An intraoral drug delivery device for long term therapies: application in Alzheimer’s disease

N-valproyl-L-tryptophan for CNS-targeting: synthesis, characterization and efficacy in vitro studies of a new potential antiepileptic drug.

A new aminoacidic derivative of valproic acid (VPA) has been synthesized and characterized by analytical and spectral data. The rationale for the preparation of such potential antiepileptic agent is based on the observation that chemical combination of the anticonvulsant pharmacophore, VPA with essential aminoacids could afford more effective and less toxic actives. The synthesis, characterization, physico-chemical parameters functional for crossing Blood Brain Barrier of N-valproyl-L-tryptophan (4) are reported. The Log D pH7.4 (0.3) indicates that (4) is adequate to cross biological membranes. Its chemical and enzymatic stability were assessed. The experiments indicate high stability of c…

A three-cell type in vitro-model of BBB

Potential dopamine prodrug-loaded liposomes: preparation, characterization and in vitro stability studies

Diffusion of naltrexone across reconstituted human oral epithelium and histomorphological features

Abstract In transbuccal absorption a major limitation could be the low permeability of the mucosa which implies low drug bioavailability. The ability of naltrexone hydrochloride (NLX) to penetrate a resembling histologically human buccal mucosa was assessed and the occurrence of any histomorphological changes observed. We used reconstituted human oral (RHO) non-keratinised epithelium as mucosal section and a Transwell diffusion cells system as bicompartmental model. Buccal permeation was expressed in terms of drug flux ( J s ) and permeability coefficients ( K p ). Data were collected using both artificial and natural human saliva. The main finding was that RHO does not restrain NLX permeat…

ChemInform Abstract: Synthesis and in vitro Studies on a Potential Dopamine Prodrug.

Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of blood-brain barrier (BBB) which is a selective interface that excludes most water-soluble molecules from entering the brain. Neutral amino acids permeate the BBB by specific transport systems. Condensation of dopamine with neutral amino acids could afford potential prodrugs able to interact with the BBB endogenous transporters and easily enter the brain. The synthesis and characterization of the dopamine derivative 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (7) is described. The chemical and enzymatic stability of 7 was evaluated. The molecular weight (300 Da) and Log Papp (…

Oral local drug delivery and new perspectives in oral drug formulation

Modern pharmaceutical science has provided us with a wide range of substances to be administered with a wide large variety of dosage forms. Local drug delivery systems have been used for a long time; in particular, for the local therapy of diseases affecting the oral cavity. Although these diseases are often extremely responsive to local therapy, the mouth often presents various difficulties in the application of topical compounds (owing to saliva and the mouth's different functions), resulting in a short retention time of dosage forms with a consequent low therapeutic efficacy. To resolve these limitations, research today concentrates on the development of bioadhesive formulations. This re…

Recent Advances in Drug Delivery from the Oral Cavity. Focus on innovative buccal drug delivery devices

In this report, the drug administration via the oral cavity is discussed. Regional variations in oral mucosae, drug delivery via the keratinised mucosae for local treatment, and drug delivery via the not keratinised mucosae for local and systemic treatments are analyzed, focusing on Buccal drug delivery devices. Finally the IntelliDrug Device is presented as a revolutionary delivery system.

Trehalose-hydroxyethylcellulose microspheres containing vancomycin for topical drug delivery.

Abstract A new formulation, in which vancomycin is entrapped into trehalose and hydroxyethylcellulose (Natrosol ® ) spherical matrices, is described. Microspheres were produced by the solvent evaporation method. The entrapped drug was fully recovered following microspheres dissolution. Differential scanning calorimetry analyses proved that Natrosol maintains trehalose in its amorphous form. The stabilizing effects of trehalose on vancomycin were evaluated even after long storage and heating of microspheres. Calorimetric data indicated no decomposition of the entrapped drug. In vitro drug release, already performed by using a general two-compartment linear time-invariant open model, suggests…

Formulazione di sistemi innovativi per la somministrazione di antitumorali per il trattamento del Carcinoma Orale Squamoso

Tablets for buccal administration of carbamazepine: comparative behavior of PAA microspheres and matrices

Medium-Term Culture of Primary Oral Squamous Cell Carcinoma in a Three-Dimensional Model: Effects on Cell Survival Following Topical 5-Fluororacile Delivery by Drug-Loaded Matrix Tablets

Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting side-effects, the design of formulations for local application on malignant lesions seems to be an efficient and promising drug delivery approach. In this study, the effect of locally applied 5-FU on cell death was evaluated both in a SCC4/HEK001 model and in a newly proposed 3D outgrowth model of oral squamous cell carcinoma (OSCC). Initially, the optimal drug dose was established by delivery of solutions containing different amounts of 5-FU. The solution containing 1% (w/v) of 5-FU resulted effective in inducing cell death with complete eradication of cell colonies. Buccal …

Evaluation of Galantamine transbuccal absorption by reconstituted human oral epithelium and porcine tissue as buccal mucosa models: Part I

Over the last decade, interest in delivering drugs through buccal mucosa has increased. As a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aim of this study was to evaluate the aptitude of galantamine, useful in Alzheimer's disease, to penetrate the buccal mucosa. The evaluation of the ability of galantamine to permeate through the buccal epithelium was investigated using two permeation models. Firstly, in vitro permeation experiments were carried out using reconstituted human oral non-keratinised epithelium and Transwell diffusion cells system. Results were validated by ex vivo experiments using porcine buccal mucosa as membrane and Franz typ…

CNS-targeted valproic-aminoacid conjugate: preliminary studies on pharmacokinetic parameters and antiepileptic activity

Movements of drugs in biological environment and thorough the membranes

Formulation and kinetic studies on matrix tablets loaded with 5-Fluorouracil useful in oral cancer treatment

Modulation of alcohol consumption using an operant self-administration paradigm: effects of a new dopamine aminoacidic conjugate, Phenylalanine-β(3,4dihydroxyphenyl)-etilamide.

