Chitosan composite microparticles: A promising gastroadhesive system for taxifolin.

Taxifolin possesses gastroprotective property but is characterized by low water solubility, is instabile in alkaline medium, and is degraded by the intestinal bacteria flora. The purpose of the work was therefore to produce a gastroadhesive formulation to prolong taxifolin residence time and release in the stomach. We first demonstrated that taxifolin is stable in simulated gastric fluid with or without pepsin and mucus, and is able to cross pig gastric mucus layer and stomach mucosa. Next, gastromucoadhesive microparticles composed of Syloid® AL-1 mesoporous silica, chitosan and HPMC were produced using spray-drying. Microparticles were characterized by a spherical shape and a mean volume-equivalent diameter around 12 µm. The optimized microparticles were able to release taxifolin and to adhere to pig stomach mucosa for 5 h.

Effect of gliclazide immobilization into layered double hydroxide on drug release.

This paper deals with a new hydrotalcite-like compound used as a matrix to improve dissolution rate of the poorly water-soluble drug gliclazide and to administer at the same time micro- and oligo-elements useful to improve insulin performance. Gliclazide is a second-generation sulfonylurea compound used in the treatment of type II diabetes mellitus. As a consequence of the poor water solubility, its absorption is limited. Thus, a new hydrotalcite-like compound containing Zinc and Chromium, micronutrients directly involved in the physiology of insulin and in the carbohydrate, lipid and protein metabolism, was synthesized. The gliclazide-hydrotalcite-like clay nanohybrid was prepared via ion-exchange in its nitrate form and was characterized by inductively coupled plasma-optical emission spectrometry and thermogravimetric analysis. The drug loading resulted in 42.9% (w/w). As a consequence of the intercalation, the interlayer distance of the host increased from 0.89 nm (interlayer distance of nitrate form) to 1.5 nm. The intercalation product was submitted to solubility measurements and in vitro dissolution test. A remarkable improvement of the apparent solubility and dissolution rate in comparison to the crystalline drug was observed in acid fluids (pH 1.2 and 3). The presence of chromium and zinc cations was also found in the medium. These results showed that the hybrid nanostructure could represent a promising system to improve drug dissolution rate and to release cations involved in the performance of insulin.

Improvement of dissolution rate of piroxicam by inclusion into MCM-41 mesoporous silicate.

The aim of the present paper was the use of mesoporous silicate MCM-41 to increase the dissolution rate of piroxicam, a non-steroidal anti-inflammatory drug-class II of the Biopharmaceutic Classification System. The inclusion/adsorption compound of piroxicam in MCM-41 was obtained with a drug loading of about 14%. X-ray powder diffraction and differential scanning calorimetry (DSC) revealed the presence of piroxicam not arranged in crystalline form and FT-IR spectroscopy showed the presence of light interactions (hydrogen bonds) between the silicate silanols and the drug. The decrease of Brunauer, Emmett and Teller (B.E.T.) specific surface area and pore volume between free MCM-41 and the inclusion/adsorption compound was a prove of the presence of piroxicam inside the mesopores. The inclusion compound was submitted to in vitro dissolution tests and a remarkable dissolution rate improvement was observed in comparison to the crystalline drug in all tested conditions. The dissolution profile at pH 1.2 was comparable to that of the marketed product Brexin, a formulation with rapid analgesic effect onset. The improvement of dissolution rate is due to both the lack of drug in the crystalline form and to the extremely large surface area of the siliceous support. Physical stability tests of the free drug and the inclusion/adsorption complex were conducted as well over one month storage at 40 degrees C at different relative humidity.

Intercalation of the radical scavenger ferulic acid in hydrotalcite-like anionic clays.

Hydrotalcite is a biocompatible lamellar anionic clay formed by double hydroxide layers with a metal cation coordinating four OH groups. The different layers are held together by anionic hosts that can be replaced by a simple ion-exchange process. The synthetic Mg-Al-hydrotalcite was used to intercalate ferulic acid, a compound that shows antioxidant properties due to its free radical scavenger capacity. Analysis of the intercalated compound showed a good intercalation percentage (35.53%) accompanied by an increase of the interlayer space from 7.8A (chloride form) to 17.1A due to the presence of the ferulate. The intercalation product was stable in water, did not show any significant degradation after UV-irradiation, had a higher capacity of UV absorption in comparison to both the pure ferulic acid and ferulic acid-hydrotalcite chloride physical mixture. The intercalated compound was formulated in a siliconic cream and the ferulate in vitro release profiles determined.

Microporous material from kanemite for drug inclusion and release.

A microporous material obtained from kanemite, a layered polysilicate, was studied in order to investigate its feasibility of including drugs and then releasing them. Diphenydramine hydrochloride was chosen as a model drug. The preparation of the microporous material and its loading with the drug are described. As kanemite is able to intercalate anions between its layers, the intercalation compound of diphenydramine and kanemite was also prepared. Both the drug-loaded microporous material and the intercalation compound were submitted to dissolution tests at pH 7.5. The drug release profiles from these two different materials and from a physical mixture were compared.

