Razvoj i biofarmaceutsko vrednovanje pripravka za povećano oslobađanje tramadol hidroklorida na principu osmotske tehnologije

Extended release formulation of tramadol hydrochloride (TRH) based on osmotic technology was developed and evaluated. Target release profile was selected and different variables were optimized to achieve the same. Formulation variables like level of swellable polymer, plasticizer and the coat thickness of semipermeable membrane (SPM) were found to markedly affect the drug release. TRH release was directly proportional to the levels of plasticizer but inversely proportional to the levels of swellable polymer and coat thickness of SPM. Drug release from developed formulations was independent of pH and agitation intensity but dependent on osmotic pressure of the release media. In vivo study was also performed on six healthy human volunteers and various pharmacokinetic parameters (cmax, tmax, AUC0-24, MRT) and relative bioavailability were calculated. The in vitro and in vivo results were compared with performance of two commercial tablets of TRH. The developed formulation provided more prolonged and controlled TRH release as compared to marketed formulation. In vitro-in vivo correlation (IVIVC) was analyzed according to Wagner-Nelson method. The optimized formulation (batch IVB) exhibited good IVIV correlation (R = 0.9750). The manufacturing procedure was found to be reproducible and formulations were stable during 6 months of accelerated stability testing.U radu je opisana priprava i evaluacija pripravaka tramadol hidroklorida (TRH) na principu osmotske tehnologije. Da bi se postigao željeni profil oslobađanja mijenjane su različite varijable. Pokazalo se da najveći utjacaj na oslobađanje ljekovite tvari imaju udjeli polimera koji bubri, plastifikatora i debljina ovojnice polupropusne membrane (SPM). TRH oslobađanje bilo je proporcionalno udjelu plastifikatora, a obrnuto proporcionalno udjelu polimera i vrijednosti SPM. Oslobađanje ljekovite tvari bilo je neovisno o pH i intenzitetu miješanja, a ovisno o osmotskom talku medija. U in vivo studiji provedenoj na šest zdravih volontera određeni su farmakokinetički parametri (cmax, tmax, AUC0-24, MRT) i izračunata relativna bioraspoloživost. Rezultati dobiveni u pokusima in vitro i in vivo uspoređeni su s dvije vrste komercijalno dostupnih tableta TRH: oslobađanje ljekovite tvari iz pripravka razvijenog u ovom radu bilo je dulje i više kontrolirano. In vitro-in vivo korelacija (IVIVC) je analizirana prema Wagner-Nelsonovoj metodi. Optimizirani pripravak (IVB) pokazao je dobru IVIV korelaciju (R = 0,9750). Proizvodni proces je bio reproducibilan i pripravci su bili stabilni tijekom 6 mjeseci u uvjetima ubrzanog starenja

Polymorphic change of a triglyceride base in hot melt coating process and stability acceleration by tempering process

In this study, the influence of hot melt coating condition on polymorphic change of a triglyceride base, hydrogenated soybean oil (HSO) was studied. Metoprolol tartrate was used as a water-soluble model drug. Coated pellets were prepared by spraying drug-lipid dispersion onto nonpareil seeds. A tempering process was employed in order to achieve the stable form of HSO. Differential scanning calorimetry was used to simulate the coating and tempering conditions prior to the processing and to characterize polymorphic change together with powder X-ray diffractometry and hot stage microscopy. Coated pellets possessed three polymorphic forms of HSO but only the stable form was dominant after tempering. Tempered pellets presented crystal growth of HSO with 1-2 mu m microstructure elements. This morphological change led to the reduced porosity and increased surface area of the pellets as well as the increased drug release. The release profile was attributable to the tempering temperature. In order to stabilize the drug release, the tempering process was suggested to perform at the temperature below the melting point of the unstable form

Development of a multi-unit floating drug delivery system by hot melt coating technique with drug-lipid dispersion

A multi-unit floating drug delivery system containing pellets with lipid coating were fabricated. Coated pellets were prepared by a fluid bed hot melt coating technique with drug-lipid dispersion. Metoprolol tartrate was used as a water soluble model drug and hydrogenated soybean oil (HSO) was used as a lipid carrier. The drug was dispersed in molten HSO and the mixture was directly sprayed on inert nonpareils in a fluid bed chamber. No major interaction between drug and HSO was observed, nevertheless, the drug could be partially dissolved in the molten HSO. Increasing coating amount or adding an inert substance, Aerosil R972, in the coating mixture reduced the initial burst release as well as the total drug release. Increasing drug particle size gave a variation in the drug release due to brittle fracture induced at the nozzle by pressurized atomization air. Coated pellets presented a good floating property in vitro regardless of the coating amount. The present study shows that a drug-lipid dispersion coating prepared by a hot melt coating technique is a promising means for the development of multi-unit floating drug delivery systems

