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P288 preparation of the enteric coated tenoxicam tablets and investigations on the in vitro dissolution profiles
190
Posters / European Journal of Pharmaceutical Sciences 2 (1994) 117-194
P2B5DEVELOPMENTOF ANTIBIOTIC-PROTECTED ARTIRCIAL HEARTVALVES d. Kreuterl, M. Cimbollekl,2, 8.Nice2 "~InMitul~r PhannazeultscheTechnologic,JohannWotlgangGoelhe-Universit~t,60439Frankturt, Germany 2 E. MerckAG, Darmstadt,Germany
The incidence of p r o s t e t i c valve e n d o c a r d i t i s may be r e d u c e d by i m p r e g n a t i o n of the p r o s t h e t i c heart valve sewing ring w i t h suitable slow release antibiotics. For this p u r p o s e T e f l o n (R) heart valve sewing rings w e r e i m p r e g n a t e d w i t h g e n t a m y c i n sulfate, gentamycin crobefate, and c l i n d a m y c i n palmitate, and their release was tested in p h o s p h a t e buffer, human serum, and in horse serum. In addition, the cleavage of clind a m y c i n p a l m l t a t e into the m i c r o b i o l o g i c l y active c l i n d a m y c i n base was i n v e s t i g a t e d in horse serum, rat blood, m a c r o p h a g e cultures, and isolated rat muscles. The results show that the above m e n t i o n e d a n t i b i o t i c c o m b i n a t i o n e x h i b i t e d ideal release kinetics and maintained s u f f i c i e n t a n t i b i o t i c levels for o v e r two weeks. These results w e r e c o n f i r m e d by i m p l a n t a t i o n of the heart valve sewing rings into the m u s c l e s of life rats. A g a i n the heart valve d e l i v e r y systems p r o v i d e d antibiotic levels above the m i n i m a l inhibition concentration. The results show that this system holds p r o m i s e for clinical use.
P287ELECTRON-MICROSCOPICCHARACTERIZATIONOF MELT-HOMOGENIZEDSOUD LIPID NANOPARTICLES B. Siekmannl, K. Westesen2 1 KabiPharmaciaOncologyAB, 251 09 Helsingborg,Sweden 2 Instituteof PharmaceuticalTechnology,Universityof Bmunschweig,38106Bmunschweig,Germany
T h e use of phosphatidylcholine-rich phospholipids (PL) as t h e only stabilizer for aqueous colloidal suspensions of solid lipid nanoparticles prepared by melt-homogenization remdts in the formation of semi-~olid gels. Gel-formation can, however, be prevented by addition of highly mobile co-surfactante such as bile salts (1). The aim of t h e present study was to investigate the internal structure of trip-imltate (TP) uanoparticle dispersions and gels by transmission electron microscopy of freeze-fractured specimen (FFTEM) and of frozen-hydrated specimen (cryo-TEM) to describe t h e physicochemical p r o c e ~ e s underlying t h e observed instability phenomena. FF-TEM and cryo-TEM of TP suspensions stabilized by PL&Osurfactant blends reveal t h a t the emulsified lipid r e c r ~ | l i ~ s as anisometrical particles of predominantly platalet-like shape. CryoTEM indicates t h e coexci~tence of PL vesicles. In FF-TEM the TP particles display a layered structure with terraces, and resemble melt-cryM~lli~d micro- and macroscopic tripa]mltate crystals of t h e beta-modification. Variations in polarity of different nanocrystal faces were detected by decorating t h e fractures with condensed water. T h e (001)-face could be identified as the prevailing crystal face. FF-TEM of PL cont-lnlng TP gels displays a coherent network of crystal platelets with a t h i c k n e ~ cm'responding to t h a t of nanocrystals in suspension. The electron microscopic structure points to preferred sites of aggregation depending on variations in polarity of different nanocrystal faces which might be caused by preferential P L adsorption. A gel-formation model considering (1.) the increase in specific surface area associated with recrystallization of melt-homogenized TP, (2.) the physicochemical characteristics of P L and co-surfactants, and (3.) t h e different polarity of TP nanocrystal faces is suggested.
(1) Siekmaun B, Westesen K (1992) Pharm Pharmacol Lett 1: 123-126.