Rewarding and reinforcing properties of alcohol have been shown to be mediated by activation of the mesolimbic dopaminergic system. Experimental evidences suggest that mesolimbic dopamine system is hypofunctional in addicted brain; further, reduced dopaminergic activity outlasts somatic signs of withdrawal and may drive craving and relapse. Boosting strategy on dopaminergic neurons could represent a valid therapy. Effects of pharmacological manipulation of brain Dopaminergic receptors by a new dopamine conjugate, Phenylalanine-β(3,4dihydroxyphenyl)-etilamide (DA-Phen), on operant behaviour and on both acute and prolonged withdrawal symptoms during ethanol abstinence have been evaluated. Mal…

Potential transbuccal delivery of l-DOPA methylester prodrug: stability in the environment of the oral cavity and ability to cross the mucosal tissue

Levodopa (l-DOPA) is the most effective pharmacologic agent in Parkinson's disease and remains the "gold standard". Nevertheless, in long-term treatments, dyskinesias and motor complications can emerge. In this work, the combined use of l-DOPA methylester hydrochloride prodrug (LDME) with transbuccal drug delivery was supposed as a good alternative method to optimize the bioavailability of l-DOPA, to maintain constant plasma levels and to decrease the drug unwanted effects. The effects of environmental pH on buccal delivery of LDME were evaluated ex vivo. The increase of pH value from 5.8 to 6.2 implies an improvement of drug permeation. Since the pH increase causes the raising of hydrolyti…

Sintesi, caratterizzazione e studio della stabilità chimica ed enzimatica di nuovi profarmaci della dopamina

New prospective in treatment of Parkinson's disease: Studies on permeation of ropinirole through buccal mucosa

The aptitude of ropinirole to permeate the buccal tissue was tested using porcine mucosa mounted on Franz-type diffusion cells as ex vivo model. Drug permeation was also evaluated in presence of various penetration enhancers and in iontophoretic conditions. Ropinirole, widely used in treatment of motor fluctuations of Parkinson's disease, passes the buccal mucosa. Flux and permeability coefficient values suggested that the membrane does not appear a limiting step to the drug absorption. Nevertheless, an initial lag time is observed but the input rate can be modulated by permeation enhancement using limonene or by application of electric fields. Absorption improvement was accompanied by the …

Matrix system development, permeation studies and histological features for transbuccal delivery of Naltrexone

Galantamine delivery on buccal mucosa: permeation enhancement and design of matrix tablets

The most important feature in transbuccal drug delivery is the low drug passage through the buccal mucosa. In our previous work we demonstrated the aptitude of Galantamine to penetrate the buccal tissue. The collected data suggested that Galantamine passively crosses the membrane, but the calculated Js and Kp values showed that the drug amount that crosses the membrane wasn’t sufficient to assure blood therapeutic level. So, in this study, ex vivo permeation tests, using porcine buccal mucosa, were performed in presence of physical or chemical enhancers. No significant differences in penetration rate were observed using chemical enhancers as sodium dehydrocholate, EDTA disodium salt and tri…

Transmucosal delivery della Galantamina attraverso mucosa buccale ex vivo

Lipid phase transition in saccharide-coated cholate-containing liposomes: coupling to the surrounding matrix.

We performed FTIR measurements on cholate-containing liposomes (CCL) embedded in saccharide (trehalose or sucrose) matrixes with different contents of residual water. We obtained information on the CCL phase transition following the thermal evolution (310-70 K) of the IR spectrum of the carbonyl moieties of phospholipids in the frequency range 4225-4550 cm(-1). Furthermore, we simultaneously followed the thermal evolution of the water association band, which gave information on the behavior of the surrounding water-saccharide matrix. The analysis revealed a small sub-band of the water association band present in CCL but not in cholate-free liposomes, the thermal evolution of which is tightl…

Aminoacidic derivatives as novel CNS-targeted neurotherapeutics

Drug delivery to the CNS is subject to the permeability limitations imposed by the BBB that regulates movements of actives in and out of the brain. During the drug discovery phase a key aspect could be the selection of the compounds properties crucial for brain penetration. Novel CNS-targeted neurotherapeutics should possess the optimal characteristics that allow passive diffusion through the BBB via the transcellular route, or have the structural features necessary to serve as a substrate for one of the endogenous transport systems of the BBB. An attractive and rewarding chemistry-based strategy, employed to increase the CNS transport of poorly penetrating therapeutic agents, is the transi…

Synthesis of polymeric derivatives of isoniazid: characterization and in vitro release from a water-soluble adduct with polysuccinimide.

Coupling of isoniazid with polysuccinimide afforded a water-insoluble polymeric pro-drug; by reaction with ethanolamine it was chemically transformed in a water-soluble adduct. The in vitro release of isoniazid from the drug-polymer adduct was studied by using an artificial stomach wall lipid membrane. The transfer rate constant from simulated gastric juice to simulated plasma was defined and compared with that of an equivalent dose of pure drug.

Physical Methods for Enhancing Oral Mucosal Delivery: Sonophoresis, Iontophoresis and Electroporation

The need for more rapid onset of action and improved absorption of medications has resulted in great development of drug delivery technologies. Transmucosal drug delivery offers a convenient route of administration for a variety of clinical indications. Unfortunately, the wide variability in structure of the oral mucosal tissues could constitute a key factor in drug penetration and absorption. To circumvent this obstacle and to increase the drug flux through the mucosal membranes, different approaches to permeation enhancement are used. This chapter describes the most significant aspects of the physical techniques widely used such as sonophoresis, iontophoresis, and electroporation. These p…

Buccal Delivery of Carbamazepine (CBZ): a New Scenario in Menagement of Trigeminal Neuralgia (TN)

Synthesis of 5H-[1,2]-benzisothiazolo[2,3-a]quinazolin-5-one

Response charactterization of ammonium tartrate solid state pellets for ESR dosimetry with radiotherapeutic photon and electron beams.