How to improve the readability of the patient package leaflet: a survey on the use of colour, print size and layout.

This paper displays the results of the second part of a survey about patient information and the use of the patient package leaflet. The aim of this research is to investigate the consumers' attitude towards written information. As the formal aspects of the written message are very important in communication, we prepared a questionnaire in order to evaluate the attitude of patients towards some typographical modifications. Patients were invited to give indications about which colours could be used in the different paragraphs of the package leaflet and which print size could be easily read. All people interviewed were asked to choose a colour, from six proposed by us, to be used for 'therapeutic indications', 'side effects', 'how to use', 'paediatric use', 'contraindications', 'use in pregnancy' and 'warnings'. Clear suggestions for the choice of colours for therapeutic indications, side effects and contraindications arose from the survey. In the other cases there was no uniformity of answers. All people complained that the print size used in the package leaflet is too small and suggested 10 and 11 points Didot. Finally, from the survey it emerged that people would appreciate a more detailed package leaflet but information should be given in a schematic and concise way.

Intercalation compounds of hydrotalcite-like anionic clays with antiinflammatory agents--I. Intercalation and in vitro release of ibuprofen.

Hydrotalcite-like compounds are layered solids having positively charged layers and interlayer charge-compensating anions. The synthetic Mg0.67Al0.33(OH)2 Cl0.33.0.6H2O, which is biocompatible, has been used to intercalate a model drug, ibuprofen, in order to prepare a modified release formulation. The intercalation compound was prepared via ion-exchange starting from the chloride form of hydrotalcite and its composition, determined both by elemental microanalysis and thermogravimetric analysis, was Mg0.67Al0.33(OH)2IBU0.33.0.47H2O, drug content 50% (w/w). As a consequence of the intercalation, the interlayer distance of the host increased from 0.78 nm (interlayer distance of chloride form) to 2.17 nm. The result of dissolution tests at pH 7.5 showed that the in vitro drug release was modified if compared with that obtained with comparative formulations. The mechanism of modified drug release has been interpreted on the basis of the ion exchange process of the ibuprofen anion intercalated in the lamellar host and phosphates contained in the intestinal fluid buffer.

Comprehensibility of the package leaflets of all medicinal products for human use: a questionnaire survey about the use of symbols and pictograms.

Directive 92/27EEC establishes that the package leaflet is a document, which must be included in the package of medicinal products for human use in EU countries. This informative leaflet is directed at the users and it must give full and comprehensible information. The Law suggests the use of symbols but it does not give advice about the subjects to be represented. In order to evaluate the attitude of patients towards package leaflets provided with symbols, we planned a survey interviewing 1004 patients in pharmacies. The data suggest that Italian patients usually read the package leaflet but they neither understand it easily nor find the needed information readily. Most respondents (74.3%) considered the use of symbols helpful in finding the needed information. We proposed five symbols for each heading (therapeutic indications, side effects, paediatric use, contraindications, use in pregnancy) and asked to select which symbol could be used. In the case of 'side effects', 'paediatric use', 'use in pregnancy' and 'dose', most of the respondents chose the same symbol. In the case of 'therapeutic indications' and 'contraindications' there was no uniformity in the answers. The choice depends greatly on education, age and employment of respondents.

[Planning a statistical inquiry for evaluation of patient information]. / Pianificazione di un'indagine statistica per la valutazione dell'informazione al paziente.

This article deals with the patient package insert and the information to the patient-consumer. The law in force states that the patient package insert is an informative instrument for the consumer so it should be exhaustive, comprehensible and immediate. A statistical investigation has been performed in order to evaluate the clearness of patient package insert and the quality of the drug information. The protocol consists of the methodology of the investigation, the study pilot, the sampling and, finally, the questionnaire.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. XI. Synthesis and biological activity of several naphtho- and quinolino-1,4-thiazine and -1,4-thiazepine derivatives containing the imidazole ring.

Several derivatives of naphthol[1,2-b]imidazo[1',2'-d]-1,4-thiazine and -1,4-thiazepine and imidazo[1',2'-4,5]-1,4-thiazino[3,2-c]quinoline and -1,4-thiazepino[3,2-c] quinoline have been synthesized. These compounds and other imidazo[2,1-d][1,5]benzothiazepine derivatives, previously synthesized, have been tested for their possible pharmacological activities. One of these substances displayed inhibitory activity on CNS, others showed an appreciable antiinflammatory effect. None of the naphtho and quinolino derivatives showed affinity for the benzodiazepine receptor.

Synthesis and antimicrobial activity of some new derivatives of 6,12-dihydroindolo[2,1-b]quinazolin-6,12-dione.