Experimental design and optimization of the hydrogenation process of soybean oil

The hydrogenated soybean oil was prepared by catalytic hydrogenation process in order to be used as a pharmaceutical excipient for hot melt applications. To optimize the hydrogenation process and produce a product whose quality conforms to the hydrogenated vegetable oil type I in the US Pharmacopoeia (USP 24), a central composite design was applied. The influence of three main process parameters, i.e. amount of catalyst, hydrogen pressure and temperature on the hydrogen consumption, the time required for the completion of the reaction and the reaction rate as well as the quality of final products was studied. The increase in the amount of catalyst and temperature significantly enhanced the reaction rate. However, at higher temperature, the acid values of the final products also increased. The thermal behavior of the product showed tolerance to high temperature exposure, i.e. 80-120 degrees C, where unchanged exothermic peaks were determined in the thermograms before and after exposure. This novel excipient is applied in a next step in the hot melt coating application for the preparation of modified release formulations

Development and evaluation of a hot-melt coating technique for enteric coating

Conventional enteric coating requires the use of organic based polymers which are equally hazardous to the environment and operating personnel. Hot-melt coating avoids the use of solvents and is a safer and time-saving process. The present study was designed to assess the efficacy of hot-melt coating (HMC) as an enteric coating technique. Pellets prepared by extrusion spheronization were selected as the core formulation for a model of the gastric irritant drug diclofenac sodium (DFS) because of their innate advantages over single-unit formulations. Stearic acid (SA) and palmitic acid (PA) were evaluated as enteric hot-melt coating materials. HMC was carried out in a specially modified coating pan by applying SA and PA in molten state onto preheated pellets to achieve a coating level of 5-15 %w/w. Hot-melt coated pellets were evaluated for disintegration pH and in vitro dissolution in the pH range 1.2 to 6.8, along with basic micromeritics. SEM of coated pellets showed a uniform and smooth coating. These results indicated that HMC of both SA and PA exhibited very good enteric coating ability. The coated pellets showed negligible drug release in acidic pH. As the pellets were subsequently transferred to a higher pH level, a gradual increase in release of the drug from the pellets was observed with increasing pH of the dissolution media. The release was dependent upon coating extent, providing sustained enteric release as opposed to abrupt release with mixed release kinetics.<br>O revestimento entérico convencional requer o uso de polímeros orgânicos os quais são igualmente danosos ao meio ambiente e ao pessoal que o executa. O revestimento por fusão a quente evita o uso de solventes e é processo mais seguro e que consome menos tempo. O presente estudo foi planejado para avaliar a eficácia do revestimento por fusão a quente (RFQ) como técnica de revestimento entérico. Os péletes preparados por esferonização por extrusão foram selecionados como formulação central para modelo de fármaco irritante gástrico, o diclofenaco sódico (DFS) em razão das vantagens inerentes sobre as formulações de única dose. O ácido esteárico (AE) e o ácido palmítico (AP) foram avaliados como materiais para o revestimento de fusão a quente. O RFQ foi realizado em recipiente especialmente modificado, aplicando AS e PA no estado fundido em péletes pré-aquecidos para atingir nível de revestimento de 5 a 15% p/P. Os péletes revestidos por fusão a quente for avaliados quanto ao pH de desintegração e à dissolução in vitro na faixa de pH de 1,2 a 6,8, juntamente com base micromerítica. O SEM dos péletes revestido mostrou revestimento uniforme e plano. Esses resultados indicaram que o RFQ tanto do AE quanto do AP apresentou capacidade de revestimento muito boa. Os péletes revestidos mostraram pouca liberação do fármaco em pH baixo. Como os péletes foram, subsequentemente, transferidos para pH mais altos, observou-se aumento gradual na liberação do fármaco dos péletes com o aumento do pH do meio de dissolução. A liberação foi dependente da extensão do revestimento, sendo a liberação entérica controlada, contrariamente à liberação abrupta com cinéticas mistas

Development and In Vitro/In Vivo Evaluation of Etodolac Controlled Porosity Osmotic Pump Tablets

The aim of the current work was the design and evaluation of etodolac controlled porosity osmotic pump (CPOP) tablets exhibiting zero-order release kinetics. Variables influencing the design of (1) core tablets viz., (a) osmogent type (sodium chloride, potassium chloride, mannitol, and fructose) and (b) drug/osmogent ratio (1:0.25, 1:0.50, and 1:0.75), and (2) CPOP tablets viz., (a) coating solution composition, (b) weight gain percentage (1–5%, w/w), and (c) pore former concentration (5%, 10%, and 20%, v/v), were investigated. Statistical analysis and kinetic modeling of drug release data were estimated. Fructose-containing core tablets showed significantly (P < 0.05) more retarded drug release rates. An inverse correlation was observed between drug/fructose ratio and drug release rate. Coating of the optimum core tablets (F4) with a mixture of cellulose acetate solution (3%, w/v), diethyl phthalate, and polyethylene glycol 400 (85:10:5, v/v, respectively) till a 4% w/w weight gain enabled zero-order sustained drug delivery over 24 h. Scanning electron microscopy micrographs of coating membrane confirmed pore formation upon contact with dissolution medium. When compared to the commercial immediate-release Napilac® capsules, the optimum CPOP tablets (F4–34) provided enhanced bioavailability and extended duration of effective etodolac plasma concentration with minimum expected potential for side effects in healthy volunteers