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Antiinflammatory drug - betacyclodextrin composite by mechanochemistry
s21
81
83
ESTRAMUSTINE PHOSPHATE/BETA-CYCLODEXTRIN FORMULATION:RATIONALE,FORMULATION DEVELOPMENT AND BIOAVAILABILITY K.Edman, B.Eriluson A.Mlrtlni LMuggetti, GColombo, GMaecari, Pharmacia & Upjohn, Pharmaceutical Development. Viale Pasteur IO, Nerviano. Italy; Phannacokiietics and Metabolism, Lund, Sweden
PHARMACOKINETICS OF SASA ADMINISTERED TO HEALTHY VOLUNTEERS USING THE TIME CLOCK’ DELIVERY SYSTEM F Mac+!, A. Colantqni, G. Fornasini, N. Monti, M Strolin M.,
Estramustine-Phosphate (EP) hard gelatine capsules have been marketed worldwide for the treatment of prostatic cancer for a long time Although effective in therapy and absorbable through the gastrointestinal wall, the active dmg has strong limitations in the oral administration due to its interaction with food and drinks. This interaction dramatically reduces the bioavailability of the drug: it is necessary to administer it in fasting condition in order to avoid the reprecipitation of the dmg that is induced by cations and in particular by calcium ions. This is of course very inconveniant for the patient and may induce gastrointestinal side effecta, which is the major side effect occurring in up to 50% ofthe patients. The object of this work has been the identification of a new robust formulation of the active with no absorption impairment due to the in viva formation of insoluble salts, thus allowing administration without the fasting restriction and with increased tolerability and convenience leadiig to a better patient compliance. The experimental observations that cycladextrins (CDs) were able not only to avoid the reprecipitation of EP in the presence of divalent cations, but also to allow the solubilisation of the drug in dissolution media where calcium ions were present and to redissolve the insoluble EP calcium salt were used as driver for the development of an EPibeta-CD capsule formulations first, and film coated tablet fommlations then, where the active drug and beta-CD were simply physically mixed. An absorption study following administration of the capsule formulations was set up. The phannacoldnetic profile was studied after single oral administration in six prostatic cancar patients. The capsules wn given to each patient under fasting or fed (standardised food or milk) conditions to assess the role of divalent cations on absorption. The administration of the conventional EP formulation to the same patients under fasting conditions was thereafter carried out as it represented the reference of the study. The absorption of the film coated tablet formulation given with standard&d food has also been studied.
Benedetb. K. Steed I.R. Wilding and S. Persian Zambon Group SpA , 20091 Bresso. Mtlan, Profiles Ltd., Nottingham. NG7 2QP. UK
‘Pharmaceuttcal
The TIME CLOCK” (TC) delivery system has been developed to deliver drugs to specific areas of the gastrointestinal (GI) tract, based on their tlmed release. The system consists of a tablet core coated with a mixture of hydrophobic material and surfactant, which is apphed as an aqueous dispersion Drug release from the core occurs after a pre-determined lag time which depends on the thickness of the coating. The tablet 1s also enteric coated to prevent dispersion of the hydrophobic layer whilst in the stomach. An open, single dose, J-way cross-over study was conducted In 0 healthy volunteers to determine the pharmacokinetics of mesalazine (5’ASA) administered as SC tablet. Three different TC tablets containing 250 mg of the drug were given to the volunteers. They differed only in the thickness of the coating, which was 20. 35 and 50% (w/w), respectively. After the 20% formulation, S’ASA appeared in plasma at 5.6tl.4 h (SD) post dosmg (flap) The increase in thickness of the coating increased the delay in the absorption with t,, of II 6+1.5 and 12.6~1.1 h for the 35% and 50% tablets, respectively. A statistically significant linear relationship was found between the mean (n-6) onset of tablet dissolution (determined in-vitro using a dissolution test at pH 6.6 which was 4.5f0.3. 6.6fO.l and 9.2tO.lh for the 20%. 35%. and 50% formulation, respectively) and S’ASA t,., in plasma (r=O.91664. p
82
84
IN VITRO EVALUATION OF COLONIC DRUG DELIVERY SYSTEM BASED ON A DISULPHIDE-LINKED POLYMER LA Michalski. MA Khan, PJ Watts. CD Melia. SS Davis. Department of Pharmaceutical Sciences, University of Nottingham NG7 2RD. UK.
