Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer.

Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of ß1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (ßCD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller alpha-cyclodextrins (αCD) also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPßCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with ßCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

Oil-cyclodextrin based beads for oral delivery of poorly-soluble drugs.

The main interest of cyclodextrins results from their ability to form inclusion complexes with hydrophobic molecules. This property is employed in pharmaceutical industry to facilitate the formulation of poorly-soluble and/or fragile drugs. Cyclodextrins are also used to form or stabilise dispersed systems. An original multiparticulate system named "beads" is obtained thanks to the interactions occurring between the molecules of α cyclodextrin and the triglycerides of vegetable oils. Beads are prepared by a simple process involving the external shaking of a mixture of an aqueous solution of α cyclodextrin with soybean oil. This is done without any organic solvent or surface-active agent. Once freezedried, beads have a diameter of 1.6 mm and a high lipid content. They consist in a partially crystalline matrix of cyclodextrin surrounding microdomains of oil. The coating of beads with a layer of α cyclodextrin improves their resistance in gastro- intestinal fluids and prolongs the release of drugs. Beads can also be manufactured from mineral oils with α cyclodextrin and from silicone oils with γ cyclodextrin. Poorly-soluble drugs which do not form inclusion complexes with α cyclodextrin are encapsulated in beads with high efficiency and drug loading. In rats, the oral bioavailability of isotretinoin is twofold enhanced with uncoated beads as compared to the lipid content of a soft capsule. The relative oral bioavailability of indomethacin is improved with both coated and uncoated beads versus a commercial hard capsule. Beads demonstrate an important potential for the encapsulation of poorly-soluble and/or fragile compounds and their delivery by oral route.

[Preparation and in vitro evaluation of self-assembled beads drug delivery system of berberine hydrochloride].

The purpose of the present work was to investigate the innovative self-assembling system, "beads", prepared by continuously shaking alpha-cyclodextrin and soybean oil without the use of organic solvents and surfactants at room temperature. Berberine hydrochloride previously dissolved in soybean oil was chosen as a model drug to explore the shape, structure, drug loading and in vitro release of beads. The particle size and drug loading of berberine hydrochloride-loaded beads were (2.25 +/- 0.23) mm and (67.02 +/- 0.64) microg x g(-1), respectively. Confocal microscopy showed that the core-shell structure of beads could contain poorly water soluble drugs or lipophilic drugs in the lipid core. The drug release rate and cumulative releases of beads were both higher than those of raw medicine of berberine hydrochloride in simulated intestinal fluid. These results suggested that beads were the novel and potential lipid-based drug delivery system for lipophilic or poorly water soluble traditional Chinese medicine.

Formulations based on alpha cyclodextrin and soybean oil: an approach to modulate the oral release of lipophilic drugs.

The purpose of this work was to investigate the potential of α-cyclodextrin combined to soybean oil-based formulations to modulate the release of a model drug, indomethacin. Dry emulsion, naked and coated beads were prepared from the same initial formulation using the same manufacturing process. Dry emulsion was selected to accelerate drug release while beads coated with α-cyclodextrin were designed to sustain it. Indomethacin-loaded systems were prepared, characterised and evaluated in vitro. Pharmacokinetic studies were performed in fasted and fed rats. The presence of the α-cyclodextrin coat was confirmed by confocal microscopy, and an increase of the mass and diameter of the beads. The layer of α-cyclodextrin improved their resistance in simulated gastro-intestinal fluids. In vitro, the dissolution of indomethacin was slower with coated beads than with emulsion and naked beads. Lipid-based formulations showed an increase of relative bioavailability of IND versus Indocid®. Whatever the formulation, greater and faster release of indomethacin was noticed in sodium taurocholate-rich medium and in fed rats. Compared to naked beads, an increased Cp(max) with a shorter T(max) was observed with the emulsion while T(max) and MRT were increased and Cp(max) reduced with the coated beads. Interestingly, formulations based on alpha cyclodextrin and soybean oil can modify the release of a lipophilic drug depending on the system formed.

[Research progress of self-assembled beads drug delivery system prepared from cyclodextrins and oils].

Recently, increasing attention has been paid to beads, an innovative self-assembled drug delivery system prepared from cyclodextrins and oils. Beads are new core-shell minispheres containing poorly water-soluble drugs or lipophilic drugs dissolved in the lipid core without the use of organic solvents and surfactants. Therefore, beads with high drug loading and improved oral bioavailability have great potential for oral delivery of poorly water-soluble drugs and lipophilic drugs. The preparation mechanisms, formulations and methods, the in vitro and in vivo properties of beads were reviewed in order to provide the theoretical basis for further application of beads.

The oligosaccharide α-cyclodextrin has modest effects to slow gastric emptying and modify the glycaemic response to sucrose in healthy older adults.

