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Transdermal penetration of a series of nitric oxide donor benzoxazinones
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PREPARATION PROCESS AND IN VITRO AND IN VII’0 PERFORMANCES OF A TIME AND/OR SITE-SPECIFIC ORAL DRUG DELIVERY SYSTEM A.Maroni’. M.E.Sangalli’. L.Z.ema’. C.Busctti’. F.Giordaoo’. A.Fauaniga’ ‘lstihno di Chimica Fannaceutica e Tossicologica. Universits di Mdano. viale Ahmzzi 42, 20131 Milaoo, 1; ‘Poli lndushia Chimica SpA, via Voltomo 48. 20089 h4ilan0, I; ‘Dipartimento F~IUI~CN~~CO. Universita d Parma. viale deUeSnenze. 43100 Panna. 1.
TRANSDERMAL PENETRATION OF A SERIES OF NITRIC OXIDE DONOR BENZOXAZINONES P.Minahetti”. A. Casiraghi”, F. Cilurzo’, L. Montanari”, G. Sertolini’. M.V. Monzani’, A Zaiianl’ ‘Istltuto dl Chimlca Farmaceutica e Tossicologica, Viala Abruzzi 42, 20131 Milano, Italy ?? ltalfarmaco Research Centra, Via dei lavoratori 54, 20092 Cinisallo 8. (Mileno), Italy Clinical trials have shown the potential of benroxazinones, a new class of organic nitrates, in the cardiovascular therapy (1).
It is by now well-known thar the symptomatology of a large tmmhec d chrooic diseases, as most biological phenomena, shows temporal rhythms. often resulting in circadian variations. Increasing interesl has been therefore turned to the possibility of pcrfmning chnmotherapy. On this basis anoral novel drug delivery system for delayedrclease has been designed. The system encompasses a drug containing core. which can consist in tablets, minitablets, pellets. soft or bard g&tine capsules. coated by a swellable hydrophilic polymeric layer. wponaible for the delay in the release onset. Fmlbermore. through the additionof an outer gasboresistant lilm. lhat allows to overcome the variability in gastric emptying time, and through the exploitatiw of the relative reproducibility of the small intestinal transit time, a colon-specific delivery can be also schicved For the. prepmticm of the hydmpbilic layer. high viscosity bydroxypmpylmcthylcellulosea (HPMC) in hydroalcoholic dispersion as well as low viscosity HPMCs in aqwous solution have heen used. In both cases it has heen pos&le to obtain, in a conventional coating eqoipmenl mxkr commonly employed process cooditions, a cwtitmoos layer exhibiting satisfactory technological chamctetistica. The in vifro lelwe proflIes reievaot to all systems have shown a p?ed+teti lag phase. the duration of which depends on the physiwchemical properties sod w the amount of the polymer applied on the cores. and y -.wintigrapbic Concerning the in viva results. both (he pharmacokinetic datahave demonrtratcdtbat the deauibedsystem is able to release drugs in the gasuointestilml tract after a progmmmedlag time. thus allowing time-specific and. in the case of gastromsistaot devices, site-specific drug delivery.
Refence: (1) Eanadini F. at al., New anti-angina1 nitroesters with reduced hypotansiva activity. Synthesis and pharmacological evaluation of 3nitrooxyalkyl-2H-l,3-benzoxazin-4(3H)-onas. J. Med. Chem. 38 130136 (1995) (2) Minghatti P. at al., In vitro skin permeation of sinitrodil, a member of a new class of nitrovasodilator drugs, Eur. J. Pharm. Sci , accepted for publication.
