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Evaluation of bioadhesive characteristics of local therapeutic system indicated in herpetic gingivostomatitis
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281
283
CONTROLLED LEAKAGE IN LIPOSOMES: SURFACTANT AS MODULATING AGENTS S. Petralite, A.Memoli* and M.C.Anneaini** * Dip. Studi Chim. eTecno1. Sostanze Biol. Attive, Universita di Roma “La Sapienza”, p.le Aldo More, 00185 Roma, Italy, **Dip. Ingegneria Chimica, Universith di Roma “La Sapienza”.
NEW ANTIARRHYTHMIC SOLID DOSAGE FORM WITH CONTROLLED RELEASE OF THREE COMPONENTS Q.N.Porharitskava. E.M.Puchkova State Academy of Chemistry and Pharmacy, 14, Prof. POpov str , 197376 St.-Petersburg, Russia
Liposomea are useful tool for the controlled release of drugs. In order to achieve this purpose more succeafully, information about the interaction of liposome with any foreign agent able to modify the bilayer struchlre and to induce the vesicle content release is required. Among these agents, surfactants play a very important role. In fact, whereas above a critical concentration they disrupt the liposomes structure with a consequent complete release of the vesicles content, at sublytic concentration, i.e. below the onset of the liposomes solubilization, they reduce the vesicle barrier efficiency and a controlled drug release (or loading) can be obtained. In spite of the large number of investigation carried out on this field, the mechanism of surfactant induced leakage at sublytic concentration is far from clarified. Different behaviours, often ascribed to the difference in liposomas size or composition and molecular structure of surfactanta, have been observed experimentally. In this work we refer about the calcein release from WV and LUV liposomes obtained with different techniques and phospolipids of different origin at sublytic Triton X-100 and Sodium Cholate concentrations.The obtained results allow us to draw the following conclusions: no significant differences appeare on the leakage process with the different liposomepreparations or surfactants tested; the calcein release is almost istantaneous and it proceeds up to an equilibrium value that increases increasing the swfactant to lipid ratio in the bilayer. These results seem to support the idea of the liposome content release as due to transient hole formation, induced by surfactant addition. The authors thank the italian h4URST for the financial support
282 EVALUATION THERAPEUTIC
Along with search of new antiarrhythmic drugs the development of the combined means, complex influencing on pathological process has the important significance. The tablet technology of a complex of medicinal substations including promaline (N(4)-propylajmalinium bromide, quaternary semisynthetic derivative of alkaloid ajmaline obtained by biotechnological method from biomass of Rauwolfiee Serpentinae) (PRO), diarepam (DIA) and trimecaine (TRI) was developed. The preliminary pharmacological researches have shown antiarrhythmic activity of a new combination. However, the initial release of PRO and DIA, and then TRI was recommended. TRI is water-soluble. TRI is fast inactivated after oral administrations. The purpose of the given work was the creation of the medicinal form with a controlled release of medicinal substances. Solid dispersions of TRI with shellac and acetylphthalylcellulose were obtained by a method of joint dissolution with the subsequent evaporation of a solvent. The inclusion complexes of TRI with P-cyclodextrin in a various molecular ratio were prepared by a precipitating method. The release of substations and coprecipitates in 0,l HCI was about 90% for PRO and DIA and 517% for TRI. Thus, the opportunity of creation of the combined medicinal form of antierrhythmic activity with controlled release of three components in depending of various part of gastr&intestinal tract was shown.
284 OF BIOADHESWE
CHARACTERISTICS
OF LOCAL
SYSTEM INDICATED IN HERPETIC GINGIYOSTOMATlTlS
sm, M.tivkovii 104 Yugoslavia,Institute,Sectorof Development, 29. Novembra I I I, 11000 Belgrade. Yugoslavia
II ISknownthat therqeutic cff~cimcy of locally apphed preparation for watmen~ of oral mucosa disorders greatly depends on snmgth and duration of contactbetween the dmg vehicle and site of its actMy. The object of OUT work was to make the choice of optimal bioadhesive dental preparation formulation indicated in therapy of herpctic gingivostomatins. Actwe subsMce. the second mnemtion synthetic nuclcoside antiviral al(ent (AVA), used in our w&k is, accord&g to r&s of several clinical studies performed, efiicienr in trutin~ lesions associatedwith viral infections mentioned at 7.5 % (w/w) concentration. In the experimental phase following samples were prep& and investigared: ?? samoles of dental bioadhesive haste made bv mechanical incorwmtion of 13% (w/w) i.;.14.5% (w/w) each - (S&ples md i, resp.) of hydmcolloid polymers (CMCNq Pectin. Hydmlized gelatin - Byca C, Croda Colloids, UK) into previously preparedchspersionof AVA in polyethylene lip@. samplu of water-pmpylm glycol 3% and 5% (w/w) Cabopol 934P gels &mplcs 3 and 4, resp.) made by dispcning polymer in AVA solution; pH of gels was6.8 -7.2. The bioadhesivcpotential of samplesstudied was evaluatedby using hvo in vitro comparative technics. The first test was based an measuring the force of detachment (Zwick-Zugpugmachm 1101) _ the lower part of the sPaMy designed cell was filled with the samples studied and brought into cantact with the upperpan coveredby the mucin gel; results were expressed88 maximal form at the nwment of detachment(kP) i.e. tensile stress(Pa). The second one was the testing of “washable properties” e.g. resistance to washing of samples studied - based on specnophatomenical determination of dye percentage winch difised from agar matrix covered by sample through to the receptor solution during 4 h The adhesive capacity of the ramples wu inversly proportional to the % of dye diffused. Sample I with 39% (w/w) of hydmcolloids in lipogel expr~sscdthe best adheswe potential. Also, if was concluded that hydrophobic formulations showed better bioadhesive characteristicscompamd to those in wluch the degree of polymer hydration process and the adhesive potmhal M influenced by prepatatmn composition and technology procedure.
