Nasal administration of carbamazepine using chitosan microspheres: in vitro/in vivo studies.

The nasal route is used both for local therapies and, more recently, for the systemic administration of drugs, as well as for the delivery of peptides and vaccines. In this study the nasal administration of Carbamazepine (CBZ) has been studied using microspheres constituted by chitosan hydrochloride (CH) or chitosan glutamate (CG). Blank microspheres were also prepared as a comparison. The microspheres were produced using a spray-drying technique and characterized in terms of morphology (scanning electron microscopy, SEM), drug content, particle size (laser diffraction method) and thermal behaviour (differential scanning calorimetry, DSC). In vitro drug release studies were performed in phosphate buffer (pH 7.0). In vivo tests were carried out in sheep using the microparticles containing chitosan glutamate, chosen on the basis of the results of in vitro studies. The results were compared to those obtained after the nasal administration of CBZ (raw material) alone. For the evaluation of in vivo data statistical analysis was carried out using the unpaired t-test. Spray-drying was a good technique of preparation of CBZ-loaded microspheres. The loading of the drug into the polymeric network always led to an increase in the dissolution rate compared to CBZ raw material. The microspheres obtained using chitosan glutamate had the best behaviour both in vitro and in vivo. They increased the drug concentration in the serum when compared to the nasal administration of the pure drug (Cmax 800 and 25 ng/ml for microspheres and pure drug, respectively). The results obtained indicate that the loading of CBZ in chitosan glutamate microspheres increases the amount of the drug absorbed through the nose.

Spray-dried microspheres containing ketoprofen formulated into capsules and tablets.

In this study, microspheres were prepared by a spray-drying technique using solutions of ketoprofen and two polymers, cellulose acetate butyrate (CAB) and hydroypropylmethylcellulose phthalate (HPMCP), in different weight ratios. Different total concentrations were used in the feed solutions: 3, 6 and 9% w/v. The spray-dried microparticles were characterized in terms of shape (SEM), size (light scattering method), production yield and encapsulation efficiency. They were formulated into capsules; tablets were prepared by direct compression of the microparticles mixed with maltose and, in some cases, hydroypropylmethylcellulose (HPMC). In vitro release studies were performed both at acidic and neutral pHs. The spray-drying process of solutions of ketoprofen with polymeric blends of cellulose derivatives leads to microparticles which, depending on their final formulation (capsules or tablets), can give a rapid or prolonged drug release. The formulations here described can be proposed for the oral administration of NSAIDs.

Pyridazine N-oxides. III. Synthesis and "in vitro" antimicrobial properties of N-oxide derivatives based on tricyclic indeno[2,1-c]pyridazine and benzo[f]cinnoline systems.

A number of 9H-indeno[2,1-c]pyridazine N-oxides (3a-c) and benzo[f]cinnoline N-oxides (4,5a-c) have been synthesized and tested for antimicrobial activity. All new products were inactive against Gram negative bacteria and fungi. In contrast, among the compounds synthesized, 3b, 4b and 5b showed a moderate activity against Gram positive Staphylococcus aureus and Staphylococcus epidermidis. Of the present series, the 9-nitro-benzo[f]cinnoline N-oxide 5b possessed the highest activity especially against Trichomonas vaginalis (MIC = 3.9 micrograms/ml).

Evaluation of alginate compressed matrices as prolonged drug delivery systems.

This research investigated the use of sodium alginate for the preparation of hydrophylic matrix tablets intended for prolonged drug release using ketoprofen as a model drug. The matrix tablets were prepared by direct compression using sodium alginate, calcium gluconate, and hydroxypropylmethylcellulose (HPMC) in different combinations and ratios. In vitro release tests and erosion studies of the matrix tablets were carried out in USP phosphate buffer (pH 7.4). Matrices consisting of sodium alginate alone or in combination with 10% and 20% of HPMC give a prolonged drug release at a fairly constant rate. Incorporation of different ratios of calcium gluconate leads to an enhancement of the release rate from the matrices and to the loss of the constant release rate of the drug. Only the matrices containing the highest quantity of HPMC (20%) maintained their capacity to release ketoprofen for a prolonged time.

Pyridazine N-oxides. II. Synthesis and in vitro antimicrobial evaluation of 3-chloro-4-carbamoyl-5-aryl-6-methyl-pyridazine N-oxides.

As a part of a research project on antimicrobial agents, various novel carbamoyl derivatives of pyridazine-N-oxides 7a-j were prepared in moderate to good yields from 3-chloro-4-ethoxycarbonyl-5-aryl-6-methyl-3-pyridazine. All compounds synthesized were ineffective against Gram+, Gram- bacteria and fungi while 7e and 7j exhibited a fairly good activity against Trichomonas vaginalis.