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EFFECT ON RHEOLOGICAL PROPERTIES OPHTALMIC HYDROGELS CONTAINING TIMOLOL MALEATE! B. P.adovanovic,J&ilic-Askrabic. M.Stopar. SSimovic Faculty of Pharmacy, Department of Pharmaceutical Technology Belgrade University
Hydrogel formulations which adhere to ocular tissues give many advantages for the ocular dtug therapy. A number of polymers with different mechanisms of solution-gel phase transitions have been investigated to develop novel ophthalmic hydrogels. The effect of changes in the vehicle Composition on the rheological behaviour of timolol meleat hydrogels was investigated. Aqueous and 971P) and an aqueous v&ides of polyacrylic add (Carbopol940 system containing combination polyacrylic acid (PAA) and hydroxypropyl methylceIlulose were prepared in the concentrations 0.3% and 0.5% w/w (Carbopol 940 and 571P) and combination 0.3% w/w PAA (Carbopol 940 and 971P) and 1.5% w/w (HPMC). 10% aqueous solution of sodium hydroxide was used for the neutralization procedure. The rheological behaviour of aqueous polymer vehicles (hydrogels) of varying composition were investigated as a function of pH and sterilization (auto&vi&). The pH value and rheological measurements were made before and after sterilization, at the end of one week and 2 and 3 months. All investigated vehicles showed pseudoplastic flow with or without negligible hysteresis. The rheological properties of aqueous v&de containing Carbopol 940 and HPMC were similar to those of pure Carbopd 940 vehicle (0.5% w/w); both form semisolid gels with pseudoplastic rheological behavior at pH * 1.4. The sterilization data demonstrated that there was no significant changes, both of flow and pH values of aqueous polymer vehicles after sterilization.
Sinitrodil (3-[Z-(nitrooxy) &hyl&?H-1,3 benzoxazin 4(3H)-one. ITF 296) has already demonstrated promising in vitro skin permeability (2). In this work the transdermal penetration of a series of eight benzoxazinones analogues of ITF 296 was studied in vitro. The selected compounds have different substiiuents on the ammatii ring. Human stratum comeum and epidermis (SCE) was used as the membrane on modiied Franz diiusion cells. Saturated solutions in water:poiyethylenQlycol 400 (80:20 v/v) were used as donor phase. Flux, permeabiliiy coefficient and lag time of the molecules WBR dstermined. The skin fluxes w8re in the range of 0.39-9.91 pg/cm*/h and ITF 296 showed the highest flux. The influence on skin permeation of solubiliiy, partition coefficient and chemicc-physical descriptors was evaluated for this series of compounds.
THE INFLUENCE OF BIOADHESNE POLYMER ON DRUG RELEASE FROM MICROSPHERES ADHERED ON PIG VESICAL MUCOSA A Mrhar. M. Burjak and M. Bogataj Faculty of Pharmacy, ASkerbva 7, 1000 Ljubljana, Slovema It is well known that infections and cane% are the most frequent diseases appearing in the urinary bladder. They ara treated either systemically or locally by instillation of drug solution. To improve the afflcacy of the therapy and diminish its toxic side affects a particulate drug delivery system for local application should be developed Moreover. it is expected that tha affect would be improved if microparticles ware adhered on bladder mucudmucosa The bladder mucus contains glycosaminoglycans which are vary hydrophilic and cany strong negative charge. Consequently, bioadhesiva polymers with certain characteristics ware choaan to prepare microspheres by solvent evaporation method. Eudragit RS was used to form matrix of microspheres and to control the release of model drug pipemldic acid, whereas CMCNa. Poryarrbophil (PC) or chitman hydrodrlorida (CH) represented bioadhesiva component. Drug disaoltiion according to USP and drug release from microspheres adhered on isolated pig unnary bladder mucusa were tested and detachmnt forces of bioadhasiva polymeric films from mucosa were determined. The results of USP dissolution tasts show that the dissolution rata from microspheres containing different bioadhesiva polymers decreases as follows: PCXH>CMCNa. The ofdar PC>CMCNa>CH was obtained by tasting the release from adhered microspheres. Repid dissolution of pipemidic add from PC miaoQph+res is probably a conrequance of fast and strong swelling of PC where no retarding affect of swelled layer was observed. CH is cationic polymer and exhibits the largest bioadhasion strength. Them-fore the slowest releasa from adhered CH micmspheres was obtained ragardless the fact that dissolution according to USP was faster for CH than for CMCNa microsphere% The release profiles from microsphere6 according to USP follow the Higuchi kinetics better than the profiles from adhered microspheras. It seams that different kinetics is a consequence of different release mechanism.