In healthy older subjects, the glycaemic response to carbohydrate-containing meals is dependent on gastric emptying and intestinal absorption; when the latter is slowed, the magnitude of the rise in glucose is attenuated. The oligosaccharide α-cyclodextrin has been reported to diminish the glycaemic response to starch in young adults; this effect has been attributed to the inhibition of pancreatic amylase. We examined the effects of α-cyclodextrin on gastric emptying of, and the glycaemic and insulinaemic responses to, oral sucrose in healthy older subjects; as sucrose is hydrolysed by intestinal disaccharides, any effect(s) of α-cyclodextrin would not be attributable to amylase inhibition. A total of ten subjects (seven males and three females, age 68-76 years) were studied on 2 d. Gastric emptying, blood glucose and serum insulin were measured after ingestion of a 300 ml drink containing 100 g sucrose, labelled with (99m)Tc-sulphur colloid, with or without 10 g α-cyclodextrin. Gastric emptying was slowed slightly by α-cyclodextrin; this effect was evident between 135 and 195 min and was associated with a slight increase (P < 0·05) in distal stomach retention. After α-cyclodextrin, blood glucose was slightly less (P < 0·05) at 60 min, and serum insulin was less (P < 0·0005) at 90 and 120 min. There was no difference in the incremental areas under the curve (iAUC) for blood glucose, but there was a trend for the iAUC for serum insulin to be lower (P = 0·09) after α-cyclodextrin. We conclude that in a dose of 10 g, α-cyclodextrin has modest effects to slow gastric emptying of, and modify the glycaemic and insulinaemic responses to, oral sucrose, probably due to delayed intestinal carbohydrate absorption.

Novel beads made of alpha-cyclodextrin and oil for topical delivery of a lipophilic drug.

PURPOSE: To investigate the potential of a novel lipid carrier, comprising beads of alpha-cyclodextrin and soybean oil, for topical drug delivery. Adapalene was chosen as a model drug to explore the ability of the beads to encapsulate and release a highly lipophilic compound. MATERIALS AND METHODS: Adapalene-loaded beads were prepared and characterised. Skin tolerance to unloaded beads was tested on human volunteers, while drug release and delivery into stratum corneum, was evaluated in pig skin ex vivo. RESULTS: The preparation and physical characteristics of the beads were not dependent on whether adapalene had been previously dissolved or dispersed in soybean oil. Drug encapsulation efficiency was high (>96%) and drug loading on the order of a therapeutic level could be achieved in freeze-dried beads prepared from an oily dispersion of adapalene. After application to human skin, unloaded beads induced no adverse reaction and were better tolerated than an alcoholic gel. Tape-stripping the stratum corneum from treated pig skin showed that adapalene release and penetration from the beads was comparable to that from gel and cream formulations available on the market. CONCLUSION: These novel beads may offer a well-tolerated and efficient system for the encapsulation and topical delivery of lipophilic drugs.

Alpha-cyclodextrin/oil beads as a new carrier for improving the oral bioavailability of lipophilic drugs.

The purpose of the present work was to investigate the potential of novel lipid-carrier "beads" consisting of minispheres made of alpha-cyclodextrin and soybean oil for the encapsulation and the oral delivery of drugs. Isotretinoin was chosen as a model of poorly-stable and lipophilic molecule. Isotretinoin-loaded beads were prepared, characterised and administrated orally in rats. Isotretinoin previously dissolved in soybean oil had no significant effect upon bead preparation and characteristics. Drug encapsulation efficiency was found to be particularly high (93+/-7%) and no isotretinoin degradation occurred during the preparation process. Freeze-drying advantageously concentrated isotretinoin in beads (3.4+/-0.2 mg/g) and facilitating ease of handling and use for oral administration. Isotretinoin exhibited good stability for at least 4 months when beads were stored protected from light. Finally, pharmacokinetics of isotretinoin in rats demonstrated that the drug was successfully released from beads in the digestive tract and that isotretinoin absolute bioavailability was doubled compared to isotretinoin lipid solution (32% and 15% respectively). In conclusion, these beads constitute a novel and efficient system for encapsulation and oral delivery of lipophilic and fragile drugs.

Differential scanning calorimetry as a screening technique in compatibility studies of DHEA extended release formulations.

Differential scanning calorimetry (DSC) was used as a screening technique for assessing the compatibility of DHEA as ternary complex with alpha-cyclodextrin and glycine (c-DHEA) with some excipients suitable for preparation of sustained-release matrix tablets by direct compression. The effect of sample mechanical treatment due to the compression process was also evaluated. In order to investigate the possible interactions between the components, the DSC curves of c-DHEA and each selected excipient were compared with those of their 1:1 w/w physical mixtures, before and after compression, in order to evaluate any possible solid state modification. FT-IR spectroscopy and X-ray powder diffractometry were used as complementary techniques to adequately implement and assist in interpretation of the DSC results. On the basis of DSC results, c-DHEA was found to be compatible with xanthan gum, hydroxypropylmethylcellulose, sodium starch glycolate (Explotab), polyvinylacetate-polyvinylpirrolidone (Kollidon SR) and sodium chloride. Some drug-excipient interaction was observed with dextrate hydrate (Emdex), mannitol and Magnesium stearate. Finally, the behaviour of the complete formulation, in the presence of all the excipients selected by means of the compatibility study, was investigated, in order to verify the absence of reciprocal interactions among the components.