AhlWNFLAMMATORY
An orally administered, colon-specific drug delivery system prevents release of drug during transit through the stomach and small intestine, discharging the drug only after arrival of the dosage form in the colon. Patented disulphide-linked (diS) polymers are designed to remain intact in the upper gastrointestinal (GI) tract and to degrade non-enzymatically under the reducing condiiions present in the colon. Modified release coatings formulated with a diS polymer were applied to prednisolone-containing non-pareils, 1-1.18 mm in diameter. Typical?. a 12% weight gain was achieved, approximately 3 mqcm The in tihu release of the model compound was studied using standard BP methods for upper GI dissolution and in a chemical reducing system used as a simple model for the colon. To achieve barrier properties under upper GI conditions, various compatible polymers were blended with the diS polymer. Blends containing 27% by weight of diS polymer obstructed release of prednisolone in O.lN HCL and in pH 7 phosphate buffer. Higher concentrations of diS in the blend did not impede drug release relative to uncoated pellets. The 27% diS formulations exhibited prednisolone release under reducing conditions in the chemical model over a 24 hour period. These in vitro results suggest that colon-specific drug delivery may be accomplished with a diS polymer coating. LAM is funded by a studentship from the West Company, Inc, Lionville PA USA.
Italy.
COMPOSITE
DRUG - BETACYCLODE%TRIN BY hfECHANOC~Y
a a,h I!,_C&lf M. Braaciani : M. Cm.4 L hfagarotto * VECTORPHARMA Int. S.p.k, Via del Follatolo 12, 31148 T&ate, Italy b DICAMP. Untvanity of T&ate, Piuula Europa 1, 34127 Trlcsta, Italy
,
Nlmeaullde Is a potat antlintbmmatory drug wry actbe In different inflamm~tfoa patboh@ea Its physko-chemic~I pmpertk~ show a scar-
ce solabIlity in water and DhysblonM
DIPS: consmumtlv tt -
decl-
dad to in&de the drug i&aa hy&o&lk’carrk;In order to incraase lb dhaotution Pmpcruaa and xoelenta tharqwtlcal blood kvels. Betacyclodextrin nrs choam aa the carrier and the Vectorpharma pmprtetay mecham&mdatry pmcaaa LI the drug-curter lnclurton prapantton technique; thla pmwa la a aoltd at& tachnotogy baa4 on the htgh ?? nergy rqlrlnding of the drug-&r mlature. ccmaquently avoiding tha w of any a&ant as in other mora popuhr ktacyckdcxtrill inclluton pmcaaaea such aa fraeae-dryiQg or tmwding. The drug-tier product mauMng by tbla machaswhamlal pmcaas is a compoatte mate&l w% tha drug dbpmad thmughout the car&r parttck both In. nuwyataillae and tn. mdaculu atate; tmtb these dnrg deatmchw&tona &nm tha orlgtnal @liac ordarad abwtura lead to a wry h&h themmdynamk Nta wtth conaquent htgh aotubtlb TM.9 nlmaaulfde-behcyclodeatrin camp&a was cturactertaed ty. by Ditlatwtlat Scmmlstg C&tmatry. X-ray Dillhetolmtry, Surface Contact Angle, ahowIng a pmlwnd dimnncr wtth a cysWlina drug miatura and Inding b a dmmatk hwaaaa of diaaoW&m PloPrun. Finally the msulttng in vtvn data ara ahown: hlghrr blood levels at shorter time wtth conreguant faatar thnpwtkal acttvlty.
