin caused fewer gastroduodenal lesions than tenoxicam. As with other NSAIDs, the majority of adverse events associated with piroxicam-beta-cyclodextrin in clinical trials were gastrointestinal in origin, with epigastric pain, heartburn and nausea the most common. Thus, piroxicam-beta-cyclodextrin is an effective agent in patients with rheumatic diseases or other pain states. When rapid analgesia is required in the initial treatment of acute pain, the faster onset of action of piroxicam-beta-cyclodextrin may be an advantage over the parent compound; however, this is unlikely to be important during long term therapy. The results of further long term trials are awaited before firm conclusions can be reached regarding the gastrointestinal tolerability of piroxicam-beta-cyclodextrin compared with that of standard piroxicam and other NSAIDs.

Colon-specific delivery of prednisolone-appended alpha-cyclodextrin conjugate: alleviation of systemic side effect after oral administration.

Prednisolone (PD), a typical glucocorticoid, has been widely used for the treatment of inflammatory bowel disease (IBD). However, when PD is administered orally, a large amount of the drug is absorbed from the upper gastrointestinal (GI) tract and causes systemic side effects. In this study, the anti-inflammatory effect and systemic side effect of the PD succinate/alpha-cyclodextrin (PDsuc/alpha-CyD) ester conjugate after oral administration were studied using IBD model rats. The anti-inflammatory effect of the PDsuc/alpha-CyD conjugate was comparable to those of PD alone. On the other hand, the systemic side effect of the PDsuc/alpha-CyD conjugate was much lower than that of PD alone when administered orally. The lower side effect of the conjugate was attributable to passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specifically in the large intestine. The oral administration of PD alone gave higher plasma concentrations of PD, giving the significant systemic side effect. The results suggested that the PDsuc/alpha-CyD conjugate is useful as a delayed-release type prodrug of PD for colon-specific delivery, owing to alleviation of the systemic side effect, while maintaining the therapeutic effect.

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.

Efficacy, safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs.

Cyclodextrins are used in nasal drug delivery as absorption enhancing compounds to increase the intranasal bioavailability of peptide and protein drugs. The most effective cyclodextrins in animal experiments are the methylated derivatives, dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin, which are active at low concentrations ranging between 2% and 5%. However, large species differences between rats, rabbits and humans exist for the nasal absorption enhancement by cyclodextrins. Based on toxicological studies of the local effects of cyclodextrins on the nasal mucosa dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin are considered safe nasal absorption enhancers. Their effects were quite similar to controls (physiological saline), but smaller than those of the preservative benzalkonium chloride in histological and ciliary beat frequency studies. In these studies, and in a study of the release of marker compounds after nasal administration, methylated beta-cyclodextrins were less toxic than sodium glycocholate, sodium taurodihydrofusidate, laureth-9 and L-alpha-phosphatidylcholine. Systemic toxicity after nasal cyclodextrin administration is not expected, because very low doses of cyclodextrins are administered and only very small amounts are absorbed. The mechanism of action of cyclodextrins may be explained by their interaction with the nasal epithelial membranes and their ability to transiently open tight junctions.

Cyclodextrins and oligonucleotide delivery to solid tumours.

Cyclodextrins (CyDs) have traditionally been used for dissolving hydrophobic chemicals into aqueous media, and more recently, for inducing cholesterol efflux from lipid-laden cells as a proposed mechanism for reversal of cardiovascular disease. This review discusses the potential of delivering therapeutic oligonucleotides to solid tumours using CyD molecules. The physicochemical properties of these oligosaccharide molecules, and the barriers posed by the solid tumour itself, factors that affect may affect the uptake of oligonucleotides by CyDs, are the major foci of this review.

Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation.

The objective of this review is to summarize recent findings on the safety profiles of three natural cyclodextrins (alpha-, beta- and gamma-CDs) and several chemically modified CDs. To demonstrate the potential of CDs in pharmaceutical formulations, their stability against non-enzymatic and enzymatic degradations in various body fluids and tissue homogenates and their pharmacokinetics via parenteral, oral, transmucosal, and dermal routes of administration are outlined. Furthermore, the bioadaptabilities of CDs, including in vitro cellular interactions and in vivo safety profiles, via a variety of administration routes are addressed. Finally, the therapeutic potentials of CDs are discussed on the basis of their ability to interact with various endogenous and exogenous lipophiles or, especially for sulfated CDs, their effects on cellular processes mediated by heparin binding growth factors.

Complexation of zolpidem with 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin: effect on aqueous solubility, dissolution rate, and ataxic activity in rat.

The effect of some chemically modified cyclodextrins [namely, 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin (HP-beta-CD, Me-beta-CD, and HP-gamma-CD, respectively)] on the aqueous solubility and dissolution rate of the hypnotic agent Zolpidem (ZP) was investigated. Solid complexes were prepared by freeze drying and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. The solubility and dissolution rate of the drug were significantly improved by complexation with HP-beta-CD or Me-beta-CD. The structure of the inclusion complex ZP-HP-beta-CD in CH(3)COOD/D(2)O was investigated by (1)H and (13)C NMR spectroscopy, including NOE measurements. These measurements revealing a weak interaction between the tolyl moiety of the guest molecule and the HP-beta-CD cavity. The ataxic activity in rat was also investigated and it was found that ZP-HP-beta-CD and ZP-Me-beta-CD complexes showed almost 2-fold longer ataxic induction times than controls.