Brunella Parodi

Development and Characterization of a Buccoadhesive Dosage Form of Oxycodone Hydrochloride

AbstractA buccoadhesive system for the delivery of oxycodone hydrochloride to the oral mucosa was prepared from a colloidal solution of gelatin used as a bioadhesive agent. An in vitro method for measuring the adhesion of release system to a substrate was developed by employing a modified balance. The eflects of thickness and of the presence of the drug on swelling and mucoadhesion properties were evaluated. The in vitro release of the buccoadhesive formulation was studied by a USP paddle dissolution apparatus and the results were fitted to an empirical equation. In vivo compliance and permanence time in 10 healthy volunteers were estimated.

An example of application of a mixture design with constraints to a pharmaceutical formulation

The aim of this tutorial is to show the application of a mixture experimental design to a problem of pharmaceutical formulation. A gel, based on poloxamer 407, useful for topical administration of tolfenamic acid, a potent anti-inflammatory drug very poorly soluble in water, has been prepared, and a mixture experimental design was used to study the influence of the components on the viscosity of the formulation. Its application allowed to identify a critical boundary, separating semisolid formulations from liquid ones, within a narrow interval of concentrations of the components, and to estimate their effects on the viscosity of the preparation.

Development and In Vitro Evaluation of Buccoadhesive Tablets Using a New Model Substrate for Bioadhesion Measures: The Eggshell Membrane

For oral delivery of antimicrobial and anti-inflammatory drug, mucoadhesive tablets based on gelatin/hydroxypropylcellulose (HPC), gelatin/hydroxypropylmethyl-cellulose (HPMC), and gelatin/sodium carboxymethylcellulose (NaCMC) at different ratios were prepared by direct compression of the mixed powders. Metronidazole and benzydamine were used as model drugs. The in vitro bioadhesive properties, evaluated by a commercial tensile tester, were significantly affected by the model substrate employed, that is, a polypropylene (PP) membrane or a biological membrane (eggshell membrane). The use of the biological substrate seemed to supply more reliable data. All studied formulations showed an erosion-diffusion mechanism of release, anomalous or non-Fickian release, in agreement with the behavior of the swellable systems.

Cytotoxicity and cellular accumulation of a new cis-diammineplatinum (II) complex containing procaine in murine L1210 cells sensitive and resistant to cis-diamminedichloroplatinum (II)

The emergence of drug resistance during tumor chemotherapy is one of the main problems associated with cancer treatment, particularly with cisplatin (cis-DDP). In the hope of overcoming this problem, various cis-DDP-derived compounds have been synthesized, and their pharmacological activity was compared with that of cis-DDP. In this paper we report on studies on the cytotoxic activity induced by cis-dia-mminechloro-[2-(diethylamino)ethyl-4-aminobenzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR), a new complex of platinum containing procaine. All experiments were carried out on murine leukemic cells, which were either sensitive (L1210) or resistant (L1210/DDP) to cis-DDP. A tetrazolium dye (MTT) assay conducted 5 days after a 2-h exposure of cells to both drugs was utilized to determine the resistance factor (RF) of L1210/DDP cells as compared with the sensitive wild-type cells. Drug accumulation and efflux, together with the amount of platinum bound to DNA, were also investigated. The activity of DPR on sensitive cells was not significantly different from that of cis-DDP. Conversely, DPR was 4.3 times more effective than cis-DDP on resistant cells. A decreased drug accumulation is one of the mechanisms of resistance to cis-DDP of L1210/DDP cells. However, DPR accumulation was not significantly different in sensitive and resistant L1210 cells. Under culture conditions that yielded similar intracellular platinum concentrations, treatment with DPR. produced significantly greater DNA platination than did treatment with cis-DDP in both cell lines. No difference in efflux was observed between L1210 and L1210/DDP cells exposed to either cis-DDP or DPR. Our results show that in parental cells, DPR is as potent as cis-DDP on a molar basis, and it is also minimally cross-resistant with cis-DDP in L1210/DDP cells. A direct implication of our results is that DPR could be useful in those human tumors showing a mechanism of resistance similar to that of L1210/ DDP cells.

Stability indicating HPLC assay for retinoic acid in hard gelatine capsules containing lactose and as bulk drug substance

A reversed phase high performance liquid chromatographic assay for determination of Retinoic Acid in raw materials and in hard gelatine capsules containing Tablettose® as excipient is described. The method uses a UV diode array detector. The solution concentrations were measured on weight basis to avoid the use of an internal standard, otherwise necessary for the presence of the undissolved matrix. The study of the recoveries, planned in a Latin square as experimental design, shows that the accuracy and precision of the method are excellent. The assay is selective and stability indicating. The method resolves three related substances (13-cisretinoic acid, 5,6-epoxy-5,6-dihydroretinoic acid and 4-oxo-retinoic acid) with quantitation in the range 0.04 % 0.2 % of the labelled amount of Retinoic Acid (10 mg).