Solid state pellets (1 mm thick) for electron spin resonance (ESR) dosimetry were made using ammonium tartrate as the radiation-sensitive substance. Their behaviour was experimentally investigated as a function of dose with 60Co gamma rays. The calibration function obtained permits measurements of absorbed dose in the 2-50 Gy range, with a combined uncertainty of +/-4%. The lowest detectable dose was about 0.5 Gy. These properties are comparable with or even better than those of ESR dosimeters made from other materials. The time stability of the ESR signal of ammonium tartrate dosimeters at different storage conditions after irradiation was studied. A rather complex behaviour was observed, …

A new dopamine amino-acid conjugate: preclinical in vitro studies and evaluation of behavioural effects in rats

It is well established that alterations in the functionality of dopaminergic transmission are associated with neurodegenerative diseases such as Parkinson’s Disease. The purpose of this study was to investigate the activity of a new dopamine amino-acid conjugate: L-phenylalanine-β-(3,4-dihydroxyphenyl) etilamide(DA-Phe) in the central nervous system, by assessing its influence on different behavioural parameters in the rat. Preliminarily, we tested the in vitro stability in plasmatic environment following the disappearance of DA-Phen from human plasma and the concurrent appearance of dopamine. Using rat brain homogenate, we also evaluated the level of DA-Phen cleavage by cerebral enzymes an…

DA-Phen as a new potential DA-mimetic agent for treatment of alcohol addiction: preclinical in vivo studies

Rewarding and reinforcing properties of alcohol are mediated by activation of the mesolimbic dopaminergic system1. This neurosystem is hypofunctional in the addicted brain, even beyond somatic and psychological signs of withdrawal. Boosting strategy on the dopaminergic tone could represent a valid approach to alcohol addiction treatment2. The effects of a new dopamine conjugate3 (2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide, DA-Phen) on operant behaviour and on withdrawal behaviour, following alcohol deprivation, were evaluated. The concentration of acetaldehyde (ACD), ethanol's first metabolite, as an indirect measure of the possible DA-Phen modulation in alcohol consum…

Trehalose-loaded liposomes to regulate skin moisturization

Dental implant for electronically controlled drug release

TRANSMUCOSAL PERMEABILITY MODEL OF AN OPIOD ANTAGONIST THROUGH PORCINE EPITHELIUM

Testing of drug permeation through reconstituted human buccal epithelium

Clinical Trial and Bioavailability of Naltrexone

Solid and Semisolid Innovative Formulations Containing Miconazole-Loaded Solid Lipid Microparticles to Promote Drug Entrapment into the Buccal Mucosa

The currently available antifungal therapy for oral candidiasis (OC) has various limita- tions restricting its clinical use, such as short retention time, suboptimal drug concentration and low patients compliance. These issues could be overcome using micro or nanotechnology. In par- ticular, solid lipid microparticles (SLMs) resulted as a particularly promising penetration enhancer carrier for lipophilic drugs, such as the antifungal miconazole (MCZ). Based on these considera- tions, cetyl decanoate (here synthesized without the use of metal catalysis) was employed together with 1-hexadecanol to prepare MCZ-loaded SLMs. These resulted in a powder composed of 45–300 µm diameter solid spheric…

New applications of Buccal delivery

Buccal delivery of Galantamine

Movement of Galantamine in biological environment and through the membranes

Buccal delivery of Methimazole as an alternative means to optimize drug bioavailability: permeation studies and matrix system design

The aim of this study was to investigate the potential for systemic administration of Methimazole (MMI) through the buccal mucosa as an alternative route for drug delivery. Considering that the most important restriction in buccal drug delivery could be the low permeability of the mucosa, the ability of MMI to cross the mucosal barrier was assessed. Permeation of MMI through porcine buccal mucosa was investigated ex vivo using Franz type diffusion cells, buffer solution simulating saliva or natural human saliva as donor phase. The collected data suggested that buccal mucosa does not hinder MMI diffusion and the drug crosses the membrane (Js = 0.068 mg cm-2 h-1 and Kp = 0.065 cm h-1). Matrix…

Transmucosal permeability model of an opioid antagonist through porcine buccal mucosal epithelium

Naltrexone-loaded matrices: preparation, drug release and absorption through reconstituted buccal human epithelium

Bioavailability in vivo of naltrexone following transbuccal administration by an electronically-controlled intraoral device: a trial on pigs.

Naltrexone (NLX), an opioid antagonist, is widely used in the treatment of opiate addiction, alcoholism and smoking cessation. Its current peroral administration induces various adverse side effects and has limited efficacy since bioavailability and patient compliance are poor. The development of a long-acting drug delivery system of NLX may overcome the current drawbacks and help in the improvement of treatment of addiction. The primary endpoints of this study were: a) to compare the NLX bioavailability and pharmacokinetics after delivering a single transbuccal dose, released by a prototype of intraoral device, versus an intravenous (I.V.) bolus of the same drug dose; b) to verify the func…

Transbuccal delivery of methimazole: ex vivo permeation studies, histomorphological features and matrix system development

ComparativeIn Vitroevaluation of cumulative release of the urinary antiseptics Nalidixic acid, Pipemidic acid, Cinoxacin, and norfloxacin from white beeswax Microspheres