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PREPARATION PROCESS AND IN VITRO AND IN VII’0 PERFORMANCES OF A TIME AND/OR SITE-SPECIFIC ORAL DRUG DELIVERY SYSTEM A.Maroni’. M.E.Sangalli’. L.Z.ema’. C.Busctti’. F.Giordaoo’. A.Fauaniga’ ‘lstihno di Chimica Fannaceutica e Tossicologica. Universits di Mdano. viale Ahmzzi 42, 20131 Milaoo, 1; ‘Poli lndushia Chimica SpA, via Voltomo 48. 20089 h4ilan0, I; ‘Dipartimento F~IUI~CN~~CO. Universita d Parma. viale deUeSnenze. 43100 Panna. 1.
TRANSDERMAL PENETRATION OF A SERIES OF NITRIC OXIDE DONOR BENZOXAZINONES P.Minahetti”. A. Casiraghi”, F. Cilurzo’, L. Montanari”, G. Sertolini’. M.V. Monzani’, A Zaiianl’ ‘Istltuto dl Chimlca Farmaceutica e Tossicologica, Viala Abruzzi 42, 20131 Milano, Italy ?? ltalfarmaco Research Centra, Via dei lavoratori 54, 20092 Cinisallo 8. (Mileno), Italy Clinical trials have shown the potential of benroxazinones, a new class of organic nitrates, in the cardiovascular therapy (1).
It is by now well-known thar the symptomatology of a large tmmhec d chrooic diseases, as most biological phenomena, shows temporal rhythms. often resulting in circadian variations. Increasing interesl has been therefore turned to the possibility of pcrfmning chnmotherapy. On this basis anoral novel drug delivery system for delayedrclease has been designed. The system encompasses a drug containing core. which can consist in tablets, minitablets, pellets. soft or bard g&tine capsules. coated by a swellable hydrophilic polymeric layer. wponaible for the delay in the release onset. Fmlbermore. through the additionof an outer gasboresistant lilm. lhat allows to overcome the variability in gastric emptying time, and through the exploitatiw of the relative reproducibility of the small intestinal transit time, a colon-specific delivery can be also schicved For the. prepmticm of the hydmpbilic layer. high viscosity bydroxypmpylmcthylcellulosea (HPMC) in hydroalcoholic dispersion as well as low viscosity HPMCs in aqwous solution have heen used. In both cases it has heen pos&le to obtain, in a conventional coating eqoipmenl mxkr commonly employed process cooditions, a cwtitmoos layer exhibiting satisfactory technological chamctetistica. The in vifro lelwe proflIes reievaot to all systems have shown a p?ed+teti lag phase. the duration of which depends on the physiwchemical properties sod w the amount of the polymer applied on the cores. and y -.wintigrapbic Concerning the in viva results. both (he pharmacokinetic datahave demonrtratcdtbat the deauibedsystem is able to release drugs in the gasuointestilml tract after a progmmmedlag time. thus allowing time-specific and. in the case of gastromsistaot devices, site-specific drug delivery.
Refence: (1) Eanadini F. at al., New anti-angina1 nitroesters with reduced hypotansiva activity. Synthesis and pharmacological evaluation of 3nitrooxyalkyl-2H-l,3-benzoxazin-4(3H)-onas. J. Med. Chem. 38 130136 (1995) (2) Minghatti P. at al., In vitro skin permeation of sinitrodil, a member of a new class of nitrovasodilator drugs, Eur. J. Pharm. Sci , accepted for publication.