Inhibition of Cell Growth, Induction of Apoptosis and Mechanism of Action of the Novel Platinum Compound cis-Diaminechloro-[2-(Diethylamino) Ethyl 4-Amino-Benzoate, N4]-Chloride Platinum (II) Monohydrochloride Monohydrate

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a new platinum triamine complex obtained from the synthesis of cisplatin and procaine. In this paper we analyzed, adopting a disease-oriented strategy, the tumour selectivity of this compound, its ability to induce apoptosis and its mechanism of interaction with DNA. The inhibition of cell proliferation was evaluated by the MTT assay using a panel of 51 tumour cell lines. Some of them were also evaluated for the induction of apoptosis by 4′-6-diamidine-2′-phenylindole (DAPI) staining, Western blot of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, interstand cross-links (ISCL) were evaluated by ethidium bromide fluorescence technique.When evaluated by the MTT assay, DPR showed a high selective activity for neuroblastoma, small cell lung cancer (SCLC), ovarian cancer and leukemia cell lines. The comparison of mean graphs of DPR and cisplatin suggested that our compound possesses a mechanism of action similar to that, at least in part, of its parent compound. Moreover, DPR showed itself to be a good trigger of programmed cell death, as demonstrated by DAPI staining, activation of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, the study of the formation of ISCLs demonstrated that DPR, despite being a monofunctional platinum compound, is able to form bifunctional adducts through the release of procaine residue.Data presented here suggest that DPR is an antitumour agent able to trigger apoptosis, and that it is endowed with a peculiar mechanism(s) of action and a special selective activity against two tumours, namely neuroblastoma and SCLC, which are still characterized by a low incidence of long-term survivors.

Preclinical in vitro evaluation of hematotoxicity of the cisplatin–procaine complex Dpr

We evaluated in vitro the inhibitory effect of cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) on colony formation by granulocyte/macrophage (CFU-GM) peripheral blood progenitor cells, representing a method to quantitate the toxicity of drugs to the hematopoietic system, and human leukemic cell lines. The results were compared with those obtained exposing cells to cisplatin and carboplatin. Our data showed that while DPR had a significantly better cytotoxic activity than cisplatin and carboplatin against HL60 and K562, and than carboplatin against Molt 4 cells, it showed 12 and 43 times less inhibitory effect on CFU-GM than cisplatin and carboplatin, respectively. These results suggest that the myelosuppressive activity of DPR could be lower than that of cisplatin and carboplatin, and, furthermore, that leukemic cells represent a preferential target for its cytotoxic activity compared to normal committed hemopoietic progenitor cells. All our results speak in favor of a better therapeutic index for DPR than for the other platinum compounds considered here.

Buccoadhesive oxycodone hydrochloride disks: plasma pharmacokinetics in healthy volunteers and clinical study

Abstract The pharmacokinetics of oxycodone hydrochloride were investigated following a single 10 mg buccal dose administered to nine healthy volunteers. Plasma samples were collected up to 24 h after administration and analyzed by an original, sensitive and specific selected ion monitoring (SIM) gas chromatography/mass spectrometry (GC-MS) assay, after purification with a solid-phase extraction procedure. The limit of quantitation was 1 ng/ml using a 1 ml plasma sample. The AUC 0–∞ and the C max data of oxycodone hydrochloride were similar to the values reported in the literature for conventional oral tablets. The t max data obtained seem greater for the buccoadhesive disks compared with other oral dosage forms. Mucoadhesion, mucosal irritation and comfort were assessed. No serious problems were encountered. The administration of the new dosage form to cancer patients produced effective pain control, allowing a reduction in the dosing frequency.

An innovative matrix controlling drug delivery produced by thermal treatment of DC tablets containing polycarbophil and ethylcellulose

An innovative matrix, produced by thermal treatment on direct compression (DC) tablets containing polycarbophil (POL) and ethylcellulose (EC), identified as matrix forming polymers, and able to control the release of diltiazem hydrochloride, was developed. At pH 7.2, 72 ± 1.2% (w/w) of drug loaded was released in 25 h, mostly at constant rate. This swellable and unerodible matrix controls drug release by an anomalous transport mechanism. The modifications induced by the thermal treatment are irreversible and can be used to control and characterize the matrix. A 3-component constrained mixture design allowed the investigation of the experimental domain in which the matrix forms and the computation of a mathematical model that can be used to optimize the formulation properties. The release rate can be modulated (0.032-0.064% drug released/min) through the choice of suitable treatment conditions and tablet composition. The maximum amount of diltiazem hydrochloride released by zero-order kinetics, at the lowest release rate, occurs for POL:EC ratio in the range of 1:1-2:3 with 20-30% of diluent. The tablets are able to load up to 50% (w/w) of diltiazem hydrochloride without losing their properties. A stability study performed on a selected formulation containing DTZ showed stability for at least 2.7 years at RT conditions.

A chitosan lactate/poloxamer 407-based matrix containing Eudragit RS microparticles for vaginal delivery of econazole: design and in vitro evaluation.

A matrix based on chitosan lactate and poloxamer 407 was evaluated as a delivery system for the vaginal administration of the antifungal drug econazole. The matrix was investigated both containing the pure drug and after introducing microparticles of Eudragit RS 100 containing econazole. Eudragit RS 100 microparticles were prepared using an emulsion-extraction method and dispersed in a solution containing chitosan lactate (2% w/w) and poloxamer 407 (1.7% w/w). The microparticles, obtained with a yield of 64% w/w and an encapsulation efficiency of 42% w/w, had a diameter of less than 2 μm and a drug loading of 13% w/w. The compressed matrices, characterized by DSC, swelling, erosion, release and mucoadhesion studies, had behaviours dependent on the relative amounts of the contained microparticles. The matrix without microparticles (MECN) showed zero-order release kinetics, with a maximum drug-release of 60% w/w, while those containing 50 or 75% w/w microparticles showed a diffusion controlled release up to 8 and 16 h, respectively, and a linear trend after those time intervals, caused by the erosion process, which allowed reaching a drug-release of approximately 100% w/w at 22 h. In in vitro experiments, the matrices were mucoadhesive and active in inhibiting the growth of Candida albicans 796.