Abstracts of papers

s of papers CHANGING THE WATER STRUCTURE IN HYDROGELS W.E.Roorda , M.A.de V r l e s , C.Kosho, J . A . B o u w s t r a , R . E . J u n g i n g e r . Because of their applicability as sustained release drug dosage forms, hydrogels have been extensively studied. Three important results of these studies are: -A model which divides the water in the gel in bound, free and intermediate water. -The assumption of a specific macromolecular ordenlng in pHEMA hydrogels, due to interactions between the polymer and the w a t e r m o l e c u l e s . -The o b s e r v a t i o n of a s t r o n g i n f l u e n c e on g e l s w e l l i n g of pREMA from s o l u t e s in the s u r r o n d i n g medium Based upon t h e s e d a t a we have d e v e l o p e d s h y p o t h e s i s : A b s o r p t i o n of s o l u t e s i n pHF.HA h y d r o g e l s i s on ly p o s s i b l e i f t h e s e s o l u t e s can b r e a k the i n t e r n a l s t r u c t u r e of the h y d r o g e l t h a t has d e v e l o p e d as a consequence of t he i n t e r actions between water and the polymer. This structure breaking allows further relaxation of the polymer chains which causes increased swelling of the gel. If absorption of the solutes is not possible, they lower the thermodynamlcal potential of the water outside the gel, which causes deswelllng of the gel until a new equilibrium is reached. A series of measurements of the absorption of organic and inorganic compounds has supported this hypothesis. DTA measurements of gels containing Nal as an absorbed solute have shown great influence of Nal on the water structure inside the gel. Using model systems we have shown that the state of swelling of a hydrogel is of enormous influence on the release profile. For this reason we are now investigating the changes in the internal structure of the hydrogel caused by absorption and release of solute compounds. Center for Bio-Pharmaceutical Sciences P.O.Box 9502 2300 RA Leiden The Netherlands RUPTURE FORMATION IN HYDROGELS W.E.Roorda, M.A.de Vries, C.Kosho, H.E.Jun~inger Hydrogels containing a relatively large amount of drug (e.g. over 15%) are known to exhibit rupture formation. ( L.G.J. de Leede, Thesis 1983, Leiden University) This rupture formation increases a.o. with increasing cross-llnker content. Unpublished explanations of this phenomenon ascribe it to the occurence of stress in the polymer, caused by excessive water uptake. This water uptake is suggested to take place because of the high , osmotic value inside the gel, caused by the presence of s large amount of drug. We have followed the behsviour of rupturing gels, measuring release profiles of model compounds and weight and size of the gel. Uptake of the model compounds caused strong swelling of the gels,but gave no rupture formation. This formation only occurred upon release of the model compounds, and was accompanied by weight loss and size decrease of the gels. We explain this as follows: a) The gel, swollen in a model compound solutlon is in a strongely expanded state at the beginning of the release experlment.(W.E.Roorda, M.A.de Vries, C.Kosho, L.G.J.de Leede, A.G.de Boer, H.E.Junginger. To be s u b m i t t e d ) b ) R e l e a s e o c c u r s f a s t e s t from the o u t e r l a y e r of the g e l . c ) C o n s e q u e n t l y , t h i s l a y e r t e n d s to s h r i n k , but i s o b s t r u c t e d by the s w o l l e n i n n e r c o r e . d)The s t r e s s e s d e v e l o p i n g t h i s way a r e r e s p o n s i b l e f o r the r u p t u r e f o r m a t i o n . The r u p t u r e f o r m a t i o n may o f f e r a compensa t i on f o r the decline in release rate in matrix type drug delivery. Recently we achieved an almost zero order release of more then I0 hours of 450 mg oxprenolol-HCl from a lO00mg gel. Center for gio-Pharmaceutical Sciences P.O.Box 9502 2300RA Leiden The Netherlands 96 Wol. 8 I986 Pharmaceutisch Weekblad Scientific Edition INFLUENCING TRANSDERMAL DRUG TRANSPORT: AN ANALYTICAL ELECTRON MICROSCOPIC STUDY H.E. Bodd@*, C. Kleinjan*, W.C. de Bruyn*, W.T. Daems+ and H.E. Junsinser* Analytical Electron Microscopy (AEM) was used to study in vitro skin penetration of tri-iode-thyronine and the influence of several agents including surface active compounds. Penetration experiments took place in a diffusion cell with human skin as a membrane; the donor compartment contained a drug solution with or without an added agent. Diffusion times ranged from 3 to 24 hours. After completion of a penetration experiment skin samples were prepared for TEM using standard methods. The topographic distribution of the iodinated drug inside the skin sections was measured in situ by X-ray micro-analysis using a solid state detector. The q u a l i t y of the f i x a t i o n was v e r i f i e d from T L C a n a l y s e s as well as from model experiments using gelatin. The results are explained in terms of possible mechanisms of penetration (enhancement). They furthermore suggest that AEM will