274
276
VEHICLE
EFFECT ON RHEOLOGICAL PROPERTIES OPHTALMIC HYDROGELS CONTAINING TIMOLOL MALEATE! B. P.adovanovic,J&ilic-Askrabic. M.Stopar. SSimovic Faculty of Pharmacy, Department of Pharmaceutical Technology Belgrade University
Hydrogel formulations which adhere to ocular tissues give many advantages for the ocular dtug therapy. A number of polymers with different mechanisms of solution-gel phase transitions have been investigated to develop novel ophthalmic hydrogels. The effect of changes in the vehicle Composition on the rheological behaviour of timolol meleat hydrogels was investigated. Aqueous and 971P) and an aqueous v&ides of polyacrylic add (Carbopol940 system containing combination polyacrylic acid (PAA) and hydroxypropyl methylceIlulose were prepared in the concentrations 0.3% and 0.5% w/w (Carbopol 940 and 571P) and combination 0.3% w/w PAA (Carbopol 940 and 971P) and 1.5% w/w (HPMC). 10% aqueous solution of sodium hydroxide was used for the neutralization procedure. The rheological behaviour of aqueous polymer vehicles (hydrogels) of varying composition were investigated as a function of pH and sterilization (auto&vi&). The pH value and rheological measurements were made before and after sterilization, at the end of one week and 2 and 3 months. All investigated vehicles showed pseudoplastic flow with or without negligible hysteresis. The rheological properties of aqueous v&de containing Carbopol 940 and HPMC were similar to those of pure Carbopd 940 vehicle (0.5% w/w); both form semisolid gels with pseudoplastic rheological behavior at pH * 1.4. The sterilization data demonstrated that there was no significant changes, both of flow and pH values of aqueous polymer vehicles after sterilization.
Sinitrodil (3-[Z-(nitrooxy) &hyl&?H-1,3 benzoxazin 4(3H)-one. ITF 296) has already demonstrated promising in vitro skin permeability (2). In this work the transdermal penetration of a series of eight benzoxazinones analogues of ITF 296 was studied in vitro. The selected compounds have different substiiuents on the ammatii ring. Human stratum comeum and epidermis (SCE) was used as the membrane on modiied Franz diiusion cells. Saturated solutions in water:poiyethylenQlycol 400 (80:20 v/v) were used as donor phase. Flux, permeabiliiy coefficient and lag time of the molecules WBR dstermined. The skin fluxes w8re in the range of 0.39-9.91 pg/cm*/h and ITF 296 showed the highest flux. The influence on skin permeation of solubiliiy, partition coefficient and chemicc-physical descriptors was evaluated for this series of compounds.
THE INFLUENCE OF BIOADHESNE POLYMER ON DRUG RELEASE FROM MICROSPHERES ADHERED ON PIG VESICAL MUCOSA A Mrhar. M. Burjak and M. Bogataj Faculty of Pharmacy, ASkerbva 7, 1000 Ljubljana, Slovema It is well known that infections and cane% are the most frequent diseases appearing in the urinary bladder. They ara treated either systemically or locally by instillation of drug solution. To improve the afflcacy of the therapy and diminish its toxic side affects a particulate drug delivery system for local application should be developed Moreover. it is expected that tha affect would be improved if microparticles ware adhered on bladder mucudmucosa The bladder mucus contains glycosaminoglycans which are vary hydrophilic and cany strong negative charge. Consequently, bioadhesiva polymers with certain characteristics ware choaan to prepare microspheres by solvent evaporation method. Eudragit RS was used to form matrix of microspheres and to control the release of model drug pipemldic acid, whereas CMCNa. Poryarrbophil (PC) or chitman hydrodrlorida (CH) represented bioadhesiva component. Drug disaoltiion according to USP and drug release from microspheres adhered on isolated pig unnary bladder mucusa were tested and detachmnt forces of bioadhasiva polymeric films from mucosa were determined. The results of USP dissolution tasts show that the dissolution rata from microspheres containing different bioadhesiva polymers decreases as follows: PCXH>CMCNa. The ofdar PC>CMCNa>CH was obtained by tasting the release from adhered microspheres. Repid dissolution of pipemidic add from PC miaoQph+res is probably a conrequance of fast and strong swelling of PC where no retarding affect of swelled layer was observed. CH is cationic polymer and exhibits the largest bioadhasion strength. Them-fore the slowest releasa from adhered CH micmspheres was obtained ragardless the fact that dissolution according to USP was faster for CH than for CMCNa microsphere% The release profiles from microsphere6 according to USP follow the Higuchi kinetics better than the profiles from adhered microspheras. It seams that different kinetics is a consequence of different release mechanism.