Spartium junceum aromatic water: chemical composition and antitumor activity.

The purpose of this study was to analyse the chemical composition of Spartium junceum L. (also known as Spanish Broom) aromatic water and to evaluate its cytotoxic activity against a series of human cancer cell lines (melanoma: RPMI 7932; leukemia: K562; breast cancer cell: MCF7-Bart and MCF7-ICLC, colon adenocarcinoma: SW480). The results show that the aromatic water was cytotoxic toward the tumor cell lines analyzed (RPMI 7932, K562, MCF7-Bart, MCF7-ICLC, SW480), while it did not appreciably alter the viability of normal keratinocytes (NCTC 2544) suggesting its potential use as an antitumor agent for cancer treatment and/or prevention.

Albumin nanoparticles carrying cyclodextrins for nasal delivery of the anti-Alzheimer drug tacrine.

Peroral administration of tacrine, the first acetylcholinestearse inhibitor licensed for the treatment of Alzheimer's disease, is associated with low bioavailability, due to an extended first-pass methabolism, short elimination half-life and hepatotoxicity. Nasal drug delivery may reduce the degree of these problems. Tacrine hydrochloride nasal delivery is here investigated by means of albumin nanoparticles carrying beta cyclodextrin and two different beta cyclodextrin derivatives (hydroxypropyl beta cyclodextrin and sulphobutylether beta cyclodextrin). Bovine serum albumin nanoparticles were obtained using a coacervation method, followed by thermal cross-linking, starting from protein solution at alkaline pH. After preparation, nanoparticles were loaded by soaking from solutions of tacrine hydrochloride and lyophilised. Thermal analysis (differential scanning calorimetry and thermogravimetric analysis) supported by Fourier Transform Infrared Spectroscopy were performed in order to confirm protein cross-linking in nanosphere structure and possible drug/carrier interaction occurred after the loading process. Moreover, size, polydispersity, zeta potential and morphology of the nanoparticles were investigated as well as drug loading, mucoadhesion properties and ex-vivo drug permeation ability. Results indicate that all the nanoparticles presented a mean size and a polydispersity lower than 300nm and 0.33nm, respectively, were spherical shaped and negatively charged even after drug loading. Moreover, the presence of the different beta cyclodextrins in the polymeric network affected drug loading and could differently modulate nanoparticle mucoadhesiveness and drug permeation behaviour.

Chitosan-based hydrogels for nasal drug delivery: from inserts to nanoparticles.

IMPORTANCE OF THE FIELD: Chitosan represents a multifunctional polymer, featuring both mucoadhesive and permeation-enhancing properties and therefore is a widely studied excipient for mucosal drug delivery. As regards nasal administration, chitosans have been used for the preparation of gels, solid inserts, powders and nanoparticles in which a three-dimensional network can be recognized. AREAS COVERED IN THIS REVIEW: This review provides a discussion of the different nasal dosage forms based on chitosan hydrogels. In the first section intranasal delivery is discuss as a useful tool for non-invasive administration of drugs intended for local or systemic treatments. Then chitosan-based hydrogels are described with a focus on their mucoadhesive and permeation-enhancing ability as well as their capacity of controlled drug release. Finally, a detailed discussion regarding several examples of the different nasal dosage forms is reported, including considerations on in vitro, ex vivo and in vivo studies. WHAT THE READER WILL GAIN: Summary and discussion of recent data on the different pharmaceutical forms based on chitosan hydrogels could be of interest to researchers dealing with nasal drug delivery. TAKE HOME MESSAGE: The aim of this review is to stimulate further investigations in order to achieve the collection of harmonized data and concrete clinical perspectives.

Hydroxypropylmethylcellulose films for prolonged delivery of the antipsychotic drug chlorpromazine.