[The possible use of a ready-to-us film system for microbiological control in drug preparation]. / Possibilità di utilizzo di un sistema a film reidratabile nel controllo microbiologico di preparati farmaceutici.

Aim of this work was to verify the possibility of using a ready-to-use plate-count method to detect the microbial and fungal contamination on pharmaceutical products. The system consists of a flexible polypropylene film, supporting a suitable dehydrated medium, a second support containing guar, and an indicator on the internal surface. 33 raw materials, 11 natural origin materials, 20 medicinal product of official formula and 18 homeopathic products were analysed. As reference we chose the Italian Pharmacopoeia method. The two methods were comparable, showing no statistical differences, but for one case. This method, if our date will be further confirmed, could be used by the pharmacies and by the homeopathic industries.

Cyclopenta[e] [1,5] benzodiazepin-10 (9H)-one derivatives as CNS depressant agents.

A series of dialkylaminoalkyl derivatives of cyclopenta[e] [1,5] benzodiazepin-10(9H)-one (E1-4) and its 6-chloro derivative (E5-8) was prepared to evaluate their CNS activity in comparison with that of isosteric pyridodiazepinones (A1-4) previously described. The results of the pharmacological screening show a significant depressant activity more remarkable in 6-chloro derivatives, which also revealed a high and lasting analgesic activity. The replacement of pyridine with benzene nucleus did not show any significant or homogeneous activity variation.

Synthesis and pharmacological activity of 4-carbamoyl-6-beta-thienyl-4,5-dihydropyridazin-3-(2H)ones.

A new series of 4-carbamoyl-6-beta-thienyl-4,5-dihydropyridazin-3-(2H)ones 4a-g have been synthesized and tested for their anti-inflammatory and analgesic properties. Among the tested compounds, only 4f at 1 mmole/Kg showed antiinflammatory activity that was comparable with that of indomethacin (5 mg/Kg) though of shorter duration. Compounds 4a, 4e and especially 4g at 0.2 mmoles/Kg displayed relevant analgesic activity, 4g being the most potent derivative in the writhing test. Compounds 4c and 4g were found to possess analgesic activity also in the hot plate test.

Cyclopentenyl ethylamines active on CNS.

Two new cyclopentenylethylamines were prepared and were submitted to a pharmacological screening together with some others previously described and now reprepared. All compounds exhibited different degrees of depressive activity on CNS and good analgesic activity. Compound 5, bearing a phenyl group on the carbon atom to which the amino group is connected, appears rather interesting being the most active as analgesic and the least toxic. Compounds 2 and 3 are able to antagonize in a certain degree lethal doses of physostigmine and also, respectively, of pentylenetetrazole and strychnine.

Antispasmodic activity of tert-aminoalkylderivatives of 3-benzyl-, 3-benzylaza- and 3-benzyldiazaquinoxalinones.

Tert-aminoalkylderivatives of quinoxalin-2-ones, aza- and diazaquinoxalin-2-ones bearing in position 3 a benzyl group were assayed to evaluate the antispasmodic activity. The tested compounds exhibited moderate aspecific antispastic properties that do not warrant further investigation.

[1,4-Disubstituted 1,3-dihydro-2H-1,5-benzo- and chlorobenzodiazepin-2-ones with activity on the central nervous system]. / 1,3-diidro-2H-1,5-benzo- e -clorobenzodiazepin-2-oni-1,4-disostituiti ad attività sul S.N.C.

In pursuing the study on pyridodiazepinone derivatives, in order to verify the variation of biological activity induced by replacement of the heteroaromatic with an aromatic nucleus and by the introduction of chlorine on the benzene ring, a series of 1-[(dialkylamino)alkyl]-4-phenyl-1,3-dihydro-2H-1,4-benzodiazepin- 2-ones and of 7-chloro-analogues were prepared. Some benzodiazepinones and their 7-chloro-analagous were subjected to pharmacological experimentation in order to evaluate and compare their effect upon mice with regard to exploratory activity, motor coordination and spontaneous motility. In addition their anti-strychnine, anti-cardiazole, anti-amphetamine and anti-reserpine activities were also evaluated.

[Tert-aminoalkyl derivatives of quinoxalinones, aza- and diazaquinoxalinones with analgesic activity]. / Terz-amminoalchilderivati di chinossalinoni, aza e diazachinossalinoni ad attività analgesica.

A series of tert-aminoalkyl-derivatives of quinoxalin-2-one, aza- and diazaquinoxalin-2-one bearing in position 3 a benzyl group was prepared in order to compare with analogous 3-methyl derivatives as regards analgesic activity. The substitution causes various effects. In compounds (I) and (VI-IX) is found the expected increase in analgesic activity but with contemporaneous rise in toxicity. The compounds (IV) and (V) are of interest due to the presence of a strong separation of DL50 from DE50.