P286PREDICTION OFTHE FLOWPROPERTIESOF MIXTURESOF BULKSOLIDSUSINGMODEL EQUATIONSBASEDONTHE SPECIRCSURFACEANDTHE JENIKE-FLOWFACTOR G.M.W. Huber, R.H M011er,R. Seeker LOSANPharmaGmbH,79395Neuenburg,Germany
For the development and scaling up of pharmaceutical solid dosage forms the flow properties of excipient-drug mixtures need to be optimized to ensure uniformity of mass and content. To accelerate dosage form development it is desirable to substitute the empirical optimization of the mixture by a mathematical prediction of the flow properties. The objective was to derive model equations based on the specific surface and the Jenike-flowfactor of the excipients and the drug(s). The influence of the specific surface and the Jenike-flowfactor on the flowability of pharmaceutical excipients have been investigated. Characterization data like water content, bulk density, real density, particle size, Jenlke shear cell parameters and specific surface of the excipients has been included. To derive two model equations the specific surface and the Jenike-flowfactor of the powders were correlated to the flow properties of the mixtures determined by the "Riescltestger~t" Dr. Pfrengle. In the first step bivariant correlations between the specific surface and the flew rates were investigated. In the second step also the Jenike-flowfactor has been used to calculate a model equation which describes the measured flow rates of the mixtures as a function of the measured parameters of the powders used in the mixture (excipient.and drug). To check whether the 2 model equations are generally valid they were employed to calculate the flow rates of mixtures not used in the study for deriving the equations. From the data obtained by now a good correlation was found between theoretically calculated an experimentally determined flow rates.
P288PREPARATIONOF THE ENTERICCOATEDTENOXlCAMTABLETSAND INVESV1GATIONSON THE IN VITRO DISSOLUTIONPRORLES A. Araman, 1& Levi Dept.Of Pharm.Tech., Collegeof Pharmacy,Universityof Islanbul,Istanbul,Turkey
Tenoxicam used in articular and extra.articular disturbances is a tienotiazine derivativet non-steroid anti-inflammatory
agent of o~cam c l a s s . Tenoxiosm is a low acidic substance (PK:5.3)and shows solubility dependlnt on I~1. In this Ertu~l~ solubility problem was eliminated by dissolving the substance in ethyl alcohol-phosphate buffer (1:24), The quantitative determination was made spec~rophotometrically at 366nm. One of the most important side effects of Tenoxicam is its irritative effect on stomach mucoSa like all other anti-infla--natory drugs. Therefore~ tablets were enteric ooatad with various film forming ~terials such as CAP, Aquateric and Eudragi% L-100 %o reduce such effects, In three different ~H values, the reXeaee of coated and uncoated tablets were e:uuninede It was observed from the dissolution curves that pH affects the solubility of the substance and disintegration of the coating materials. At 3 different pH values the release of active ingredient had a hi~her rate in Aquateric co~p~red to that of CAP and Eu~ragit L-IOO. Based on the data obtained from in vitro dissolution s~udies, Aquaterio is the b e ~ film forming agent for the preparation of enteric coated Tenoxicam tablets.
Posters / European Journal of Pharmaceutical Sciences 2 (1994) 117-194
P2B5DEVELOPMENTOF ANTIBIOTIC-PROTECTED ARTIRCIAL HEARTVALVES d. Kreuterl, M. Cimbollekl,2, 8.Nice2 "~InMitul~r PhannazeultscheTechnologic,JohannWotlgangGoelhe-Universit~t,60439Frankturt, Germany 2 E. MerckAG, Darmstadt,Germany
The incidence of p r o s t e t i c valve e n d o c a r d i t i s may be r e d u c e d by i m p r e g n a t i o n of the p r o s t h e t i c heart valve sewing ring w i t h suitable slow release antibiotics. For this p u r p o s e T e f l o n (R) heart valve sewing rings w e r e i m p r e g n a t e d w i t h g e n t a m y c i n sulfate, gentamycin crobefate, and c l i n d a m y c i n palmitate, and their release was tested in p h o s p h a t e buffer, human serum, and in horse serum. In addition, the cleavage of clind a m y c i n p a l m l t a t e into the m i c r o b i o l o g i c l y active c l i n d a m y c i n base was i n v e s t i g a t e d in horse serum, rat blood, m a c r o p h a g e cultures, and isolated rat muscles. The results show that the above m e n t i o n e d a n t i b i o t i c c o m b i n a t i o n e x h i b i t e d ideal release kinetics and maintained s u f f i c i e n t a n t i b i o t i c levels for o v e r two weeks. These results w e r e c o n f i r m e d by i m p l a n t a t i o n of the heart valve sewing rings into the m u s c l e s of life rats. A g a i n the heart valve d e l i v e r y systems p r o v i d e d antibiotic levels above the m i n i m a l inhibition concentration. The results show that this system holds p r o m i s e for clinical use.