81
83
ESTRAMUSTINE PHOSPHATE/BETA-CYCLODEXTRIN FORMULATION:RATIONALE,FORMULATION DEVELOPMENT AND BIOAVAILABILITY K.Edman, B.Eriluson A.Mlrtlni LMuggetti, GColombo, GMaecari, Pharmacia & Upjohn, Pharmaceutical Development. Viale Pasteur IO, Nerviano. Italy; Phannacokiietics and Metabolism, Lund, Sweden
PHARMACOKINETICS OF SASA ADMINISTERED TO HEALTHY VOLUNTEERS USING THE TIME CLOCK’ DELIVERY SYSTEM F Mac+!, A. Colantqni, G. Fornasini, N. Monti, M Strolin M.,
Estramustine-Phosphate (EP) hard gelatine capsules have been marketed worldwide for the treatment of prostatic cancer for a long time Although effective in therapy and absorbable through the gastrointestinal wall, the active dmg has strong limitations in the oral administration due to its interaction with food and drinks. This interaction dramatically reduces the bioavailability of the drug: it is necessary to administer it in fasting condition in order to avoid the reprecipitation of the dmg that is induced by cations and in particular by calcium ions. This is of course very inconveniant for the patient and may induce gastrointestinal side effecta, which is the major side effect occurring in up to 50% ofthe patients. The object of this work has been the identification of a new robust formulation of the active with no absorption impairment due to the in viva formation of insoluble salts, thus allowing administration without the fasting restriction and with increased tolerability and convenience leadiig to a better patient compliance. The experimental observations that cycladextrins (CDs) were able not only to avoid the reprecipitation of EP in the presence of divalent cations, but also to allow the solubilisation of the drug in dissolution media where calcium ions were present and to redissolve the insoluble EP calcium salt were used as driver for the development of an EPibeta-CD capsule formulations first, and film coated tablet fommlations then, where the active drug and beta-CD were simply physically mixed. An absorption study following administration of the capsule formulations was set up. The phannacoldnetic profile was studied after single oral administration in six prostatic cancar patients. The capsules wn given to each patient under fasting or fed (standardised food or milk) conditions to assess the role of divalent cations on absorption. The administration of the conventional EP formulation to the same patients under fasting conditions was thereafter carried out as it represented the reference of the study. The absorption of the film coated tablet formulation given with standard&d food has also been studied.
Benedetb. K. Steed I.R. Wilding and S. Persian Zambon Group SpA , 20091 Bresso. Mtlan, Profiles Ltd., Nottingham. NG7 2QP. UK
‘Pharmaceuttcal
The TIME CLOCK” (TC) delivery system has been developed to deliver drugs to specific areas of the gastrointestinal (GI) tract, based on their tlmed release. The system consists of a tablet core coated with a mixture of hydrophobic material and surfactant, which is apphed as an aqueous dispersion Drug release from the core occurs after a pre-determined lag time which depends on the thickness of the coating. The tablet 1s also enteric coated to prevent dispersion of the hydrophobic layer whilst in the stomach. An open, single dose, J-way cross-over study was conducted In 0 healthy volunteers to determine the pharmacokinetics of mesalazine (5’ASA) administered as SC tablet. Three different TC tablets containing 250 mg of the drug were given to the volunteers. They differed only in the thickness of the coating, which was 20. 35 and 50% (w/w), respectively. After the 20% formulation, S’ASA appeared in plasma at 5.6tl.4 h (SD) post dosmg (flap) The increase in thickness of the coating increased the delay in the absorption with t,, of II 6+1.5 and 12.6~1.1 h for the 35% and 50% tablets, respectively. A statistically significant linear relationship was found between the mean (n-6) onset of tablet dissolution (determined in-vitro using a dissolution test at pH 6.6 which was 4.5f0.3. 6.6fO.l and 9.2tO.lh for the 20%. 35%. and 50% formulation, respectively) and S’ASA t,., in plasma (r=O.91664. p
82
84
IN VITRO EVALUATION OF COLONIC DRUG DELIVERY SYSTEM BASED ON A DISULPHIDE-LINKED POLYMER LA Michalski. MA Khan, PJ Watts. CD Melia. SS Davis. Department of Pharmaceutical Sciences, University of Nottingham NG7 2RD. UK.