OBJECTIVES: The aim of this study was to develop transdermal films based on hydroxypropylmethylcellulose with the purpose of improving transdermal permeation of chlorpromazine hydrochloride, an antipsychotic drug used to alleviate the symptoms and signs of psychosis. METHODS: Hydroxypropylmethylcellulose films were prepared and evaluated for their drug content, film thickness, residual water content and bioadhesive properties. In-vitro permeation experiments were performed in the absence and in the presence of permeation enhancers (oleic acid, polysorbate 80, or both) with the purpose of improving drug availability. Other formulative parameters, such as drug and plasticizer concentration and hydroxypropylmethylcellulose type, were investigated. KEY FINDINGS: Both oleic acid and polysorbate 80 had significant effect on drug permeation with respect to the control formulation. In particular films containing a mixture of oleic acid and polysorbate 80 provided the best enhancement activity for chlorpromazine. Moreover, a decrease in propylene glycol or chlorpromazine content or an increase of hydroxypropylmethylcellulose viscosity provided lower cumulative amounts of drug permeated. CONCLUSIONS: The results obtained confirm that chlorpromazine permeation can be easily modulated by varying the composition of hydroxypropylmethylcellulose-based films. These formulations could serve as candidates for transdermal delivery of antipsychotic drugs.

Freeze-dried chitosan/pectin nasal inserts for antipsychotic drug delivery.

The objective of this investigation was the development of chitosan/pectin based nasal inserts to improve bioavailability of antipsychotic drugs in the treatment of psychotic symptoms. In fact, the nasal route of administration ensures systemic availability avoiding the first-pass metabolism and obtaining more efficacious treatments. Chitosan/pectin polyelectrolyte complexes were prepared at pH 5.0 with different polycation/polyanion molar ratios and lyophilized in small inserts in the presence of chlorpromazine hydrochloride. The results show that higher amount of pectin in the complexes, with respect to higher amount of chitosan, produced a more evident porous structure of the nasal inserts, improving water uptake ability and mucoadhesion capacity. Finally, the presence of increasing amounts of pectin allowed the interaction with chlorpromazine hydrochloride inducing the formation of less hydratable inserts thus limiting drug release and permeation. This investigation verifies the formation of polyelectrolyte complexes between chitosan and pectin at pH values in the vicinity of the pKa interval of the two polymers and confirms the potential of these complexes, capable of achieving antipsychotic drug delivery in the nasal cavity.

Gastroresistant microcapsules: new approaches for site-specific delivery of ketoprofen.

Ketoprofen is a potent non-steroidal anti-inflammatory drug (NSAID) that has been widely used in the treatment of rheumatoid arthritis and other related conditions. However, it carries the risk of undesirable systemic side effects and gastrointestinal irritation at the usual dose of oral administration. The aim of this study was to prepare and evaluate gastroresistant microcapsules containing ketoprofen. Microcapsules were obtained by a spray-drying process starting from an O/A emulsion in the presence of different pH-dependent materials (Eudragit L100, Eudragit S100, and stearic acid) dissolved in the external phase. The influence of formulation factors (oily phase employed for drug solubilization, type of coating) on the morphology, particle size distribution, drug loading capacity, in-vitro release, and ex-vivo permeation characteristics were investigated. Drug loading capacity was very high for all the microcapsules prepared. Formulation factors did not significatively influence the mean particle size, but modified microcapsule in-vitro and ex-vivo behavior.

Pectin-based microspheres for colon-specific delivery of vancomycin.