Some derivatives of tryptantrine were prepared in order either to increase solubility and to study structure-activity relationship. All synthesized compounds were tested for antimicrobial activity.

Synthesis and SAR study of imidazo[2,1-b]benzothiazole acids and some related compounds with anti-inflammatory and analgesic activities.

Some (un)substituted imidazo[2,1-b]benzothiazole carboxylic or acetic acids and some related compounds, i.e. imidazo[2,1-b]naphthol[2,1-d]thiazole, 4H-imidazo[2,1-c][1,4]benzothiazine, 4,5-dihydroimidazo[2,1-d][1,5]benzothiazepine carboxylic and acetic acids were synthesized and tested in vivo in order to study the structure-activity relationships (SAR) of their antiinflammatory and analgesic activities. Pharmacological assays confirmed the interest of this class of compounds as potential antiinflammatory and analgesic drugs with low side effects.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. X--Synthesis and inhibition of benzodiazepine receptor binding of new 1,4-thiazine and 1,5-thiazepine polycondensed heterocycles with steroidal structure.

Some naphtho[1,2,-b]-s-triazolo[4,3-d]-1,4-thiazine and 1,5-thiazepine and s-triazolo[4', 3'-4,5]-1,4-thiazino[3,2-c]quinoline derivatives have been synthesized and tested for their ability to displace [3H]RO 15-1788 binding from bovine brain membranes. Several compounds showed moderate binding affinity for the benzodiazepine receptor.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. VIII-Synthesis and inhibition of benzodiazepine receptor binding of some derivatives of triazino[3,4-c]-1,4-benzothiazine and triazino[3,4-d]-1,5-benzothiazepine, two new heterocyclic ring systems.

Several series of triazino[3,4-c]-1,4-benzothiazines and triazino[3,4-d]-1,5-benzothiazepines were synthesized. Tentative syntheses performed to obtain 5H-as-triazino[3,4-c]-1,4-benzothiazin-1,2-diones and 5,6-dihydro-as-triazino[3,4-d]-1,5-benzothiazepin-1,2-diones gave rise to s-triazolo derivatives. Only in one case was the reaction successful, affording the 3,5-dihydro-as-triazino[3,4-c]-1,4-benzothiazin-1,2-dione 9a. All the final compounds were tested for their ability to displace [3H]flunitrazepam from bovine brain membranes.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. VI. Synthesis and preliminary pharmacological evaluation of 1-alkylaminomethyl-4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepines.

A series of new 1-alkylaminomethyl derivatives of 4,5-dihydro-s- triazolo[3,4-d]-1,5-benzothiazepines has been prepared using chloromethyltriazolobenzothiazepines 4a-g as key intermediates. The 1-alkylaminomethyl derivatives were tested for CNS activity on mice and some of them caused remarkable decrease of spontaneous motor activity.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. VII. Synthesis and inhibition of benzodiazepine receptor binding of some 4,5-dihydro-tetrazolo[5,1-d]-1,5-benzothiazepines and 5-phenyl-s-triazolo[3,4-d]-1,5-benzothiazepines.

The 4,5-dihydro-tetrazolo[5,1-d]-1,5-benzothiazepines 3a-k and the 5-phenyl-s-triazolo[3,4-d]-1,5-benzothiazepines 6a-f and 11a-c have been prepared and tested for their ability to displace [3H] flunitrazepam binding from bovine brain membranes. Some of the triazoloderivatives showed moderate binding affinity for the benzodiazepine receptor.

Synthesis and antimicrobial activity of some new indolo[2,1-b]quinazolin-6(12H)ones.

A series of indolo[2,1-b]quinazolin-6(12H)ones 4a-i was prepared and tested for the antimicrobial activity. The synthesis of the new compounds and the results of the antimicrobial screening are reported.

Synthesis and pharmacological activity of imidazo[2,1-b]benzothiazole acids.

We have prepared twelve imidazo[2,1-b]benzothiazole carboxylic and acetic acids by reaction of substituted 2-aminobenzothiazoles with ethyl bromopyruvate and 4-chloroacetoacetate, respectively. The acids, obtained from esters by hydrolysis, were tested for their antiinflammatory, analgesic and ulcerogenic activities.

Studies on annelated [1,4]benzothiazines and [1,5]benzothiazepines, V. Synthesis and biological activity of N-2 alkylamino derivatives of 4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepine.

The synthesis of a new series of N-2 alkylamino derivatives of 4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepine has been accomplished starting from 2,3-dihydro-1,5-benzothiazepin-4(5H)ones and their 2-methyl and 2-aryl derivatives. All the compounds were tested in vitro for their antimicrobial activity, but none of them showed remarkable activity. The tricyclic compounds 7a-j, 8a-j, 9a-j, 10a-j, and 11a-j were also screened for their CNS activity in mice and several of them showed interesting activity.