AbstractThe in vitro diffusion of nalidixic acid (1), pipemidic acid (2), cinoxacin (3), and norfloxacin (4) was studied. The transfer rate constants (kd) from simulated gastro-intestinal juices to simulated plasma, throughout artificial wall lipid membranes, were defined. The kd values suggested that the four drugs are absorbed both in gastric and intestinal environments in similar amounts. To obtain lack of gastric unwanted effects white beeswax microspheres containing 1, 2, 3, and 4 were investigated as a vehicle for the drug intestinal release; they were prepared by the meltable dispersion process using wetting agents. Discrete, reproducible free flowing microspheres were obtained. The …

Controlled Drug delivery in Parkinson's Disease - Progress beyond the state-of-the-art

Preparation of drugs in matrices

Effects of DA-Phen, a dopamine-aminoacidic conjugate, on alcohol intake and forced abstinence

The mesolimbic dopamine (DA) system plays a key role in drug reinforcement and is involved in the development of alcohol addiction. Manipulation of the DAergic system represents a promising strategy to control drug-seeking behavior. Previous studies on 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) showed in vivo effects as a DA-ergic modulator. This study was aimed at investigate DA-Phen effects on operant behavior for alcohol seeking behavior, during reinstatement following subsequent periods of alcohol deprivation. For this purpose, male Wistar rats were tested in an operant paradigm of self-administration; behavioral reactivity and anxiety like-behavior durin…

Potential dopamine prodrug-loaded liposomes: preparation, characterization, andin vitrostability studies

Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of the blood-brain barrier (BBB). Condensation of dopamine with neutral amino acids could afford potential pro- drugs able to interact with the BBB endogenous transporters and easily enter the brain. To improve the bio-availability of the dopamine prodrug, 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DOPH), it was encapsulated in unilamellar liposomes of dimiristoylphosphatidylcholine (DMPC)and cholesterol. Vesicles were characterized by dynamic light scattering in order to evaluate their dimensions and vesicle stability, by zeta-potential measurements, by means of electronic mi…

Controlled delivery of naltrexone by an intraoral device: in vivo study on human subjects.

Naltrexone is widely used in the treatment of opiate addiction but its current peroral administration is characterized by low bioavailability with various side effects. The development of a long-acting transbuccal delivery device (IntelliDrug) for NLX may be useful to improve patient compliance and the therapy effectiveness. The aims of the study are (a) to test basic safety and effectiveness of controlled transbuccal drug delivery on human subjects; (b) to compare NLX bioavailability following transbuccal delivery vs per os conventional delivery; and (c) to test the hypothesis that transbuccal delivery is more efficient than the conventional route. In this randomized cross-over pilot study…

5-Fluororacile-loaded matrix tablets for locoregional delivery: effects on a three-dimensional culture model of primary oral squamous cell carcinoma

Carbamazepine transbuccal delivery: the histo-morphological features of reconstituted human oral epithelium and buccal porcine mucosae in the transmucosal permeation.

Transbuccal drug delivery is an attractive way of administration since several well-known advantages are provided, especially with respect to peroral management. Carbamazepine (CBZ) is an anticonvulsant which is useful in controlling neuropathic pain, and it is currently administered by peroral route, although its absorption and bioavailability is limited due to various factors. The oral cavity could be an interesting site for transbuccal CBZ delivery due to two properties: slow administration of constant low drug doses and less dose-related side effects. However, in transbuccal absorption a major limitation could be the low permeability of the mucosa which results in low drug bioavailabil…

5-Fluorouracil Buccal Tablets for Locoregional Chemotherapy of Oral Squamous Cell Carcinoma: Formulation, Drug Release and Histological Effects on Reconstituted Human Oral Epithelium and Porcine Buccal Mucosa

5-Fluorouracil (5-FU) is currently used for treatment of oral squamous cell carcinoma (OSCC). 5-FU is given by i.v. although the systemic administration is associated with severe toxic effects and no topical formulations of 5-FU for buccal drug delivery have been reported. In this study we would report the development of buccal tablets suitable for direct application of low-doses of 5-FU on cancer lesions. The topical administration could be effective on tumor area while systemic undesired side effects are avoided. Preliminarily, the limited tendency of 5-FU to cross the buccal tissue was established using reconstituted human oral epithelium (RHOE, in vitro) and porcine buccal mucosa (ex vi…

Buccal delivery as a new challenge for treatment of motor fluctuations in Parkinson's Disease

Preparation of white beeswax microspheres loaded with valproic acid and kinetic study of drug release

AbstractThe well known antiepileptic valproic acid (1) due to the long treatment of epilepsy may induce many adverse side effects on various systems. To minimize unwanted toxic effects by kinetic control of drug release, 1 was physically entrapped into white beeswax microspheres using the meltable dispersion process utilizing wetting agents. Solid, discrete, reproducible free flowing microspheres were obtained converting the liquid drug droplets into solid material. The average drug content was 17% w/w. More than 95% of the isolated microspheres were of particle size range 200-425 µm. The microspheres were analyzed to quantify the amount of incorporated drug and to characterize the in vitro…

Aloin loaded matrix tablets for topical treatment of oral cancer

Carnauba wax microspheres loaded with valproic acid: Preparation and evaluation of drug release

AbstractTo minimize unwanted toxic effects of valproic acid (1) by the kinetic control of drug release, gastroresistant carnauba wax microspheres loaded with the antiepileptic agent were prepared. The preparation was based on a technique involving melting and dispersion of drug-containing wax in an aqueous medium. The resulting emulsion after cooling under rapid stirring produced solid, discrete, reproducible free flowing microspheres which converted the liquid drug droplets into solid material. About 94% of the isolated microspheres were of particle size range 200-425 μm. The microspheres were analyzed to determine the drug content in various particle size range and to characterize the in …

Buccal delivery for systemic and local therapies: new in vitro studies

A NEW DOPAMINE-AMINOACID CONJUGATE: SYNTHESIS AND DETERMINATION OF PHYSICO-CHEMICAL PROPERTIES USEFUL TO CROSS THE BBB

ORAL CANDIDOSIS IN PATIENTS WITH CANCER:COMMENTARY OF COCHRANE REVIEWS

DOPAMINE PRO-DRUGS FOR CNS TARGETING: SYNTHESIS, CHARACTERIZATION AND HYDROLYSIS BY BRAIN ENZYMES.