P287ELECTRON-MICROSCOPICCHARACTERIZATIONOF MELT-HOMOGENIZEDSOUD LIPID NANOPARTICLES B. Siekmannl, K. Westesen2 1 KabiPharmaciaOncologyAB, 251 09 Helsingborg,Sweden 2 Instituteof PharmaceuticalTechnology,Universityof Bmunschweig,38106Bmunschweig,Germany
T h e use of phosphatidylcholine-rich phospholipids (PL) as t h e only stabilizer for aqueous colloidal suspensions of solid lipid nanoparticles prepared by melt-homogenization remdts in the formation of semi-~olid gels. Gel-formation can, however, be prevented by addition of highly mobile co-surfactante such as bile salts (1). The aim of t h e present study was to investigate the internal structure of trip-imltate (TP) uanoparticle dispersions and gels by transmission electron microscopy of freeze-fractured specimen (FFTEM) and of frozen-hydrated specimen (cryo-TEM) to describe t h e physicochemical p r o c e ~ e s underlying t h e observed instability phenomena. FF-TEM and cryo-TEM of TP suspensions stabilized by PL&Osurfactant blends reveal t h a t the emulsified lipid r e c r ~ | l i ~ s as anisometrical particles of predominantly platalet-like shape. CryoTEM indicates t h e coexci~tence of PL vesicles. In FF-TEM the TP particles display a layered structure with terraces, and resemble melt-cryM~lli~d micro- and macroscopic tripa]mltate crystals of t h e beta-modification. Variations in polarity of different nanocrystal faces were detected by decorating t h e fractures with condensed water. T h e (001)-face could be identified as the prevailing crystal face. FF-TEM of PL cont-lnlng TP gels displays a coherent network of crystal platelets with a t h i c k n e ~ cm'responding to t h a t of nanocrystals in suspension. The electron microscopic structure points to preferred sites of aggregation depending on variations in polarity of different nanocrystal faces which might be caused by preferential P L adsorption. A gel-formation model considering (1.) the increase in specific surface area associated with recrystallization of melt-homogenized TP, (2.) the physicochemical characteristics of P L and co-surfactants, and (3.) t h e different polarity of TP nanocrystal faces is suggested.
(1) Siekmaun B, Westesen K (1992) Pharm Pharmacol Lett 1: 123-126.
P286PREDICTION OFTHE FLOWPROPERTIESOF MIXTURESOF BULKSOLIDSUSINGMODEL EQUATIONSBASEDONTHE SPECIRCSURFACEANDTHE JENIKE-FLOWFACTOR G.M.W. Huber, R.H M011er,R. Seeker LOSANPharmaGmbH,79395Neuenburg,Germany
For the development and scaling up of pharmaceutical solid dosage forms the flow properties of excipient-drug mixtures need to be optimized to ensure uniformity of mass and content. To accelerate dosage form development it is desirable to substitute the empirical optimization of the mixture by a mathematical prediction of the flow properties. The objective was to derive model equations based on the specific surface and the Jenike-flowfactor of the excipients and the drug(s). The influence of the specific surface and the Jenike-flowfactor on the flowability of pharmaceutical excipients have been investigated. Characterization data like water content, bulk density, real density, particle size, Jenlke shear cell parameters and specific surface of the excipients has been included. To derive two model equations the specific surface and the Jenike-flowfactor of the powders were correlated to the flow properties of the mixtures determined by the "Riescltestger~t" Dr. Pfrengle. In the first step bivariant correlations between the specific surface and the flew rates were investigated. In the second step also the Jenike-flowfactor has been used to calculate a model equation which describes the measured flow rates of the mixtures as a function of the measured parameters of the powders used in the mixture (excipient.and drug). To check whether the 2 model equations are generally valid they were employed to calculate the flow rates of mixtures not used in the study for deriving the equations. From the data obtained by now a good correlation was found between theoretically calculated an experimentally determined flow rates.
P288PREPARATIONOF THE ENTERICCOATEDTENOXlCAMTABLETSAND INVESV1GATIONSON THE IN VITRO DISSOLUTIONPRORLES A. Araman, 1& Levi Dept.Of Pharm.Tech., Collegeof Pharmacy,Universityof Islanbul,Istanbul,Turkey
Tenoxicam used in articular and extra.articular disturbances is a tienotiazine derivativet non-steroid anti-inflammatory
agent of o~cam c l a s s . Tenoxiosm is a low acidic substance (PK:5.3)and shows solubility dependlnt on I~1. In this Ertu~l~ solubility problem was eliminated by dissolving the substance in ethyl alcohol-phosphate buffer (1:24), The quantitative determination was made spec~rophotometrically at 366nm. One of the most important side effects of Tenoxicam is its irritative effect on stomach mucoSa like all other anti-infla--natory drugs. Therefore~ tablets were enteric ooatad with various film forming ~terials such as CAP, Aquateric and Eudragi% L-100 %o reduce such effects, In three different ~H values, the reXeaee of coated and uncoated tablets were e:uuninede It was observed from the dissolution curves that pH affects the solubility of the substance and disintegration of the coating materials. At 3 different pH values the release of active ingredient had a hi~her rate in Aquateric co~p~red to that of CAP and Eu~ragit L-IOO. Based on the data obtained from in vitro dissolution s~udies, Aquaterio is the b e ~ film forming agent for the preparation of enteric coated Tenoxicam tablets.