AhlWNFLAMMATORY
An orally administered, colon-specific drug delivery system prevents release of drug during transit through the stomach and small intestine, discharging the drug only after arrival of the dosage form in the colon. Patented disulphide-linked (diS) polymers are designed to remain intact in the upper gastrointestinal (GI) tract and to degrade non-enzymatically under the reducing condiiions present in the colon. Modified release coatings formulated with a diS polymer were applied to prednisolone-containing non-pareils, 1-1.18 mm in diameter. Typical?. a 12% weight gain was achieved, approximately 3 mqcm The in tihu release of the model compound was studied using standard BP methods for upper GI dissolution and in a chemical reducing system used as a simple model for the colon. To achieve barrier properties under upper GI conditions, various compatible polymers were blended with the diS polymer. Blends containing 27% by weight of diS polymer obstructed release of prednisolone in O.lN HCL and in pH 7 phosphate buffer. Higher concentrations of diS in the blend did not impede drug release relative to uncoated pellets. The 27% diS formulations exhibited prednisolone release under reducing conditions in the chemical model over a 24 hour period. These in vitro results suggest that colon-specific drug delivery may be accomplished with a diS polymer coating. LAM is funded by a studentship from the West Company, Inc, Lionville PA USA.
Italy.
COMPOSITE
DRUG - BETACYCLODE%TRIN BY hfECHANOC~Y
a a,h I!,_C&lf M. Braaciani : M. Cm.4 L hfagarotto * VECTORPHARMA Int. S.p.k, Via del Follatolo 12, 31148 T&ate, Italy b DICAMP. Untvanity of T&ate, Piuula Europa 1, 34127 Trlcsta, Italy
,
Nlmeaullde Is a potat antlintbmmatory drug wry actbe In different inflamm~tfoa patboh@ea Its physko-chemic~I pmpertk~ show a scar-
ce solabIlity in water and DhysblonM
DIPS: consmumtlv tt -
decl-
dad to in&de the drug i&aa hy&o&lk’carrk;In order to incraase lb dhaotution Pmpcruaa and xoelenta tharqwtlcal blood kvels. Betacyclodextrin nrs choam aa the carrier and the Vectorpharma pmprtetay mecham&mdatry pmcaaa LI the drug-curter lnclurton prapantton technique; thla pmwa la a aoltd at& tachnotogy baa4 on the htgh ?? nergy rqlrlnding of the drug-&r mlature. ccmaquently avoiding tha w of any a&ant as in other mora popuhr ktacyckdcxtrill inclluton pmcaaaea such aa fraeae-dryiQg or tmwding. The drug-tier product mauMng by tbla machaswhamlal pmcaas is a compoatte mate&l w% tha drug dbpmad thmughout the car&r parttck both In. nuwyataillae and tn. mdaculu atate; tmtb these dnrg deatmchw&tona &nm tha orlgtnal @liac ordarad abwtura lead to a wry h&h themmdynamk Nta wtth conaquent htgh aotubtlb TM.9 nlmaaulfde-behcyclodeatrin camp&a was cturactertaed ty. by Ditlatwtlat Scmmlstg C&tmatry. X-ray Dillhetolmtry, Surface Contact Angle, ahowIng a pmlwnd dimnncr wtth a cysWlina drug miatura and Inding b a dmmatk hwaaaa of diaaoW&m PloPrun. Finally the msulttng in vtvn data ara ahown: hlghrr blood levels at shorter time wtth conreguant faatar thnpwtkal acttvlty.