Buccal Delivery of Methimazole as an Alternative Means for Improvement of Drug Bioavailability: Permeation Studies and Matrix System Design

The aim of this study was to investigate the potential for systemic administration of Methimazole (MMI) through the buccal mucosa as an alternative route for drug delivery. Considering that the most important restriction in buccal drug delivery could be the low permeability of the mucosa, the ability of MMI to cross the mucosal barrier was assessed. Permeation of MMI through porcine buccal mucosa was investigated ex vivo using Franz type diffusion cells, buffer solution simulating saliva or natural human saliva as donor phase. The collected data suggested that buccal mucosa does not hinder MMI diffusion and the drug crosses the membrane (J(s) = 0.068 mg cm(-2) h(-1) and K(p) = 0.065 cm h(-1…

Neurons and ECM regulate occludin localization in brain endothelial cells

We report that extracellular matrix and neurons modulate the expression of occludin, one of the main components of tight junctions, by rat brain endothelial cells (RBE4.B). Of the three extracellular matrix proteins which we tested (collagen I, collagen IV, and laminin), collagen IV stimulated at the best the expression of occludin mRNA. The corresponding protein, however, was not synthesized. Significant amounts of occludin accumulated only when RBE4.B cells were cultured on collagen IV-coated inserts, in the presence of cortical neurons, plated on laminin-coated companion wells. Finally, occludin segregated at the cell periphery, only when endothelial cells were co- cultured with neurons …

DA-Phen, a new dopamine aminoacid conjugate: in vivo testing and molecular modeling as dopaminergic modulator

Ambulante Therapie & Telemonitoring von Patienten mit Parkinson

Körpernahe Sensornetzwerke können schon heute zur Steigerung der Lebensqualität beitragen, indem der Patient sein gewohntes Umfeld nicht zwingend verlassen muss. Der natürliche und nächste Schritt zur Verbesserung dieser wertvollen Diagnosesysteme beruht auf die Einbeziehung körpernaher Aktuatoren, welche auch eine gleichzeitige Therapierung erlauben. Durch einen interdisziplinären Ansatz, der klinische und technologische Erkenntnisse vereint, entsteht ein Sen-sor- und Aktuatornetzwerk, das am Beispiel eines sich in Entwicklung befindlichen innovativen Systems zur Behandlung von Parkinson vorgestellt wird.

The passive mechanisms in a controlled release device.

Comparative Study of the Effects Exerted by N-Valproyl-L-Phenylalanine and N-valproyl-L-tryptophan on CA1 Hippocampal Epileptiform Activity in Rat

Background: The research on the improvement of epilepsy therapy is constantly growing. Valproyl-LPhenylalanine (VPA-Phen) and N-valproyl-L-tryptophan (VPA-Tryp) were synthesized to increase the antiepileptic efficacy of valproic acid. Methods: VPA-Phen and VPA-Tryp were comparatively tested on CA1 hippocampal epileptiform bursting activity obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 mM) of VPA-Phen or VPA-Tryp. Both burst duration and interburst frequency, during and after treatment, were off-line compared with baseline values. For both parameters,…

Trehalose/hydroxyethylcellulose ocular gelling microspheres.

High-performance liquid chromatography with fluorimetric detection in biological tissues of the 4-bromomethyl-7-methoxycoumarin ester derivative of 5-pyrrolidone-2-carboxylic acid

Drug delivery from the oral cavity: focus on a novel mechatronic delivery device

Dental drug delivery systems have been used for a long time, in particular for the local therapy of diseases affecting the oral cavity. Research today concentrates on the design of formulations to increase their retention time. Even today, however, prosthetic devices incorporating drug delivery are rarely used. Mainly, they are focused on prophylaxis and the release of antibacterial agents. However, as buccal delivery, because of its undeniable advantages, has become popular for systemic drug delivery, and prolonged well-controlled release has been identified as beneficial, especially for chronic diseases, a new class of delivery systems is evolving: highly miniaturized computerized deliver…

A new intraoral device to home assist Parkinson’s disease patients by distant control

Cyanoacrylate matrices loaded with Naltrexone and release tests

MEDIUM-TERM CULTURE OF THE NORMAL ORAL MUCOSA: A NOVEL THREE-DIMENSIONAL MODEL TO STUDY THE EFFECTIVENESS OF DRUGS ADMINISTRATION

Iontoforesis and drug absorption through reconstituted buccal human epithelium

Transmucosal permeability model of 5-fluorouracil through porcine and reconstituted oral epithelium

Sistema electronico de administracion bucal de medicamentos para tratar addicin y enfermedades cronicas: ensayo en cerdos en el marco del proyecyo "IntelliDrug"

Is Acetaldehyde a substance of abuse? Evidence from a free-access, three-bottle choice paradigm

At present, neuroscience literature dealing with Acetaldehyde (ACD), ethanol first metabolite, as a drug of abuse, reported conditioned taste aversion paradigm and conditioned place preference, following ICV or i.p. administration. No reports exist on ACD oral self-administration probably because of its high volatility. For this reason, this pilot study was aimed at the evaluation of ACD concentration in aqueous solutions, and consequently to the rat drinking behaviour when acetaldehyde was presented in a free-access paradigm together with water and a sweet solution. Preliminarly we investigated the loss of ACD content in aqueous standard solutions. For the investigation of ACD concentratio…

Effects of gamma-irradiation on trehalose–hydroxyethylcellulose microspheres loaded with vancomycin

Ionizing radiation can be used as a drug sterilization technique, provided that the drug itself is not modified and that no toxic products are produced; moreover, if the irradiated product is a drug delivery system, the drug release characteristics must not be significantly altered by radiation. The aim of this work was to study the effects of sterilization by ionizing radiation on hydroxyethylcellulose/trehalose spherical micromatrices, containing the antibiotic vancomycin. Our experimental results showed that gamma-rays did not alter the chromophore groups of vancomycin (UV measurements), and did not modify the kinetic behavior of drug release from microspheres. Moreover, no significant c…

Progettazione e realizzazione di sistemi di rilascio programmato nella terapia delle ferite da ustione

Loaded sulfamethoxazole/trimethoprim soft films for treatment of burn wounds.

Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen, a new dopaminergic agent

Abstract The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate. The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) − a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-m…

In situ delivery of corticosteroids for treatment of oral diseases.

In many mucocutaneous disorders, corticosteroids therapy is currently central. Systemic therapy is restricted to severe disorders whereas topical applications are considered as the first-line treatment. The oral cavity environment, the medication form and other factors related to the delivery method are key factors for the therapy efficiency and effectiveness. Current marketed medications are not able to avoid wrong drug exposure and scarce patients’ compliance. Innovative in situ delivery systems are able to prolong the drug retention time on the mucosa and to avoid the drawbacks of conventional formulations. This review is intended to give a general overview of oral mucocutaneous patholo…

New Prospectives in the Delivery of Galantamine for Elderly Patients Using the IntelliDrug Intraoral Device: In Vivo Animal Studies

The transbuccal delivery of drugs could assist several categories of chronic, especially elderly, patients in adhering to a correct dosage regimen. In particular, patients suffering from dementia have several difficulties in following the prescribed dosage, in addition to problems associated with swallowing tablets. Galantamine is currently used for treating patients with mild to moderate Alzheimer's-type dementia. The transbuccal delivery of this drug could be an interesting non- invasive and safe administration route. Several studies have been performed in vitro and ex vivo within the framework of a European Commission funded Project (IntelliDrug-FP6), aimed at developing a device which w…

Physical methods to promote drug delivery on mucosal tissues of the oral cavity.

Introduction: The successful of drug delivery through the mucosal tissue of the oral cavity represents a current challenge as well as a great future perspective. The need for more rapid onset of action and improved absorption of medications has resulted in great development of drug delivery technologies that use physical methods to overcome the barrier properties of oral mucosae. Areas covered: This review discusses the various physical techniques which have been, and are being, explored to sustain drug delivery in the oral cavity. In particular, supersaturation, eutectic formation, iontophoresis, electroporation, sonophoresis, laser radiation, photomechanical waves, and needleless injectio…

Buccal delivery in treatment of Alzheimer disease: enhancement of galantamine absorption

Small endogenous molecules as moiety to improve targeting of CNS drugs.

A major challenge in the development of novel neuro-therapeutic agents is to effectively overcome the blood-brain barrier (BBB), which acts as a 'working dynamic barrier'. The core problem in the treatment of neurodegenerative diseases is failed delivery of potential medicines due to their inadequate permeation rate. Areas covered: The present review gives a summary of endogenous moieties used in synthesizing prodrugs, derivatives and bioisosteric drugs appositely designed to structurally resemble physiological molecular entities able to be passively absorbed or carried by specific carrier proteins expressed at BBB level. In particular, this overview focuses on aminoacidic, glycosyl, purine…

Electronic buccal drug delivery system to treat addiction and chronic diseases,porcine study in the frame of "Intellidrug"project

AMINOACID PRO-DRUG TO SHUTTLE VALPROIC ACID INTO CNS

Human buccal mucosa as an innovative site of drug delivery.

The authors review the ultra-structural aspects and permeability features of normal human oral mucosa, after having recently tested and used it as a new site of systemic drug delivery. The pertinent scientific literature from 1975 through 2009 has been analysed and discussed. Buccal epithelium is a relatively permeable, robust non-keratinized tissue and blood vessels drain directly into the jugular vein; due to its particular features, it has been of increasing interest to researchers as an alternative site of drug administration. The review describes the structure and function of the buccal mucosa, the rationale for transbuccal drug delivery and the main transmucosal drug delivery systems.…

A new delivery system of clobetasol-17-propionate (lipid-loaded microspheres 0.025%) compared with a conventional formulation (lipophilic ointment in a hydrophilic phase 0.025%) in topical treatment of atrophic/erosive oral lichen planus. A Phase IV, randomized, observer-blinded, parallel group clinical trial.

Summary Background  Topical application of clobetasol-17-propionate has been diffusely reported as an efficacious therapy in atrophic/erosive oral lichen planus (OLP), without exposing the patient to systemic side-effects. However, prolonged contact and respective topical effects on the oral mucosa should be avoided. Objectives  The aim of the present study was to evaluate efficacy and compliance of new lipid microspheres loaded with 0·025% of clobetasol propionate (formulation A) compared with a commonly used formulation (a sort of dispersion of a lipophilic ointment in a hydrophilic phase) with the same amount of drug (formulation B) in the topical treatment of OLP. Patients and methods  …

Evaluation of the aptitude to cross the BBB of a new dopamine aminoacidic prodrug

One of the most important factors limiting the development of new drugs for the CNS is the ability to cross the BBB which is a barrier that controls the entrance and exit of both endogenous and exogenous compounds. BBB expresses several transport systems that carry actively into the brain important nutrients (e.g. glucose and amino acids) and are able to import or export various xenobiotics including drugs and their metabolites. The content of active in the brain depends on the overall difference between the drug uptake and drug efflux processes [1]. Dopamine (DA) is a crucial neurotransmitter; its striatal depletion is responsible of clinical signs of Parkinson’s disease (PD). Owing to the…

Ocular gelling microspheres: in vitro precorneal retention time and drug permeation through reconstituted corneal epithelium.