OBJECTIVES: The aim of this study was to describe a colon-specific delivery system based on pectin hydrogels formed by complexation with chitosan. METHODS: Hydrogels were prepared at different weight ratios (4:1, 7:1, 10:1; pectin/chitosan), loaded with vancomycin hydrochloride (2:1, 4:1; polymer/drug weight ratio) and collected by spray-drying. The microspheres obtained were characterized in terms of morphology, swelling behaviour, mucoadhesive properties and drug loading efficiency. The influence of different pectin/chitosan hydrogels on the release behaviour of microspheres at pH 2.0, 5.5 and 7.4 were evaluated in vitro with and without pectinolytic enzyme. KEY FINDINGS: The results showed that water uptake was increased by raising the environmental pH (from 2.0 to 7.4) and the pectin/chitosan weight ratio, while drug availability was increased by raising the environmental pH (from 2.0 to 7.4) and decreased by raising the pectin/chitosan weight ratio. In the presence of pectinase, the glycoside bonds of pectin were degraded and a considerable amount of drug was released in a short time. CONCLUSIONS: This study suggested that pectin/chitosan microspheres were able to limit the release of vancomycin under acidic conditions and release it under simulated colonic conditions, confirming their potential for a colon-specific drug delivery system.

Novel mucoadhesive nasal inserts based on chitosan/hyaluronate polyelectrolyte complexes for peptide and protein delivery.

OBJECTIVES: The purpose of this study was the preparation and characterisation of mucoadhesive nasal inserts based on chitosan/hyaluronate polyelectrolyte complexes prepared at various pHs and at different molar ratios. METHODS: A suspension of chitosan/hyaluronate complexes with or without the model drugs (vancomycin or insulin) was lyophilised into small inserts. Complexation yield, FT-IR spectra and thermogravimetric analysis were used to study the degree of interactive strength between polyions. In-vitro swelling, mucoadhesion and release tests were performed in order to investigate delivery of vancomycin and insulin in the nasal cavity. KEY FINDINGS: The results indicated that the selection of complex preparative conditions allows modulation of insert swelling and mucoadhesion ability. Nasal inserts containing vancomycin or insulin had showed completely different drug release behaviour. CONCLUSIONS: Chitosan/hyaluronate polyelectrolyte complexes can be used for the formulation of mucoadhesive nasal inserts for the delivery of peptide and protein drugs.

Determination of insulin in innovative formulations by means of LC coupled to fluorescence detection.

A fast and simple method based on LC with fluorescence detection has been developed for the determination of insulin in innovative formulations consisting of microparticles and inserts for oral and nasal drug administration, respectively. A reverse-phase C8 column and a mobile phase composed of pH 3.7, 40 mM sodium sulphate solution and acetonitrile (24%, v/v) were employed. Using isocratic elution at 1.0 mL/min flow, analysis is completed within 7 min. Three different kinds of spray-dried microparticles were analysed, consisting of an insulin loaded core composed of chitosan salts (chitosan succinate, chitosan adipate or chitosan suberate) coated with stearic acid. Nasal inserts consisted of chitosan/hyaluronate polyelectrolyte complexes which were loaded with insulin and freeze-dried. Insulin was extracted from both the oral and nasal formulations using pH 7.4 phosphate buffer. The employment of fluorescence detection (lambda(exc) = 276 nm, lambda(em) = 306 nm) granted high selectivity, with no interference from the matrix. Full method validation was performed with good results in terms of linearity (insulin concentration range 0.10-30.0 microg/mL), LOD (0.03 microg/mL) and LOQ (0.10 microg/mL), precision (R.S.D.%<3.6) and accuracy (recovery percentage>90.0%). Insulin content in innovative formulations, expressed as percentage w/w, resulted to be between 0.90 and 0.97 for oral innovative formulations, while an average value of 342 microg of insulin was found in a single nasal insert, in good agreement with preparative protocols.

Chitosan salts coated with stearic acid as colon-specific delivery systems for vancomycin.

Site-specific controlled release systems have been extensively investigated during the last decade. The aim of this study was to describe a pH-dependent drug release system based on chitosan salts for vancomycin hydrochloride delivery. Chitosan salts with succinic acid, adipic acid, and suberic acid were prepared by spray-drying and were coated with stearic acid by the same technique. This study characterized the carriers in terms of morphology, size, swelling, mucoadhesive properties, and drug loading and focused on the in vitro, influence of chitosan salts on the release behavior of vancomycin hydrochloride from the uncoated and coated systems at pH levels of 2.0, 5.5, and 7.6.