be particularly useful for studying the penetration of peptldes through the skin and other epithelial tissues of interest. *Division of Pharmaceutical Technology, Center for BioPharmaceutical Sciences, Leiden University, The Netherlands +Department of Electron Microscopy, Leiden University, The Netherlands A MICROPOROUS POLYMER DEVICE FOR INTRA-ORAL DELIVERY OF ANTIMICROBIAL DRUGS H.E. godd~ R. Roosjen* and H.F.L. Guiot + Leukemia patients often develop serious infections due to immune dificiency and hence require special treatment to eliminate potentially pathogenic bacteria from the digestive tract. Local antimicrobial treatment inside the oral cavity is problematic since applied drugs are constantly removed by the oral fluid; furthermore, since the oral tissues are often in a bad condition, drug delivery systems for intraoral application have to be carefully selected. They should comply with the oral tissues and maintain therapeutic drug levels intra-orally for at least several hours. This paper deals with a polymer device for (sub) lingual application, obtained by direct compression of microporous polypropylene particles together with suitable additives and antibiotic drugs (Polymyxine, Neomycine and Amphotericine). Drug release from the devices was measured both in vitro, in an artificial mouth designed to mimic saliva flow, and in vivn, as a function of compression load and initial drug content. Drug concentrations were measured either using a chemical (e.g. the nlnhydrine) method or a microbiological one, or both. The results show that within a range of compression load values and initial drug contents, the device meets the imposed requirements. Current studies are focussed on alternative hydrogel devices for both sublingual and epidental application. *Division of Pharmaceutical Technology, Center for BioPharmaceutical Sciences, Leiden University, The Netherlands +Department of infectious Diseases, University Hospital, Leiden HYDROGELS FOR TRANSDERMAL DRUG DELIVERY; SKIN COMPLIANCE AND WATER EXCHANGE IN VIVO H.E. Bodd~ T. Kranenbur~ + and L.M.J. van Driel + In a previous ~tudy we have shown that currently used (most silicon based) transdermal drug delivery systems tend to produce skin irritation due to occlusion, when applied for 5 days or more. Rydrogels reduced this effect, most likely by absorbing water. This paper presents additional data on the skin compliance and water exchange capacity of hydrogel films designed for transdermal drug delivery. Hydrogel films were casted onto alumlnium foil from solutions of a commercial acrylic polymer (Eudraglt | E 30D, RShm Pharma, Darmstadt, Germany; a cnpolymer of methyland ethyl esters of acrylic and methacrylic acid) and subsequently provided with an ultrathin acrylic adhesive layer (Avery International, Turnhout, Belgium). The aluminium foil ~erved as a backing membrane. Circular patches were then cut from the films and used in the experiments. The skin compliance of the patches was verified on 39 patients, both in short term tests over 48 and 72 hours in routine clinical trials and in long term tests lasting 14 days, to check for existing hypersensitlvities as well as senslbilization. The water exchange between the patches and the skin was measured in vivo on 6 volunteers at 4 to 16 hours Intervals over a 5 days period, using Thermogravimetry. The skin compliance tests did not reveal any allergic reaction, not even in patients who showed positive 'plaster reactions.' The water exchange experiments revealed a net water uptake by the patches after 5 days without being saturated: however, on all subjects simultaneous fluctuations were measured at daily intervals, most likely due to thermal sweating. It is concluded, that the hydrogel patches have a high degree of skin compliance because they are able to maintain a reasonable water balance at the skin surface. Hence they may well be applied in transdermal delivery systems. Furthermore, the supposedly thermosensitlve water exchange pattern may serve to control delivery rates of drugs from such systems. *Division of Pharmaceutical Technology, Center for BioPharmaceutical Sciencs, Leiden University, The Netherlands. + I Dermatology Department, Unlvero!ty Hospital. CHARACTERIZATION OF THE GEL STRUCTURE IN A NONIONIC O/W CREAM T. de Vrlnser, H.E. JunBin~er and J.G.H. Joosten Colloidal structures determine the visoelastic properties of creams and influence the release of water and drugs from these frequently used administration vehicles. Therefore, in order to develop creams with optimal properties, knowledge about colloidal structures in existing formulations is important. In their most simple form creams consist of oil, surfactant and water. We studied mixtures of cetylstearylalcolhol, pnly(oxyethylen)20 glycerolmonostearate and water. These components are believed to determine the colloidal structures in the nonlonlc D.A.C. cream "Unguentem Hydrophilicum Nonionicum Aquaosum." Microscopic methods (Electron Microscopy, Po