Purpose: The model drug norfloxacin (NOR)was encapsulated into trehalose (TRH) and hydroxyethylcellulose(NAT) microspheres to obtain a novel gelling ophthalmic delivery system for prolonged release on corneal tissue. Methods: We assessed NOR release from microspheres, prepared by the emulsion-solvent evaporation method. A new in vitro tear turnover model, including inserts containing reconstituted human corneal epithelium (RHC), was designed to evaluate the TRH/NAT microspheres’ precorneal retention time. Bioadhesive properties of TRH/NAT microspheres were validated by using drug-loaded microspheres prepared with gelatine (GLT) commonly used as reference material in adhesion studies. Result…

Entrapment of Phenytoin into Microspheres of Oleaginous Materials: Process Development and in Vitro Evaluation of Drug Release

AbstractA novel multiparticulate preparation of the antiepileptic agent phenytoin (1) was developed and evaluated in vitro. The preparation consists of gastroresistant microparticulate drug delivery system formulated with oleaginous material (lipospheres) to minimize unwanted effects of l on gastric apparatus. The drug was dispersed in a spherical micromatrix consisting of a mixture of stearyl alcohol and glycerol esters of various fatty acids. The best mixture to obtain discrete, reproducible, free-flowing lipospheres consisted of glyceryl monostearate dilaurate and stearyl alcohol (ratio 3: 17). The lipospheres were obtained by a technique involving melting and dispersion of drug-containi…

Inclusion of Trehalose (TRH) into liposomes to regulate uptake of this cryoprotectant into human hepatocytes.

Purpose. Problems with the limited availability of human hepatocytes for cell transplantation may be overcome by improving the efficiency of their cryopreservation. TRH-loaded liposomes could enhance epatocyte viability by regulating the intracellular uptake of the cryoprotectant [1]. Methods. TRH-loaded liposomes were prepared by film hydration method (EPC, sodium cholate, 200mM TRH solution) [2]. Liposomal size was determined by dynamic light scattering. Intraliposomal TRH content was measured using the Megazyme spectrophotometric method. After incubation (1-5 h, 37°C, 5% CO2, 95% RH) of human hepatocytes with TRH-loaded liposomes or equivalent TRH solution, intracellular sugar content wa…

Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation.

2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-PHEN) has been previously synthesized to obtain a potential prodrug capable of release dopamine (DA) into CNS. However, DA-PHEN could act per se as a dopaminergic drug. In this study, the permeability transport (Pe), obtained by parallel artificial permeability assay (PAMPA), indicated a low passive transcellular transport (Pe = 0.32 ± 0.01 × 10(-6 )cm/s). Using the Caco-2 cell system, the Papp AP-BL in absorptive direction (3.36 ± 0.02 × 10(-5 )cm/s) was significantly higher than the Papp BL-AP in secretive direction (1.75 ± 0.07 × 10(-5 )cm/s), suggesting a polarized transport. The efflux ratio (Papp AP-BL/Papp BL-AP = 0…

Trehalose stabilizing effects on L-DOPA aqueous solutions

Ambulatory Treatment and Telemonitoring of Patients with Parkinson’s Disease

Body sensor networks (BSN) promise to enhance quality of life in common human habitats. The very next and natural step towards the improvement of the already valuable applications based on BSN is the incorporation of body actuator devices which adapt its actuation dynamically based on the information provided by the body sensors, thus forming Body Sensor and actuator Networks (BS&AN). This paper shows how BS&AN can be exploited to create an innovative system to support the treatment of patients affected by Parkinson’s Disease (PD). The combination of clinical and technological knowledge in BS&AN allows to significantly improve the quality of life of patients suffering from PD.

TRANSMUCOSAL PERMEABILITY MODEL OF 5-FLUOROURACIL THROUGH PORCINE AND RECOSTITUTED ORAL EPITHELIUM

Movement of drugs in biologic environment and through the membranes

Ex vivo transbuccal delivery of carbamazepine across porcine mucosa

Enteric Aloin loaded microparticles for treatment of colorectal cancer

N-Valproyl-L-Phenylalanine as new potential antiepileptic drug: Synthesis, characterization and in vitro studies on stability, toxicity and anticonvulsant efficacy

Valproic acid (VPA) is considered first-line drug in treatment of generalized idiopathic seizures such as absence, generalized tonic-clonic and myoclonic seizures. Among major antiepileptic drugs, VPA is also considered effective in childhood epilepsies and infantile spasms. Due to its broad activity, VPA acts as a mood stabilizer in bipolar disorder and it is useful in migraine prophylaxis. Despite its long-standing usage, severe reactions to VPA, such as liver toxicity and teratogenicity, are reported. To circumvent side effects due to structural characteristics of VPA, we synthesized in good yield a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, and characterized by FT-IR, …

Galantamine permeation through buccal mucosa: studies on reconstituted human oral epithelium and porcine tissue

Acetaldehyde self-administration by a two-bottle choice paradigm: Consequences on emotional reactivity, spatial learning, and memory

Abstract Acetaldehyde, the first alcohol metabolite, is responsible for many pharmacological effects that are not clearly distinguishable from those exerted by its parent compound. It alters motor performance, induces reinforced learning and motivated behavior, and produces different reactions according to the route of administration and the relative accumulation in the brain or in the periphery. The effective activity of oral acetaldehyde represents an unresolved field of inquiry that deserves further investigation. Thus, this study explores the acquisition and maintenance of acetaldehyde drinking behavior in adult male rats, employing a two-bottle choice paradigm for water and acetaldehyd…

How a buccal device should deliver drugs: aspects of drug formulation related to taste and penetration enhancers

The Home-based Empowered Living for Parkinson's disease patients

Functional feature of a novel model of blood brain barrier: Studies on permeation of test compounds

Drug delivery to the central nervous system (CNS) is subject to the permeability limitations imposed by the blood-brain barrier (BBB). Several systems in vitro have been described to reproduce the physical and biochemical behavior of intact BBB, most of which lack the feature of the in vivo barrier. We developed a fully formed monolayer of RBE4.B immortalized rat brain microvessel endothelial cells (ECs), grown on top of polycarbonate filter inserts with cortical neuronal cells grown on the outside. Neurons induce ECs to synthesize and sort occludin to the cell periphery. Occludin localization is regulated by both compositions of the substratum and soluble signals released by cortical co-cu…

Drug movements in biologic environment and through the membranes

Efficacy of 5-FU topically applied on a buccal mucosal model resembling human tissue. A new chance for OSCC chemotherapy.