[Pyrido[2,3-b][1,4]diazepinones with CNS activity]. / Pirido[2,3-b][1,4]diazepinoni ad attività sul S.N.C.

In the interests of developing our research on compounds with a pyrazinone nucleus, cyclohomologues, characterised by the presence of one diazepinone nucleus, were prepared. The 5-[(dialkylamino)alkyl]-3,5-dihydro-2-methyl/phenyl-4H-pyrido[2,3- b][1,4]diazepin-4-ones obtained by means of condensation of the 2-(dialkylamino)alkylamino-3-aminopyridines with ethyl acetyl- or benzoyl- acetate, were subjected to pharmacological experimentation in order to evaluate their effect upon mice with regard to exploratory activity, motor coordination, and spontaneous activity. In addition their analgesic activity was evaluated and also their anti-strychnine, anti-cardiazole, anti-amphetamine and anti-reserpine activities.

[Preparation and pharmacologic activity of 1-dimethylaminopropyl-3-methyl-6-chlorquinoxaline-2(1H)-one]. / Preparazione ed attività farmacologica dell'1-dimetilamminopropil-3-metil-6-clorochinossalin-2(1H)-one.

In continuation of previous research 1-dimetilaminopropyl-3-methyl-6-chlorquinoxaline-2(1H)-one was prepared. This compound shows affects on conditioned avoidance response together with analgesic action and inhibition of explorative activity, while it induces only a small degree of motor incoordination and does not protect the animals from toxic doses of strychinine and physostigmine.

[Pharmacologic activity of tert-aminoalkyl derivates of quinoxalinone, aza- and diaza-quinoxalinone]. / Attività farmacologica di terz-amminoalchilderivati di chinossalinoni aza- e diaza-chinossalinoni.

Eight tert-aminoalkyl derivatives of 3-methyl-6R-quinoxalin-2-one, 3-methyl-6/8-azaquinoxalin-2-ones and 3-methyl-6,8-diazaquinoxalin-2-one, previously selected for their deconditioning activity in rats were now tested in mice for analgesic, explorative and incoordinating (muscle relaxant) activities; acute toxicity was also determined. Several compounds show a good degree of activity in the tests used.

[Anilides with analgesic and antipyretic activity]. / Anilidi ad attività analgesica ed antipiretica.

Several trimethylcyclopentyl and trimethylcyclopentenyl acetanilides, mono- and di-substituted on the aromatic nucleus as well as the corresponding acyl derivatives from aniline it self and corresponding phenylacetanilides, were prepared and tested as analgesics and antipyretics. Several compounds exhibit considerable activity in some cases superior to that of acetanilide.

[Tert-aminoalkyl derivatives of 3-methyl-6,8-diazaquinoxaline-2(1H)-ones. Effect on the acquisition and modification of a conditioned avoidance response in rats]. / Terz-amminoalchilderivati di 3-metil-6,8-diazachinossalin-2(1H)-oni. Effetto sull'acquisizione e sulla modificazione di una risposta condizionata di "avoidance" nel ratto.

By condensating ethyl pyruvate with 4-dialkylaminoalkyl-5-aminopyrimidine, obtained by hydrogenolysis of the corresponding 6-chloroderivatives, were prepared 3-methyl-6,8-diazaquinoxalinee-2(1H)-ones which carry on position 1 a tert-aminoalkyl chain (dimethylaminoethyl-, morpholinylethyl-, dimethylaminopropyl- and N-methylpiperazinylpropyl-). The synthetized compounds were tested to verify the effects on acquisition and modification of a conditioned avoidance response (C.A.R.) in rats. In these tests 1-dimethylaminoethyl-3-methyl-6,8-diazaquinoxalin-2(1H)-one, shows activity comparable with that of the cloropromazine.

[Tertiary aminoalkyl derivatives of 3-methyl-6- or -8-azaquinoxalin-2(1H)ones. Effect on acquisition and modification of a conditioned avoidance response in rats]. / Terz-amminoalchilderivati di 3-metil-6/8-azachinossalin-2(1H)oni. Effetto sull'acquisizione e sulla modificazione di una risposta condizionata di "avoidance" nel ratto.

Eight derivatives of 3-methyl-6-azaquinoxalin-2(1H)-one and of 3-methyl-8-azaquinoxalin-2(1H)-one were prepared. They bear on position 1 an aminoalkyl chain (dimethylaminoethyl, morpholinylethyl, dimethylaminopropyl and N-methylpiperazinylpropyl). Three of these compounds exhibit a high degree of deconditioning activity on rats; compound (I) is particularly active on the acquisition of a conditioned avoidance response, while compound (II) is more active than chloropromazine on the modification of a C.A.R. Compound (II) is characterized also by low toxicity.