New environmental sensitive system for colon-specific delivery of peptidic drugs.

Nano and micro preparative technologies for the realization of pharmaceutical carriers represent an actual strategy for reaching the therapeutic success of drugs, particularly in the case of peptidic drugs. Vancomycin is here entrapped in carriers composed by a swellable, mucoadhesive and biodegradable albumin core, coated with fatty acids able to improve a colon-specific release. Bovine serum albumin nanospheres (core) were prepared from protein solutions using a coacervation method followed by thermal cross-linking at different temperature, or from protein solutions at different pHs using a coacervation method followed by thermal cross-linking at 75 degrees C. Solid nanospheres were collected by freeze-drying, loaded by soaking from solutions of vancomycin and subsequently coated with myristic, palmitic or stearic acid by spray-drying technique obtaining microcapsules. Nanosphere dimensions and polydispersity, drug loading capacity, swelling ability and mucoadhesion properties were evaluated, as well as in vitro release behaviour. The results indicated that nanospheres present an adequate loading capacity, a great swelling tendency and good mucoadhesion ability. Moreover, albumin cores showed a pH-dependent release according to the structure of thermally denaturated protein in different experimental conditions, while microcapsules showed a pH-dependent release according to the different fatty acids solubility in acidic and alkaline media.

Substituted polyvinylalcohol as a drug carrier for beta-carotene.

The objective of this study was to evaluate the in vitro characteristics of polyvinylalcohol 10,000 (PVA10,000) and polyvinylalcohol 15,000 (PVA15,000) substituted with different alkyl chains (Iodododecane, Bromotetradecane) and crosslinked with Bis-chloro-ethoxy-ethane as an injectable drug carrier. beta-carotene was used as a lipophilic model drug. Physical mixtures of the drug and the spray-dried polymers were prepared and the release of the drug from the mixtures was evaluated in vitro at pH 7.4. The results indicated that the substituted PVA10,000 and PVA15,000 provided faster drug release with respect to the pure drug at pH 7.4. In particular, among the substituted PVA used, PVA10,000 and PVA15,000 substituted with Iodododecane and crosslinked with Bis-chloro-ethoxy-ethane improved drug release.

pH-sensitive polymeric physical-mixture for possible site-specific delivery of ibuprofen.

Delivery of drugs to the large bowel has been extensively investigated during the last decade. The aim of this work was to study polymethacrylic acid-co-methylmethacrylate substituted with fatty acids (lauric, myristic, palmitic and stearic) at 20% substitution degree (PMA-LAUR20, PMA-MIR20, PMA-PALM20 and PMA-STEA20) or 40% substitution degree (PMA-LAUR40, PMA-MIR40, PMA-PALM40 and PMA-STEA40) for preparing a pH-sensitive physical mixture for site-specific delivery of ibuprofen chosen as a model drug. The preparation and characterization of the substituted polymers were described. In vitro release studies were conducted at different pH levels (3 h at pH 2.0, 2 h at pH 5.5, 4 h at pH 7.4 and until 24 h at pH 7.0) and phase-solubility diagrams of ibuprofen with the different substituted polymers were obtained at pH 7.0 to obtain information on the influence of amphiphilic polymers in increasing drug solubility and drug availability in the colon.

Polyvinylalcohol substituted with triethyleneglycolmonoethylether as a new material for preparation of solid dispersions of hydrophobic drugs.

Among the different methods used to increase the aqueous drug solubility, the preparation of a solid dispersion with a soluble carrier represents an interesting formulative approach. We substituted polyvinylalcohol with triethyleneglycolmonoethylether and obtained a suitable material for the formulation of a solid dispersion of progesterone, by spray-drying. In particular, we evaluated the influence of the polyvinylalcohol substitution degree and the polymer-drug weight ratios in the preparative mixture on the progesterone dissolution rate in the aqueous environment.