Release of naltrexone on buccal mucosa: Permeation studies, histological aspects and matrix system design

Transbuccal drug delivery has got several well-known advantages especially with respect to peroral way. Since a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aptitude of NLX to penetrate the mucosal barrier was assessed. Ex vivo permeation across porcine buccal mucosa 800 microm thick was investigated using Franz type diffusion cells and compared with in vitro data previously obtained by reconstituted human oral epithelium 100 microm thick. Both fluxes (Js) and permeability coefficients (K(p)) are in accordance, using either buffer solution simulating saliva or natural human saliva. Permeation was evaluated also in presence of chemical enhance…

DESIGN AND CHARACTERIZATION OF MUCOADHESIVE SUBLINGUAL FILMS CONTAINING FUROSEMIDE

Synthesis and in vitro studies on a potential dopamine prodrug.

Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of blood-brain barrier (BBB) which is a selective interface that excludes most water-soluble molecules from entering the brain. Neutral amino acids permeate the BBB by specific transport systems. Conden- sation of dopamine with neutral amino acids could afford potential prodrugs able to interact with the BBB endogenous transporters and easily enter the brain. The synthesis and characterization of the dopamine derivative 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (7) is de- scribed. The chemical and enzymatic stability of 7 was evaluated. The molecular weight (300 Da) and Log P …

Buccal drug delivery: what's new and what does the future hold?

The buccal mucosa is the stratified squamous epithelial tissue inside lining of the cheeks. It is a favorable site of drug absorption since the tissue is non-keratinized, relatively immobile and strongly supplied with blood by a dense capillary-vessel network; moreover, it is highly tolerant to allergens, resistant to potentially harmful agents and has a relatively low enzymatic activity. The tissue consents quick onset of effect, offers an easily accessible and generally well-accepted site for drug delivery, is a useful route of administration in patients in an unconscious state (e.g., when swallowing is impaired), and is suitable for retentive dosage forms of administration. Buccal mucosa…

Medium-Term Culture of Primary Oral Squamous Cell Carcinoma in a Three- Dimensional Model: Effects on Cell Survival Following Topical 5-Fluororacile Delivery by Drug-Loaded Matrix Tablets

Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting side-effects, the design of formulations for local application on malignant lesions seems to be an efficient and promising drug delivery approach. In this study, the effect of locally applied 5-FU on cell death was evaluated both in a SCC4/HEK001 model and in a newly proposed 3D outgrowth model of oral squamous cell carcinoma (OSCC). Initially, the optimal drug dose was established by delivery of solutions containing different amounts of 5-FU. The solution containing 1% (w/v) of 5-FU resulted effective in inducing cell death with complete eradication of cell colonies. Buccal …

Inhibitory effects of N-valproyl-L-tryptophan on high potassium, low calcium and low magnesium-induced CA1 hippocampal epileptiform bursting activity in rat brain slices.

N-valproyl-l-tryptophan (VPA-Tryp), new antiepileptic drug, was tested on CA1 hippocampal epileptiform bursting activity obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 or 2 mM) of Valproate (VPA) or VPA-Tryp. Both burst duration and interburst frequency during and after treatment were off-line compared with baseline values. For both parameters, the latency and the length of statistically significant response periods as well as the magnitude of drug-induced responses were calculated. VPA-Tryp evoked fewer and weaker early excitatory effects than VPA on …

Aloin delivery on buccal mucosa: ex vivo studies and design of a new locoregional dosing system

Context: Chemoprevention of potential malignant disorders or cancerous lesions that affect oral mucosae requires extended duration of treatment. Locoregional delivery of natural products could represent a promising strategy for this purpose. Objective: To investigate the aptitude of aloin to permeate through, or accumulate in, the buccal mucosa and to develop a new prolonged oro-mucosal drug delivery system. Materials and Methods: Permeation/accumulation of aloin from Curacao Aloe (containing 50% barbaloin) was evaluated ex vivo, using porcine buccal mucosa as the most useful model to simulate human epithelium. Oro-mucosal matrix tablets were prepared by dispersing aloin (10% w/w) in Eudrag…

Optimization of local delivery of antifungal agents in the oral cavity by a new formulation

In recent years, with the increased use of antibiotics and immunosuppres-sive agents, there was an increased incidence of oral mycosis and Candida albicans is the most common etiologic agent in oropharyngeal candidiasis, especially in patients with HIV. The aim of this work is to develop a new dosage form containing miconazole (MN) to be topically applied on oral mucosa, allowing for a massive penetration of the drug in the tissue. The vehicle for the drug delivery was lipid microparticles incorporated in a hydrophilic gel. The lipospheres were obtained by hot melt encapsulation method using as matrix ingredients a mixtures of esters of fatty acids with higher fatty alcohols, having low mel…

Transbuccal delivery of l-dopa methyl ester: ex vivo permeation studies

Somministrazione transbuccale vs somministrazione endovenosa della Galantamina: studio sperimentale in vivo

“In vitro studies, emphasis on the preparation of the drugs in matrices”.