I
IN VITRO EVALUATION OF ACYLOXYALKYL ESTERS OF KETOPROFEN AND NAPROXEN AS DERMAL PRODRUGS J. Rautig’, H. Taipale’, J. Gynthep, J. Vepsl18inenb, T. Nevalaine@ and T. Jiirvinena. ‘Dept. of Pharm. Chem. or bChem., University of Kuopio, P.O. Box 1627, FIN-7021 I Kuopio, Finland. In the present study, a series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and evaluated with the aim of improving the dermal delivery of the parent drugs. The prodrugs of ketoprofen and naproxen were synthesized, their aqueous solubilities, lipophilicities and hydrolysis rates in buffer, human serum and skin homogenate were determined. The permeation of selected naproxen prodrugs across the excised human skin from buffer solution of pH 7.4 was studied in vifro.The prodrugs were more lipophilic (log Pipp = 2.8-3.6) than their parent molecules (ketoprofen; log P,, = 0.3, naproxen; log P BPP = -0.2), as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log P,,,). However, their aqueous solubilities decreased markedly compared to the parent molecules. The prodrugs were stable towards chemical hydrolysis in aqueous solutions (pH 7.4). but hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The hydrolysis of the acyloxyalkyl esters take place enzymatically by attack on the carbonyl of the parent drug rather than the carbonyl of the promoiety. In the diffusion cell experiments the steady-state flux values of total naproxen delivered by prodrugs were similar or slower than that delivered by naproxen. The results show that for this series of lipophilic prodrugs of naproxen, the acetyloxyethyl ester with most highest aqueous solubility is the most effective prodrug to deliver total naproxen through excised human skin. This work was supported by the Academy of Finland and Technology Development Centre (Finland).
281
283
CONTROLLED LEAKAGE IN LIPOSOMES: SURFACTANT AS MODULATING AGENTS S. Petralite, A.Memoli* and M.C.Anneaini** * Dip. Studi Chim. eTecno1. Sostanze Biol. Attive, Universita di Roma “La Sapienza”, p.le Aldo More, 00185 Roma, Italy, **Dip. Ingegneria Chimica, Universith di Roma “La Sapienza”.
NEW ANTIARRHYTHMIC SOLID DOSAGE FORM WITH CONTROLLED RELEASE OF THREE COMPONENTS Q.N.Porharitskava. E.M.Puchkova State Academy of Chemistry and Pharmacy, 14, Prof. POpov str , 197376 St.-Petersburg, Russia
Liposomea are useful tool for the controlled release of drugs. In order to achieve this purpose more succeafully, information about the interaction of liposome with any foreign agent able to modify the bilayer struchlre and to induce the vesicle content release is required. Among these agents, surfactants play a very important role. In fact, whereas above a critical concentration they disrupt the liposomes structure with a consequent complete release of the vesicles content, at sublytic concentration, i.e. below the onset of the liposomes solubilization, they reduce the vesicle barrier efficiency and a controlled drug release (or loading) can be obtained. In spite of the large number of investigation carried out on this field, the mechanism of surfactant induced leakage at sublytic concentration is far from clarified. Different behaviours, often ascribed to the difference in liposomas size or composition and molecular structure of surfactanta, have been observed experimentally. In this work we refer about the calcein release from WV and LUV liposomes obtained with different techniques and phospolipids of different origin at sublytic Triton X-100 and Sodium Cholate concentrations.The obtained results allow us to draw the following conclusions: no significant differences appeare on the leakage process with the different liposomepreparations or surfactants tested; the calcein release is almost istantaneous and it proceeds up to an equilibrium value that increases increasing the swfactant to lipid ratio in the bilayer. These results seem to support the idea of the liposome content release as due to transient hole formation, induced by surfactant addition. The authors thank the italian h4URST for the financial support
282 EVALUATION THERAPEUTIC
Along with search of new antiarrhythmic drugs the development of the combined means, complex influencing on pathological process has the important significance. The tablet technology of a complex of medicinal substations including promaline (N(4)-propylajmalinium bromide, quaternary semisynthetic derivative of alkaloid ajmaline obtained by biotechnological method from biomass of Rauwolfiee Serpentinae) (PRO), diarepam (DIA) and trimecaine (TRI) was developed. The preliminary pharmacological researches have shown antiarrhythmic activity of a new combination. However, the initial release of PRO and DIA, and then TRI was recommended. TRI is water-soluble. TRI is fast inactivated after oral administrations. The purpose of the given work was the creation of the medicinal form with a controlled release of medicinal substances. Solid dispersions of TRI with shellac and acetylphthalylcellulose were obtained by a method of joint dissolution with the subsequent evaporation of a solvent. The inclusion complexes of TRI with P-cyclodextrin in a various molecular ratio were prepared by a precipitating method. The release of substations and coprecipitates in 0,l HCI was about 90% for PRO and DIA and 517% for TRI. Thus, the opportunity of creation of the combined medicinal form of antierrhythmic activity with controlled release of three components in depending of various part of gastr&intestinal tract was shown.
284 OF BIOADHESWE
CHARACTERISTICS
OF LOCAL
SYSTEM INDICATED IN HERPETIC GINGIYOSTOMATlTlS
sm, M.tivkovii 104 Yugoslavia,Institute,Sectorof Development, 29. Novembra I I I, 11000 Belgrade. Yugoslavia
II ISknownthat therqeutic cff~cimcy of locally apphed preparation for watmen~ of oral mucosa disorders greatly depends on snmgth and duration of contactbetween the dmg vehicle and site of its actMy. The object of OUT work was to make the choice of optimal bioadhesive dental preparation formulation indicated in therapy of herpctic gingivostomatins. Actwe subsMce. the second mnemtion synthetic nuclcoside antiviral al(ent (AVA), used in our w&k is, accord&g to r&s of several clinical studies performed, efiicienr in trutin~ lesions associatedwith viral infections mentioned at 7.5 % (w/w) concentration. In the experimental phase following samples were prep& and investigared: ?? samoles of dental bioadhesive haste made bv mechanical incorwmtion of 13% (w/w) i.;.14.5% (w/w) each - (S&ples md i, resp.) of hydmcolloid polymers (CMCNq Pectin. Hydmlized gelatin - Byca C, Croda Colloids, UK) into previously preparedchspersionof AVA in polyethylene lip@. samplu of water-pmpylm glycol 3% and 5% (w/w) Cabopol 934P gels &mplcs 3 and 4, resp.) made by dispcning polymer in AVA solution; pH of gels was6.8 -7.2. The bioadhesivcpotential of samplesstudied was evaluatedby using hvo in vitro comparative technics. The first test was based an measuring the force of detachment (Zwick-Zugpugmachm 1101) _ the lower part of the sPaMy designed cell was filled with the samples studied and brought into cantact with the upperpan coveredby the mucin gel; results were expressed88 maximal form at the nwment of detachment(kP) i.e. tensile stress(Pa). The second one was the testing of “washable properties” e.g. resistance to washing of samples studied - based on specnophatomenical determination of dye percentage winch difised from agar matrix covered by sample through to the receptor solution during 4 h The adhesive capacity of the ramples wu inversly proportional to the % of dye diffused. Sample I with 39% (w/w) of hydmcolloids in lipogel expr~sscdthe best adheswe potential. Also, if was concluded that hydrophobic formulations showed better bioadhesive characteristicscompamd to those in wluch the degree of polymer hydration process and the adhesive potmhal M influenced by prepatatmn composition and technology procedure.
I
IN VITRO EVALUATION OF ACYLOXYALKYL ESTERS OF KETOPROFEN AND NAPROXEN AS DERMAL PRODRUGS J. Rautig’, H. Taipale’, J. Gynthep, J. Vepsl18inenb, T. Nevalaine@ and T. Jiirvinena. ‘Dept. of Pharm. Chem. or bChem., University of Kuopio, P.O. Box 1627, FIN-7021 I Kuopio, Finland. In the present study, a series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and evaluated with the aim of improving the dermal delivery of the parent drugs. The prodrugs of ketoprofen and naproxen were synthesized, their aqueous solubilities, lipophilicities and hydrolysis rates in buffer, human serum and skin homogenate were determined. The permeation of selected naproxen prodrugs across the excised human skin from buffer solution of pH 7.4 was studied in vifro.The prodrugs were more lipophilic (log Pipp = 2.8-3.6) than their parent molecules (ketoprofen; log P,, = 0.3, naproxen; log P BPP = -0.2), as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log P,,,). However, their aqueous solubilities decreased markedly compared to the parent molecules. The prodrugs were stable towards chemical hydrolysis in aqueous solutions (pH 7.4). but hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The hydrolysis of the acyloxyalkyl esters take place enzymatically by attack on the carbonyl of the parent drug rather than the carbonyl of the promoiety. In the diffusion cell experiments the steady-state flux values of total naproxen delivered by prodrugs were similar or slower than that delivered by naproxen. The results show that for this series of lipophilic prodrugs of naproxen, the acetyloxyethyl ester with most highest aqueous solubility is the most effective prodrug to deliver total naproxen through excised human skin. This work was supported by the Academy of Finland and Technology Development Centre (Finland).